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Sriretnakumar V, Harripaul R, Kennedy JL, So J. When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population. Am J Med Genet A 2024; 194:e63609. [PMID: 38532509 DOI: 10.1002/ajmg.a.63609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 03/06/2024] [Accepted: 03/13/2024] [Indexed: 03/28/2024]
Abstract
Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is nonresponsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next-generation sequencing of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 48 putative affected and 180 putative carriers for TGDs were identified, with known or likely pathogenic variants in 79 genes. Despite screening for only 108 genetic disorders, this study showed a two-fold (2.09%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases is greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.
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Affiliation(s)
- Venuja Sriretnakumar
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Ricardo Harripaul
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - James L Kennedy
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Joyce So
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
- Division of Medical Genetics, Departments of Medicine and Pediatrics, University of California, San Francisco, California, USA
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2
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Shchelochkov OA, Farmer CA, Chlebowski C, Adedipe D, Ferry S, Manoli I, Pass A, McCoy S, Van Ryzin C, Sloan J, Thurm A, Venditti CP. Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology. Mol Psychiatry 2024; 29:974-981. [PMID: 38200289 PMCID: PMC11176071 DOI: 10.1038/s41380-023-02385-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/13/2023] [Accepted: 12/14/2023] [Indexed: 01/12/2024]
Abstract
Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.
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Affiliation(s)
- Oleg A Shchelochkov
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Cristan A Farmer
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Colby Chlebowski
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dee Adedipe
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Susan Ferry
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Irini Manoli
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Alexandra Pass
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Samantha McCoy
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Carol Van Ryzin
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jennifer Sloan
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Audrey Thurm
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Charles P Venditti
- Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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Commey KL, Enaka A, Nakamura R, Yamamoto A, Tsukigawa K, Nishi K, Iohara D, Hirayama F, Otagiri M, Yamasaki K. Development of α-Cyclodextrin-Based Orally Disintegrating Tablets for 4-Phenylbutyrate. Pharmaceutics 2024; 16:82. [PMID: 38258093 PMCID: PMC10818935 DOI: 10.3390/pharmaceutics16010082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Despite major improvements brought about by the introduction of taste-masked formulations of 4-phenylbutyrate (PB), poor compliance remains a significant drawback to treatment for some pediatric and dysphagic patients with urea cycle disorders (UCDs). This study reports on the development of a cyclodextrin (CD)-based orally disintegrating tablet (ODT) formulation for PB as an alternative to existing formulations. This is based on previous reports of the PB taste-masking potential of CDs and the suitability of ODTs for improving compliance in pediatric and dysphagic populations. In preliminary studies, the interactions of PB with α and βCD in the solid state were characterized using X-ray diffraction, scanning electron microscopy, dissolution, and accelerated stability studies. Based on these studies, lyophilized PB-CD solid systems were formulated into ODTs after wet granulation. Evaluation of the ODTs showed that they had adequate physical characteristics, including hardness and friability and good storage stability. Notably, the developed αCD-based ODT for PB had a disintegration time of 28 s and achieved a slightly acidic and agreeable pH (≈5.5) in solution, which is suitable for effective PB-CD complexation and taste masking. The developed formulation could be helpful as an alternative to existing PB formulations, especially for pediatric and dysphagic UCD patients.
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Affiliation(s)
- Kindness L. Commey
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
| | - Airi Enaka
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
| | - Ryota Nakamura
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
| | - Asami Yamamoto
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
| | - Kenji Tsukigawa
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
| | - Koji Nishi
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
| | - Daisuke Iohara
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
| | - Fumitoshi Hirayama
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
| | - Keishi Yamasaki
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; (K.L.C.); (A.E.); (R.N.); (A.Y.); (K.T.); (K.N.); (D.I.); (F.H.)
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
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Burlina A, Gasperini S, la Marca G, Pession A, Siri B, Spada M, Ruoppolo M, Tummolo A. Long-Term Management of Patients with Mild Urea Cycle Disorders Identified through the Newborn Screening: An Expert Opinion for Clinical Practice. Nutrients 2023; 16:13. [PMID: 38201843 PMCID: PMC10780676 DOI: 10.3390/nu16010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/05/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate-Talk-Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring.
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Affiliation(s)
- Albero Burlina
- Division of Inherited Metabolic Diseases, Reference Centre for Expanded Newborn Screening, University Hospital of Padova, 35128 Padova, Italy
| | - Serena Gasperini
- Inherited Metabolic Unit Disorders, Pediatric Department, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy;
| | - Giancarlo la Marca
- Newborn Screening Lab, IRCCS Meyer Children’s Hospital, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Firenze, Italy;
| | - Andrea Pession
- Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Barbara Siri
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
| | - Marco Spada
- Department of Pediatrics, University of Turin, 10124 Turin, Italy;
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples, Federico II, 80138 Naples, Italy;
- CEINGE–Biotecnologie Avanzate S.C.A.R.L., 80145 Naples, Italy
| | - Albina Tummolo
- Department of Metabolic Diseases and Clinical Genetics and Diabetology, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy;
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Lichter-Konecki U, Sanz JH, McCarter R. Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders. Pediatr Res 2023; 94:2005-2015. [PMID: 37454183 DOI: 10.1038/s41390-023-02722-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 05/29/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment. METHODS Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated. RESULTS Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI. CONCLUSION VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management. IMPACT The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD). This is the first report of longitudinal biomarkers for treatment outcome in UCD. These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.
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Affiliation(s)
- Uta Lichter-Konecki
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
- UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
| | - Jacqueline H Sanz
- Department of Pediatrics, George Washington University School of Medicine, Washington, DC, USA
- Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine, Washington, DC, USA
- Children's National Hospital, Washington, DC, USA
| | - Robert McCarter
- Department of Pediatrics, George Washington University School of Medicine, Washington, DC, USA
- Children's National Hospital, Washington, DC, USA
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Glinton KE, Minard CG, Liu N, Sun Q, Elsea SH, Burrage LC, Nagamani SCS. Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn. Mol Genet Metab 2023; 140:107699. [PMID: 37717413 PMCID: PMC11162249 DOI: 10.1016/j.ymgme.2023.107699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/19/2023]
Abstract
Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). Plasma concentrations of their primary metabolite, phenylacetate (PAA), as well as the ratio of PAA to phenylacetylglutamine (PAGN) are useful for guiding dosing and detecting toxicity. However, the frequency of toxic elevations of metabolites and associated clinical covariates is relatively unknown. A retrospective analysis was conducted on 1255 plasma phenylbutyrate metabolite measurements from 387 individuals. An additional analysis was also conducted on a subset of 68 individuals in whom detailed clinical information was available. In the course of these analyses, abnormally elevated plasma PAA and PAA:PAGN were identified in 39 individuals (4.15% of samples) and 42 individuals (4.30% of samples), respectively. Abnormally elevated PAA and PAA:PAGN values were more likely to occur in younger individuals and associate positively with dose of NAPBA and negatively with plasma glutamine and glycine levels. These results demonstrate that during routine clinical management, the majority of patients have PAA levels that are deemed safe. As age is negatively associated with PAA levels however, children undergoing treatment with NaPBA may need close monitoring of their phenylbutyrate metabolite levels.
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Affiliation(s)
- Kevin E Glinton
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
| | - Charles G Minard
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Ning Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics, Houston, TX, USA
| | - Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics, Houston, TX, USA
| | - Sarah H Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA
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Posset R, Zielonka M, Gleich F, Garbade SF, Hoffmann GF, Kölker S. The challenge of understanding and predicting phenotypic diversity in urea cycle disorders. J Inherit Metab Dis 2023; 46:1007-1016. [PMID: 37702610 DOI: 10.1002/jimd.12678] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023]
Abstract
The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long-term follow-up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease-immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long-term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries.
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Affiliation(s)
- Roland Posset
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Zielonka
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
- Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany
| | - Florian Gleich
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Sven F Garbade
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Georg F Hoffmann
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Kölker
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
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Vockley J, Burton B, Jurecka A, Ganju J, Leiro B, Zori R, Longo N. Challenges and strategies for clinical trials in propionic and methylmalonic acidemias. Mol Genet Metab 2023; 139:107612. [PMID: 37245378 DOI: 10.1016/j.ymgme.2023.107612] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/19/2023] [Accepted: 05/19/2023] [Indexed: 05/30/2023]
Abstract
Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. Here, we review strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias. Specifically, we discuss crucial decisions that may significantly impact success of the study, including patient selection, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families.
