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Lundqvist T, Stenlid R, Halldin M. Hormonal Crossroads in Inborn Errors of the Metabolism Impact of Puberty and Dietary Interventions on Metabolic Health. Metabolites 2025; 15:235. [PMID: 40278364 PMCID: PMC12029320 DOI: 10.3390/metabo15040235] [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: 02/28/2025] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/26/2025] Open
Abstract
Background/Objectives: Inborn errors of metabolism (IEMs) represent a diverse group of genetic disorders characterized by enzymatic defects that disrupt metabolic pathways, leading to toxic metabolite accumulation, deficits, or impaired macromolecule synthesis. While strict dietary interventions are critical for managing many of these conditions, hormonal and metabolic changes during puberty introduce new challenges. Advancements in early diagnosis and treatment have significantly extended the lifespan of individuals with IEMs. However, this increased longevity is associated with heightened risks of new medical problems, including obesity, insulin resistance, and type 2 diabetes mellitus (T2DM), as these complications share mechanistic features with those seen in obesity and T2DM. Methods: This mini-review examines current knowledge of the intricate interplay between pubertal hormones and metabolic pathways in IEM patients. Results: We address critical questions, such as if puberty intensifies the risk of metabolic derangements in these individuals and if there is a metabolic intersection where these disorders converge, leading to shared complications. We highlight the impact of puberty-induced hormonal fluctuations, such as growth hormone (GH) surges and sex steroid activity, on disorders like phenylketonuria, urea cycle defects, and fatty acid oxidation disorders. Moreover, we explore the role of dietary interventions in mitigating or exacerbating these effects, emphasizing the importance of balancing nutritional needs during growth spurts. Conclusions: A multidisciplinary approach integrating endocrinology, nutrition, and emerging therapies is advocated to optimize metabolic health during puberty. Addressing these challenges is critical for improving long-term outcomes for individuals with IEMs, particularly during this pivotal developmental phase.
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Affiliation(s)
- Thomas Lundqvist
- Department of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden
- Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, 171 76 Stockholm, Sweden
| | - Rasmus Stenlid
- Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden
| | - Maria Halldin
- Department of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden
- Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, 171 76 Stockholm, Sweden
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2
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Roth DM, Piña JO, MacPherson M, Budden C, Graf D. Physiology and Clinical Manifestations of Pathologic Cranial Suture Widening. Cleft Palate Craniofac J 2024; 61:1750-1759. [PMID: 37271984 PMCID: PMC11468227 DOI: 10.1177/10556656231178438] [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] [Indexed: 06/06/2023] Open
Abstract
Cranial sutures are complex structures integrating mechanical forces with osteogenesis which are often affected in craniofacial syndromes. While premature fusion is frequently described, rare pathological widening of cranial sutures is a comparatively understudied phenomenon. This narrative review aims to bring to light the biologically variable underlying causes of widened sutures and persistent fontanelles leading to a common outcome. The authors herein present four syndromes, selected from a literature review, and their identified biological mechanisms in the context of altered suture physiology, exploring the roles of progenitor cell differentiation, extracellular matrix production, mineralization, and bone resorption. This article illustrates the gaps in understanding of complex craniofacial disorders, and the potential for further unification of genetics, cellular biology, and clinical pillars of health science research to improve treatment outcomes for patients.
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Affiliation(s)
- Daniela M. Roth
- School of Dentistry, University of Alberta, Edmonton, Canada
| | - Jeremie Oliver Piña
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
| | | | - Curtis Budden
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Daniel Graf
- School of Dentistry, University of Alberta, Edmonton, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, Canada
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3
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Pretese R, Bonfanti C, Faraguna MC, Fantasia M, Crescitelli V, Barzaghi S, Botti M, Mezzanotti G, Gasperini S. The Impact of Diet on Body Composition in a Cohort of Pediatric and Adult Patients with Maple Syrup Urine Disease. Nutrients 2024; 16:3145. [PMID: 39339744 PMCID: PMC11434745 DOI: 10.3390/nu16183145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
The treatment for Maple Syrup Urine Disease (MSUD) consists of a hypoproteic diet with integration therapy to limit leucine intake, ensuring adequate energy, macronutrients, and micronutrients to prevent catabolism and promote anabolism. We conducted a retrospective cross-sectional study at the Metabolic Rare Disease Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. Patients with MSUD who were over 3 years old, not treated with liver transplantation, and who provided written consent, were included. The study aimed to describe the dietary treatment of patients with MSUD, evaluate growth data, and analyze the effect of a low-protein and semi-synthetic diet on body composition. Data on height, weight, BMI, waist circumference, food intake, physical activity, and DEXA scans were collected. Thirteen subjects (11 classic MSUD, 2 intermediate MSUD) were included, of which 5 < 18 years old. Results indicated that patients with MSUD follow a balanced diet and have body compositions like healthy subjects in terms of fat and lean mass. A high incidence of osteopenia was observed from a young age, with a positive correlation between protein intake and lean mass and a negative correlation between BCAA-free mixture consumption and bone mineral density z-score. The study highlights the positive effects and potential consequences of the semi-synthetic diet on the body composition of patients with MSUD. A similar study involving all Italian metabolic centers treating MSUD is recommended.
