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Abstract
Background
Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome.
Methods
We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations.
Results
Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts.
Conclusions
The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.
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Details
1 Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
2 Department of Clinical Genomics, St Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
3 Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA
4 Department of Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
5 Eugene McDermott Center for Human Growth and Development, Department of Population and Data Sciences, and Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA
6 Department of Medicine, Western University, London, Ontario, Canada
7 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
8 Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA
9 Physician Sarah Network of Rehabilitation Hospitals (Unit Belo Horizonte), Internal Medicine, Preoperative Outpatient Clinic, Osteometabolism, Belo Horizonte, Brazil
10 Department of Pathology, University of Washington, Seattle, Washington, USA
11 Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, and Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas, USA