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Affiliation(s)
- Jerry Vockley
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, School of Medicine, Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Barbara Burton
- Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA
| | - Agnieszka Jurecka
- CoA Therapeutics, Inc., a BridgeBio company, San Francisco, CA, USA.
| | - Jitendra Ganju
- Independent Consultant to BridgeBio, San Francisco, CA, USA
| | - Beth Leiro
- Independent Consultant to BridgeBio, San Francisco, CA, USA
| | - Roberto Zori
- Department of Pediatrics, Division of Genetics and Metabolism, University of Florida, Gainesville, FL, USA
| | - Nicola Longo
- Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA
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9
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Eriksen PL, Djernes L, Vilstrup H, Ott P. Clearance and production of ammonia quantified in humans by constant ammonia infusion - the effects of cirrhosis and ammonia targeting treatments. J Hepatol 2023:S0168-8278(23)00220-9. [PMID: 37061198 DOI: 10.1016/j.jhep.2023.03.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/17/2023] [Accepted: 03/26/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND & AIMS Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting HE drugs. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. METHODS Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production as clearance times baseline ammonia concentration. Participants were re-investigated after the ammonia targeting interventions. RESULTS In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and production 49 (35-63) μmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p=0.009). Patients with cirrhosis had a 20% decreased ammonia clearance of 2.7 (2.1-3.3) L/min (p = 0.02) and a nearly tripled production to 131 (102-159) μmol/min (p<0.0001). Lactulose + rifaximin reduced production by 20% (2-37%, p=0.03). The infusion was generally well-tolerated save one hyperammonaemic patient with cirrhosis with possible bleeding unrelated to the infusion who developed clinical HE that reverted when infusion was discontinued. CONCLUSIONS Whole-body ammonia clearance and production may be measured separately by the technique used. The method identified a lower clearance and a higher production in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. The method may be used to examine a range of questions related to normo-/pathophysiology and ammonia-targeting treatment mechanisms. IMPACT AND IMPLICATIONS High blood ammonia plays a key role in liver cirrhosis related brain dysfunction. However, the relative roles of increased ammonia production and reduced ammonia clearance are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By use of this test, it was possible to show that patients with liver cirrhosis have decreased ammonia clearance and increased ammonia production compared with healthy persons and to quantify distinctively different ammonia-targeting treatment effects. The test presented holds several perspectives for future studies of normal physiology and pathophysiology, not least in regard to elucidating effects of ammonia-targeting therapies. CLINICAL TRIAL NUMBER ClinicalTrials.gov (1-16-02-297-20).
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Affiliation(s)
- Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark.
| | - Lars Djernes
- Department of Anaesthesiology and Intensive Care, Viborg Regional Hospital, Denmark; Department of Anaesthesiology and Intensive Care, Aarhus University Hospital, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark
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Commey K, Nakatake A, Enaka A, Nishi K, Tsukigawa K, Yamaguchi K, Ikeda H, Iohara D, Hirayama F, Otagiri M, Yamasaki K. Study of the inclusion complexes formed between 4-phenylbutyrate and α-, β- and γ-cyclodextrin in solution and evaluation on their taste-masking properties. J Pharm Pharmacol 2023; 75:236-244. [PMID: 36548517 DOI: 10.1093/jpp/rgac090] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/11/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES 4-Phenylbutyrate (PB), which is used in the management of urea cycle disorders, has an unpleasant taste leading to poor patient compliance. Existing PB formulations though helpful, have some limitations in their use. This study reports on attempts to mask this unpleasant taste by complexing PB with cyclodextrins (CDs) to improve patient compliance. METHODS α, β and γCD were used as CDs. Phase solubility studies, circular dichroism, 1H-NMR spectroscopy, including ROESY, and molecular modelling were used to investigate and characterize the PB-CD interactions in solution. The taste-masking effect of the CDs was evaluated using in vitro taste sensor measurements. KEY FINDINGS PB interacts with α, β and γCD in solution to form 1:1, 1:1 and 1:2 CD: PB inclusion complexes, respectively, with stability constants in the order αCD > βCD > γCD. Taste evaluation revealed that the CDs significantly mask the taste of PB through the formation of the inclusion complexes. Notably, αCD masked the bitter taste of PB to 30% of the initial taste at a 1:1 molar ratio. CONCLUSION αCD significantly masks the unpleasant taste of PB in solution and can be used to formulate PB to address the limitations of existing formulations and improve patient compliance and quality of life.
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Affiliation(s)
- Kindness Commey
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Akari Nakatake
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Airi Enaka
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Koji Nishi
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Kenji Tsukigawa
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Koki Yamaguchi
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Hirohito Ikeda
- Faculty of Pharmaceutical Sciences, Fukuoka University, Jonan-ku, Fukuoka, Japan
| | - Daisuke Iohara
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Fumitoshi Hirayama
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
| | - Keishi Yamasaki
- Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.,DDS Research Institute, Sojo University, Nishi-ku, Kumamoto, Japan
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11
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Deka D, D'Incà R, Sturniolo GC, Das A, Pathak S, Banerjee A. Role of ER Stress Mediated Unfolded Protein Responses and ER Stress Inhibitors in the Pathogenesis of Inflammatory Bowel Disease. Dig Dis Sci 2022; 67:5392-5406. [PMID: 35318552 DOI: 10.1007/s10620-022-07467-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 02/28/2022] [Indexed: 01/05/2023]
Abstract
Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress. Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.
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Affiliation(s)
- Dikshita Deka
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Renata D'Incà
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy
| | - Alakesh Das
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India.
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12
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Ribas GS, Lopes FF, Deon M, Vargas CR. Hyperammonemia in Inherited Metabolic Diseases. Cell Mol Neurobiol 2022; 42:2593-2610. [PMID: 34665389 PMCID: PMC11421644 DOI: 10.1007/s10571-021-01156-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/10/2021] [Indexed: 12/13/2022]
Abstract
Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.
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Affiliation(s)
- Graziela Schmitt Ribas
- Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil.
| | - Franciele Fátima Lopes
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil
| | - Marion Deon
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil
| | - Carmen Regla Vargas
- Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil.
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13
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Xie QQ, Wang JF, Zhang YF, Xu DH, Zhou B, Li TH, Li ZP. Glucose substrate in the hydrogen breath test for gut microbiota determination: A recommended noninvasive test. World J Clin Cases 2022; 10:9536-9538. [PMID: 36159421 PMCID: PMC9477675 DOI: 10.12998/wjcc.v10.i26.9536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/06/2022] [Accepted: 08/06/2022] [Indexed: 02/05/2023] Open
Abstract
Intestinal dysbiosis and small intestinal bacterial overgrowth (SIBO) are common in patients with liver cirrhosis. Existing studies have not explored the association between gut dysbiosis and SIBO. We propose some suggestions for the authors' experimental methods and concepts, and we hope these suggestions can be adopted. The hydrogen breath test is worthy of recommendation due to its high accuracy and convenient operation. We suggest changing the substrate of the hydrogen breath test from lactulose to glucose to improve the accuracy of each parameter. SIBO is a small subset of gut dysbiosis, and we propose clarifying the concept of both. SIBO may be caused by liver cirrhosis or one of the pathogeneses of gastrointestinal diseases. Therefore, interference from other gastrointestinal diseases should be excluded from this study.
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Affiliation(s)
- Qi-Qi Xie
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Jia-Feng Wang
- Town Hospital of Gaodu, Mengyin County, Linyi 276200, Shandong Province, China
| | - Yang-Fen Zhang
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Dong-Hui Xu
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Bo Zhou
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Ting-Hui Li
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Zhi-Peng Li
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang Province, China
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14
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Martín-Hernández E, Quijada-Fraile P, Correcher P, Meavilla S, Sánchez-Pintos P, de las Heras Montero J, Blasco-Alonso J, Dougherty L, Marquez A, Peña-Quintana L, Cañedo E, García-Jimenez MC, Moreno Lozano PJ, Murray Hurtado M, Camprodon Gómez M, Barrio-Carreras D, de los Santos M, del Toro M, Couce ML, Vitoria Miñana I, Morales Conejo M, Bellusci M. Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain. J Clin Med 2022; 11:jcm11175045. [PMID: 36078975 PMCID: PMC9457033 DOI: 10.3390/jcm11175045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/30/2022] Open
Abstract
Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 μmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.
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Affiliation(s)
- Elena Martín-Hernández
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, CIBERER, 28041 Madrid, Spain
- Correspondence:
| | - Pilar Quijada-Fraile
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, CIBERER, 28041 Madrid, Spain
| | - Patricia Correcher
- Centro de Referencia Nacional de Enfermedades Metabólicas (CSUR), Hospital La Fé de Valencia, 46026 Valencia, Spain
| | - Silvia Meavilla
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital San Joan de Deu Barcelona, 08950 Esplugues de Llobregat, Spain
| | - Paula Sánchez-Pintos
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital Clínico Universitario de Santiago de Compostela, IDIS, CIBERER, 15706 Santiago de Compostela, Spain
| | - Javier de las Heras Montero
- Division of Pediatric Metabolism, CIBERER, MetabERN, Cruces University Hospital, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, 48903 Barakaldo, Spain
| | - Javier Blasco-Alonso
- Sección de Gastroenterología y Nutrición Infantil, Unidad de Enfermedades Metabólicas Hereditarias, Grupo IBIMA Multidisciplinar Pediátrico, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Lucy Dougherty
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital Vall D’Hebrón, 08035 Barcelona, Spain
| | - Ana Marquez
- Unidad de Gastroenterología y Enfermedades Metabólicas, Hospital de Badajoz, 06002 Badajoz, Spain
| | - Luis Peña-Quintana
- Unidad de Gastroenterología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil de Las Palmas, CIBEROBN, ISCIII, ACIP, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
| | - Elvira Cañedo
- Unidad de Gastroenterología y Nutrición, Hospital del Niño Jesús, 28009 Madrid, Spain
| | | | - Pedro Juan Moreno Lozano
- Unidad de Enfermedades Musculares y Metabólicas Hereditarias, Departamento de Medicina Interna, Hospital Clinic, 08036 Barcelona, Spain
| | - Mercedes Murray Hurtado
- Pediatría, Sección de Nutrición y Errores Innatos del Metabolismo, Complejo Hospitalario Universitario de Canarias, 38320 San Cristóbal de La Laguna, Spain
| | - María Camprodon Gómez
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital Vall D’Hebrón, 08035 Barcelona, Spain
| | - Delia Barrio-Carreras
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, CIBERER, 28041 Madrid, Spain
| | - Mariela de los Santos
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital San Joan de Deu Barcelona, 08950 Esplugues de Llobregat, Spain
| | - Mireia del Toro
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital Vall D’Hebrón, 08035 Barcelona, Spain
| | - María L. Couce
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) de Enfermedades Metabólicas, Hospital Clínico Universitario de Santiago de Compostela, IDIS, CIBERER, 15706 Santiago de Compostela, Spain
| | - Isidro Vitoria Miñana
- Centro de Referencia Nacional de Enfermedades Metabólicas (CSUR), Hospital La Fé de Valencia, 46026 Valencia, Spain
| | - Montserrat Morales Conejo
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, CIBERER, 28041 Madrid, Spain
| | - Marcello Bellusci
- Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, CIBERER, 28041 Madrid, Spain
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15
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Hepatic Encephalopathy: Current and Emerging Treatment Modalities. Clin Gastroenterol Hepatol 2022; 20:S9-S19. [PMID: 35940731 DOI: 10.1016/j.cgh.2022.04.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neurocognitive complication of cirrhosis. It has been reported in at least 30% of patients with cirrhosis and imposes a significant economic burden on caregivers and the healthcare system. Ammonia has been recognized as the culprit in HE development, and all the currently approved treatments mostly act on this toxin to help with HE resolution. After a brief overview of HE characteristics and pathophysiology, this review explores the current accepted treatments for this debilitating complication of cirrhosis. This is followed by an overview of the novel available therapies and a brief focus on future treatment modalities for HE.
