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Kalay I, Aykut H, Caliskan Z, Yigit G, Wollnik B. Lysinuric protein intolerance caused by a homozygous SLC7A7 deletion and presented with hyperferritinemia and osteoporosis in two siblings. Mol Genet Metab Rep 2023; 37:101022. [PMID: 38053936 PMCID: PMC10694772 DOI: 10.1016/j.ymgmr.2023.101022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/08/2023] [Accepted: 11/08/2023] [Indexed: 12/07/2023] Open
Abstract
Lysinuric protein intolerance (LPI) is a rare, inherited aminoaciduria caused by biallelic pathogenic variants in the amino acid transporter gene SLC7A7 (OMIM *603593). Individuals with LPI show extreme variability in their clinical presentation, and LPI is included in the differential diagnosis of several disorders such as urea cycle disorders, lysosomal storage diseases, malabsorption diseases, autoimmune disorders, hemochromatosis, and osteoporosis. The phenotypic variability of LPI and the lack of a specific clinical presentation have caused various misdiagnoses. Here, we report two siblings diagnosed in their 4th decade of life with LPI, manifesting rare hyperferritinemia. Additionally, they presented with short stature, multiple bone fractures due to osteoporosis, and they showed an aversion to protein-rich food. Using a combination of exome sequencing, microarray analysis and qPCR, we identified a novel homozygous deletion in SLC7A7 encompassing exons 3 to 10, which is predicted to lead to disruption of SLC7A7 function. This is the first report of lysinuric protein intolerance in a Turkish family associated with this so far unknown deletion in SLC7A7.
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Affiliation(s)
- Irem Kalay
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- Department of Medical Genetics, Umraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Hüseyin Aykut
- Department of Gastroenterology, Umraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Zuhal Caliskan
- Department of Gastroenterology, Umraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Gökhan Yigit
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
| | - Bernd Wollnik
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
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2
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Stroup BM, Li X, Ho S, Zhouyao H, Chen Y, Ani S, Dawson B, Jin Z, Marom R, Jiang MM, Lorenzo I, Rosen D, Lanza D, Aceves N, Koh S, Seavitt JR, Heaney JD, Lee B, Burrage LC. Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance. Dis Model Mech 2023; 16:dmm050118. [PMID: 37486182 PMCID: PMC10445726 DOI: 10.1242/dmm.050118] [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: 02/07/2023] [Accepted: 07/14/2023] [Indexed: 07/25/2023] Open
Abstract
SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, but no differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell-autonomous and non-cell-autonomous mechanisms underlying phenotypes in LPI.
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Affiliation(s)
- Bridget M. Stroup
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiaohui Li
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sara Ho
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Haonan Zhouyao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yuqing Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Safa Ani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zixue Jin
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
| | - Ming-Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Isabel Lorenzo
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Daniel Rosen
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Denise Lanza
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nathalie Aceves
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sara Koh
- Rice University, Houston, TX 77005, USA
| | - John R. Seavitt
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason D. Heaney
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lindsay C. Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
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Abstract
The foundation of bone health is established in utero. Bone accrual starts from the developing fetus and continues throughout childhood and adolescence. This process is crucial to achieve peak bone mass. Understanding factors that influence bone accrual before attainment of peak bone mass is thus critical to improve bone health and prevent osteoporosis, thereby reducing the burden of osteoporotic fractures in older women. In this review, we broadly outline factors influencing peak bone mass from pregnancy to infancy, childhood and adolescence with potential diseases and medications that may affect the optimum trajectory to maximizing bone health. It is estimated that a 10% increase in peak bone mass will delay the onset of osteoporosis by 13 years in a woman.
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Affiliation(s)
- R F Vasanwala
- KK Women's and Children's Hospital, Singapore, Singapore
| | - L Gani
- Changi General Hospital, Singapore, Singapore
| | - S B Ang
- KK Women's and Children's Hospital, Singapore, Singapore.,Duke-NUS Medical School, Singapore, Singapore.,Lee Kong Chian School of Medicine, Singapore, Singapore
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4
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Avci Durmusalioglu E, Isik E, Ayyildiz Emecen D, Goksen D, Ozen S, Onay H, Kose M, Atik T, Darcan S, Cogulu O, Ozkinay F. The utility of reverse phenotyping: a case of lysinuric protein intolerance presented with childhood osteoporosis. J Pediatr Endocrinol Metab 2021; 34:957-960. [PMID: 33823103 DOI: 10.1515/jpem-2021-0018] [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: 01/10/2021] [Accepted: 02/18/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Childhood osteoporosis is often a consequence of a chronic disease or its treatment. Lysinuric protein intolerance (LPI), a rare secondary cause of the osteoporosis, is an autosomal recessive disorder with clinical features ranging from minimal protein intolerance to severe multisystemic involvement. We report a case diagnosed to have LPI using a Next Generation Sequencing (NGS) panel and evaluate the utility of reverse phenotyping. CASE PRESENTATION A fifteen-year-old-boy with an initial diagnosis of osteogenesis imperfecta, was referred due to a number of atypical findings accompanying to osteoporosis such as splenomegaly and bicytopenia. A NGS panel (TruSight One Sequencing Panel) was performed and a novel homozygous mutation of c.257G>A (p.Gly86Glu) in the SLC7A7 gene (NM_001126106.2), responsible for LPI, was detected. The diagnosis was confirmed via reverse phenotyping. CONCLUSIONS Reverse phenotyping using a multigene panel shortens the diagnostic process.
