Limb girdle muscular dystrophies (LGMD) are characterized by genetic and clinical heterogeneity: seven autosomal dominant and 12 autosomal recessive loci have so far been identified. Aims of this study were to evaluate the relative proportion of the different types of LGMD in 181 predominantly Italian LGMD patients (representing 155 independent families), to describe the clinical pattern of the different forms, and to identify possible correlations between genotype, phenotype, and protein expression levels, as prognostic factors. Based on protein data, the majority of probands (n=72) presented calpain-3 deficiency; other defects were as follows: dysferlin (n=31), sarcoglycans (n=32), alpha-dystroglycan (n=4), and caveolin-3 (n=2). Genetic analysis identified 111 different mutations, including 47 novel ones. LGMD relative frequency was as follows: LGMD1C (caveolin-3) 1.3%; LGMD2A (calpain-3) 28.4%; LGMD2B (dysferlin) 18.7%; LGMD2C (gamma-sarcoglycan) 4.5%; LGMD2D (alpha-sarcoglycan) 8.4%; LGMD2E (beta-sarcoglycan) 4.5%; LGMD2F (delta-sarcoglycan) 0.7%; LGMD2I (Fukutin-related protein) 6.4%; and undetermined 27.1%. Compared to Northern European populations, Italian patients are less likely to be affected with LGMD2I. The order of decreasing clinical severity was: sarcoglycanopathy, calpainopathy, dysferlinopathy, and caveolinopathy. LGMD2I patients showed both infantile noncongenital and mild late-onset presentations. Age at disease onset correlated with variability of genotype and protein levels in LGMD2B. Truncating mutations determined earlier onset than missense substitutions (20+/-5.1 years vs. 36.7+/-11.1 years; P=0.0037). Similarly, dysferlin absence was associated with an earlier onset when compared to partial deficiency (20.2+/-standard deviation [SD] 5.2 years vs. 28.4+/-SD 11.2 years; P=0.014).
Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive muscle disease due to defect on the gene encoding dystrophin. The lack of a functional dystrophin in muscles results in the fragility of the muscle fiber membrane with progressive muscle weakness and premature death. There is no cure for DMD and current treatment options focus primarily on respiratory assistance, comfort care, and delaying the loss of ambulation. Recent works support the idea that stem cells can contribute to muscle repair as well as to replenishment of the satellite cell pool. Here we tested the safety of autologous transplantation of muscle-derived CD133+ cells in eight boys with Duchenne muscular dystrophy in a 7-month, double-blind phase I clinical trial. Stem cell safety was tested by measuring muscle strength and evaluating muscle structures with MRI and histological analysis. Timed cardiac and pulmonary function tests were secondary outcome measures. No local or systemic side effects were observed in all treated DMD patients. Treated patients had an increased ratio of capillary per muscle fibers with a switch from slow to fast myosin-positive myofibers.
Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.
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