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Rajpurohit S, Musunuri B, Shailesh, Basthi Mohan P, Shetty S. Novel Drugs for the Management of Hepatic Encephalopathy: Still a Long Journey to Travel. J Clin Exp Hepatol 2022; 12:1200-1214. [PMID: 35814520 PMCID: PMC9257922 DOI: 10.1016/j.jceh.2022.01.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.
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Key Words
- ALC, acetyl-L-carnitine
- BCAA, branched-chain amino acid
- BD, twice a day
- BDI, Beck Depression Inventory
- BUN, blood urea nitrogen
- CHESS, Clinical Hepatic Encephalopathy Staging Scale
- CLDQ, Chronic Liver Disease Questionnaire
- ECT, estimated completion time
- EEG, electroencephalogram
- FMT, fecal microbiota transplantation
- GPB, glycerol phenylbutyrate
- HESA, Hepatic Encephalopathy Scoring Algorithm
- HRQOL, health-related quality of life
- IV, intravenous
- MED, Modified Encephalopathy Scale
- MELD, Model for End-stage Liver Disease
- MMSE, Mini-Mental State Examination
- NTZ, nitazoxanide
- Nal, naloxone
- OD, once a day
- ORT, object recognition test
- PEG, polyethylene glycol
- QID, four times a day
- QOL, quality of life
- RBNS, Repeatable Battery for the Assessment of Neuropsychological Status
- RCT, randomized control trial
- RT-qPCR, real-time quantitative polymerase chain reaction
- TID, three times a day
- VSL#3, high concentration probiotic preparations
- hepatic encephalopathy
- liver cirrhosis
- novel drugs
- treatment outcome
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Affiliation(s)
- Siddheesh Rajpurohit
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Balaji Musunuri
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shailesh
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
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Bin Sawad A, Pothukuchy A, Badeaux M, Hodson V, Bubb G, Lindsley K, Uyei J, Diaz GA. Natural history of arginase 1 deficiency and the unmet needs of patients: A systematic review of case reports. JIMD Rep 2022; 63:330-340. [PMID: 35822089 PMCID: PMC9259395 DOI: 10.1002/jmd2.12283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 12/20/2022] Open
Abstract
Background Arginase 1 deficiency (ARG1-D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures, developmental delay, and intellectual disability. The aim of this systematic review was to identify and summarize the natural history of ARG1-D and the unmet needs of patients. Methods A comprehensive search of published case reports was undertaken to identify patients with ARG1-D regardless of interventions, comparisons, or outcomes. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other evidence-based medicine literature databases were searched on 20 April 2020. Quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. (PROSPERO registration: CRD42020212142.). Results One hundred and fifty seven ARG1-D patients were included from 111 publications (good overall quality based on JBI's Checklist); 84 (53.5%) were males. Motor deficits (including spasticity), intellectual disability, and seizures were reported in >50% of the cases. Mean age (SD) at diagnosis was 6.4 years and the laboratory findings most commonly reported to support diagnosis included elevated plasma arginine (81.5%), mutation in ARG1 gene through genetic testing (60%), and absence/reduction of red blood cell arginase activity (51%). Reported management approaches mainly included dietary protein restriction (68%), nitrogen scavengers (45%), and essential amino acid supplements (21%). Author-reported clinical improvement was documented for 26% of patients, 15% deteriorated, and 19% had limited or no change; notably, no indication of clinical outcome was reported for 40% cases. Conclusion This review illustrates a significant burden of disease and highlights a considerable unmet need for clinically effective treatment options for patients with ARG1-D.
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Affiliation(s)
| | | | | | | | | | - Kristina Lindsley
- Health Economics and Outcomes Research ‐ Evidence SynthesisIQVIA, Inc.San FranciscoCaliforniaUSA
| | - Jennifer Uyei
- Health Economics and Outcomes Research ‐ Evidence SynthesisIQVIA, Inc.San FranciscoCaliforniaUSA
| | - George A. Diaz
- Division of Medical Genetics and Genomics, Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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Generation of resolving memory neutrophils through pharmacological training with 4-PBA or genetic deletion of TRAM. Cell Death Dis 2022; 13:345. [PMID: 35418110 PMCID: PMC9007399 DOI: 10.1038/s41419-022-04809-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023]
Abstract
Neutrophils are the dominant leukocytes in circulation and the first responders to infection and inflammatory cues. While the roles of neutrophils in driving inflammation have been widely recognized, the contribution of neutrophils in facilitating inflammation resolution is under-studied. Here, through single-cell RNA sequencing analysis, we identified a subpopulation of neutrophils exhibiting pro-resolving characteristics with greater Cd200r and Cd86 expression at the resting state. We further discovered that 4-PBA, a peroxisomal stress-reducing agent, can potently train neutrophils into the resolving state with enhanced expression of CD200R, CD86, as well as soluble pro-resolving mediators Resolvin D1 and SerpinB1. Resolving neutrophils trained by 4-PBA manifest enhanced phagocytosis and bacterial-killing functions. Mechanistically, the generation of resolving neutrophils is mediated by the PPARγ/LMO4/STAT3 signaling circuit modulated by TLR4 adaptor molecule TRAM. We further demonstrated that genetic deletion of TRAM renders the constitutive expansion of resolving neutrophils, with an enhanced signaling circuitry of PPARγ/LMO4/STAT3. These findings may have profound implications for the effective training of resolving neutrophils with therapeutic potential in the treatment of both acute infection as well as chronic inflammatory diseases.
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Bin Sawad A, Jackimiec J, Bechter M, Hull M, Yeaw J, Wang Y, Diaz GA. Health care resource utilization in the management of patients with Arginase 1 Deficiency in the US: a retrospective, observational, claims database study. J Med Econ 2022; 25:848-856. [PMID: 35695271 DOI: 10.1080/13696998.2022.2089517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Arginase 1 Deficiency (ARG1-D) is an inherited metabolic disease that leads to significant morbidity. AIMS Despite the recognized burden of disease, information on health care resource utilization (HCRU) among patients with ARG1-D is lacking. We, therefore, sought to evaluate HCRU in ARG1-D relative to non-ARG1-D cohort. MATERIALS AND METHODS Patients with ≥2 ICD-10-CM diagnosis codes for ARG1-D were identified (first diagnosis code = index date) using professional fee claims linked with prescription claims. Patients with ARG1-D were matched 1:1 to a comparator cohort of patients with other medical conditions. Matching variables included age, sex, index year, payer type (Medicare, Medicaid, third party) and geographic region. RESULTS A total of 77 patients met the inclusion criteria for the ARG1-D cohort, with a median age of 15 years, 52% <18 years, and 52% male. Several concurrent diagnoses were recorded at a higher frequency in the ARG1-D cohort versus the matched comparator (spasticity 7 times higher; developmental delay ∼2 times higher; intellectual disability 5 times higher; and seizures 8 times higher). Emergency room visits occurred twice as often, laboratory tests were performed 1.5 times more often, hospitalization was required 3 times more often, and mean length of stay was longer for patients with ARG1-D than the comparator cohort (2.4 days vs. 0.3 days). LIMITATIONS A relatively short study period while the burden of ARG1-D increases over a lifetime due to disease progression. CONCLUSIONS Patients with ARG1-D had significantly greater HCRU compared with those without the disease; they presented with a more extensive comorbidity profile, accessed the health care system more frequently, required more intense monitoring and management, and had more frequent and longer hospitalizations relative to the comparator group. These findings demonstrate a high health burden in ARG1-D that is not mitigated by standard-of-care measures and emphasize the need for improved treatment options.
