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

TitleEarly-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: a morphological, biochemical and molecular-genetic study.
Publication TypeJournal Article
Year of Publication1995
AuthorsMariotti, C, Uziel, G, Carrara, F, Mora, M, Prelle, A, Tiranti, V, DiDonato, S, Zeviani, M
JournalJ Neurol
Volume242
Issue9
Pagination547-56
Date Published1995 Sep
ISSN0340-5354
KeywordsAge of Onset, Animals, Biopsy, Blotting, Southern, Cell Differentiation, Cells, Cultured, Disease Progression, DNA Replication, DNA, Mitochondrial, Humans, Infant, Newborn, Male, Mitochondrial Encephalomyopathies, Molecular Sequence Data, Muscle, Skeletal, Oxidative Phosphorylation, Pedigree, Rats, Syndrome
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 ragged-red and cytochrome c 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 and mtSSB, 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.

DOI10.1007/bf00868806
Alternate JournalJ. Neurol.
Citation Key10.1007/bf00868806
PubMed ID8551315
Grant List456 / / Telethon / Italy