Sara Benedetti1, Luciano Merlini. 1. Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, Milan, Italy.
Abstract
PURPOSE OF REVIEW: This review outlines recent advances in the clinical, genetic and molecular aspects of laminopathies, an expanding group of disorders caused by mutations of the lamin A/C gene. RECENT FINDINGS: Mutations in lamin A/C were originally described in skeletal and cardiac muscle disorders. It has subsequently been shown that partial lipodystrophy syndromes with or without developmental abnormalities and premature ageing are also associated with lamin A/C alterations. Concomitantly, peripheral nerve involvement with autosomal recessive and dominant inheritance is adding to the picture. The clinical heterogeneity of laminopathies ranges from intrafamilial variability to the description of overlapping phenotypes. A large variability in clinical presentation and the course of cardiomyopathy occurs, including sudden death despite pacemaker implant and embolic stroke in young patients. Similarly, premature ageing syndromes encompass classic and atypical forms of varying severity with the involvement of diverse tissues. In addition, an association of myopathic and neuropathic phenotypes is now emerging. SUMMARY: Advances in molecular genetics of apparently unrelated disorders, involving muscle, heart, nerve, fat, bone, liver, skin tissues and premature ageing, have enriched our knowledge of the diverse phenotypes associated with lamin A/C mutations. Nevertheless, the understanding of pathogenetic mechanisms still remains speculative. More basic and clinical research is needed in order to identify genes concurring in determining the lamin A/C phenotypes and to envisage proper treatment strategies.
PURPOSE OF REVIEW: This review outlines recent advances in the clinical, genetic and molecular aspects of laminopathies, an expanding group of disorders caused by mutations of the lamin A/C gene. RECENT FINDINGS: Mutations in lamin A/C were originally described in skeletal and cardiac muscle disorders. It has subsequently been shown that partial lipodystrophy syndromes with or without developmental abnormalities and premature ageing are also associated with lamin A/C alterations. Concomitantly, peripheral nerve involvement with autosomal recessive and dominant inheritance is adding to the picture. The clinical heterogeneity of laminopathies ranges from intrafamilial variability to the description of overlapping phenotypes. A large variability in clinical presentation and the course of cardiomyopathy occurs, including sudden death despite pacemaker implant and embolic stroke in young patients. Similarly, premature ageing syndromes encompass classic and atypical forms of varying severity with the involvement of diverse tissues. In addition, an association of myopathic and neuropathic phenotypes is now emerging. SUMMARY: Advances in molecular genetics of apparently unrelated disorders, involving muscle, heart, nerve, fat, bone, liver, skin tissues and premature ageing, have enriched our knowledge of the diverse phenotypes associated with lamin A/C mutations. Nevertheless, the understanding of pathogenetic mechanisms still remains speculative. More basic and clinical research is needed in order to identify genes concurring in determining the lamin A/C phenotypes and to envisage proper treatment strategies.