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Affiliation(s)
| | | | | | | | | | - Yi Wang
- IQVIA, Inc, Falls Church, VA, USA
| | - George A Diaz
- Division of Medical Genetics and Genomics in the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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20
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Hasan LZ, Wu GY. Novel Agents in the Management of Hepatic Encephalopathy: A Review. J Clin Transl Hepatol 2021; 9:749-759. [PMID: 34722190 PMCID: PMC8516841 DOI: 10.14218/jcth.2021.00102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.
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Affiliation(s)
- Leen Z. Hasan
- Correspondence to: Leen Z. Hasan, Department of Medicine, Internal Medicine Residency Program, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-1235, USA. ORCID: https://orcid.org/0000-0003-3852-8591. Tel: +1-617-283-6633, Fax: +1-860-679-4613, E-mail: ,
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21
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Yeowell G, Burns DS, Fatoye F. The burden of pharmacological treatment on health-related quality of life in people with a urea cycle disorder: a qualitative study. J Patient Rep Outcomes 2021; 5:110. [PMID: 34694515 PMCID: PMC8546029 DOI: 10.1186/s41687-021-00387-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 10/11/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Urea cycle disorders (UCD) are inborn errors of metabolism, typically presenting neonatally. Excess ammonia builds rapidly within the body risking hyperammonemic episodes and potentially death. Long-term management of the condition includes restrictive protein consumption, pharmacological interventions and, in extreme cases, liver transplantation. Pharmacological treatments such as sodium benzoate and sodium phenylbutyrate have proven effective but not without a multitude of negative attributes including poor taste, higher dosage and associated gastrointestinal discomfort that impacts health-related quality of life. Glycerol phenylbutyrate (GPB) has recently become a widely available pharmacological treatment with early reports of improved qualities, including taste and administration method. The following study aims to explore the burden of pharmacological treatment and the effects of the transition to GPB on health-related quality of life in people with a UCD. RESULTS Nine carers of children living with a UCD (mean age = 12.44, SD = 10.26) were interviewed regarding their experiences of pharmacological treatment in relation to their, and their child's, health-related quality of life after transitioning to GPB. Three main themes were identified: psychological health, physical health and social participation. Carers struggled with anxiety surrounding their child's condition and the battle of administering medication. Medication administration was perceived to have improved since the transition to GPB, alleviating distress for both carer and child. Issues involving school were described, ranging from difficulties integrating their child into mainstream schooling and the impact of treatment on participation in school and extracurricular activities. Carers encountered issues sourcing syringes to administer GPB, which induced stress. It could be suggested that some burden had been relieved by the transition to GPB. However, it appeared that difficulties associated with the illness would persist despite treatment, owing to the continuing nature of the condition. CONCLUSIONS Adhering to a strict pharmacological regime caused immense stress for both carers and children, severely impacting on typical social activities such as eating at a restaurant or going on holiday. GPB was perceived to have alleviated some burden in terms of administration given improved characteristics concerning taste and dosage, important characteristics for both carers and children living with UCD. Practitioners should consider these findings when making clinical decisions for children with UCD and the effect of pharmacological treatment on carer's health-related quality of life. Outreach work to facilitate greater understanding of the condition should be conducted with key locations, such as children's schools. This would also help to alleviate carer burden.
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Affiliation(s)
- Gillian Yeowell
- Department of Health Professions, Manchester Metropolitan University, 53 Bonsall Street, Manchester, M15 6GX, UK.
| | - Danielle Stephanie Burns
- Department of Health Professions, Manchester Metropolitan University, 53 Bonsall Street, Manchester, M15 6GX, UK
| | - Francis Fatoye
- Department of Health Professions, Manchester Metropolitan University, 53 Bonsall Street, Manchester, M15 6GX, UK
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22
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Longo N, Diaz GA, Lichter-Konecki U, Schulze A, Inbar-Feigenberg M, Conway RL, Bannick AA, McCandless SE, Zori R, Hainline B, Ah Mew N, Canavan C, Vescio T, Kok T, Porter MH, Berry SA. Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders. Mol Genet Metab 2021; 132:19-26. [PMID: 33388234 PMCID: PMC8655853 DOI: 10.1016/j.ymgme.2020.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND/AIMS Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
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Affiliation(s)
| | - George A Diaz
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Andreas Schulze
- Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | - Shawn E McCandless
- University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO, USA
| | | | - Bryan Hainline
- Indiana University School of Medicine, Indianapolis, IN, USA
| | | | | | | | - Teresa Kok
- Horizon Therapeutics plc, Deerfield, IL, USA.
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23
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Breilyn MS, Wasserstein MP. Established and Emerging Treatments for Patients with Inborn Errors of Metabolism. Neoreviews 2020; 21:e699-e707. [PMID: 33004565 DOI: 10.1542/neo.21-10-e699] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inborn errors of metabolism (IEMs) are inherited defects in a metabolic pathway resulting in clinical disease. The overall goal of therapy is to restore metabolic homeostasis while minimizing the deleterious effects of the interruption. Conventional treatments focus on decreasing substrate, providing product, and replacing deficient enzyme or cofactor. We discuss examples of established, novel, and emerging therapies to provide a framework for understanding the principles of management for patients with IEMs.
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Affiliation(s)
- Margo Sheck Breilyn
- Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, NY
| | - Melissa P Wasserstein
- Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, NY
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24
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Hidaka M, Higashi E, Uwatoko T, Uwatoko K, Urashima M, Takashima H, Watanabe Y, Kitazono T, Sugimori H. Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults. Acute Med Surg 2020; 7:e565. [PMID: 32995020 PMCID: PMC7507316 DOI: 10.1002/ams2.565] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/16/2020] [Accepted: 07/31/2020] [Indexed: 11/12/2022] Open
Abstract
Background Ornithine transcarbamylase is an enzyme of the urea cycle, which produces urea from ammonia. Although ornithine transcarbamylase deficiency mainly occurs as a severe neonatal-onset disease, a late-onset form that could become symptomatic from infancy to adulthood is also known. Case presentation A 34-year-old man presented with sudden onset of abnormal behavior, lethargy, and hyperammonemia (108 µmol/L). He had recently increased daily protein intake, which suggested urea cycle disorder. After initiation of protein-restricted diet and treatment with arginine and sodium phenylbutyrate, his symptoms resolved, along with a decrease in the ammonia level. An R40H(c.119G > A) mutation in the OTC gene was identified. Conclusion Awareness of adult onset ornithine transcarbamylase deficiency in a patient with acute psychiatric symptoms due to hyperammonemia is important.
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Affiliation(s)
- Masaoki Hidaka
- Department of Cerebrovascular Medicine Stroke Center Saga Prefecture Medical Centre Koseikan Saga Japan
| | - Eiji Higashi
- Department of Cerebrovascular Medicine Stroke Center Saga Prefecture Medical Centre Koseikan Saga Japan
| | - Takeshi Uwatoko
- Department of Cerebrovascular Medicine Stroke Center Saga Prefecture Medical Centre Koseikan Saga Japan
| | - Kiku Uwatoko
- Department of Neurology Stroke Center Saga Prefecture Medical Centre Koseikan Saga Japan
| | - Mayumi Urashima
- Department of Pediatrics Saga Prefecture Medical Centre Koseikan Saga Japan
| | - Hiroshi Takashima
- Department of Neurology Stroke Center Saga Prefecture Medical Centre Koseikan Saga Japan
| | - Yoriko Watanabe
- Research Institute of Medical Mass Spectrometry Kurume University School of Medicine Kurume Japan.,Department of Pediatrics and Child Health Kurume University School of Medicine Kurume Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Hiroshi Sugimori
- Department of Cerebrovascular Medicine Stroke Center Saga Prefecture Medical Centre Koseikan Saga Japan
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25
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Matoori S, Bao Y, Schmidt A, Fischer EJ, Ochoa-Sanchez R, Tremblay M, Oliveira MM, Rose CF, Leroux JC. An Investigation of PS-b-PEO Polymersomes for the Oral Treatment and Diagnosis of Hyperammonemia. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1902347. [PMID: 31721441 DOI: 10.1002/smll.201902347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 10/02/2019] [Indexed: 05/17/2023]
Abstract
Ammonia-scavenging transmembrane pH-gradient poly(styrene)-b-poly(ethylene oxide) polymersomes are investigated for the oral treatment and diagnosis of hyperammonemia, a condition associated with serious neurologic complications in patients with liver disease as well as in infants with urea cycle disorders. While these polymersomes are highly stable in simulated intestinal fluids at extreme bile salt and osmolality conditions, they unexpectedly do not reduce plasmatic ammonia levels in cirrhotic rats after oral dosing. Incubation in dietary fiber hydrogels mimicking the colonic environment suggests that the vesicles are probably destabilized during the dehydration of the intestinal chyme. The findings question the relevance of commonly used simulated intestinal fluids for studying vesicular stability. With the encapsulation of a pH-sensitive dye in the polymersome core, the local pH increase upon ammonia influx could be exploited to assess the ammonia concentration in the plasma of healthy and cirrhotic rats as well as in other fluids. Due to its high sensitivity and selectivity, this polymersome-based assay could prove useful in the monitoring of hyperammonemic patients and in other applications such as drug screening tests.
