Mitochondrial DNA G8363A mutation in the tRNALys gene: Clinical, biochemical and pathological study

The G8363A is a very rare mtDNA tRNALys gene mutation that has been associated to MERRF-like syndrome, cardiomyopathy or Leigh syndrome. Here, we describe the clinical and molecular features of a new large multigenerational family and we review the literature of cases with this mutation.In our family seven members presented a heterogeneous mitochondrial disease phenotype, from MERRF-like syndrome to isolated psychiatric disorder, associated with the G8363A mutation. The two probands are dizygotic twin sisters affected by mental retardation, neural deafness, myopathy, myoclonic epilepsy and ataxia. Twins' muscle biopsies showed a severe cytochrome c oxidase (COX) deficiency and ragged-red fibers. Their mitochondrial respiratory chain was defective in complexes I and IV in muscle. A severe reduction in complex IV activity was also observed in fibroblasts and myoblasts. Molecular analysis showed a G8363A transition in the mtDNA tRNALys gene. The mutation was almost homoplasmic (> 90%) in muscle and blood of the twins and heteroplasmic (55 ± 8%) in blood sample from affected maternal relatives. Based on our family data and the meta-analysis of the literature, we confirm that mutational load directly correlates with severity of the disease (severe vs mild/moderate phenotype; P = 0.00168) and with disease onset (P < 0.00001). However the presence of several exceptions and overlaps among patients with different clinical severity limits the clinical usefulness of this observation.Although the pathogenicity of the G8363A mutation is well established, counselling is a difficult task for clinicians because of the large phenotypical variability. Our study contributes further data on the clinical spectrum and its relation with the level of G8363A tRNALys mtDNA mutation.