The Italian registry of limb girdle muscular dystrophy : natural history, genotype-phenotype correlations and outcome measures

Limb girdle muscular dystrophies (LGMD) are genetic heterogeneous disorders characterized by slow but progressive muscular impairment. Despite the recent identification of new genes, about 30% of these LGMDs remain without molecular diagnosis. However clinical-genetic correlations are fundamental for genetic counselling, definition of natural history and insight into pathogenesis. We collected detailed clinical, biochemical, histological and molecular data of 467 Italian LGMD patients, belonging to 8 neuromuscular Italian centres. Detailed data about neuromuscular, cardiological, respiratory involvement as far as molecular analysis and muscle biopsy were collected. Molecular analysis identified mutations in LGMD causative genes in 312 patients; 109 patients (23.1%) are still without a molecular diagnosis and 46 subjects (9.8%) carried heterozygous mutations in genes responsible for autosomal recessive forms. The relative frequency was as follows: 5.8% LGMD1B, 11.2% LGMD1C, 24.3% LGMD2A, 25.6% LGMD2B, 9.6% LGMD2I, 9.9% LGMD2D, 6.4% LGMD2E, 4.2% LGMD2C, 1.9% LGMD2L, 0.3% LGMD2F. Interestingly 1 LGMD patient (0.3%) carried mutations in ISPD and one patient in LAMA2 gene. Onset spans from the first decade to adulthood; LGMD2E being the most precocious (6.2 ± 5.3 years) and LGMD2L the latest (36.6 ± 7.1 years). Creatine-kinase values were generally increased, especially in sarcoglycanopathies, LGMD2B, LGMD1C. Cardiomyopathy was more frequent in LGMD1B (100%), LGMD2E (47%) and LGMD2I (50%) and restrictive pulmonary involvement in LGMD2I (53%) and LGMD2E (47%). About 30% of patients were wheelchair bound. The study of undiagnosed patients will potentially lead to identification of new LGMD causative genes. Overall this study defined the relative frequency of Italian LGMD and improved the knowledge about clinical, morphological and molecular spectrum as far as their natural history as far as the parameters that can better define the clinical evolution of these forms.