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

L. Subramanyam, V. Simha, A. Garg

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)66-73
Number of pages8
JournalClinical Genetics
Volume78
Issue number1
DOIs
StatePublished - Jul 2010

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Keywords

  • Cardiomyopathy
  • Lamin A/C
  • Lipodystrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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