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Affiliation(s)
- Roberta Pretese
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
| | - Cristina Bonfanti
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
| | - Martha Caterina Faraguna
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
- Residency in Pediatrics, University of Milano Bicocca, 20126 Milano, Italy
| | - Marialetizia Fantasia
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
- Residency in Pediatrics, University of Milano Bicocca, 20126 Milano, Italy
| | - Viola Crescitelli
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
| | - Silvia Barzaghi
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
| | - Mara Botti
- Rare Disease Centre, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy;
| | - Giulia Mezzanotti
- Deparment of Biology Applied to Nutrition Sciences, University of Milano Statale, 20122 Milano, Italy;
| | - Serena Gasperini
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (R.P.); (C.B.); (M.C.F.); (M.F.); (V.C.); (S.B.)
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Li M, Lin ZH, Chen YC, Lin P, Xie YX, Wei JCC. A case report on multiple acyl-CoA dehydrogenase deficiency with severe myopathy and osteoporosis. Int J Rheum Dis 2024; 27:e14906. [PMID: 37737545 DOI: 10.1111/1756-185x.14906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 08/10/2023] [Accepted: 08/26/2023] [Indexed: 09/23/2023]
Abstract
A 35-year-old male patient presented fluctuating bilateral lower extremity weakness for 3 years. Physical examination showed grade 4 proximal muscle weakness in both lower extremities and grade 5 distal muscle weakness. Laboratory data revealed elevated creatine kinase, triglycerides, and cholesterol. Muscle pathology showed deposition of lipid droplet under the sarcolemma. Bone densitometry indicated severe osteoporosis. Next-generation sequencing revealed a pathogenic mutation in the ETFDH gene. The patient was diagnosed with late-onset multiple acyl-CoA dehydrogenase deficiency. After riboflavin treatment, symptoms of the patient were relieved, physical endurance was restored, and bone mineral density was improved.
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Affiliation(s)
- Man Li
- The Second Hospital of Longyan, Longyan, China
| | - Zong-Han Lin
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ying-Cheng Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Pan Lin
- The Second Hospital of Longyan, Longyan, China
| | | | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan
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Montaño AM, Różdżyńska-Świątkowska A, Jurecka A, Ramirez AN, Zhang L, Marsden D, Wang RY, Harmatz P. Growth patterns in patients with mucopolysaccharidosis VII. Mol Genet Metab Rep 2023; 36:100987. [PMID: 37415957 PMCID: PMC10320588 DOI: 10.1016/j.ymgmr.2023.100987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/08/2023] Open
Abstract
Objective This study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy. Methods Height, weight, and body mass index (BMI) measurements and Z-scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively. Results Among 20 enrolled patients with MPS VII, height Z-scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight Z-score. BMI Z-scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight Z-scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight Z-scores in female patients. Conclusions In patients with MPS VII, declines in height Z-score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height Z-score with age than did patients without a history of NIHF.Clinical trial registration: This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results.
