emerin and Muscular-Dystrophies--Limb-Girdle

Mutations in the lamin A/C gene (LMNA) are known to be involved in several diseases such as Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B and dilated cardiomyopathies with conduction disease, with considerable phenotype heterogeneity. Here we report on a novel autosomal dominant mutation in LMNA in two direct relatives presenting with different clinical phenotypes, characterized by severe life-threatening limb-girdle muscle involvement and cardiac dysfunction treated with heart transplantation in the proband, and by ventricular tachyarrhythmias with preserved cardiac and skeletal muscle function in her young son. To our knowledge, this is the first report of a duplication in the LMNA gene. The two phenotypes described could reflect different clinical stages of the same disease. We hypothesize that early recognition and initiation of therapeutic manoeuvres in the younger patient may retard the rate of progression of the cardiomyopathy.

Topics: Adult; Amino Acid Sequence; Cardiomyopathy, Dilated; Electrocardiography; Female; Gene Duplication; Heart; Heart Diseases; Heart Transplantation; Humans; Immunohistochemistry; Lamin Type A; Membrane Proteins; Middle Aged; Molecular Sequence Data; Muscle Weakness; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Nuclear Proteins; Pedigree; Phenotype; Stroke Volume; Tomography, X-Ray Computed

The frequency of various limb-girdle muscular dystrophy (LGMD) molecular diagnoses has previously been investigated only in cohorts of patients presenting LGMD phenotype.. A total of 550 muscle biopsies underwent multiple protein screening (including calpain-3 functional assay) and extensive gene mutation analysis to examine the frequency of LGMD subtypes in patients with distinct clinical phenotypes (severe childhood-onset LGMD, adult-onset LGMD, distoproximal myopathy, and asymptomatic hyperCKemia).. The percentage of molecularly ascertained cases directly relates with the degree of clinical involvement: 60% of total LGMD (77% of childhood-onset, 46% of adult-onset, 66% of distoproximal myopathy) and 14% of hyperCKemia. The higher number of molecular diagnoses in severe phenotypes might suggest that genes selected for our screening are those more frequently associated with severe LGMD, and that the hyperCKemia group includes heterogeneous diagnoses. The probability of obtaining a molecular diagnosis increases when a protein defect is found in a muscle biopsy: in such cases, we diagnosed 87% of LGMD and 76% of hyperCKemia.. Diagnosing 77% of childhood-onset limb-girdle muscular dystrophy (LGMD) and 60% of total LGMD is an important result. The missing identification of gene mutations in about 40% of patients with typical LGMD phenotype suggests that unknown genetic or nongenetic etiologies are still to be recognized. Dysferlin, caveolin-3, and emerin protein defects invariably corresponded to primary disorders (100%), whereas a lower correlation was found for sarcoglycans (77%) and calpain-3 (84%). The different efficiency of genetic diagnosis after the identification of a protein defect in the various disorders is possibly due to different pathogenetic effects of mutations.

Topics: Adult; Age of Onset; Calpain; Caveolin 3; Child; Cohort Studies; Creatine Kinase; DNA Mutational Analysis; Dysferlin; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Italy; Male; Membrane Proteins; Muscle Proteins; Muscular Dystrophies, Limb-Girdle; Mutation; Nuclear Proteins; Phenotype; Sarcoglycans

Emery-Dreifuss muscular dystrophy, caused by EMD gene mutations, is characterized by humeroperoneal muscular dystrophy, joint contractures, and conduction defects and is often associated with sudden cardiac death, even without prior cardiac symptoms.. To describe the clinical and molecular features of 2 patients with limb-girdle muscular dystrophy with mutations in EMD.. Case reports.. Academic research.. Two male patients manifested proximal dominant muscle involvement, with minimal or no joint and cardiac involvement.. Muscle biopsy and mutation analysis results.. Immunohistochemistry revealed an absence of emerin staining in muscle biopsy specimens. Mutation analysis identified nonsense mutations in EMD.. Mutations in EMD may indicate a limb-girdle muscular dystrophy phenotype. Identification of emerin deficiency among patients with limb-girdle muscular dystrophy is essential to prevent cardiac catastrophe.

Topics: Biopsy; Child; Codon, Nonsense; DNA Mutational Analysis; Extremities; Gene Deletion; Genetic Markers; Genetic Predisposition to Disease; Heart Block; Humans; Immunohistochemistry; Male; Membrane Proteins; Middle Aged; Muscle, Skeletal; Muscular Atrophy; Muscular Dystrophies, Limb-Girdle; Mutation; Myocardium; Nuclear Proteins