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Affiliation(s)
- Enise Avci Durmusalioglu
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Esra Isik
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Durdugul Ayyildiz Emecen
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Damla Goksen
- Department of Pediatric Endocrinology and Diabetes, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Samim Ozen
- Department of Pediatric Endocrinology and Diabetes, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Huseyin Onay
- Department of Medical Genetics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Melis Kose
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Tahir Atik
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Sukran Darcan
- Department of Pediatric Endocrinology and Diabetes, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Ozgur Cogulu
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Ferda Ozkinay
- Pediatric Genetics Subdivision, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
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Contreras JL, Ladino MA, Aránguiz K, Mendez GP, Coban-Akdemir Z, Yuan B, Gibbs RA, Burrage LC, Lupski JR, Chinn IK, Vogel TP, Orange JS, Poli MC. Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature. Front Pediatr 2021; 9:673957. [PMID: 34095032 PMCID: PMC8172984 DOI: 10.3389/fped.2021.673957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/14/2021] [Indexed: 12/14/2022] Open
Abstract
Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in SLC7A7. The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.
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Affiliation(s)
| | - Mabel A. Ladino
- Universidad de Chile, Reumatóloga Pediátrica Hospital San Juan de Dios, Santiago, Chile
| | - Katherine Aránguiz
- Unidad de Inmunología y Reumatología Hospital Luis Calvo Mackenna, Providencia, Chile
| | - Gonzalo P. Mendez
- Patológo Renal, Departamento de Anatomía Patológica, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Zeynep Coban-Akdemir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Bo Yuan
- Department of Laboratories, Seattle Children's Hospital, Seattle, WA, United States
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| | - Richard A. Gibbs
- Sequencing Center, Baylor College of Medicine, Houston, TX, United States
| | - Lindsay C. Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Texas Children's Hospital, Houston, TX, United States
| | - James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Sequencing Center, Baylor College of Medicine, Houston, TX, United States
- Texas Children's Hospital, Houston, TX, United States
| | - Ivan K. Chinn
- Texas Children's Hospital, Houston, TX, United States
- Department of Pediatrics, Division of Allergy, Immunology and Retrovirology, Baylor College of Medicine, Houston, TX, United States
| | - Tiphanie P. Vogel
- Texas Children's Hospital, Houston, TX, United States
- Department of Pediatrics, Division of Rheumatology, Baylor College of Medicine, Houston, TX, United States
| | - Jordan S. Orange
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York Presbyterian Morgan Stanley Children's Hospital, Columbia University, New York, NY, United States
| | - M. Cecilia Poli
- Facultad de Medicina Universidad del Desarrollo-Clínica Alemana, Santiago, Chile
- Department of Pediatrics, Division of Allergy, Immunology and Retrovirology, Baylor College of Medicine, Houston, TX, United States
- Unidad de Inmunología y Reumatología, Hospital Roberto del Río, Santiago, Chile
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6
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Al-Qattan S, Malcolmson C, Mercimek-Andrews S. Lysinuric protein intolerance mimicking N-acetylglutamate synthase deficiency in a nine-year-old boy. Mol Genet Metab Rep 2021; 27:100741. [PMID: 33763330 PMCID: PMC7973239 DOI: 10.1016/j.ymgmr.2021.100741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/28/2021] [Accepted: 03/01/2021] [Indexed: 12/01/2022] Open
Abstract
We report a 9-year-old boy with lysinuric protein intolerance (LPI). He had developmental delay, short stature, failure to thrive, high-protein food aversion, hypothyroidism, growth hormone deficiency, features of hemophagocytic lymphohistiocytosis (HLH), decreased bone mineral density and multiple thoracic spine compression fractures on X-ray. LPI was suspected, but urine amino acid profile and normal orotic acid did not suggest biochemical diagnosis of LPI. Targeted next generation sequencing panel for HLH (including SLC7A7) was organized. Due to elevated glutamine in plasma amino acid analysis, a metabolic consultation was initiated and his asymptomatic post-prandial ammonia was 295 μmol/L. We then suspected n-acetylglutamate synthase or carbamoyl-phosphate synthase I deficiency due to marked hyperammonemia, elevated glutamine level, normal orotic acid, and normalization of ammonia at 2 h of carglumic acid (200 mg/kg/d). His targeted next generation sequencing panel for HLH revealed homozygous pathogenic variant in SLC7A7 ((NM_001126106.2): c.726G>A (p.Trp242*)) and confirmed the diagnosis of LPI. We emphasize the importance of genetic investigations in the diagnosis of LPI.
LPI associated hyperammonemia responds to carbaglumic acid. Protein aversion, and failure to thrive should warrant for ammonia measurement. Multisystem disease should include LPI into the differential diagnosis even in the absence of typical biochemical features.
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Affiliation(s)
- Sarah Al-Qattan
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Caroline Malcolmson
- Division of Hematology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Saadet Mercimek-Andrews
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Medical Genetics, University of Alberta, Stollery Children's Hospital, Edmonton, Alberta, Canada
- Corresponding author at: Department of Medical Genetics, University of Alberta, Stollery Children's Hospital, Alberta Health Services, 8-39 Medical Sciences Building, 8613 – 114 Street, Edmonton, Alberta T6G 2H7, Canada.
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7
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Stroup BM, Marom R, Li X, Hsu CW, Chang CY, Truong LD, Dawson B, Grafe I, Chen Y, Jiang MM, Lanza D, Green JR, Sun Q, Barrish JP, Ani S, Christiansen AE, Seavitt JR, Dickinson ME, Kheradmand F, Heaney JD, Lee B, Burrage LC. A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance. Hum Mol Genet 2020; 29:2171-2184. [PMID: 32504080 PMCID: PMC7399531 DOI: 10.1093/hmg/ddaa107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 04/30/2020] [Accepted: 05/19/2020] [Indexed: 12/18/2022] Open
Abstract
Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.