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Affiliation(s)
- Adriana M. Montaño
- Department of Pediatrics, and Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, St. Louis, MO, USA
| | | | | | | | - Lin Zhang
- Ultragenyx Pharmaceutical Inc., Novato, CA, USA
| | | | - Raymond Y. Wang
- Division of Metabolic Disorders, Children's Hospital of Orange County, USA
- Division of Pediatrics, University of California-Irvine School of Medicine, Orange, CA, USA
| | - Paul Harmatz
- UCSF Benioff Children's Hospital, Oakland, CA, USA
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Batycka M, Lange E, Ehmke vel Emczyńska-Seliga E, Jaworski M, Kobylińska M, Lech N, Samborowska E, Lipiński P, Perkowska B, Pokora P, Rokicki D. Relationship between Bone Mineral Density and Selected Parameters of Calcium-Phosphate Economy with Dietary Management and Metabolic Control in Polish Pediatric Patients with Classical Homocystinuria-A Preliminary Study. Nutrients 2023; 15:2112. [PMID: 37432246 PMCID: PMC10181419 DOI: 10.3390/nu15092112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Classical homocystinuria (HCU) is an inborn defect of methionine metabolism caused by a deficiency of the enzyme cystathionine β-synthase (CBS). The main symptoms of classical homocystinuria are lens subluxation, bone lesions, vascular disease and developmental delay/intellectual disability. The treatment method for HCU is a methionine-poor diet supplemented with amino acid preparations. The aim of the study was to examine the relationship of dietary factors, metabolic compensation and selected skeletal parameters in patients with HCU. METHODS Bone mineral density measurements (DXA) were performed in pediatric patients with HCU, and blood levels of selected amino acids, minerals and vitamins, as well as dietary nutritional value, were analyzed. RESULTS A total of 11 patients with HCU whose median age was 9.3 years were enrolled in the study. The median DXA total body less head of HCU patients was -0.4 z-score, and the lumbar spine was -1.4 z-score. Despite supplementation, calcium intake was below the age norm. Average vitamin D3 intake was in line with recommendations, but 36% of patients had reduced blood levels. Bone mineral density depended on blood levels of 25-hydroxyvitamin D, homocysteine and methionine, as well as on BMI, age and intake of natural protein (R2 = 98.5%, p = 0.015; R2 = 86.7%, p = 0.0049) and protein from an amino acid preparation (r = 0.69, p = 0.026). CONCLUSION The results of the study indicate the need for regular densitometry in patients with HCU and also the use of additional calcium and vitamin D3 supplementation. It is also necessary to perform a comprehensive analysis of the diet and metabolic controls.
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Affiliation(s)
- Małgorzata Batycka
- Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.B.)
| | - Ewa Lange
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
| | - Ewa Ehmke vel Emczyńska-Seliga
- Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.B.)
| | - Maciej Jaworski
- Laboratory of Densitometry, Department of Biochemistry, Radioimmunology and Experimental Medicine, Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Maria Kobylińska
- Laboratory of Densitometry, Department of Biochemistry, Radioimmunology and Experimental Medicine, Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Natalia Lech
- Laboratory of Fundamental Research, Department of Biochemistry, Radioimmunology and Experimental Medicine, Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Emilia Samborowska
- Laboratory of Metabolism Defects, Department of Biochemistry, Radioimmunology and Experimental Medicine, Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Patryk Lipiński
- Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.B.)
| | - Barbara Perkowska
- Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.B.)
| | - Paulina Pokora
- Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.B.)
| | - Dariusz Rokicki
- Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (M.B.)
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7
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Zhu L, Zhou C, Chen S, Huang D, Jiang Y, Lan Y, Zou S, Li Y. Osteoporosis and Alveolar Bone Health in Periodontitis Niche: A Predisposing Factors-Centered Review. Cells 2022; 11:3380. [PMID: 36359775 PMCID: PMC9657655 DOI: 10.3390/cells11213380] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 11/26/2023] Open
Abstract
Periodontitis is a periodontal inflammatory condition that results from disrupted periodontal host-microbe homeostasis, manifested by the destruction of tooth-supporting structures, especially inflammatory alveolar bone loss. Osteoporosis is characterized by systemic deterioration of bone mass and microarchitecture. The roles of many systemic factors have been identified in the pathogenesis of osteoporosis, including endocrine change, metabolic disorders, health-impaired behaviors and mental stress. The prevalence rate of osteoporotic fracture is in sustained elevation in the past decades. Recent studies suggest that individuals with concomitant osteoporosis are more vulnerable to periodontal impairment. Current reviews of worse periodontal status in the context of osteoporosis are limited, mainly centering on the impacts of menopausal and diabetic osteoporosis on periodontitis. Herein, this review article makes an effort to provide a comprehensive view of the relationship between osteoporosis and periodontitis, with a focus on clarifying how those risk factors in osteoporotic populations modify the alveolar bone homeostasis in the periodontitis niche.
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Affiliation(s)
| | | | | | | | | | | | | | - Yuyu Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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8
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Tummolo A, Carella R, Paterno G, Bartolomeo N, Giotta M, Dicintio A, De Giovanni D, Fischetto R. Body Composition in Adolescent PKU Patients: Beyond Fat Mass. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9091353. [PMID: 36138662 PMCID: PMC9497631 DOI: 10.3390/children9091353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/10/2022] [Accepted: 08/31/2022] [Indexed: 11/21/2022]
Abstract
There is a lack of evidence on the impact on body composition of high protein intake and types of protein substitutes in PKU patients—particularly in adolescents, who are more inclined to dietary transgressions. In this observational, cross-sectional study, PKU patients were observed during prepubertal age (p) or after the pubertal spurt (P), assessing body composition and bone quality and correlating these parameters with dietary compliance and types of protein substitutes. Anthropometric and dietary data were evaluated together with bioelectrical impedance analysis (BIA), quantitative ultrasound (QUS) and branched-chain amino acids (BCAAs). A total of 36 patients (16 males, 17 prepubertal and 19 post-pubertal; mean ± SD age 11.4 ± 3.9 years) were included. A higher BMI was observed in adolescents (p-value: 0.018). The BIA revealed a significant increase in total body water (TBW) and muscle mass (MM) in P subjects either compliant (p-value: 0.001) or non-compliant with the diet (p-value: 0.001). MM content correlated with increased Phe intake (r = 0.63; p < 0.001). In the subgroup of five patients taking L-AAs and glycomacropeptides (GMPs), BCAA values tended to be lower than those taking only L-AA mixtures, with a significant trend for valine. Maintenance of body composition parameters within the normal range—for both fat and muscle mass—and levels of BCAAs can be helpful in reducing the risk of becoming overweight in adulthood. Further studies are needed to confirm these findings.
