laminopathies

Laminopathies are a group of genetic disorders caused by mutations in genes that encode lamins and lamin-associated proteins, most notably LMNA, which produces lamins A and C, and LMNB1/LMNB2, which encode lamins B1 and B2. Lamins form the nuclear lamina, a structural meshwork beneath the inner nuclear membrane that supports the nucleus and participates in chromatin organization, gene regulation, DNA replication and repair, and signaling.

Genetic basis and spectrum: LMNA mutations give rise to a wide range of phenotypes, including Emery-Dreifuss muscular dystrophy (EDMD) type 2, and Dunnigan-type familial partial lipodystrophy (FPLD2). Other LMNA-associated conditions affect skeletal muscle, the heart, adipose tissue, and the nervous system. LMNB1 duplications cause adult-onset autosomal dominant leukodystrophy (ADLD). Additional disorders arise from LMNA-related defects in lamin A maturation, such as mandibuloacral dysplasia, and from progerin production in Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder linked to LMNA.

Clinical features: manifestations are heterogeneous. Muscular dystrophy can present with early contractures and progressive weakness; lipodystrophy features partial loss of subcutaneous fat with metabolic disturbances such as insulin resistance and hyperlipidemia; cardiac involvement includes cardiomyopathy and conduction defects; central nervous system involvement can include demyelinating leukodystrophy in LMNB1-related disease. Progeroid syndromes reflect accelerated aging due to defective lamin A processing.

Diagnosis and management: diagnosis relies on genetic testing for LMNA, LMNB1, and related genes, supported by clinical and laboratory findings. Management is multidisciplinary and focused on treating specific manifestations (cardiac monitoring and management of conduction blocks, metabolic control for lipodystrophy, physical therapy for muscle disease). There is no universal cure; research continues toward targeted therapies addressing nuclear envelope defects.