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Affiliation(s)
- Simon Matoori
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Yinyin Bao
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Aaron Schmidt
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Eric J Fischer
- Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | | | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Montréal, H2X 0A9, Québec, Canada
| | | | | | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
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26
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Waisbren SE, Stefanatos AK, Kok TMY, Ozturk‐Hismi B. Neuropsychological attributes of urea cycle disorders: A systematic review of the literature. J Inherit Metab Dis 2019; 42:1176-1191. [PMID: 31268178 PMCID: PMC7250134 DOI: 10.1002/jimd.12146] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 06/25/2019] [Accepted: 07/01/2019] [Indexed: 12/30/2022]
Abstract
Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35 000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the eight UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and compared for each UCD. Since diagnoses for UCDs tended to occur earlier and better treatments became more readily available after the turn of the century, this assessment will characterize the extent that current management strategies have improved neuropsychological outcomes. The pooled sample included data on cognitive abilities of 1649 individuals reported in 58 citations. A total of 556 patients (34%) functioned in the range of intellectual disabilities. The decline in the proportion of intellectual disabilities in six disorders, ranged from 7% to 41%. Results from various studies differed and the cohorts varied with respect to age at symptom onset, age at diagnosis and treatment initiation, current age, severity of the metabolic deficiency, management strategies, and ethnic origins. The proportion of cases with intellectual disabilities ranged from 9% to 65% after 2000 in the seven UCDs associated with cognitive deficits. Positive outcomes from some studies suggest that it is possible to prevent or reverse the adverse impact of UCDs on neuropsychological functioning. It is time to "raise the bar" in terms of expectations for treatment effectiveness.
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Affiliation(s)
- Susan E. Waisbren
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's HospitalBostonMassachusetts
- Department of Medicine, Harvard Medical SchoolBostonMassachusetts
| | - Arianna K. Stefanatos
- Department of Child & Adolescent Psychiatry and Behavioral Sciences, Children's Hospital of PhiladelphiaPhiladelphiaPennsylvania
| | | | - Burcu Ozturk‐Hismi
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's HospitalBostonMassachusetts
- Tepecik Education and Research HospitalIzmirTurkey
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Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis 2019; 42:1192-1230. [PMID: 30982989 DOI: 10.1002/jimd.12100] [Citation(s) in RCA: 294] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023]
Abstract
In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.
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Affiliation(s)
- Johannes Häberle
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Alberto Burlina
- Division of Inborn Metabolic Disease, Department of Pediatrics, University Hospital Padua, Padova, Italy
| | - Anupam Chakrapani
- Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Marjorie Dixon
- Dietetics, Great Ormond Street Hospital for Children, NHS Trust, London, UK
| | - Daniela Karall
- Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin Lindner
- University Children's Hospital, Frankfurt am Main, Germany
| | - Hanna Mandel
- Institute of Human Genetics and metabolic disorders, Western Galilee Medical Center, Nahariya, Israel
| | - Diego Martinelli
- Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy
| | - Guillem Pintos-Morell
- Centre for Rare Diseases, University Hospital Vall d'Hebron, Barcelona, Spain
- CIBERER_GCV08, Research Institute IGTP, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - René Santer
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anastasia Skouma
- Institute of Child Health, Agia Sofia Children's Hospital, Athens, Greece
| | - Aude Servais
- Service de Néphrologie et maladies métaboliques adulte Hôpital Necker 149, Paris, France
| | - Galit Tal
- The Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Vicente Rubio
- Instituto de Biomedicina de Valencia (IBV-CSIC), Centro de Investigación Biomédica en Red para Enfermedades Raras (CIBERER), Valencia, Spain
| | - Martina Huemer
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
- Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria
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28
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Sun Y, Jia L, Yu H, Zhu M, Sheng M, Yu W. The Effect of Pediatric Living Donor Liver Transplantation on Neurocognitive Outcomes in Children. Ann Transplant 2019; 24:446-453. [PMID: 31371696 PMCID: PMC6690216 DOI: 10.12659/aot.914164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Neurocognitive dysfunction commonly occurs after solid organ transplantation and affects 15–30% of liver transplant recipients. The aim of this study was to evaluate the neurocognitive changes pre- and post-operation and the relative factors affecting those changes. Material/Methods Children with biliary atresia who underwent pediatric living donor-related liver transplantation before the age of 2 years were given Bayley Scale of Infant Development-II test (BSID-II), including Mental Development Index (MDI) and Psychomotor Development Index (PDI) the week before and again half a year after transplantation to assess the effect of transplantation on neurocognition. According to the test outcome, the children were divided into a normal group and an abnormal group. The association of clinical data with neurocognitive development between the 2 groups was analyzed by logistic regression analysis. Results There was a certain degree of improvement in neurocognition half a year after surgery compared with preoperative. The BSID-II subscales were significantly lower than expected before and after transplantation. Preoperative blood ammonia and bilirubin levels were independent risk factors for MDI half a year after transplantation, and preoperative albumin and bilirubin levels were risk factors for PDI. Conclusions Liver transplantation clearly improves children’s neurocognitive function. The postoperative neurocognition is closely related to pre-operation nutritional development.
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Affiliation(s)
- Ying Sun
- Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, China (mainland)
| | - Lili Jia
- Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, China (mainland)
| | - Hongli Yu
- Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, China (mainland)
| | - Min Zhu
- Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, China (mainland)
| | - Mingwei Sheng
- Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, China (mainland)
| | - Wenli Yu
- Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, China (mainland)
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29
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Diaz GA, Schulze A, Longo N, Rhead W, Feigenbaum A, Wong D, Merritt JL, Berquist W, Gallagher RC, Bartholomew D, McCandless SE, Smith WE, Harding CO, Zori R, Lichter-Konecki U, Vockley J, Canavan C, Vescio T, Holt RJ, Berry SA. Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. Mol Genet Metab 2019; 127:336-345. [PMID: 31326288 DOI: 10.1016/j.ymgme.2019.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/20/2019] [Accepted: 07/09/2019] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB. METHODS This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. RESULTS A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 µmol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure. CONCLUSION Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.
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Affiliation(s)
- George A Diaz
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andreas Schulze
- University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada
| | | | | | - Annette Feigenbaum
- University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada
| | - Derek Wong
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - William Berquist
- Stanford University Medical Center & Lucile Packard Children's Hospital, Stanford, CA, USA
| | | | - Dennis Bartholomew
- Ohio State University and Nationwide Children's Hospital, Columbus, OH, USA
| | - Shawn E McCandless
- Children's Hospital Colorado and University of Colorado Denver, Aurora, CO, USA
| | | | | | | | | | - Jerry Vockley
- Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Posset R, Gropman AL, Nagamani SCS, Burrage LC, Bedoyan JK, Wong D, Berry GT, Baumgartner MR, Yudkoff M, Zielonka M, Hoffmann GF, Burgard P, Schulze A, McCandless SE, Garcia-Cazorla A, Seminara J, Garbade SF, Kölker S. Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders. Ann Neurol 2019; 86:116-128. [PMID: 31018246 DOI: 10.1002/ana.25492] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/02/2019] [Accepted: 04/21/2019] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs. METHODS This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years. RESULTS The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms. INTERPRETATION Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019.
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Affiliation(s)
- Roland Posset
- Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Andrea L Gropman
- Children's National Health System and George Washington School of Medicine, Washington, DC
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Jirair K Bedoyan
- Center for Human Genetics and Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH
| | - Derek Wong
- David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA
| | - Gerard T Berry
- Harvard Medical School and Boston Children's Hospital, Boston, MA
| | - Matthias R Baumgartner
- University Children's Hospital Zurich and Children's Research Center, Zurich, Switzerland
| | - Marc Yudkoff
- University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA
| | - Matthias Zielonka
- Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.,Heidelberg Research Center for Molecular Medicine, Heidelberg, Germany
| | - Georg F Hoffmann
- Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Burgard
- Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Andreas Schulze
- Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
| | - Shawn E McCandless
- Children's Hospital Colorado and University of Colorado, School of Medicine, Aurora, CO
| | - Angeles Garcia-Cazorla
- Hospital San Joan de Deu, Institut Pediàtric de Recerca. Servicio de Neurologia and CIBERER, ISCIII, Barcelona, Spain
| | - Jennifer Seminara
- Children's National Health System and George Washington School of Medicine, Washington, DC
| | - Sven F Garbade
- Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Kölker
- Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
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Berry SA, Vockley J, Vinks AA, Dong M, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Perdok R, Robinson B, Holt RJ, Longo N. Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders. Mol Genet Metab 2018; 125:251-257. [PMID: 30217721 DOI: 10.1016/j.ymgme.2018.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 07/27/2018] [Accepted: 09/02/2018] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Glycerol phenylbutyrate (GPB) is approved in the US and EU for the chronic management of patients ≥2 months of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB is a pre-prodrug, hydrolyzed by lipases to phenylbutyric acid (PBA) that upon absorption is beta-oxidized to the active nitrogen scavenger phenylacetic acid (PAA), which is conjugated to glutamine (PAGN) and excreted as urinary PAGN (UPAGN). Pharmacokinetics (PK) of GPB were examined to see if hydrolysis is impaired in very young patients who may lack lipase activity. METHODS Patients 2 months to <2 years of age with UCDs from two open label studies (n = 17, median age 10 months) predominantly on stable doses of nitrogen scavengers (n = 14) were switched to GPB. Primary assessments included traditional plasma PK analyses of PBA, PAA, and PAGN, using noncompartmental methods with WinNonlin™. UPAGN was collected periodically throughout the study up to 12 months. RESULTS PBA, PAA and PAGN rapidly appeared in plasma after GPB dosing, demonstrating evidence of GPB cleavage with subsequent PBA absorption. Median concentrations of PBA, PAA and PAGN did not increase over time and were similar to or lower than the values observed in older UCD patients. The median PAA/PAGN ratio was well below one over time, demonstrating that conjugation of PAA with glutamine to form PAGN did not reach saturation. Covariate analyses indicated that age did not influence the PK parameters, with body surface area (BSA) being the most significant covariate, reinforcing current BSA based dosing recommendations as seen in older patients. CONCLUSION These observations demonstrate that UCD patients aged 2 months to <2 years have sufficient lipase activity to adequately convert the pre-prodrug GPB to PBA. PBA is then converted to its active moiety (PAA) providing successful nitrogen scavenging even in very young children.
