ClinVar Genomic variation as it relates to human health

McFarland et al. (2002) reported the case of a 35-year-old woman who had 1 surviving child with mitochondrial Leigh syndrome (MILS; 500017) from 10 pregnancies with 4 unrelated partners. A number of her relatives died in early infancy, including her 3 sibs. She had suffered occasional migraine headaches, and examination demonstrated very mild proximal muscle weakness. In contrast, all of her offspring showed evidence of profound mitochondrial dysfunction. One was delivered by cesarean at 32 weeks' gestation because of deteriorating cardiac function. Despite immediate clinical intervention, the baby died of severe cardiac failure at 21 hours of life. Autopsy showed biventricular hypertrophic cardiomyopathy. Six infants died in the early neonatal period with lacticacidosis, the longest survivor dying 85 hours after birth. Although several changes in mitochondrial DNA were found, McFarland et al. (2002) concluded that a C-to-T transition of nucleotide 1624, present in homoplasmic state in the gene encoding mitochondrial tRNA(Val), was responsible for the findings. The change was expected to affect a basepair in the dihydrouridine loop that is highly conserved in species from yeast to human. A marked, selective reduction of the steady-state level of mitochondrial tRNA(Val) in cardiac and skeletal muscle was found in one of the infants that died neonatally and in skeletal muscle from the mother. These and other data suggested that the 1624C-T mutant was rapidly degraded. The marked difference in phenotype between the mother and her offspring was not explained by this defect; the authors suggested that other factors, such as nuclear-encoded components or epigenetic phenomena, might be involved. Given the severe biochemical defect and the low level of mitochondrial tRNA(Val), what was surprising about this family was not that the children were severely affected but that the mother had survived and had so few clinical problems. (less)