Mitochondrial Respiratory Chain Dysfunction in Muscle From Patients With Amyotrophic Lateral Sclerosis

作者：Crugnola Veronica; Lamperti Costanza; Lucchini Valeria; Ronchi Dario; Peverelli Lorenzo; Prelle Alessandro; Sciacco Monica; Bordoni Andreina; Fassone Elisa; Fortunato Francesco; Corti Stefania; Silani Vincenzo; Bresolin Nereo; Di Mauro Salvatore; Comi Giacomo Pietro; Moggio Maurizio^*

来源：Archives of Neurology, 2010, 67(7): 849-854.

DOI：10.1001/archneurol.2010.128

Background: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear.
Objective: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment.
Design: Retrospective histochemical, biochemical, and molecular studies of muscle specimens.
Setting: Tertiary care university.
Subjects: Fifty patients with typical sporadic ALS (mean age, 55 years).
Main Outcome Measure: Number of patients showing a clear muscle mitochondrial dysfunction assessed through histochemical and biochemical muscle analysis.
Results: Histochemical data showed cytochrome c oxidase (COX)-negative fibers in 46% patients. Based on COX histochemical activity, patients fell into 4 groups: 27 had normal COX activity; and 8 had mild (2-4 COX-negative fibers of 100 fibers), 8 had moderate (5-10 COX-negative fibers of 100), and 7 had severe (>10 COX-negative fibers of 100) COX deficiency. Spectrophotometric measurement of respiratory chain activities showed that 3 patients with severe histochemical COX deficiency also showed combined enzyme defects. In 1 patient, COX deficiency worsened in a second biopsy taken 9 months after the first. Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis.
Conclusions: Our data confirm that the histochemical finding of COX-negative fibers is common in skeletal muscle from patients with sporadic ALS. We did not find a correlation between severity of the oxidative defect and age of the patients or duration of the disease. However, the only patient who underwent a second muscle biopsy did show a correlation between severity of symptoms and worsening of the respiratory chain defect. In 7 patients, the oxidative defect was severe enough to support the hypothesis that mitochondrial dysfunction must play a role in the pathogenesis of the disease.

• 出版日期2010-7