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Affiliation(s)
- Bridget M Stroup
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
| | - Xiaohui Li
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chih-Wei Hsu
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cheng-Yen Chang
- Department of Medicine-Pulmonary, Baylor College of Medicine, Houston, TX 77030, USA
| | - Luan D Truong
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Center for Healthy Aging, University Clinic, Dresden D-01307, Germany
| | - Yuqing Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ming-Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Denise Lanza
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jennie Rose Green
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Baylor Genetics, Houston, TX 77021, USA
| | - J P Barrish
- Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Safa Ani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Audrey E Christiansen
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - John R Seavitt
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mary E Dickinson
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Farrah Kheradmand
- Department of Medicine-Pulmonary, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason D Heaney
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
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8
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Abstract
Inborn errors of metabolism encompass a wide spectrum of disorders, frequently affecting bone. The most important metabolic disorders that primarily influence calcium or phosphate balance, resulting in skeletal pathology, are hypophosphatemic rickets and hypophosphatasia. Conditions involving bone marrow or affecting skeletal growth and development are mainly the lysosomal storage disorders, in particular the mucopolysaccharidoses. In these disorders skeletal abnormalities are often the presenting symptom and early recognition and intervention improves outcome in many of these diseases. Many disorders of intermediary metabolism may impact bone health as well, resulting in higher frequencies of osteopenia and osteoporosis. In these conditions factors contributing to the reduced bone mineralization can be the disorder itself, the strict dietary treatment, reduced physical activity or sunlight exposure and/or early ovarian failure. Awareness of these primary or secondary bone problems amongst physicians treating patients with inborn errors of metabolism is of importance for optimization bone health and recognition of skeletal complications.
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Affiliation(s)
- M Langeveld
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
| | - C E M Hollak
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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9
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Estève E, Krug P, Hummel A, Arnoux JB, Boyer O, Brassier A, de Lonlay P, Vuiblet V, Gobin S, Salomon R, Piètrement C, Bonnefont JP, Servais A, Galmiche L. Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions. Hum Pathol 2017; 62:160-169. [PMID: 28087478 DOI: 10.1016/j.humpath.2016.12.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 11/25/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022]
Abstract
Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1κ MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up.
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Affiliation(s)
- Emmanuel Estève
- Pathology Department Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Pauline Krug
- Pediatric Nephrology Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Aurélie Hummel
- Nephrology Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Jean-Baptiste Arnoux
- Metabolic Diseases Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Olivia Boyer
- Pediatric Nephrology Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Anais Brassier
- Metabolic Diseases Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Pascale de Lonlay
- Metabolic Diseases Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Vincent Vuiblet
- Nephrology and Renal Transplantation Department and Pathology Department, Centre Hospitalier et Universitaire de Reims, Reims, France.
| | - Stéphanie Gobin
- Molecular Genetics Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France
| | - Rémi Salomon
- Pediatric Nephrology Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Christine Piètrement
- Department of Paediatrics, Nephrology Paediatric Unit, Centre Hospitalier et Universitaire de Reims, Reims, France.
| | - Jean-Paul Bonnefont
- Molecular Genetics Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France
| | - Aude Servais
- Nephrology Department, Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
| | - Louise Galmiche
- Pathology Department Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France.
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Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, Roda C, Pinto G, Moshous D, Ghalim F, Krug P, Deltour N, Pontoizeau C, Dubois S, Assoun M, Galmiche L, Bonnefont JP, Ottolenghi C, de Blic J, Arnoux JB, de Lonlay P. Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood. Orphanet J Rare Dis 2017; 12:3. [PMID: 28057010 PMCID: PMC5217205 DOI: 10.1186/s13023-016-0550-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/07/2016] [Indexed: 12/11/2022] Open
Abstract
Background Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit y+LAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management. Results Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n = 9), gastrointestinal disorders (n = 2), cytopenia (n = 6), hyperammonemia (n = 10) with acute encephalopathy (n = 4) or developmental disability (n = 3), and proteinuria (n = 1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p = 0.08; logrank, p = 0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p = 0.16). Conclusions As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.
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Affiliation(s)
- Wladimir Mauhin
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Florence Habarou
- Metabolic Biochemistry, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Stéphanie Gobin
- Molecular Genetics, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Aude Servais
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.,Nephrology Unit, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Anaïs Brassier
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Coraline Grisel
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Célina Roda
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Graziella Pinto
- Endocrinoloy Unit, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Despina Moshous
- Paediatric Immunology, Haematology and Rheumatology, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Fahd Ghalim
- Gastroenterology, Kremlin Bicêtre Hospital, AP-HP, University Paris Sud, Paris, France
| | - Pauline Krug
- Nephrology, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Nelly Deltour
- Molecular Genetics, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Clément Pontoizeau
- Metabolic Biochemistry, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Sandrine Dubois
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Murielle Assoun
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Louise Galmiche
- Anatomopathology, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Jean-Paul Bonnefont
- Molecular Genetics, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Chris Ottolenghi
- Metabolic Biochemistry, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Jacques de Blic
- Pneumology, Hospital Necker Enfants Malades, AP-HP, University Paris Descartes, Paris, France
| | - Jean-Baptiste Arnoux
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France
| | - Pascale de Lonlay
- Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France. .,Reference Center of Metabolic Disease Unit, Université Paris Descartes, Hôpital Necker-Enfants Malades, Institute Imagine, INSERM-U781, 149 rue de Sèvres, 75015, Paris, France.
