Complex Neurologic Syndrome Associated With the G1606A Mutation of Mitochondrial DNA

Abstract

This second patient with the G1606A mutation confirms both the pathogenicity of the mutation and its association with a characteristic complex neurologic phenotype.

Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies

“…Our patient presented a more severe clinical phenotype, including cardiac involvement, which was absent in the aforementioned case report; this could be due to a higher heteroplasmy percentage in the muscle of our patient (94.4%) compared to that observed in the previously described patient (85%) (Tanji et al, 2008). In addition, it is worth mentioning that the heteroplasmy percentage is higher in skeletal muscle of patients with MCMs and mutations in the MT-TV gene (Chalmers et al, 1997;McFarland et al, 2002;Blakely et al, 2004) than in patients without heart defects and mutations in the same gene (Taylor et al, 1996;De Coo et al, 1998;Tiranti et al, 1998;Sacconi et al, 2002;Tanji et al, 2008;Horváth et al, 2009). …”

“…In accordance with these three reported cases, our two patients developed cardiac conduction abnormalities and hypertrophic cardiomyopathy within a neurological presentation, and because of this, together with radiographic findings, MD was suspected in both cases. Muscle biopsies did not confirm the clinical impression of MD as they were morphologically and histochemically normal in the two patients, in contrast with biopsy findings of patients with mutations in the MT-TV gene previously described (Chalmers et al, 1997;Tiranti et al, 1998;Sacconi et al, 2002;McFarland et al, 2002;Tanji et al, 2008;Horváth et al, 2009;Yan et al, 2010). On the other hand, biochemical analysis showed a decrease in MRC complex I activity in muscle homogenate from patient 1, and a combined deficiency in the activity of MRC complexes I and IV from patient 2, as in most previous reports on mutations in the MT-TV gene (Chalmers et al, 1997;Tiranti et al, 1998;Sacconi et al, 2002;McFarland et al, 2002;Tanji et al, 2008;Horváth et al, 2009;Yan et al, 2010).…”

Mitochondrial tRNA Valine in Cardiomyopathies

“…Among them are the nuclear background, the heteroplasmy levels and its tissue distribution, the mtDNA haplotype, or the total mtDNA copy number [ 35 ]. The importance of the nuclear background in the clinical phenotype is highlighted in a recent study, in which the tRNA Val steady-state level in transmitochondrial cybrids carrying the m.1624C > T mutation in homoplasmy (10 % referred to controls) differs significantly of the level observed in muscle biopsy with the same mutation in homoplasmy (<1 % referred Table unpublished 7 Mitochondrial tRNA Valine in Cardiomyopathies to controls) [ 32 ].…”

Cardiac Dysfunction in Mitochondrial Disease

“…In addition, the heteroplasmy percentage is higher in skeletal muscle of patients with MCM and mutations in the MT-TV gene than in patients without heart defects and mutations in the same gene. [35][36][37][38][39][40] For that reason, around a 100% mutant level in skeletal muscle is probably required to affect the myocardium in patients with MD associated with mutations in the MT-TV gene. This was the situation in the present patients.…”