Overlapping syndrome with familial partial lipodystrophy, Dunnigan variety and cardiomyopathy due to amino-terminal heterozygous missense lamin A/C mutations

Abstract

Familial partial lipodystrophy, Dunnigan variety (FPLD) is a well-recognized autosomal dominant disorder due to heterozygous missense mutations in lamin A/C (LMNA) gene. Most of the FPLD patients harbor mutations in the C-terminal of the lamin A/C and do not develop cardiomyopathy. On the other hand, affected subjects from three FPLD pedigrees with heterozygous R28W, R60G and R62G LMNA mutations in the amino-terminal had associated cardiomyopathy presenting as premature onset of congestive heart failure, dilated cardiomyopathy and conduction system disturbances. We report three new FPLD pedigrees presenting with cardiomyopathy associated with heterozygous LMNA mutations in the amino-terminal region. Two of them had previously reported R60G and R62G mutations and one has a novel D192V mutation. Affected subjects belonging to the pedigree with heterozygous R62G mutation had atrial fibrillation and required pacemaker implantation. The affected subjects from the other pedigrees with R60G and D192V mutations developed severe cardiomyopathy requiring defibrillator implantation and cardiac transplantation before 30 years of age in some and premature death in the fourth decade in others. Thus, our report provides further evidence of association of a multisystem dystrophy syndrome in FPLD patients harboring amino-terminal mutations in LMNA. Increased understanding of the genotype-phenotype association might help devise clinical strategies aimed at preventing devastating manifestations of cardiomyopathy including heart failure, arrhythmias and sudden death. Furthermore, the underlying molecular mechanisms by which these amino-terminal mutations cause lipodystrophy as well as cardiomyopathy remain to be understood.

Fig. 1

Pedigree of families with FPL, Dunnigan and cardiomyopathy. Panels A, B and C show the pedigrees. Circles denote females and squares represent males. Arrows indicate probands. Half-filled symbols indicate affected subjects based on clinical information and unfilled symbols indicate unaffected subjects. A diagonal line across a symbol indicates a deceased subject. The genotypes of the subjects for whom DNA was available are given under the symbols. Patients with heterozygous mutations are shown as RG or DV and unaffected subjects with RR and DD. Panel D Sequence electropherogram of exon 3 of LMNA showing the novel heterozygous mutation (Asp192Val) in the proband from F9800 pedigree. The arrow indicates the site of mutation. The numbers below the electropherogram represent amino acid numbers in lamin A protein.

Fig. 2

Body fat distribution pattern in Patients with FPLD and cardiomyopathy overlap syndrome. (A) A 40-year-old male (FPL7200.7) with R62G LMNA mutation showing marked loss of subcutaneous fat from the upper and lower extremities and accumulation of sc fat in the face, chin and axillary region (B) A 26-year-old female (FPL9800.6) with D192V LMNA mutation showing marked loss of sc fat from the upper and lower extremities and accumulation of sc fat in the face and chin; (C) A 26-year-old female (FPL139.13) with R60G LMNA mutation showing marked loss of sc fat from the upper and lower extremities and accumulation of sc fat in the face and chin.

Fig. 3

The structure of lamins A and C with site of mutations described in patients with FPLD. Lamin A and C isoforms share the same 566 amino acids. Lamin C has 6 unique carboxy-terminal amino acids and the precursor of lamin A, prelamin A, has 98 unique carboxy-terminal amino acids. Post-translational processing of prelamin A including proteolysis of 18 C-terminal amino acids (indicated by a triangle) is catalyzed by zinc metalloproteinase. Most of the mutations in familial partial lipodystrophy are located in the tail region. Peculiar phenotypic features associated with various mutations are represented by symbols. For example, *, represents associated cardiomyopathy; †, associated Emery-Dreifuss muscular dystrophy; ‡, associated limb-girdle muscular dystrophy; #, mild myopathy; and § mild lipodystrophy.