Iram Hussain1, Nivedita Patni2, Masako Ueda3, Ekaterina Sorkina4,5, Cynthia M Valerio6, Elaine Cochran7, Rebecca J Brown7, Joseph Peeden8, Yulia Tikhonovich4, Anatoly Tiulpakov4, Sarah R S Stender9, Elisabeth Klouda10, Marwan K Tayeh11, Jeffrey W Innis12, Anders Meyer13, Priti Lal13, Amelio F Godoy-Matos6, Milena G Teles14, Beverley Adams-Huet15, Daniel J Rader3, Robert A Hegele16, Elif A Oral17, Abhimanyu Garg18. 1. Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas. 2. Division of Pediatric Endocrinology, Department of Pediatrics, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas. 3. Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 4. Endocrinology Research Centre, Moscow, Russia. 5. Laboratory of Molecular Endocrinology, Medical Scientific Educational Centre, Lomonosov Moscow State University, Moscow, Russia. 6. Division of Metabology, State Institute of Diabetes and Endocrinology, Rio de Janeiro, Brazil. 7. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. 8. East Tennessee Children's Hospital, University of Tennessee Department of Medicine, Knoxville, Tennessee. 9. Department of Pediatrics, University of California San Francisco-Fresno, Fresno, California. 10. University of Tennessee College of Medicine, Memphis, Tennessee. 11. Division of Pediatric Genetics, Metabolism and Genomic Medicine, Division of Genetics, Metabolism and Genomic Medicine and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan. 12. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan. 13. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 14. Monogenic Diabetes Group, Genetic Endocrinology Unit (LIM25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil. 15. Department of Clinical Sciences, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas. 16. Department of Medicine, Western University, London, Ontario, Canada. 17. Metabolism, Endocrinology and Diabetes Division, Department of Internal of Medicine, Brehm Center for Diabetes, University of Michigan, Ann Arbor, Michigan. 18. Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas.
Abstract
Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNAp.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNAp.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNAp.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNAp.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
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