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11
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Valimahamed-Mitha S, Berteloot L, Ducoin H, Ottolenghi C, de Lonlay P, de Blic J. Lung involvement in children with lysinuric protein intolerance. J Inherit Metab Dis 2015; 38:257-63. [PMID: 25335805 DOI: 10.1007/s10545-014-9777-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 09/21/2014] [Accepted: 09/25/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES Lysinuric protein intolerance (LPI) is a rare multisystemic metabolic disease. The objective of the study was to describe presentation and course of lung involvement in a cohort of ten children. PATIENTS AND METHODS Retrospective review of patients followed at Necker-Enfants Malades University Hospital between 1980 and 2012 for a LPI. In patients with lung involvement, clinical data, chest radiographs, pulmonary function tests, bronchoalveolar lavages, and lung biopsies were analyzed. The first and last high-resolution computed tomography (HRCT) were also reviewed. RESULTS Lung involvement was observed in ten of 14 patients (71 %). Five patients had an acute onset of respiratory symptoms, three had a progressive onset and two were free of symptoms. During the period studied, six patients (60 %) died, all in a context of respiratory failure. Clinical presentation and course were highly variable, even in the same family. HRCT were performed in seven cases, showing in all cases an interstitial pattern and fibrosis in four. All ten patients had pulmonary alveolar proteinosis (PAP) confirmed by histopathological analysis. Five patients had pulmonary fibrosis (at biopsy and/or HRCT scan). Two patients underwent whole lung lavages, without efficiency. CONCLUSION PAP is a constant feature in children with LPI and lung involvement. Pulmonary fibrosis is frequent and these two pathologies may develop independently. This study shows the heterogeneity of presentation and outcome. Lung injury could be secondary to impaired phagocytic function and abnormal inflammatory and immune responses intrinsic to the SLC7A7 mutant phenotype. HRCT is recommended to detect lung involvement.
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MESH Headings
- Adolescent
- Adult
- Amino Acid Metabolism, Inborn Errors/complications
- Amino Acid Metabolism, Inborn Errors/diagnosis
- Amino Acid Metabolism, Inborn Errors/mortality
- Amino Acid Metabolism, Inborn Errors/therapy
- Amino Acid Transport System y+L
- Autoimmune Diseases/diagnosis
- Autoimmune Diseases/etiology
- Autoimmune Diseases/mortality
- Autoimmune Diseases/physiopathology
- Autoimmune Diseases/therapy
- Biopsy
- Bronchoalveolar Lavage
- Child
- Child, Preschool
- Disease Progression
- Female
- Fusion Regulatory Protein 1, Light Chains/genetics
- Genetic Predisposition to Disease
- Hospitals, Pediatric
- Hospitals, University
- Humans
- Infant
- Infant, Newborn
- Lung/diagnostic imaging
- Lung/pathology
- Lung/physiopathology
- Male
- Mutation
- Paris
- Predictive Value of Tests
- Pulmonary Alveolar Proteinosis/diagnosis
- Pulmonary Alveolar Proteinosis/etiology
- Pulmonary Alveolar Proteinosis/mortality
- Pulmonary Alveolar Proteinosis/physiopathology
- Pulmonary Alveolar Proteinosis/therapy
- Pulmonary Fibrosis/diagnosis
- Pulmonary Fibrosis/etiology
- Pulmonary Fibrosis/mortality
- Pulmonary Fibrosis/physiopathology
- Pulmonary Fibrosis/therapy
- Respiratory Function Tests
- Respiratory Insufficiency/diagnosis
- Respiratory Insufficiency/etiology
- Retrospective Studies
- Time Factors
- Tomography, X-Ray Computed
- Young Adult
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Affiliation(s)
- Sarah Valimahamed-Mitha
- Service de Pneumologie pédiatrique, Hôpital Jeanne de Flandre, CHRU de Lille, Paris, France,
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12
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Parvaneh N, Quartier P, Rostami P, Casanova JL, de Lonlay P. Inborn errors of metabolism underlying primary immunodeficiencies. J Clin Immunol 2014; 34:753-71. [PMID: 25081841 DOI: 10.1007/s10875-014-0076-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 07/02/2014] [Indexed: 01/19/2023]
Abstract
A number of inborn errors of metabolism (IEM) have been shown to result in predominantly immunologic phenotypes, manifesting in part as inborn errors of immunity. These phenotypes are mostly caused by defects that affect the (i) quality or quantity of essential structural building blocks (e.g., nucleic acids, and amino acids), (ii) cellular energy economy (e.g., glucose metabolism), (iii) post-translational protein modification (e.g., glycosylation) or (iv) mitochondrial function. Presenting as multisystemic defects, they also affect innate or adaptive immunity, or both, and display various types of immune dysregulation. Specific and potentially curative therapies are available for some of these diseases, whereas targeted treatments capable of inducing clinical remission are available for others. We will herein review the pathogenesis, diagnosis, and treatment of primary immunodeficiencies (PIDs) due to underlying metabolic disorders.
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Affiliation(s)
- Nima Parvaneh
- Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran,
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13
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Posey JE, Burrage LC, Miller MJ, Liu P, Hardison MT, Elsea SH, Sun Q, Yang Y, Willis AS, Schlesinger AE, Bacino CA, Lee BH. Lysinuric Protein Intolerance Presenting with Multiple Fractures. Mol Genet Metab Rep 2014; 1:176-183. [PMID: 25419514 PMCID: PMC4235665 DOI: 10.1016/j.ymgmr.2014.03.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism caused by mutations in SLC7A7, which encodes a component of the dibasic amino acid transporter found in intestinal and renal tubular cells. Patients typically present with vomiting, diarrhea, irritability, failure to thrive, and symptomatic hyperammonemia after protein-rich meals. Long-term complications may include pulmonary alveolar proteinosis, renal disease, and osteoporosis. We present a 5-year-old male who was followed in our skeletal dysplasia clinic for 3 years for multiple fractures, idiopathic osteoporosis, and short stature in the absence of typical features of LPI. Whole exome sequencing performed to determine the etiology of the osteoporosis and speech delay identified a nonsense mutation in SLC7A7. Chromosome microarray analysis identified a deletion involving the second allele of the same gene, and biochemical analysis supported the diagnosis of LPI. Our patient's atypical presentation underscores the importance of maintaining a high index of suspicion for LPI in patients with unexplained fractures and idiopathic osteoporosis, even in the absence of clinical symptoms of hyperammonemia after protein rich meals or other systemic features of classical LPI. This case further demonstrates the utility of whole exome sequencing in diagnosis of unusual presentations of rare disorders for which early intervention may modify the clinical course.
