ABSTRACT
The authors analyzed muscle biopsy specimens of 104 patients with creatine kinase activity greater than 500 UI/L (normal 10 to 170 UI/L) without signs of muscle weakness. They achieved a definite or probable diagnosis in 55% of cases. The most frequently identified diseases were glycogen storage diseases, muscular dystrophies, and inflammatory myopathies. The probability of making a diagnosis was higher in children and when creatine kinase level was greater than 2,000 UI/L.
Subject(s)
Creatine Kinase, MM Form/blood , Neuromuscular Diseases/blood , Adolescent , Adult , Aged , Biomarkers , Biopsy , Child , Child, Preschool , Cohort Studies , Dystrophin/deficiency , Fatigue/blood , Fatigue/etiology , Female , Glycogen Storage Disease Type II/blood , Glycogen Storage Disease Type II/diagnosis , Glycogen Storage Disease Type V/blood , Glycogen Storage Disease Type V/diagnosis , Humans , Male , Middle Aged , Muscle Cramp/blood , Muscle Cramp/etiology , Muscle, Skeletal/enzymology , Muscle, Skeletal/pathology , Neuromuscular Diseases/diagnosis , Retrospective StudiesABSTRACT
Multiple mitochondrial DNA (mtDNA) deletions have been reported in patients with autosomal dominant and recessive disorders. We studied several affected and one non-affected individuals belonging to a pedigree in which the inheritance of the pathological trait was compatible with an autosomique dominant transmission. Affected members had late-onset multisystem disorders with multiple mtDNA deletions in skeletal muscle. But this family presented a striking difference from previously described cases, because none of the patients had progressive external ophthalmoplegia (PEO). We also studied one young boy with a no contributary family history. He had a cerebellar ataxia with PEO and multiple mtDNA deletions in muscle. Molecular analysis revealed that in the first family, repeated sequences were present at the breakpoint junctions, whereas such motifs were not found in the young patient's case. In the first family, we evidenced mtDNA point mutations in clones containing breakpoint junctions and a 9-bp motif triplication in the intergenic COII/tRNA(Lys) region, whereas this sequence is repeated twice in the wild type mtDNA. Our results suggest that multiple deletions observed in the two pedigrees result from different molecular mechanisms and point out the role of repeated sequences in the first pedigree. No mtDNA repair system has been described in mammals so far, but the molecular abnormalities found in the first family suggest that a defect in an mtDNA repair system, homologous to the E. coli MutHLS pathway, could be responsible for such a phenotype.
Subject(s)
DNA, Mitochondrial/genetics , Gene Deletion , Child , DNA, Mitochondrial/analysis , Female , Humans , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Repetitive Sequences, Nucleic Acid , Sequence Analysis, DNAABSTRACT
UNLABELLED: We studied a 3-month-old girl who was admitted to hospital because of respiratory distress. The clinical course was characterized by a rapidly progressive generalized hypotonia with lactic acidosis and she died at 4 months of age. A muscle biopsy showed few ragged-red fibres and lack of histochemical cytochrome c oxidase reaction in all fibres. Enzyme activities of the respiratory chain complexes containing subunits encoded by the mitochondrial DNA (mtDNA) were markedly decreased. A quantitative Southern blot analysis revealed 99% depletion of mtDNA in muscle and normal amounts in blood. There was no family history and the dizygotic twin sister of the patient was no symptomatic. CONCLUSION: This new case confirms the rapidly fatal evolution associated with severe depletion of muscle mtDNA.