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Affiliation(s)
- Albina Tummolo
- Department of Metabolic Diseases and Clinical Genetics, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy
- Correspondence:
| | - Rosa Carella
- Department of Metabolic Diseases and Clinical Genetics, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy
| | - Giulia Paterno
- Department of Metabolic Diseases and Clinical Genetics, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy
| | - Nicola Bartolomeo
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Massimo Giotta
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Annamaria Dicintio
- Department of Metabolic Diseases and Clinical Genetics, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy
| | - Donatella De Giovanni
- Department of Metabolic Diseases and Clinical Genetics, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy
| | - Rita Fischetto
- Department of Metabolic Diseases and Clinical Genetics, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy
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Drapela S, Ilter D, Gomes AP. Metabolic reprogramming: a bridge between aging and tumorigenesis. Mol Oncol 2022; 16:3295-3318. [PMID: 35666002 PMCID: PMC9490145 DOI: 10.1002/1878-0261.13261] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/07/2022] [Accepted: 05/23/2022] [Indexed: 12/01/2022] Open
Abstract
Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build‐up of metabolic byproducts and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age‐driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell‐autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, antiaging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard‐of‐care anticancer therapies.
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Affiliation(s)
- Stanislav Drapela
- Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
| | - Didem Ilter
- Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
| | - Ana P Gomes
- Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
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10
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Mauhin W, Borie R, Dalbies F, Douillard C, Guffon N, Lavigne C, Lidove O, Brassier A. Acid Sphingomyelinase Deficiency: Sharing Experience of Disease Monitoring and Severity in France. J Clin Med 2022; 11:920. [PMID: 35207195 PMCID: PMC8877564 DOI: 10.3390/jcm11040920] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/14/2022] [Accepted: 01/28/2022] [Indexed: 12/19/2022] Open
Abstract
Acid sphingomyelinase deficiency (ASMD) is a rare inherited lipid storage disorder caused by a deficiency in lysosomal enzyme acid sphingomyelinase which results in the accumulation of sphingomyelin, predominantly within cells of the reticuloendothelial system located in numerous organs, such as the liver, spleen, lungs, and central nervous system. Although all patients with ASMD share the same basic metabolic defect, a wide spectrum of clinical presentations and outcomes are observed, contributing to treatment challenges. While infantile neurovisceral ASMD (also known as Niemann-Pick disease type A) is rapidly progressive and fatal in early childhood, and the more slowly progressive chronic neurovisceral (type A/B) and chronic visceral (type B) forms have varying clinical phenotypes and life expectancy. The prognosis of visceral ASMD is mainly determined by the association of hepatosplenomegaly with secondary thrombocytopenia and lung disease. Early diagnosis and appropriate management are essential to reduce the risk of complications and mortality. The accessibility of the new enzyme replacement therapy olipudase alfa, a recombinant human ASM, has been expedited for clinical use based on positive clinical data in children and adult patients, such as improved respiratory status and reduced spleen volume. The aim of this article is to share the authors experience on monitoring ASMD patients and stratifying the severity of the disease to aid in care decisions.