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Affiliation(s)
- Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Marcus J Miller
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Matthew T Hardison
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Sarah H Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Yaping Yang
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Alecia S Willis
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Alan E Schlesinger
- Department of Pediatric Radiology, Texas Children's Hospital, 6701 Fannin, Suite 470, Houston, TX, 77030, USA
| | - Carlos A Bacino
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA
| | - Brendan H Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Suite R814, Houston, TX, 77030-3411, USA ; Howard Hughes Medical Institute, Houston, TX, USA
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14
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Legumes and meat analogues consumption are associated with hip fracture risk independently of meat intake among Caucasian men and women: the Adventist Health Study-2. Public Health Nutr 2013; 17:2333-43. [PMID: 24103482 DOI: 10.1017/s1368980013002693] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE In contrast to non-vegetarians, vegetarians consume more legumes and meat analogues as sources of protein to substitute for meat intake. The present study aimed to assess the association between foods with high protein content (legumes, meat, meat analogues) by dietary pattern (vegetarians, non-vegetarians) and hip fracture incidence, adjusted for selected lifestyle factors. DESIGN A prospective cohort of Adventist Health Study-2 (AHS-2) enrollees who completed a comprehensive lifestyle and dietary questionnaire between 2002 and 2007. SETTING Every two years after enrolment, a short questionnaire on hospitalizations and selected disease outcomes including hip fractures was sent to these members. SUBJECTS Respondents (n 33,208) to a baseline and a follow-up questionnaire. RESULTS In a multivariable model, legumes intake of once daily or more reduced the risk of hip fracture by 64% (hazard ratio = 0·36, 95% CI 0·21, 0·61) compared with those with legumes intake of less than once weekly. Similarly, meat intake of four or more times weekly was associated with a 40% reduced risk of hip fracture (hazard ratio = 0·60, 95% CI 0·41, 0·87) compared with those whose meat intake was less than once weekly. Furthermore, consumption of meat analogues once daily or more was associated with a 49 % reduced risk of hip fracture (hazard ratio = 0·51, 95% CI 0·27, 0·98) compared with an intake of less than once weekly. CONCLUSIONS Hip fracture incidence was inversely associated with legumes intake and, to a lesser extent, meat intake, after accounting for other food groups and important covariates. Similarly, a high intake of meat analogues was associated with a significantly reduced risk of hip fracture.
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15
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Update on nutrients involved in maintaining healthy bone. ACTA ACUST UNITED AC 2012; 60:197-210. [PMID: 23273614 DOI: 10.1016/j.endonu.2012.09.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Revised: 08/30/2012] [Accepted: 09/12/2012] [Indexed: 11/22/2022]
Abstract
Osteoporosis is a leading cause of morbidity and mortality in the elderly and influences quality of life, as well as life expectancy. Currently, there is a growing interest among the medical scientists in search of specific nutrients and/or bioactive compounds of natural origin for the prevention of disease and maintenance of bone health. Although calcium and vitamin D have been the primary focus of nutritional prevention of osteoporosis, a recent research has clarified the importance of several additional nutrients and food constituents. Based on this review of the literature, supplementation with vitamins B, C, K, and silicon could be recommended for proper maintenance of bone health, although further clinical studies are needed. The results of studies on long-chain polyunsaturated fatty acids, potassium, magnesium, copper, selenium, and strontium are not conclusive, although studies in vitro and in animal models are interesting and promising.
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16
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Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab 2012; 106:12-7. [PMID: 22402328 DOI: 10.1016/j.ymgme.2012.02.010] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Revised: 02/08/2012] [Accepted: 02/09/2012] [Indexed: 12/26/2022]
Abstract
Lysinuric protein intolerance (LPI) is an inherited defect of cationic amino acid (lysine, arginine and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding the y(+)LAT1 protein. LPI has long been considered a relatively benign urea cycle disease, when appropriately treated with low-protein diet and l-citrulline supplementation. However, the severe clinical course of this disorder suggests that LPI should be regarded as a severe multisystem disease with uncertain outcome. Specifically, immune dysfunction potentially attributable to nitric oxide (NO) overproduction secondary to arginine intracellular trapping (due to defective efflux from the cell) might be a crucial pathophysiological route explaining many of LPI complications. The latter comprise severe lung disease with pulmonary alveolar proteinosis, renal disease, hemophagocytic lymphohistiocytosis with subsequent activation of macrophages, various auto-immune disorders and an incompletely characterized immune deficiency. These results have several therapeutic implications, among which lowering the l-citrulline dosage may be crucial, as excessive citrulline may worsen intracellular arginine accumulation.
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Affiliation(s)
- Hélène Ogier de Baulny
- APHP, Reference Center for Inherited Metabolic Disease, Hôpital Robert Debré, F-75019 Paris, France
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17
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Misra D, Berry SD, Broe KE, McLean RR, Cupples LA, Tucker KL, Kiel DP, Hannan MT. Does dietary protein reduce hip fracture risk in elders? The Framingham Osteoporosis Study. Osteoporos Int 2011; 22:345-9. [PMID: 20442986 PMCID: PMC2950889 DOI: 10.1007/s00198-010-1179-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Accepted: 12/18/2009] [Indexed: 01/16/2023]
Abstract
UNLABELLED Association between dietary protein and fracture risk is unclear. We examined association between energy-adjusted protein intake and hip fracture risk in elders. The risk of hip fracture was reduced in upper quartiles of protein intake when compared with lowest quartile. INTRODUCTION Studies of the association between dietary protein intake and hip fracture risk are conflicting. Therefore, we examined protein intake and hip fracture risk in a population-based group of elderly men and women. METHODS Five hundred seventy-six women and 370 men from the Framingham Osteoporosis Study with no previous history of hip fracture completed Food Frequency Questionnaires. Energy-adjusted protein intake was evaluated as a continuous variable and as quartiles. Incidence rates and hazard ratios were calculated, adjusting for age, BMI, sex, and energy intake. RESULTS Among 946 participants (mean age 75 years), mean protein intake was found to be 68 gm/d. Increased protein intake was associated with a decreased risk of hip fracture compared to those in the lowest quartile of protein intake (Q2 HR = 0.70, Q3 HR = 0.56, and Q4 HR = 0.63; all p values ≥ 0.044), p for trend was 0.07. When a threshold effect was considered (Q2-4 vs Q1), intakes in the higher quartiles combined were associated with a significantly lower risk for hip fracture (HR = 0.63; p = 0.04). CONCLUSION Our results are consistent with reduced risk of hip fracture with higher dietary protein intake. Larger prospective studies are needed to confirm and extend this finding in elderly men and women.
