A new mtDNA mutation associated with a progressive encephalopathy and cytochrome c oxidase deficiency

Abstract

The authors describe a novel pathogenic G5540A transition in the mitochondrial transfer RNA (tRNA)Trp gene of a sporadic encephalomyopathy characterized by spinocerebellar ataxia. Clinical features also included neurosensorial deafness, peripheral neuropathy, and dementia. Biochemistry revealed a severe reduction of cytochrome c oxidase (COX) activity. Single-fiber PCR demonstrated higher levels of mutant genomes in COX-negative ragged red fibers than in normal fibers. These findings confirm that COX is more susceptible than other respiratory chain complexes to mutations in the mitochondrial tRNATrp gene.

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

“…The fact that complex IV is more susceptible to tRNA Trp mutations could be explained by the higher percentage of tryptophan in the subunits COI and COIII as compared with other complex subunits, as has been proposed before. 26,27 Nonetheless, a correlation between the relative amount of tryptophan in individual subunits and the reduction of their mitochondrial translation rates in our patient was not evident, which has also been observed by Sacconi et al for the m.5545C4T mutation. 24 They found COI and COIII translation to be most severely disturbed, but in contrast to our results ATP6 showed a profoundly decreased synthesis as well.…”

“…A common feature of most tRNA Trp mutations is a profound complex IV defect. [22][23][24][25][26][27][28] In some cases complex IV is selectively decreased, in other cases complex I is affected to a similar extent and occasionally complex III is involved as well. Biochemical analysis revealed a combined complex I, III and IV deficiency in patient T, in which complex IV was most severely affected (on average, 28% of control levels), followed by complex I (38%) and last by complex III (51%).…”

“…22,24,25,28 In addition, visual defects, deafness, epilepsy and neurodegenerative disease are frequently observed in other patients. [22][23][24][25][26][27][28]33 In the mitochondrial tRNA Arg gene only two pathogenic mutations have been reported so far: m.10406G4A and m.10438A4G. 2 In the patient with the m.10438A4G mutation, no clear OXPHOS deficiency was found, only a minor decrease in complex IV activity.…”

Central-peripheral sensory axonopathy in a juvenile case of Alpers-Huttenlocher disease

“…In addition he was affected with a slowly progressive ataxia, due to a selective involvement of the sensory pathways, as confirmed by both ENG and SEPs. Sensory neuropathy has been reported in mitochondrial diseases associated with either mtDNA mutations or depletion [7], and sensory ataxia mimicking a spino-cerebellar atrophy was recently observed in a patient bearing a new mutation of mitochondrial DNA [10]. Sensory ataxia due to involvement of the central-peripheral axons is the characteristic feature of this juvenile case.…”

Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

“…Clinical features also included sensorineural deafness, peripheral neuropathy, and dementia. 221 The tRNA Val T1659C heteroplasmic mutation has been described in a 17-year-old girl who presented learning difficulties, hemiplegia and movement disorder. 222 The tRNA Glu T14709C heteroplasmic mutation has been detected in two family members presented congenital myopathy and mental retardation and subsequently developed cerebellar ataxia.…”