Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA^ser(UCN) gene

Abstract

We report seven unrelated families with mitochondrial tRNA(Ser(UCN)) gene mutations at three different loci. A novel G7497A mutation is found in two families, both of which present with progressive myopathy, ragged-red fibers, lactic acidosis, and deficiency of respiratory chain complexes I and IV. This mutation presumably affects the tertiary tRNA(Ser(UCN)) dihydrouridine interaction. Mutations 7472 insC and T7512C, found in three and two families, respectively, are associated with myoclonus epilepsy, deafness, ataxia, cognitive impairment, and complex IV deficiency. No ragged-red fibers or ultrastructural abnormalities are seen. It is interesting that 6 of our 7 index patients are apparently homoplasmic, indicating a minor pathogenetic power of the tRNA(Ser(UCN)) mutations.

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

“…Assignment of these mutations as pathological is based upon their absence from unaffected families, their ability to produce a biochemical phenotype in cultured cell models such as rho-zero cybrids and demonstrable effects on mitochondrial protein synthesis. 8 -13 A number of other mutations in tRNA Ser(UCN) , that is, T7510C, 14,15 T7511C 16,17 and T7512C, 18 as well as one other mutation in 12S rRNA (C1494T) 19 have been reported in cases of similar phenotypes (syndromic hearing impairment in the case of T7512C). The latter tRNA, as well as tRNA Leu(UUR) , may be hotspots for such mutations, although other tRNAs have not been systematically excluded.…”

Extended screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

“…21 The phenotypes of this mutation, however, vary even among individuals within the same family. 22 The audiogram of TMD368 showed moderate SNHL (Figure 2b), although this patient mtDNA mutation screening for hearing loss T Kato et al was still just 35 years old. He had no other clinical disorders such as myoclonus or family history of HL or neurological disorders.…”

Multiple origins of the mtDNA 7472insC mutation associated with hearing loss and neurological dysfunction

“…3 Affected individuals suffer sensorineural hearing loss often with ataxia and myoclonus when the mutation is present at greater than 95%. G1-3: These three families from Germany have previously been described 4,5 corresponding to families A, B and C. All index patients had sensorineural hearing loss and progressive myoclonic epilepsy. Nl:…”

“…In some individuals where levels of the mutation are greater than 95% neurological features such as ataxia and myoclonus also occur. 3,4 To date the 7472insC mutation has been found in six families, all from Western Europe, 3 ± 6 raising the possibility that the presence of this mutation in Europe is primarily due to a founder effect. Alternatively, the finding may be due to chance sampling, the 7472insC mutation having occurred multiple times on different mtDNA backgrounds.…”