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Affiliation(s)
- D Misra
- Department of Rheumatology, Boston University Medical Center, Boston, MA, USA.
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18
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Tanner LM, Näntö-Salonen K, Venetoklis J, Kotilainen S, Niinikoski H, Huoponen K, Simell O. Nutrient intake in lysinuric protein intolerance. J Inherit Metab Dis 2007; 30:716-21. [PMID: 17588131 DOI: 10.1007/s10545-007-0558-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2007] [Revised: 04/25/2007] [Accepted: 04/27/2007] [Indexed: 02/07/2023]
Abstract
Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder characterized by defective transport of cationic amino acids. Poor intestinal absorption and increased renal loss of arginine, ornithine and lysine lead to low plasma concentrations of these amino acids and, subsequently, to impaired urea cycle function. The patients therefore have decreased nitrogen tolerance, which may lead to hyperammonaemia after ingestion of normal amounts of dietary protein. As a protective mechanism, most patients develop strong aversion to protein-rich foods early in life. Oral supplementation with citrulline, which is absorbed normally and metabolized to arginine and ornithine, improves protein tolerance to some extent, as do sodium benzoate and sodium phenylbutyrate also used by some patients. Despite effective prevention of hyperammonaemia, the patients still consume a very restricted diet, which may be deficient in energy, essential amino acids and some vitamins and minerals. To investigate the potential nutritional problems of patients with lysinuric protein intolerance, 77 three- to four-day food records of 28 Finnish LPI patients aged 1.5-61 years were analysed. The data suggest that the patients are clearly at risk for many nutritional deficiencies, which may contribute to their symptoms. Their diet is highly deficient in calcium, vitamin D, iron and zinc. Individualized nutritional supplementation accompanied by regular monitoring of dietary intake is therefore an essential part of the treatment of LPI.
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Affiliation(s)
- L M Tanner
- Department of Pediatrics, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland.
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19
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Tanner LM, Näntö-Salonen K, Niinikoski H, Jahnukainen T, Keskinen P, Saha H, Kananen K, Helanterä A, Metso M, Linnanvuo M, Huoponen K, Simell O. Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance. J Pediatr 2007; 150:631-4, 634.e1. [PMID: 17517249 DOI: 10.1016/j.jpeds.2007.01.043] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2006] [Revised: 11/28/2006] [Accepted: 01/31/2007] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To analyze systemically the prevalence of renal involvement in a cohort of Finnish patients with lysinuric protein intolerance (LPI) and to describe the course and outcome of end-stage renal disease in 4 patients. STUDY DESIGN The clinical information in a cohort of 39 Finnish patients with LPI was analyzed retrospectively. RESULTS Proteinuria was observed in 74% of the patients and hematuria was observed in 38% of the patients during follow-up. Elevated blood pressure was diagnosed in 36% of the patients. Mean serum creatinine concentration increased in 38% of the patients, and cystatin C concentration increased in 59% of the patients. Four patients required dialysis, and severe anemia with poor response to erythropoietin and iron supplementation also developed in these patients. CONCLUSIONS Our findings suggest that renal function of patients with LPI needs to be carefully monitored, and hypertension and hyperlipidemia should be treated effectively. Special attention also should be paid to the prevention of osteoporosis and carnitine deficiency in the patients with end-stage renal disease associated with LPI. The primary disease does not prohibit treatment by dialysis and renal transplantation.
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Affiliation(s)
- Laura M Tanner
- Department of Pediatrics, University of Turku, Turku, Finland.
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Tanner LM, Näntö-Salonen K, Niinikoski H, Huoponen K, Simell O. Long-term oral lysine supplementation in lysinuric protein intolerance. Metabolism 2007; 56:185-9. [PMID: 17224331 DOI: 10.1016/j.metabol.2006.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2006] [Accepted: 09/07/2006] [Indexed: 02/04/2023]
Abstract
In lysinuric protein intolerance (LPI), defective transport of cationic amino acids at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules leads to decreased intestinal absorption and excessive renal loss of lysine, arginine, and ornithine. Citrulline supplementation partially restores the function of the urea cycle that is impaired by deficiency of arginine and ornithine, but does not correct the chronic lysine deficiency. Previous attempts to supplement lysine orally have been hindered by profuse diarrhea, probably caused by excess lysine remaining unabsorbed in the gut. However, individually adjusted minute doses of L-lysine hydrochloride at mealtimes are tolerated well, but the long-term benefits of this therapy remain unknown. The aim of the study was to investigate the long-term benefits and possible adverse effects of oral lysine supplementation in patients with LPI. Supplementation of meals with low doses of oral lysine improved fasting plasma lysine concentrations in 27 Finnish patients with LPI without causing hyperammonemia or other recognizable side effects during 12 months of follow-up. In conclusion, low-dose oral lysine supplementation is potentially beneficial to patients with LPI and can be started safely at an early age.
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Affiliation(s)
- Laura M Tanner
- Department of Pediatrics, University of Turku, 20520 Turku, Finland.
