title: Skeletal muscle mitochondrial defects in nonspecific neurologic disorders.
abstract: A group of 25 children (5 months to 20 years of age) presenting with intractable seizures, developmental delay, and severe hypotonia, who did not fall into the known categories of mitochondrial encephalomyopathies, underwent muscle biopsy for evaluation of mitochondrial function and were compared with age-matched control subjects. Biopsied skeletal muscle was analyzed for six mitochondrial enzyme-specific activities, mitochondrial DNA point mutations and deletions, and mitochondrial DNA levels. The data reveal a high incidence of specific mitochondrial enzyme activity defects. Reduced activity levels were evident in complex I (11 patients), III (24 patients), IV (nine patients), and V (10 patients). Two patients also exhibited pronounced reduction in mitochondrial DNA levels (80% reduction compared with control subjects). Two patients manifested increased levels of 5-kb and 7.4-kb mitochondrial DNA deletions. Pathogenic mutations previously described in association with mitochondrial encephalomyopathies were not evident. The data suggest that mitochondrial dysfunction, including extensive defects in specific enzyme activities, may be frequently present in children with seizures, developmental delay, and hypotonia that do not fall within the known mitochondrial encephalomyopathies. These mitochondrial deficiencies can be primarily ascertained by biochemical analysis and are rarely accompanied by mitochondrial ultrastructural changes. The molecular basis of these defects, their role in these disorders, and potential treatment warrant further study.
authors.affiliation: Molecular Cardiology Institute, Highland Park, New Jersey 08904, USA.
authors.forename: J
authors.initials: J
authors.lastname: Marin-Garcia
authors.forename: R
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: M J
authors.initials: MJ
authors.lastname: Goldenthal
authors.forename: J J
authors.initials: JJ
authors.lastname: Filiano
authors.forename: H B
authors.initials: HB
authors.lastname: Sarnat
mesh_terms: D000328:Adult; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000032:analysis* / Q000235:genetics; D002658:Developmental Disabilities / Q000201:enzymology* / Q000235:genetics; D014450:Electron Transport Complex III / Q000172:deficiency / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics; D009123:Muscle Hypotonia / Q000201:enzymology* / Q000235:genetics; D018482:Muscle, Skeletal / Q000737:chemistry*; D010088:Oxidoreductases / Q000378:metabolism*; D012640:Seizures / Q000201:enzymology* / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D010088:Oxidoreductases; D014450:Electron Transport Complex III