ClinVar Genomic variation as it relates to human health

In a series of 7 Ashkenazi Jewish families with dihydrolipoyl dehydrogenase deficiency (DLDD; 246900), Shaag et al. (1999) identified a mutation in the DLD gene resulting in a gly229-to-cys (G229C) substitution at a highly conserved residue in the NAD(+)-binding domain. The G229C mutation accounted for 12 of 14 mutant alleles. G229C corresponds to G194C in the mature protein (Odievre et al., 2005). In a sample of 845 anonymous individuals of Ashkenazi Jewish origin, 9 heterozygotes for the G194C mutation were identified, yielding a carrier rate of 1:94. The other 2 alleles in the series had a previously identified insertion mutation (238331.0003). The disease course and age at onset were highly variable. Some patients had few neurologic sequelae and long survival. Two patients presented immediately after birth, 9 around age 2 years, and 2 as adults. All had recurrent episodes of vomiting, abdominal pain, and hepatomegaly, usually associated with neurologic signs during the episodes. Episodes were associated with lactic acidosis, abnormal liver enzymes, and prolonged prothrombin time. Biochemical anomalies, such as increased branched-chain amino acids and increased alpha-ketoacids were not commonly found. The 2 patients who presented neonatally had residual neurologic damage with attention deficit-hyperactivity disorder, mild ataxia, motor incoordination, muscle hypotonia, and weakness. Nine patients who presented in early childhood or as adults suffered from exertional fatigue between episodes of decompensation but were otherwise asymptomatic and showed normal psychomotor development. Two patients died because of intractable metabolic acidosis and multiorgan failure. In all patients, E3 activity was reduced to 8 to 21% of the control value in muscle or lymphocytes. In 4 patients tested, the E3 protein in muscle was reduced to 20 to 60% of control. Hong et al. (2003) reported 2 sibs, born of consanguineous Palestinian Arab Muslim parents, with E3 deficiency due to homozygosity for the G194C mutation. A girl died in infancy during an episode of repeated vomiting associated with encephalopathy. Two previous sibs had died under similar circumstances. A brother had recurrent episodes of vomiting associated with encephalopathy from age 8 months. