Résumé :
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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of spinal cord anterior horn presenting with weakness and muscular atrophy. It is caused by mutations in SMN1 gene (Brahe C. 2001) and it is transmitted as an autosomal recessive disorder (Engel A.G. 2004). Based on age of onset and clinical course, patients can be divided into three main groups (type I, II and III). Severe depletion of mitochondrial DNA is reported in patients affected with SMA and it is considered a consequence of important fiber atrophy (Berger A. 2003). Defects of the mitochondrial respiratory chain complexes are also reported, but their pathogenic significance is unclear.On this basis, we made a systematic revision of our collection of 20 genetically-determined SMA skeletal muscle samples and we decided to investigate the oxidative defect from a morphological point of view. In detail, we studied 9 type I, 4 type II and 7 type III SMA samples.Besides routine histological and histochemical reactions, we performed histochemistry for COX, SDH, and combined COX/SDH stains.In all patients, skeletal muscle biopsy showed a chronic neurogenic pattern, with groups of atrophic fibers and fiber type grouping. In addition, variable, but unequivocal COX deficiency was evident in almost all samples, being very severe in SMA 1 ones, where the enzymatic activity was totally lacking. In all specimens, the enzymatic defect was evident in both atrophic and normal/hypertrophic fibers. No histochemical defect was found in healthy control muscles and in skeletal muscle samples from patients with chronic neurogenic disorders.Quantitative mtDNA studies are underway.Our data show that histochemical COX deficiency is a common finding in skeletal muscle from SMA patients. We found a correlation between severity of the oxidative defect and both age of patients and disease onset/duration. However, we found no correlation between denervation and COX-deficiency for two main reasons: first, both normal-sized and hypertrophic muscle fibers were also COX-deficient in SMA patients; second, we found no enzymatic defect in skeletal muscles from patients with non-SMA neurogenic atrophy. Our findings support the hypothesis that mitochondrial dysfunction could play a role in the pathogenesis of the disease.
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