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Wengreen HJ, Munger RG, West NA, Cutler DR, Corcoran CD, Zhang J, Sassano NE. Dietary protein intake and risk of osteoporotic hip fracture in elderly residents of Utah. J Bone Miner Res 2004; 19:537-45. [PMID: 15005839 DOI: 10.1359/jbmr.040208] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2003] [Revised: 09/08/2003] [Accepted: 11/20/2003] [Indexed: 11/18/2022]
Abstract
UNLABELLED The role of protein intake in osteoporosis is unclear. In a case-control study in Utah (n = 2501), increasing level of protein intake was associated with a decreased risk of hip fracture in men and women 50-69 years of age but not in those 70-89 years of age. Protein intake may be important for optimal bone health. INTRODUCTION Protein is an important component of bone, but the role of dietary protein intake in osteoporosis and fracture risk remains controversial. MATERIAL AND METHODS The role of dietary protein intake in osteoporotic hip fracture was evaluated in a statewide case-control study in Utah. Patients, 50-89 years of age, with hip fracture (cases) were ascertained through surveillance of 18 Utah hospitals during 1997-2001. Age- and gender-matched controls were randomly selected. Participants were interviewed in their place of residence, and diet was assessed using a picture-sort food frequency questionnaire previously reported to give a useful measure of usual dietary intake in the elderly Utah population. The association between protein intake and risk of hip fracture was examined across quartiles of protein intake and stratified by age group for 1167 cases (831 women, 336 men) and 1334 controls (885 women, 449 men). RESULTS In logistic regression analyses that controlled for gender, body mass index, smoking status, alcohol use, calcium, vitamin D, potassium, physical activity, and estrogen use in women, the odds ratios (OR) of hip fracture decreased across increasing quartiles of total protein intake for participants 50-69 years of age (OR: 1.0 [reference]; 0.51 [95% CI: 0.30-0.87]; 0.53 [0.31-0.89]; 0.35 [0.21-0.59]; p < 0.001). No similar associations were observed among participants 70-89 years of age. Results from analyses stratified by low and high calcium and potassium intake did not differ appreciably from the results presented above. CONCLUSION Higher total protein intake was associated with a reduced risk of hip fracture in men and women 50-69 years of age but not in men and women 70-89 years of age. The association between dietary protein intake and risk of hip fracture may be modified by age. Our study supports the hypothesis that adequate dietary protein is important for optimal bone health in the elderly 50-69 years of age.
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Affiliation(s)
- Heidi J Wengreen
- Department of Nutrition and Food Sciences, Utah State University, Logan, Utah 84322-4450, USA
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Lukkarinen M, Näntö-Salonen K, Pulkki K, Aalto M, Simell O. Oral supplementation corrects plasma lysine concentrations in lysinuric protein intolerance. Metabolism 2003; 52:935-8. [PMID: 12870174 DOI: 10.1016/s0026-0495(03)00089-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In lysinuric protein intolerance (LPI), intestinal absorption and renal tubular reabsorption of arginine, ornithine, and lysine are impaired due to a defective cationic amino acid transporter. Deficiency of arginine and ornithine restricts the function of the urea cycle, leading to hyperammonemia after protein load, and to strong protein aversion. Mealtime supplements of citrulline, another urea cycle intermediate that uses other transport mechanisms, prevent postprandial hyperammonemia and improve protein tolerance. Deficiency of lysine, an essential amino acid, most probably also contributes to the symptoms of LPI. We investigated possibilities to improve the availability of lysine for tissues by increasing plasma lysine concentration. Six patients with LPI were started on short-term oral lysine supplementation that was administered with their regular citrulline doses and standard low-protein meals. L-Lysine in consecutive doses of 0.55 and 1.1 mmol/kg caused profuse diarrhea in first 3 patients. To avoid gastrointestinal side effects, the 3 other patients were started on smaller lysine supplements of only 0.05 mmol/kg per dose, given 3 times daily for 3 days. All pre- and postprandial plasma lysine concentrations remained within normal range in 2 of the 3 patients studied. Even after the larger doses, no significant effects on the urea cycle were seen. We conclude that low-dose oral lysine supplementation normalizes plasma lysine concentration in patients with LPI, and is safe and well tolerated at least in short-term use.
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Conconi MT, Tommasini M, Muratori E, Parnigotto PP. Essential amino acids increase the growth and alkaline phosphatase activity in osteoblasts cultured in vitro. FARMACO (SOCIETA CHIMICA ITALIANA : 1989) 2001; 56:755-61. [PMID: 11718268 DOI: 10.1016/s0014-827x(01)01126-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
An inadequate protein intake seems to be involved in the pathogenesis of osteoporosis. Moreover, protein from animal sources appears to protect against hip fracture, while protein from vegetable sources, which present low levels of essential amino acids, has no effect. In this preliminary work, the growth, the alkaline phosphatase activity and the collagen synthesis were evaluated in osteoblast cultures obtained from calvaria of newborn Sprague-Dawley rats and incubated with lysine, threonine, methionine, triptophan and arginine. Our results have shown that the essential amino acids can modulate the growth and the differentiation of osteoblasts cultured in vitro, confirming the relationship between osteoporotic hip fracture and inadequate protein intake. The compounds have mainly enhanced cell growth and alkaline phosphatase activity, and, to a lower degree, collagen synthesis. In summary, the essential amino acids can stimulate bone formation and could represents useful agents for the prevention and therapy of osteoporosis.
