ClinVar

In a 13-year-old boy with a mitochondrial encephalocardiomyopathy, Sacconi et al. (2008) identified a heteroplasmic 5545C-T transition in the MTTW gene, which was present at unusually low levels (less than 25%) in affected tissues. In vitro functional expression studies in cybrid cell lines showed that the pathogenic threshold for the mutation was between 4 and 8%, suggesting a dominant mechanism of action. The mutation affects the central base of the anticodon triplet of tRNA-Trp, which may alter the codon specificity of the affected tRNA. The patient presented at age 5 months with hypertrophic cardiomyopathy, truncal hypotonia, and lactic acidosis. Skeletal muscle showed defective respiratory chain complex activity. He progressively lost acquired developmental milestones, developed seizures, and, at 3 years of age, he showed slowly progressive chorea. Brain MRI showed mild diffuse brain atrophy and bilateral hyperintensities in the putamen. At 13 years of age, he was microcephalic, hypotonic but hyperreflexic, ataxic and dysmetric, and had choreic movements. Sacconi et al. (2008) emphasized the unusual finding of a mitochondrial mutation that behaves like a true dominant allele.