G8363A mitochondrial DNA mutation is not a rare cause of Leigh syndrome – clinical, biochemical and pathological study of an affected child

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, having relatively homogeneous clinical symptomatology and pattern of neuropathological changes, shows remarkable heterogeneity in biochemical and molecular background. G8363A mitochondrial DNA mutation typical for MERRF syndrome and progressive cardiomyopathy may also be associated with LS. Clinical, biochemical and pathological findings in a boy aged 28 months who died with classical COX-deficient LS associated with mtG8363A is described in detail. Hyperlactataemia, LCHAD-like organic acids profile and respiratory alkalosis (pH 7.47, pCO2 4.9 mmHg, HCO3 3.0 mmol/l) were observed. Spectrophotometric assay showed deficit of respiratory chain complexes IV and I. Skeletal muscle biopsy revealed mosaic cytochrome oxidase deficit, lipid accumulation and ultrastructural abnormalities of mitochondria. Post mortem examination confirmed the presence of typical LS central nervous system lesions as well as hypertrophy of the left ventricle of the heart. Conclusion: mtG8363A “MERRF-like” mutation should be included in the differential diagnosis of classical LS in infants. This case is in agreement with our hypothesis that hyperventilation plays a substantial role in progression of central nervous system damage.