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Affiliation(s)
- Susan A Berry
- University of Minnesota Department of Pediatrics, Minneapolis, MN, USA
| | - Jerry Vockley
- University of Pittsburgh School of Medicine and the Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Alexander A Vinks
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
| | - Min Dong
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
| | - George A Diaz
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shawn E McCandless
- University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
| | | | | | | | - Can Ficicioglu
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | | | | | - Robert J Holt
- Horizon Pharma USA, Inc, Lake Forest, IL, USA; University of Illinois-Chicago, Chicago, IL, USA.
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Hediger N, Landolt MA, Diez-Fernandez C, Huemer M, Häberle J. The impact of ammonia levels and dialysis on outcome in 202 patients with neonatal onset urea cycle disorders. J Inherit Metab Dis 2018. [PMID: 29520739 DOI: 10.1007/s10545-018-0157-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Neonatal onset hyperammonemia in patients with urea cycle disorders (UCDs) is still associated with high morbidity and mortality. Current protocols consistently recommend emergency medical and dietary management. In case of increasing or persistent hyperammonemia, with continuous or progressive neurological signs, dialysis is performed, mostly as ultima ratio. It is presently unknown whether the currently defined ammonia threshold (e.g., at 500 μmol/L) to start dialysis is useful to improve clinical outcome. A systematic review of clinical and biochemical data from published neonatal onset UCD patients was performed to identify factors determining clinical outcome and to investigate in which clinical and biochemical setting dialysis was most effective. A total of 202 patients (118 proximal and 84 distal UCDs) described in 90 case reports or case series were included according to predefined inclusion/exclusion criteria. Median age at onset was three days and mean ammonia that triggered start of dialysis was 1199 μmol/L. Seventy-one percent of all patients received any form of dialysis. Total mortality was 25% and only 20% of all patients had a "normal" outcome. In general, patients with higher ammonia levels were more likely to receive dialysis, but this had for most patients no influence on outcome. In conclusion, in severe neonatal onset hyperammonemia, the current practice of dialysis, which effectively clears ammonia, had no impact on outcome. It may be essential for improving outcome to initiate all available treatment options, including dialysis, as early as possible.
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Affiliation(s)
- Nina Hediger
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, 8032, Zurich, Switzerland
| | - Markus A Landolt
- Department of Psychosomatics and Psychiatry, University Children's Hospital Zurich, 8032, Zurich, Switzerland
- Division of Child and Adolescent Health Psychology, Department of Psychology, University of Zurich, Zurich, Switzerland
| | - Carmen Diez-Fernandez
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, 8032, Zurich, Switzerland
| | - Martina Huemer
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, 8032, Zurich, Switzerland
- Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria
| | - Johannes Häberle
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, 8032, Zurich, Switzerland.
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Gambello MJ, Li H. Current strategies for the treatment of inborn errors of metabolism. J Genet Genomics 2018; 45:61-70. [PMID: 29500085 DOI: 10.1016/j.jgg.2018.02.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/14/2017] [Accepted: 02/11/2018] [Indexed: 12/23/2022]
Abstract
Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.
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Affiliation(s)
- Michael J Gambello
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Hong Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
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Španěl P, Smith D. What is the real utility of breath ammonia concentration measurements in medicine and physiology? J Breath Res 2018; 12:027102. [PMID: 28972201 DOI: 10.1088/1752-7163/aa907f] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Much effort continues to be devoted to the development of devices to analyse breath ammonia with the anticipation that breath ammonia analyses will be useful in clinical practice. In this perspective we refer to the analytical techniques that have been used to measure breath ammonia, focusing on selected ion flow tube mass spectrometry, SIFT-MS, of which we have special knowledge and understanding. From the collected data obtained using the different techniques, we exam the origins of mouth- and nose-exhaled ammonia and conclude that mouth-exhaled ammonia is always elevated above a concentration that would be equilibrated with blood ammonia and is largely produced by the action of enzymes on salivary urea. Support to this conclusion is given by the reasonable correlation between blood urea concentration and mouth-exhaled ammonia concentration. Further, it is discussed that nose-exhaled ammonia largely originates at the alveolar interface and so its concentration more closely relates to the expected alveolar blood ammonia concentration. Ingestion of proteins results in increased blood/saliva urea and ultimately mouth-exhaled ammonia as does the generation of urease by H. pylori infection. It is also concluded that when mouth-exhaled ammonia is elevated then it may be due to either abnormally high blood urea, a high pH of the saliva/mouth/airways mucosa, poor oral hygiene or a combinations of these.
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Affiliation(s)
- Patrik Španěl
- J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Dolejškova 3, 182 23 Prague 8, Czechia
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Longo N, Holt RJ. Glycerol phenylbutyrate for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1405807] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Nicola Longo
- Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA
| | - Robert J. Holt
- Medical Affairs, Horizon Pharma, Lake Forest, IL, USA
- Department of Pharmacy Practice, University of Illinois, Chicago, IL, USA
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Berry SA, Longo N, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Robinson B, Vockley J. Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years. Mol Genet Metab 2017; 122:46-53. [PMID: 28916119 DOI: 10.1016/j.ymgme.2017.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/01/2017] [Accepted: 09/01/2017] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients. METHODS Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100μmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development. RESULTS 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule. CONCLUSION GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.
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Affiliation(s)
| | | | - George A Diaz
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shawn E McCandless
- Center for Human Genetics, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA
| | | | | | | | - Can Ficicioglu
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | | | - Jerry Vockley
- Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Jiang Y, Almannai M, Sutton VR, Sun Q, Elsea SH. Quantitation of phenylbutyrate metabolites by UPLC-MS/MS demonstrates inverse correlation of phenylacetate:phenylacetylglutamine ratio with plasma glutamine levels. Mol Genet Metab 2017; 122:39-45. [PMID: 28888854 DOI: 10.1016/j.ymgme.2017.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 08/27/2017] [Accepted: 08/27/2017] [Indexed: 12/31/2022]
Abstract
Urea cycle disorders (UCDs) are genetic conditions characterized by nitrogen accumulation in the form of ammonia and caused by defects in the enzymes required to convert ammonia to urea for excretion. UCDs include a spectrum of enzyme deficiencies, namely n-acetylglutamate synthase deficiency (NAGS), carbamoyl phosphate synthetase I deficiency (CPS1), ornithine transcarbamylase deficiency (OTC), argininosuccinate lyase deficiency (ASL), citrullinemia type I (ASS1), and argininemia (ARG). Currently, sodium phenylbutyrate and glycerol phenylbutyrate are primary medications used to treat patients with UCDs, and long-term monitoring of these compounds is critical for preventing drug toxic levels. Therefore, a fast and simple ultra-performance liquid chromatography (UPLC-MS/MS) method was developed and validated for quantification of phenylbutyrate (PB), phenylacetate (PA), and phenylacetylglutamine (PAG) in plasma and urine. The separation of all three analytes was achieved in 2min, and the limits of detection were <0.04μg/ml. Intra-precision and inter-precision were <8.5% and 4% at two quality control concentrations, respectively. Average recoveries for all compounds ranged from 100% to 106%. With the developed assay, a strong correlation between PA and the PA/PAG ratio and an inverse correlation between PA/PAG ratio and plasma glutamine were observed in 35 patients with confirmed UCDs. Moreover, all individuals with a ratio ≥0.6 had plasma glutamine levels<1000μmol/l. Our data suggest that a PA/PAG ratio in the range of 0.6-1.5 will result in a plasma glutamine level<1000μmol/l without reaching toxic levels of PA.
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Affiliation(s)
- Yi Jiang
- Division of Biochemical Genetics, Baylor Genetics Laboratories, Houston, TX, United States
| | - Mohammed Almannai
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - V Reid Sutton
- Division of Biochemical Genetics, Baylor Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Qin Sun
- Division of Biochemical Genetics, Baylor Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Sarah H Elsea
- Division of Biochemical Genetics, Baylor Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
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Ono K, Nimura S, Hideshima Y, Nabeshima K, Nakashima M. Orally administered sodium 4-phenylbutyrate suppresses the development of dextran sulfate sodium-induced colitis in mice. Exp Ther Med 2017; 14:5485-5490. [PMID: 29285080 DOI: 10.3892/etm.2017.5251] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 03/23/2017] [Indexed: 12/14/2022] Open
Abstract
Sodium 4-phenylbutyrate (PBA) exerts therapeutic effects in a wide range of pathologies. A previous study by the present authors revealed that intraperitoneal administration of PBA suppresses the onset of dextran sulfate sodium (DSS)-induced colitis in mice. In the present study, the effects of orally administered PBA are investigated, as this route of administration is more clinically relevant. The therapeutic efficacy of PBA (10 mg/12 h) in mice with experimental colitis was assessed based on the disease activity index, production of inflammatory cytokines, colon length and histopathological investigations. The results of the present study demonstrated a significantly higher survival rate in the PBA-treated group compared with the PBA-untreated (DSS control) group (P=0.0156). PBA treatment improved pathological indices of experimental colitis (P<0.05). Furthermore, the oral administration of PBA significantly inhibited the DSS-induced shortening of the colon (P<0.05) and overproduction of interleukin (IL)-1β and IL-6 (both P<0.05) as measured in colonic lavage fluids. A marked attenuation of the DSS-induced overproduction of tumor necrosis factor was also observed. For histopathological analysis, a marked decrease in mature goblet cells and increase in enlarged nuclei of the absorptive cells was observed in colon lesions of DSS control mice as compared with normal untreated mice. However, in the PBA-treated mice, no such lesions were observed and the mucosa resembled that of DSS-untreated mice. The results of the present study, combined with those results of a previous study, suggest that oral and intraperitoneal administration of PBA have similar preventative effects on DSS-induced colitis, achieved by suppressing its pathogenesis.
