Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an LMNA p.R349W Variant

Abstract

BACKGROUND Pathogenic variants in 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 now report 6 new patients with 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 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 two 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 Heterozygous LMNA p.R349W variant in affected subjects have several distinct phenotypic features and 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 as hyperglycemia, hypertriglyceridemia, FSGS and cardiomyopathy cause major morbidity and mortality.

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

“…However, proteinuria has been reported in several cases with LMNA mutations, and to our knowledge, nine patients were confirmed with FSGS by kidney biopsy ( 23 , 24 , 26 , 37 – 41 ) ( Table 1 ). The primary diagnosis of these cases was lipodystrophy with or without APS.…”

“…The primary diagnosis of these cases was lipodystrophy with or without APS. Their presentations of proteinuria were all during adulthood, and two of them with APS features required kidney replacement therapy ( 23 , 26 ). Since the others with the same mutation ( p .Arg349Trp) had normal to impaired kidney function, the kidney outcome seems variable ( 23 , 26 , 37 , 41 ), and proteinuria might have been present since their childhood as in our case, but not detected earlier.…”

“…Their presentations of proteinuria were all during adulthood, and two of them with APS features required kidney replacement therapy ( 23 , 26 ). Since the others with the same mutation ( p .Arg349Trp) had normal to impaired kidney function, the kidney outcome seems variable ( 23 , 26 , 37 , 41 ), and proteinuria might have been present since their childhood as in our case, but not detected earlier. Therefore, if possible, our patient also needs careful follow-up and intervention since some required dialysis in their 30s, although their variant site was different from ours.…”

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

“…242 Induced pluripotent stem cell (iPSC)-derived adipocytes mimicking FPLD2 cell model also show increased autophagy to degrade triglycerides. 243 In addition to obesity, fatty liver, fat loss in lower limbs, and diabetes, FPLD2 affected individuals occasionally exhibit progeroid features, 244 cardiac abnormalities, 244 pancreatitis, 245 and renal failure. 246 Therefore, cohorts of FPLD2 individuals exhibit varying degrees of heterogeneity in disease phenotypes.…”

Post-acute cardiac complications following SARS-CoV-2 infection in partial lipodystrophy due to LMNA gene p.R349W mutation

“…APS is caused by different LMNA mutations that have in common an early and accelerated aging process and is also characterized by variable degrees of fat loss (partial or generalized lipodystrophy), metabolic alterations and comorbidities that affect skeleton, muscles and heart. Twenty patients with LMNA p.R349W mutation have been reported so far, all presenting with very similar features [ 3 , 4 ]. Lipodystrophic patients display reduced or absent adipose tissue amounts and this condition cause a proportional reduction of circulating levels of adipocyte-derived hormones, especially leptin.…”