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Affiliation(s)
- Wladimir Mauhin
- Service de Médecine Interne, Centre de Référence Maladies Lysosomales, Groupe Hospitalier Diaconesses Croix Saint-Simon, 75020 Paris, France;
| | - Raphaël Borie
- Service de Pneumologie A, Hôpital Bichat, 75018 Paris, France;
- Unité de Recherche, INSERM, Unité 1152, Université Paris Diderot, 75018 Paris, France
| | - Florence Dalbies
- Institut de Cancéro-Hématologie, CHU Morvan, 29200 Brest, France;
| | - Claire Douillard
- Centre de Référence des Maladies Héréditaires du Métabolisme, Avenue Avinée, Hôpital Jeanne de Flandres, CHU Lille, 59000 Lille, France;
| | - Nathalie Guffon
- Centre de Référence Lyonnais des Maladies Héréditaires du Métabolisme, Hospices Civils de Lyon, HCL, 69677 Bron, France;
| | - Christian Lavigne
- Service de Médecine Interne et Immunologie Clinique, Centre de Compétence des Maladies Métaboliques Héréditaires, CHU Angers, 49933 Angers, France;
| | - Olivier Lidove
- Service de Médecine Interne, Centre de Référence Maladies Lysosomales, Groupe Hospitalier Diaconesses Croix Saint-Simon, 75020 Paris, France;
| | - Anaïs Brassier
- Service de Pédiatrie et Maladies du Métabolisme, APHP Necker, 75015 Paris, France;
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11
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Stefanaki C. Osteosarcopenia as a lifetime syndrome: Could it be prevented? OSTEOSARCOPENIA 2022:77-90. [DOI: 10.1016/b978-0-12-820088-9.00012-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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12
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Patel R, Bajpai A. Evaluation of Short Stature in Children and Adolescents. Indian J Pediatr 2021; 88:1196-1202. [PMID: 34398416 DOI: 10.1007/s12098-021-03880-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 06/09/2021] [Indexed: 11/28/2022]
Abstract
Short stature is a common presentation to pediatricians with a significant overlap between physiology and pathology. Thus, while most short children have a physiological cause, growth failure may be the only manifestation of severe underlying disease. Growth failure evaluation aims to avoid unnecessary investigations in children with a physiological cause without missing pathology. Guidelines for the evaluation of short stature allow stepwise evaluation but are limited by their resource-intense nature. An objective application of anthropometric indices and careful clinical evaluation allows rational growth failure workup. The use of height standard deviation score (SDS) for determining the need for evaluation (no evaluation above -2, follow-up between -2 to -3, and immediate workup with height below -3), corrected height SDS to identify familial short stature (above -1.5), height SDS for bone age for constitutional delay of puberty and growth (above -2), and BMI SDS for nutritional pattern growth failure (below -1) helps reduce the burden of investigations. The present review provides a framework for comprehensive growth evaluation across resource levels and settings.
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Affiliation(s)
- Riddhi Patel
- Department of Pediatric Endocrinology, Regency Center for Diabetes Endocrinology & Research, Regency City Clinic, Opposite PPN Market, Kanpur, Uttar Pradesh, 208001, India.,Kanpur & GROW Society, Growth & Obesity Workforce, Kanpur, Uttar Pradesh, India
| | - Anurag Bajpai
- Department of Pediatric Endocrinology, Regency Center for Diabetes Endocrinology & Research, Regency City Clinic, Opposite PPN Market, Kanpur, Uttar Pradesh, 208001, India. .,Kanpur & GROW Society, Growth & Obesity Workforce, Kanpur, Uttar Pradesh, India.
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Dimitrova N, Glaus J, Urben S, Wüthrich V, Morisod Harari M, Ballhausen D. The impact of disease severity on the psychological well-being of youth affected by an inborn error of metabolism and their families: A one-year longitudinal study. Mol Genet Metab Rep 2021; 29:100795. [PMID: 34504770 PMCID: PMC8414531 DOI: 10.1016/j.ymgmr.2021.100795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 08/21/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Inborn errors of metabolism (IEMs) refer to rare heterogeneous genetic disorders with various clinical manifestations that can cause serious physical and psychological sequelae. Results of previous studies on the impact of an IEM on health-related quality of life (HR-QoL) were incongruent and only few studies considered more broadly the psychological well-being of children with IEM and their families. Our objectives were to examine: (1) the impact of the IEM severity on the HR-QoL and psychological functioning of patients and their parents at baseline; and (2) its evolution over time; and (3) the correlation between parental and children's perspectives. Methods: The sample included 69 pediatric patients (mean age = 7.55 y, SD = 4.59) with evaluations at baseline and after one year. We collected data on HR-QoL, child mental health and emotional regulation as well as on parental mood and stress using different validated questionnaires. IEM severity was rated by a clinician through the biological subdomain of the pediatric INTERMED instrument. Results: Two groups of patients based on IEM severity scores were created (n = 31 with low and n = 38 with moderate/high IEM severity). The two groups differed with respect to age, diet and supplement intake. IEM severity had an impact on HR-QoL and behavioral symptoms in children, as well as on HR-QoL and stress in parents. For patients with moderate/high IEM severity, child and parental HR-QoL improved after 1-year of follow-up. We did not observe any significant difference between evaluations by patients versus parents. Conclusions: Our findings demonstrate that moderate/high IEM severity altered child and parental psychological well-being, but also revealed a significant improvement after one-year follow-up. This observation suggests that patients with a moderate/high IEM severity and their families benefit from the care of an interdisciplinary team including a child psychologist specialized in IEMs. Moreover, in patients with higher IEM severity there may also be more room for improvement compared to patients with low IEM severity. Future studies should focus on observations over a larger time span, particularly during adolescence, and should include objective measurements.