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Affiliation(s)
- Kazuhiko Ono
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
| | - Satoshi Nimura
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
| | - Yuko Hideshima
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
| | - Kazuki Nabeshima
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
| | - Manabu Nakashima
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
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Peña-Quintana L, Llarena M, Reyes-Suárez D, Aldámiz-Echevarria L. Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Prefer Adherence 2017; 11:1489-1496. [PMID: 28919721 PMCID: PMC5593420 DOI: 10.2147/ppa.s136754] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Urea-cycle disorders are a group of rare hereditary metabolic diseases characterized by deficiencies of one of the enzymes and transporters involved in the urea cycle, which is necessary for the removal of nitrogen produced from protein breakdown. These hereditary metabolic diseases are characterized by hyperammonemia and life-threatening hyperammonemic crises. Pharmacological treatment of urea-cycle disorders involves alternative nitrogen-scavenging pathways. Sodium benzoate combines with glycine and phenylacetate/phenylbutyrate with glutamine, forming, respectively, hippuric acid and phenylacetylglutamine, which are eliminated in the urine. Among the ammonia-scavenging drugs, sodium phenylbutyrate is a well-known long-term treatment of urea-cycle disorders. It has been used since 1987 as an investigational new drug, and was approved for marketing in the US in 1996 and the EU in 1999. However, sodium phenylbutyrate has an aversive odor and taste, which may compromise patients' compliance, and many patients have reported difficulty in taking this drug. Sodium phenylbutyrate granules are a new tasteless and odor-free formulation of sodium phenylbutyrate, which is indicated in the treatment of urea-cycle disorders. This recently developed taste-masked formulation of sodium phenylbutyrate granules was designed to overcome the considerable issues that taste has on adherence to therapy. Several studies have reported the clinical experience of patients with urea-cycle disorders treated with this new tasteless formulation of sodium phenylbutyrate. Analysis of the data indicated that this taste-masked formulation of sodium phenylbutyrate granules improved quality of life for urea-cycle disorder patients. Furthermore, a postmarketing report on the use of the product has confirmed the previous observations of improved compliance, efficacy, and safety with this taste-masked formulation of sodium phenylbutyrate.
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Affiliation(s)
- Luis Peña-Quintana
- Pediatric Gastroenterology, Hepatology, and Nutrition Unit, Universitario Materno-Infantil Hospital de Canarias, University of Las Palmas de Gran Canaria
- Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas
- CIBEROBN, Madrid
| | - Marta Llarena
- Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas
| | - Desiderio Reyes-Suárez
- Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas
| | - Luis Aldámiz-Echevarria
- Unit of Metabolism, Cruces University Hospital, BioCruces Health Research Institute, GCV-CIBER de Enfremedades Raras (CIBERER), Barakaldo, Spain
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Diez-Fernandez C, Häberle J. Targeting CPS1 in the treatment of Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea cycle disorder. Expert Opin Ther Targets 2017; 21:391-399. [PMID: 28281899 DOI: 10.1080/14728222.2017.1294685] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged. Additionally, in many cases, current management (protein-restriction and supplementation with citrulline and/or arginine and ammonia scavengers) is insufficient for achieving metabolic stability, highlighting the importance of developing alternative therapeutic approaches. Areas covered: After describing UCDs and CPS1D, we give an overview of the structure- function of CPS1. We then describe current management and potential novel treatments including N-carbamoyl-L-glutamate (NCG), pharmacological chaperones, and gene therapy to treat hyperammonemia. Expert opinion: Probably, the first novel CPS1D therapies to reach the clinics will be the already commercial substance NCG, which is the standard treatment for N-acetylglutamate synthase deficiency and has been proven to rescue specific CPS1D mutations. Pharmacological chaperones and gene therapy are under development too, but these two technologies still have key challenges to be overcome. In addition, current experimental therapies will hopefully add further treatment options.
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Affiliation(s)
- Carmen Diez-Fernandez
- a Division of Metabolism , University Children's Hospital Zurich and Children's Research Center , Zurich , Switzerland
| | - Johannes Häberle
- a Division of Metabolism , University Children's Hospital Zurich and Children's Research Center , Zurich , Switzerland
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41
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Goldstein A, Vockley J. Clinical trials examining treatments for inborn errors of amino acid metabolism. Expert Opin Orphan Drugs 2016. [DOI: 10.1080/21678707.2017.1275565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Amy Goldstein
- Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jerry Vockley
- Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Mohamed S, Hamad MH, Kondkar AA, Abu-Amero KK. A novel mutation in ornithine transcarbamylase gene causing mild intermittent hyperammonemia. Saudi Med J 2016; 36:1229-32. [PMID: 26446336 PMCID: PMC4621731 DOI: 10.15537/smj.2015.10.12127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
We report a 3-year-old Saudi boy with recurrent episodes of vomiting, poor feeding, and altered mental status accompanied by an intermittent mild hyperammonemia, and a large elevation of urinary orotic acid. Sanger sequencing of the ornithine transcarbamylase (OTC) gene revealed a novel hemizygous deletion at the fourth nucleotide of intron 4 (c.386+4delT) in the proband and his asymptomatic mother. This novel mutation in the OTC gene is responsible for the late-onset phenotype of OTC deficiency.
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Affiliation(s)
- Sarar Mohamed
- Department of Pediatrics (39), College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. E-mail.
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Kibleur Y, Guffon N. Long-Term Follow-Up on a Cohort Temporary Utilization Authorization (ATU) Survey of Patients Treated with Pheburane (Sodium Phenylbutyrate) Taste-Masked Granules. Paediatr Drugs 2016; 18:139-44. [PMID: 26747635 DOI: 10.1007/s40272-015-0159-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVES The aim was to describe the status of patients with urea cycle disorders (UCD) at the latest long-term clinical follow-up of treatment with a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane). These patients are a subset of those treated under a cohort temporary utilisation study (ATU) previously reported and now followed for 2 years. METHODS From a French cohort temporary utilization authorization (ATU) set up to monitor the use of Pheburane on a named-patient basis in UCD patients in advance of its marketing authorization, a subset of patients were followed up in the long term. Data on demographics, dosing characteristics of NaPB, concomitant medications, adverse events and clinical outcomes were collected at a follow-up visit after 1-2 years of treatment with the drug administered under marketing conditions. This paper reports on the subset of patients who were included in further long-term follow-up at the principal recruiting metabolic reference center involved in the original cohort. RESULTS No episode of metabolic decompensation was observed over a treatment period ranging from 8 to 30 months with Pheburane, and the range of ammonia and glutamine levels continued to improve and remained within the normal range, thus adding valuable longer-term feedback to the original ATU report. In all, no adverse events were reported with Pheburane treatment. These additional data demonstrate the maintenance of the safety and efficacy of Pheburane over time. CONCLUSIONS The recently developed taste-masked formulation of NaPB granules (Pheburane) improved the quality of life for UCD patients. The present post-marketing report on the use of the product confirms the original observations of improved compliance, efficacy and safety with this taste-masked formulation of NaPB.
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Affiliation(s)
- Yves Kibleur
- Lucane Pharma, 172 rue de Charonne, 75011, Paris, France.
| | - Nathalie Guffon
- Hôpital Femme-Mère-Enfant, Centre de Référence des maladies héréditaires du métabolisme, 59 Boulevard Pinel, 69577, Bron Cedex, France
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Switch from Sodium Phenylbutyrate to Glycerol Phenylbutyrate Improved Metabolic Stability in an Adolescent with Ornithine Transcarbamylase Deficiency. JIMD Rep 2016; 31:11-14. [PMID: 27000017 DOI: 10.1007/8904_2016_551] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 02/25/2016] [Accepted: 02/29/2016] [Indexed: 12/30/2022] Open
Abstract
A male patient, born in 1999, was diagnosed with ornithine transcarbamylase deficiency as neonate and was managed with a strict low-protein diet supplemented with essential amino acids, L-citrulline, and L-arginine as well as sodium benzoate. He had an extensive history of hospitalizations for hyperammonemic crises throughout childhood and early adolescence, which continued after the addition of sodium phenylbutyrate in 2009. In December 2013 he was switched to glycerol phenylbutyrate, and his metabolic stability was greatly improved over the following 7 months prior to liver transplant.