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Affiliation(s)
- M T Conconi
- Department of Pharmaceutical Sciences, University of Padua, Italy
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Kauffman RP, Overton TH, Shiflett M, Jennings JC. Osteoporosis in children and adolescent girls: case report of idiopathic juvenile osteoporosis and review of the literature. Obstet Gynecol Surv 2001; 56:492-504. [PMID: 11496161 DOI: 10.1097/00006254-200108000-00023] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
UNLABELLED The diagnosis and treatment of osteoporosis is an important aspect of gynecologic training and practice. Idiopathic juvenile osteoporosis (IJO) is a rare disease of children and adolescents that resolves after the onset of puberty. A case report is presented and current methods of diagnosis and treatment of IJO are discussed as well as the differential diagnosis. A MEDLINE search was performed of the following terms: idiopathic juvenile osteoporosis, pediatric osteoporosis, adolescent osteoporosis, bisphosphonates pediatric adolescent, and pregnancy osteoporosis, and references from bibliographies of selected papers were used as well. All papers in English, French, and German are considered in this review. There were 114 papers selected as relevant to the topic. Data relevant to the diagnosis, pathogenesis, methods of imaging, laboratory evaluation, differential diagnosis, and treatment of IJO are presented. IJO is a diagnosis of exclusion in the pediatric and adolescent patient with osteoporosis. Although bone density gradually improves after the onset of puberty, treatment of currently affected children and adolescents involves activity restriction, calcium, vitamin D, and bisphosphonate therapy. Future reproductive concerns are discussed and areas requiring additional study are reviewed. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES After completion of this article, the reader will be able to describe the condition idiopathic juvenile osteoporosis, compare the clinical features of this condition to other similar conditions, outline the diagnostic workup of a child with this condition, and list the potential therapeutic options for a patient with idiopathic juvenile osteoporosis.
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Affiliation(s)
- R P Kauffman
- Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, Amarillo, 79106, USA.
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Lukkarinen M, Näntö-Salonen K, Pulkki K, Mattila K, Simell O. Effect of lysine infusion on urea cycle in lysinuric protein intolerance. Metabolism 2000; 49:621-5. [PMID: 10831173 DOI: 10.1016/s0026-0495(00)80038-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Poor intestinal absorption and excessive renal loss of dibasic amino acids result in low plasma concentrations in patients with lysinuric protein intolerance (LPI). Arginine and ornithine deficiency impair the function of the urea cycle and cause hyperammonemia after protein intake, while chronic lysine deficiency may cause growth failure and lead to reduced bone density in such patients. Since high lysine concentrations inhibit several enzymes of the urea cycle in the liver, lysine supplementation may induce hyperammonemia in LPI. We thus studied how LPI patients tolerate high plasma lysine by intravenous (IV) infusion of 3.3 mmol/kg lysine hydrochloride over 90 minutes in 6 adult patients and 4 healthy controls. The plasma lysine concentration (mean +/- SD, range) peaked in the patients (9,114 +/- 1,864, 7,156 to 12,044 micromol/L) and controls (10,185 +/- 2,253, 7,714to 13,122 micromol/L) at 90 minutes. Urinary lysine excretion peaked in the second 2-hour urine collection in the patients (4,582 +/- 1,276, 3,018 to 6,315 micromol/m2 body surface area per hour) and in the first 2-hour collection in the controls (5,373 +/- 1,766, 3,551 to 7,286 micromol/m2/h). Two patients had mild nausea but no hyperammonemia and one patient had moderate hyperammonemia (peak, 112 micromol/L) at the end of the infusion. Orotic acid excretion increased in 2 subjects with a peak excretion rate of 33 and 251 micromol/m2/h in the third 2-hour collection after starting the load. All other subjects remained asymptomatic and showed no change in plasma ammonia or urinary orotic acid excretion. We thus conclude that an acute increase in plasma lysine caused minimal clinical or biochemical untoward effects in patients with LPI. Moderate increases in plasma lysine after low-dose oral supplementation with lysine or well-absorbed lysine derivatives are probably well tolerated in LPI.
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Affiliation(s)
- M Lukkarinen
- Department of Pediatrics and Clinical Chemistry, University of Turku, Finland
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Munger RG, Cerhan JR, Chiu BC. Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women. Am J Clin Nutr 1999; 69:147-52. [PMID: 9925137 DOI: 10.1093/ajcn/69.1.147] [Citation(s) in RCA: 215] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The role of dietary protein intake in osteoporosis remains controversial. Protein is an important structural component of bone and protein supplementation improves the medical outcome of hip fracture patients, but it is unknown whether protein intake can reduce the incidence risk of hip fracture. OBJECTIVE The relation between intake of protein and other nutrients and subsequent incidence of hip fracture was evaluated. DESIGN Nutrient intake was assessed with a food-frequency questionnaire in a cohort of Iowa women aged 55-69 y at baseline in 1986. Incident hip fractures were ascertained through follow-up questionnaires mailed to participants in 1987 and 1989 and verified by physician reports. RESULTS Forty-four cases of incident hip fractures were included in the analyses of 104338 person-years (the number of subjects studied times the number of years of follow-up) of follow-up data. The risk of hip fracture was not related to intake of calcium or vitamin D, but was negatively associated with total protein intake. Animal rather than vegetable sources of protein appeared to account for this association. In a multivariate model with inclusion of age, body size, parity, smoking, alcohol intake, estrogen use, and physical activity, the relative risks of hip fracture decreased across increasing quartiles of intake of animal protein as follows: 1.00 (reference), 0.59 (95% CI: 0.26, 1.34), 0.63 (0.28, 1.42), and 0.31 (0.10, 0.93); P for trend = 0.037. CONCLUSION Intake of dietary protein, especially from animal sources, may be associated with a reduced incidence of hip fractures in postmenopausal women.
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Affiliation(s)
- R G Munger
- Department of Nutrition and Food Sciences, Utah State University, Logan 84322-8700, USA.
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Parsons H, Snyder F, Bowen T, Klassen J, Pinto A. Immune complex disease consistent with systemic lupus erythematosus in a patient with lysinuric protein intolerance. J Inherit Metab Dis 1996; 19:627-34. [PMID: 8892019 DOI: 10.1007/bf01799838] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- H Parsons
- Department of Pediatrics, University of Calgary, Alberta, Canada
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