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

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Pathogenic variants in lamin A/C (LMNA) are associated with various progeroid disorders.
• A specific heterozygous LMNA c.1045C>T; p.R349W variant has been linked to partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS).

Purpose of the Study:

• To define the unique characteristics of a distinct progeroid syndrome caused by the LMNA p.R349W variant.
• To investigate the underlying mechanisms of clinical manifestations through functional studies.

Main Methods:

• Clinical data from 6 new patients with the LMNA p.R349W variant were collected.
• Phenotypes of previously reported patients were reviewed.
• Functional studies were performed on skin fibroblasts from a patient.

Main Results:

• A total of 17 patients with the LMNA p.R349W variant were analyzed, exhibiting peculiar lipodystrophy, proteinuric nephropathy with FSGS, and cardiomyopathy.
• Common features included premature graying, alopecia, micrognathia, hearing loss, and scoliosis.
• Metabolic complications like diabetes mellitus, hypertriglyceridemia, and hepatomegaly were highly prevalent; no abnormal splicing or nuclear morphology was observed.

Conclusions:

• The heterozygous LMNA p.R349W variant defines a distinct multisystem progeroid syndrome (MSPS).
• MSPS patients require careful, regular evaluations for metabolic, renal, and cardiac complications due to significant morbidity and mortality risks.