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Stuy M, Chen GF, Masonek JM, Scharschmidt BF. Refeeding syndrome in a young woman with argininosuccinate lyase deficiency. Mol Genet Metab Rep 2016; 4:6-8. [PMID: 26937403 PMCID: PMC4750572 DOI: 10.1016/j.ymgmr.2015.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
A severely chronically protein and calorie restricted young woman with argininosuccinate lyase deficiency developed transient refeeding syndrome (RFS) and hyperammonemia after modest diet liberalization following initiation of glycerol phenylbutyrate (GPB). The patient required IV supportive care and supplementation with potassium, magnesium and calcium. She is now doing well on GPB and an appropriate maintenance diet. Susceptibility to RFS should be considered in chronically nutritionally restricted patients with metabolic disorders after liberalization of diet.
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Affiliation(s)
- M Stuy
- Department of Medical and Molecular Genetics, Division of Clinical and Biochemical Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - G-F Chen
- Hyperion Therapeutics, Inc., Brisbane, CA, United States
| | - J M Masonek
- Hyperion Therapeutics, Inc., Brisbane, CA, United States
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Hook D, Diaz GA, Lee B, Bartley J, Longo N, Berquist W, Le Mons C, Rudolph-Angelich I, Porter M, Scharschmidt BF, Mokhtarani M. Protein and calorie intakes in adult and pediatric subjects with urea cycle disorders participating in clinical trials of glycerol phenylbutyrate. Mol Genet Metab Rep 2016; 6:34-40. [PMID: 27014577 PMCID: PMC4789342 DOI: 10.1016/j.ymgmr.2015.11.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 12/30/2022] Open
Abstract
Background Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals. Objective To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys. Design Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB. Protein and calorie intakes were compared to UCD treatment guidelines, average nutrient intakes of a healthy US population based on the National Health and Nutrition Examination Survey (NHANES) and Recommended Daily Allowances (RDA). Results In adults, mean protein intake was higher than UCD recommendations but lower than RDA and NHANES values, while calorie intake was lower than UCD recommendations, RDA and NHANES. In pediatric subjects, prescribed protein intake was higher than UCD guidelines, similar to RDA, and lower than NHANES data for all age groups, while calorie intake was at the lower end of the recommended UCD range and close to RDA and NHANES data. In pediatric subjects height, weight, and body mass index (BMI) Z-scores were within normal range (− 2 to 2). Conclusions Pediatric patients treated with phenylbutyrate derivatives exhibited normal height and weight. Protein and calorie intakes in adult and pediatric UCD subjects differed from UCD dietary guidelines, suggesting that these guidelines may need to be reconsidered.
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Affiliation(s)
- Debra Hook
- Miller Children's Hospital/Long Beach Medical Center, United States
| | - George A Diaz
- Mount Sinai School of Medicine, Department of Genetics and Genomic Sciences, Department of Pediatrics, United States
| | | | - James Bartley
- Miller Children's Hospital/Long Beach Medical Center, United States
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Lee B, Diaz GA, Rhead W, Lichter-Konecki U, Feigenbaum A, Berry SA, Le Mons C, Bartley J, Longo N, Nagamani SC, Berquist W, Gallagher RC, Harding CO, McCandless SE, Smith W, Schulze A, Marino M, Rowell R, Coakley DF, Mokhtarani M, Scharschmidt BF. Glutamine and hyperammonemic crises in patients with urea cycle disorders. Mol Genet Metab 2016; 117:27-32. [PMID: 26586473 PMCID: PMC4915945 DOI: 10.1016/j.ymgme.2015.11.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/10/2015] [Accepted: 11/10/2015] [Indexed: 12/30/2022]
Abstract
UNLABELLED Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. METHODS The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. RESULTS The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 μmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]μmol/L) than patients with baseline glutamine ≤ 900 μmol/L (26.6 [18.0]μmol/L). Glutamine values >900 μmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia ≥ 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 μmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia ≥ 1.0 ULN (HR=4.62; p=0.0011). CONCLUSIONS The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.
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Affiliation(s)
- B Lee
- Baylor College of Medicine, Houston, TX, USA.
| | - G A Diaz
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - W Rhead
- The Medical College of Wisconsin, Milwaukee, WI, USA
| | | | | | - S A Berry
- Univ. of Minnesota, Minneapolis, MN, USA
| | - C Le Mons
- National Urea Cycle Disorders Foundation, Pasadena, CA, USA
| | - J Bartley
- Miller Children's Hospital, Long Beach, CA, USA
| | - N Longo
- Univ. of UT, Salt Lake City, UT, USA
| | | | | | | | | | - S E McCandless
- Case Western Reserve Univ. Medical Center, Cleveland, OH, USA
| | - W Smith
- Maine Medical Ctr., Portland, ME, USA
| | - A Schulze
- The Hospital for Sick Children, Univ. of Toronto, Canada
| | - M Marino
- Oregon Health Sciences, Portland, OR, USA
| | - R Rowell
- MED Technical Consulting, Inc., Union City, CA, USA
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Urinary phenylacetylglutamine (U-PAGN) concentration as biomarker for adherence in patients with urea cycle disorders (UCD) treated with glycerol phenylbutyrate. Mol Genet Metab Rep 2015. [PMID: 28649536 PMCID: PMC5471406 DOI: 10.1016/j.ymgmr.2015.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age- and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (<~9000 μg/mL for < 2 years old patients, < 7000 μg/mL for > 2 years with BSA ≤ 1.3 m2, and <~5000 μg/mL for > 2 years of age with BSA > 1.3 m2) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed.
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Nagamani SCS, Diaz GA, Rhead W, Berry SA, Le Mons C, Lichter-Konecki U, Bartley J, Feigenbaum A, Schulze A, Longo N, Berquist W, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Vockley J, Kronn D, Zori R, Cederbaum S, Merritt JL, Wong D, Coakley DF, Scharschmidt BF, Dickinson K, Marino M, Lee BH, Mokhtarani M. Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials. Mol Genet Metab 2015; 116:29-34. [PMID: 26296711 PMCID: PMC4804346 DOI: 10.1016/j.ymgme.2015.08.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 08/03/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. METHODS Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). RESULTS After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. CONCLUSIONS The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.
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Affiliation(s)
- Sandesh C S Nagamani
- Baylor College of Medicine, One Baylor Plaza, Room R814, Houston, TX 77030, USA.
| | - George A Diaz
- Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Department of Pediatrics, 1428 Madison Avenue, New York, NY 10029, USA
| | - William Rhead
- The Medical College of Wisconsin, MS 716, 9000 W. Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Susan A Berry
- University of Minnesota, 420 Delaware St. SE, MMC 75, Minneapolis, MN 55455, USA
| | - Cynthia Le Mons
- National Urea Cycle Disorders Foundation, 75 S. Grand Ave, Pasadena, CA 91105, USA
| | | | - James Bartley
- Long Beach Memorial Hospital, 2801 Atlantic Avenue, Long Beach, CA 90806, USA
| | | | - Andreas Schulze
- The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G1X8, Canada
| | - Nicola Longo
- The University of Utah, Division of Medical Genetics, 2C412 SOM, 50 North Mario Capecchi Drive, Salt Lake City, UT 84132, USA
| | - William Berquist
- Stanford University, 750 Welch Road, #116, Palo Alto, CA 94305, USA
| | - Renata Gallagher
- UCSF School of Medicine, 550 16th Street, San Francisco, CA 94158, USA
| | - Dennis Bartholomew
- Nationwide Children's Hospital, 545 South 18th Street, TH485, Columbus, OH 43205, USA
| | - Cary O Harding
- Oregon Health & Science University, 3181 SW Sam Jackson Park Road, A036/B198, Mail code L103, Portland, OR 97239, USA
| | - Mark S Korson
- Tufts Medical Center, Floating Building, 3rd Floor, 800 Washington Street, Boston, MA 02111, USA
| | - Shawn E McCandless
- Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Wendy Smith
- Maine Medical Center, 1577 Congress Street, 2nd Floor, Portland, ME 04102, USA
| | - Jerry Vockley
- Children's Hospital of Pittsburgh, One Children's Hospital Drive, 4401 Penn Avenue, Rangos Floor 5, Pittsburgh, PA 15224, USA
| | - David Kronn
- Westchester Medical Center, 503 Grasslands Road, Valhalla, NY 10595, USA
| | - Robert Zori
- University of Florida, UFHSC Box 100296, Gainesville, FL 32610, USA
| | - Stephen Cederbaum
- University of California, Los Angeles, 10833 Le Conte Avenue CHS 32-225, Los Angeles, CA 90095, USA
| | - J Lawrence Merritt
- Seattle Children's Hospital, 4800 Sand Point Way NE M/S W-65945, Seattle, WA 98105, USA
| | - Derek Wong
- University of California, Los Angeles, 10833 Le Conte Avenue CHS 32-225, Los Angeles, CA 90095, USA
| | - Dion F Coakley
- Horizon Therapeutics Inc., 2000 Sierra Point Parkway Suite 400, Brisbane, CA 94005, USA
| | - Bruce F Scharschmidt
- Horizon Therapeutics Inc., 2000 Sierra Point Parkway Suite 400, Brisbane, CA 94005, USA
| | - Klara Dickinson
- Anthera Pharmaceuticals, 25801 Industrial Blvd. Suite B, Hayward, CA 94545, USA
| | - Miguel Marino
- Oregon Health & Science University, 3181 SW Sam Jackson Park Road, A036/B198, Mail code L103, Portland, OR 97239, USA
| | - Brendan H Lee
- Baylor College of Medicine, One Baylor Plaza, Room R814, Houston, TX 77030, USA
| | - Masoud Mokhtarani
- Horizon Therapeutics Inc., 2000 Sierra Point Parkway Suite 400, Brisbane, CA 94005, USA
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