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Key Words
- CERQ, Cognitive Emotional Regulation Questionnaire
- Disease severity
- ER, Emotion Regulation
- HADS, Hospital anxiety and depression scale
- HR-QoL, Health-Related Quality of Life
- IEM, Inborn Errors of Metabolism
- Inborn errors of metabolism
- Mental health
- PIP, Pediatric Inventory for Parents
- PKU, Phenylketonuria
- Quality of life
- SD, Standard Deviation
- SDQ, Strengths and Difficulties Questionnaire
- SE, Standard Error.
- Well-being
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Affiliation(s)
- Nevena Dimitrova
- Research Unit, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Av. d'Echallens 9, 1004 Lausanne, Switzerland
| | - Jennifer Glaus
- Research Unit, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Av. d'Echallens 9, 1004 Lausanne, Switzerland
| | - Sébastien Urben
- Research Unit, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Av. d'Echallens 9, 1004 Lausanne, Switzerland
| | - Valentine Wüthrich
- Pediatric unit for metabolic diseases, Woman-Mother-Child Department, Lausanne University Hospital, Chemin du Mont-Paisible 18, 1011 Lausanne, Switzerland
| | - Mathilde Morisod Harari
- Liaison Psychiatry Unit, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Hôpital Nestlé, Niv. 05, Av. Pierre-Decker 5, 1011 Lausanne, Switzerland
| | - Diana Ballhausen
- Pediatric unit for metabolic diseases, Woman-Mother-Child Department, Lausanne University Hospital, Chemin du Mont-Paisible 18, 1011 Lausanne, Switzerland
- Corresponding author at: Unité pédiatrique des maladies métaboliques Service de Pédiatrie, Département Femme-Mère-Enfant Centre Hospitalier Universitaire Vaudois CHUV MP18-05/565 Chemin du Mont-Paisible 18 CH-1011 Lausanne, Switzerland.
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Prasad N, Hamosh A, Sponseller P. Orthopaedic Manifestations of Inborn Errors of Metabolism. JBJS Rev 2021; 9:01874474-202107000-00003. [PMID: 34257233 DOI: 10.2106/jbjs.rvw.20.00245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
» Inborn errors of metabolism are disorders of carbohydrate, amino acid, organic acid, or purine and pyrimidine metabolism; disorders of fatty acid oxidation; disorders of metal metabolism; and lysosomal storage defects that can cause metabolic derangements that have secondary musculoskeletal effects. » Orthopaedic surgeons should be aware that patients with inborn errors of metabolism may be at high risk for spasticity, which may cause joint subluxations, scoliosis, and contractures, as well as poor bone quality, which is caused by malnutrition or disordered bone growth. » Multidisciplinary care and follow-up are important to identify musculoskeletal problems in a timely manner in order to provide effective treatment.
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Affiliation(s)
- Niyathi Prasad
- Departments of Orthopaedic Surgery and Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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15
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Evaluation of Body Composition, Physical Activity, and Food Intake in Patients with Inborn Errors of Intermediary Metabolism. Nutrients 2021; 13:nu13062111. [PMID: 34202936 PMCID: PMC8233825 DOI: 10.3390/nu13062111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/11/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022] Open
Abstract
Children with inborn errors of intermediary metabolism (IEiM) must follow special diets that restrict their intake of essential nutrients and may compromise normal growth and development. We evaluated body composition, bone mineral density, physical activity, and food intake in IEiM patients undergoing dietary treatment. IEiM patients (n = 99) aged 5–19 years and healthy age- and sex-matched controls (n = 98) were recruited and underwent dual-energy X-ray absorptiometry to evaluate anthropometric characteristics and body composition. Data on food intake and physical activity were also collected using validated questionnaires. The height z-score was significantly lower in IEiM patients than controls (−0.28 vs. 0.15; p = 0.008), particularly in those with carbohydrate and amino acid metabolism disorders. Significant differences in adiposity were observed between patients and controls for the waist circumference z-score (−0.08 vs. −0.58; p = 0.005), but not the body mass index z-score (0.56 vs. 0.42; p = 0.279). IEiM patients had a significantly lower total bone mineral density (BMD) than controls (0.89 vs. 1.6; p = 0.001) and a higher risk of osteopenia (z-score < −2, 33.3% vs. 20.4%) and osteoporosis (z-score < −2.5, 7.1% vs. 0%), but none presented fractures. There was a significant positive correlation between natural protein intake and BMD. Our results indicate that patients with IEiM undergoing dietary treatment, especially those with amino acid and carbohydrate metabolism disorders, present alterations in body composition, including a reduced height, a tendency towards overweight and obesity, and a reduced BMD.
