Original Communication

Journal of Neurology

, Volume 242, Issue 9, pp 547-556

First online:

Early-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: A morphological, biochemical and molecular-genetic study

  • Caterina MariottiAffiliated withDivision of Biochemistry and Genetics, National Neurological Institute “Carlo Besta”
  • , Graziella UzielAffiliated withDivision of Child Neurology, National Neurological Institute “Carlo Besta”
  • , Franco CarraraAffiliated withDivision of Biochemistry and Genetics, National Neurological Institute “Carlo Besta”
  • , Marina MoraAffiliated withDivision of Muscle Pathology, National Neurological Institute “Carlo Besta”
  • , Alessandro PrelleAffiliated withInstitute of Clinical Neurology, Universita Statale
  • , Valeria TirantiAffiliated withDivision of Biochemistry and Genetics, National Neurological Institute “Carlo Besta”
  • , Stefano DiDonatoAffiliated withDivision of Biochemistry and Genetics, National Neurological Institute “Carlo Besta”
  • , Massimo ZevianiAffiliated withDivision of Biochemistry and Genetics, National Neurological Institute “Carlo Besta”

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Abstract

A male infant, born from consanguineous parents, suffered from birth with a progressive neuromuscular disorder characterized by psychomotor delay, hypotonia, muscle weakness and wasting, deep-tendon areflexia and spastic posture. High levels of lactic acid in blood and cerebrospinal fluid suggested a mitochondrial respiratory chain defect. Muscle biopsy revealed raggedred and cytochromec oxidase-negative fibres, lipid accumulation and dystrophic changes. Multiple defects of respiratory complexes were detected in muscle homogenate, but cultured fibroblasts, myoblasts and myotubes were normal. Southern blot analysis showed markedly reduced levels of mitochondrial DNA (mtDNA) in muscle, while lymphocytes, fibroblasts and muscle precursor cells were normal. Neither depletion of mtDNA nor abnormalities of the respiratory complexes were observed in innervated muscle fibres cultured for as long as 4 months. No mutations were observed in two candidate nuclear genes,mtTFA andmtSSB, retro-transcribed, amplified and sequenced from the proband's mRNA. Sequence analysis of the mtDNA D-loop and of the origin of replication of the mtDNA light strand failed to identify potentially pathogenic mutations of these replicative elements in the proband's muscle mtDNA. Our findings indicate that mtDNA depletion is due to a nuclear encoded gene and suggest that the abnormality underlying defective mtDNA propagation must occur after muscle differentiation in vivo.

Key words

Early-onset encephalomyopathy Mitochondrial DNA depletion