Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation

Abstract

Mutations of mitochondrial DNA (mtDNA) are an important cause of genetic disease. We describe a family with an unusual homoplasmic mutation that resulted in six neonatal deaths and one surviving child with Leigh syndrome. The mother is clinically normal, but a severe biochemical and molecular genetic defect was present in both a fatally affected child and the mother. This family highlights the role of homoplasmic mt-tRNA mutations in genetic disease.

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

“…This (Chalmers et al, 1997;McFarland et al, 2002;Blakely et al, 2004). 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.…”

“…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).…”

“…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). …”

“…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). McFarland et al, 2002;DiMauro, 2006;DiMauro, 2011). Although funcional analysis of this mutation was not possible due to the lack of sample, molecular data support that this nucleotide variation could be relevant from a functional point of view.…”

A collection of 33 novel human mtDNA homoplasmic variants

“…Indeed, certain mtDNA variants have been demonstrated to either ameliorate (El Meziane et al, 1998) or worsen (Pulkes et al, 2001) the clinical picture of patients already affected with known mitochondrial mutations, or to increase the susceptibility to severe cardiac diseases in apparently healthy populations (Shin et al, 2000;Khogali et al, 2001). In addition, the presence of a non-synonymous homoplasmic mtDNA mutation has been recently associated with severe COX deficiency, multiple neonatal deaths and Leigh syndrome (McFarland et al, 2002). It is therefore quite probable that novel mtDNA variants also play either a direct or indirect disease-role, and, also, we cannot exclude that the association of two or more variants in the same patient has a pathogenic outcome.…”