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16
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Langston SJ, Krakow D, Chu A. Revisiting Skeletal Dysplasias in the Newborn. Neoreviews 2021; 22:e216-e229. [PMID: 33795397 DOI: 10.1542/neo.22-4-e216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
With over 400 reported disorders, the skeletal dysplasias represent a myriad of molecularly-based skeletal abnormalities. Arising from errors in skeletal development, the clinical spectrum of disease evolves through an affected individual's life. The naming and grouping of these disorders are ever-changing, but the fundamentals of diagnosis remain the same and are accomplished through a combination of prenatal ultrasonography and postnatal physical examination, radiography, and genetic analysis. Although some disorders are lethal in the perinatal and neonatal periods, other disorders allow survival into infancy, childhood, and even adulthood with relatively normal lives. The foundation of management for an affected individual is multidisciplinary care. Medical advances have offered new insights into reducing common morbidities through pharmacologic means. This review summarizes the normal skeletal development and discusses the 3 most common skeletal dysplasias that can affect the newborn.
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Affiliation(s)
- Seth J Langston
- Division of Neonatology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Deborah Krakow
- Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA
| | - Alison Chu
- Division of Neonatology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA
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17
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Dietrich K, Fiedler IA, Kurzyukova A, López-Delgado AC, McGowan LM, Geurtzen K, Hammond CL, Busse B, Knopf F. Skeletal Biology and Disease Modeling in Zebrafish. J Bone Miner Res 2021; 36:436-458. [PMID: 33484578 DOI: 10.1002/jbmr.4256] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022]
Abstract
Zebrafish are teleosts (bony fish) that share with mammals a common ancestor belonging to the phylum Osteichthyes, from which their endoskeletal systems have been inherited. Indeed, teleosts and mammals have numerous genetically conserved features in terms of skeletal elements, ossification mechanisms, and bone matrix components in common. Yet differences related to bone morphology and function need to be considered when investigating zebrafish in skeletal research. In this review, we focus on zebrafish skeletal architecture with emphasis on the morphology of the vertebral column and associated anatomical structures. We provide an overview of the different ossification types and osseous cells in zebrafish and describe bone matrix composition at the microscopic tissue level with a focus on assessing mineralization. Processes of bone formation also strongly depend on loading in zebrafish, as we elaborate here. Furthermore, we illustrate the high regenerative capacity of zebrafish bones and present some of the technological advantages of using zebrafish as a model. We highlight zebrafish axial and fin skeleton patterning mechanisms, metabolic bone disease such as after immunosuppressive glucocorticoid treatment, as well as osteogenesis imperfecta (OI) and osteopetrosis research in zebrafish. We conclude with a view of why larval zebrafish xenografts are a powerful tool to study bone metastasis. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Kristin Dietrich
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Imke Ak Fiedler
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anastasia Kurzyukova
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Alejandra C López-Delgado
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Lucy M McGowan
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Karina Geurtzen
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Chrissy L Hammond
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Interdisciplinary Competence Center for Interface Research (ICCIR), Hamburg, Germany
| | - Franziska Knopf
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
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Abstract
Many children with chronic disease are now surviving into adulthood. As a result, there is a growing interest in optimizing bone health early in the disease course with the dual goals of improving quality of life during childhood and reducing life-long fracture risk. Risk factors for impaired bone health in these children include immobility, nutritional deficiency, exposure to bone toxic therapies, hormonal deficiencies affecting growth and pubertal development, and chronic inflammation. This review focuses on the chronic diseases of childhood most commonly associated with impaired bone health. Recent research findings and clinical practice recommendations, when available, for specific disorders are summarized.
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Affiliation(s)
- David R Weber
- Department of Pediatrics - Endocrinology, Golisano Children's Hospital, University of Rochester, Rochester, NY, USA.
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19
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Isoalantolactone inhibits RANKL-induced osteoclast formation via multiple signaling pathways. Int Immunopharmacol 2020; 84:106550. [PMID: 32388216 DOI: 10.1016/j.intimp.2020.106550] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/27/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022]
Abstract
The metabolicosteopathy known as postmenopausal osteoporosisiscaused by disruption of the balance between bone resorption and osteogenesis, processes that are mediated by osteoclasts and osteoblasts, respectively. The current therapeutic approaches to treating osteoporosis have several limitations. In this study, we demonstrated that the natural chemical compound isoalantolactone (IAL) could inhibit osteoclastogenesis, without affecting osteogenesis. This is the first study reporting a role of IAL in suppressing the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in a dose-dependent manner, and downregulating the expression of osteoclast-related marker genes. Furthermore, IAL abrogated the phosphorylation of c-Jun N-terminal kinase (JNK)/p38, NF-κB, and phosphatidylinositol 3-kinase (PI3K)-AKT, and also diminished the expression of osteoclastogenesis-related proteins. In conclusion, our results indicated that IAL has promise for the treatment of osteoporosis and other metabolicbone diseases.
