EARLY-ONSET ENCEPHALOMYOPATHY ASSOCIATED WITH TISSUE-SPECIFIC MITOCHONDRIAL-DNA DEPLETION - A MORPHOLOGICAL, BIOCHEMICAL AND MOLECULAR-GENETIC STUDY

A male infant, born from consanguineous parents, suffered from birth w ith a progressive neuro-muscular disorder characterized by psychomotor delay, hypotonia, muscle weakness and wasting, deep-tendon areflexia and spastic posture. High levels of lactic acid in blood and cerebrosp inal fluid suggested a mitochondrial respiratory chain defect. Muscle biopsy revealed ragged-red and cytochrome c oxidase-negative fibres, l ipid accumulation and dystrophic changes. Multiple defects of respirat ory complexes were detected in muscle homogenate, but cultured fibrobl asts, myoblasts and myotubes were normal. Southern blot analysis showe d markedly reduced levels of mitochondrial DNA (mtDNA) in muscle, whil e lymphocytes, fibroblasts and muscle precursor cells were normal. Nei ther depletion of mtDNA nor abnormalities of the respiratory complexes were observed in innervated muscle fibres cultured for as long as 4 m onths. No mutations were observed in two candidate nuclear genes, mtTF A and mtSSB, retro-transcribed, amplified and sequenced from the proba nd's mRNA. Sequence analysis of the mtDNA D-loop and of the origin of replication of the mtDNA light strand failed to identify potentially p athogenic mutations of these replicative elements in the proband's mus cle mtDNA. Our findings indicate that mtDNA depletion is due to a nucl ear encoded gene and suggest that the abnormality underlying defective mtDNA propagation must occur after muscle differentiation in vivo.