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20
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Abstract
Metabolic skeletal dysplasias comprise an extensive group of diseases capable of causing changes, usually progressive, in the bone and are due to hereditary disorders in many cases. The diagnosis and treatment of these diseases are not without difficulty, both because of their rarity and their possible confusion with more common diseases. A paradigmatic case of these metabolic skeletal dysplasias is X-linked hypophosphataemic rickets, which causes phosphaturia, a condition that alters the phosphate-calcium metabolism balance consequently causing, among other conditions, skeletal deformities and short stature. The genetic advances in recent years allow a much more accurate diagnosis of this disease when suspected, making differential diagnosis easier with similar entities but whose real causes are different. A better understanding of the phosphate-calcium metabolism allows us to replace the symptomatic treatment currently available with one that involves rebalancing the excess of fibroblast growth factor 23 (FGF23) by using monoclonal antibodies. In November 2018, a symposium sponsored by Kyowa Kirin Pharmaceuticals took place in Madrid, in which national and international experts addressed several aspects of these rare kidney diseases. Some topics addressed were the present and future genetic diagnosis, the use of multi-gene panels in renal or skeletal diseases, the role of animal models to better understand underlying skeletal changes, and the role of conventional radiology and surgery in the diagnosis and final treatment of bone deformities; all these without forgetting the important role of FGF23 and Klotho imbalances that result in the genetic change causing this disease. The optimization and limitations of conventional treatments currently available was also a topic addressed extensively, as well as the implications that new treatments against FGF23 could have in the future. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.
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Affiliation(s)
- Antonio González-Meneses López
- Unidad de Dismorfología, Unidad de Gestión Clínica de Pediatría, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
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21
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Vardy ERLC, MacDonald A, Ford S, Hofman DL. Phenylketonuria, co-morbidity, and ageing: A review. J Inherit Metab Dis 2020; 43:167-178. [PMID: 31675115 DOI: 10.1002/jimd.12186] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/27/2019] [Accepted: 10/28/2019] [Indexed: 12/17/2022]
Abstract
Phenylketonuria (PKU) is a metabolic condition which, left untreated, results in severe and irreversible brain damage. Newborn screening and the development of the low phenylalanine (Phe) diet have transformed the outcomes for people with PKU. Those who have benefited from early treatment are now approaching their fifth and sixth decade. It is therefore timely to consider multi-morbidity in PKU and the effects of ageing, in parallel with the wider benefits of emerging treatment options in addition to dietary relaxation. We have conducted the first literature review of co-morbidity and ageing in the context of PKU. Avenues explored have emerged from limited study of multi-morbidity to date and the knowledge and critical enquiry of the authors. Findings suggest PKU to have a wider impact than brain development, and result in several intriguing questions that require investigation to attain the best outcomes for people with PKU in adulthood moving through to older age. We recognise the difficulty in studying longitudinal outcomes in rare diseases and emphasise the necessity to develop PKU registries and cohorts that facilitate well-designed studies to answer some of the questions raised in this review. Whilst awaiting new information in these areas we propose that clinicians engage with patients to make personalised and well-informed decisions around Phe control and assessment for co-morbidity.
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Affiliation(s)
- Emma R L C Vardy
- Department of Ageing and Complex Medicine, Salford Royal NHS Foundation Trust, Salford Care Organisation, Part of Northern Care Alliance NHS Group, Salford, UK
| | - Anita MacDonald
- Department of dietetics, Birmingham Women's and Children's NHS Trust, Birmingham, UK
| | - Suzanne Ford
- National Society for Phenylketonuria, Preston, UK
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Wit JM, Kamp GA, Oostdijk W. Towards a Rational and Efficient Diagnostic Approach in Children Referred for Growth Failure to the General Paediatrician. Horm Res Paediatr 2020; 91:223-240. [PMID: 31195397 DOI: 10.1159/000499915] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 03/25/2019] [Indexed: 11/19/2022] Open
Abstract
Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.
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Affiliation(s)
- Jan M Wit
- Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands,
| | - Gerdine A Kamp
- Department of Paediatrics, Tergooi Hospital, Blaricum, The Netherlands
| | - Wilma Oostdijk
- Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands
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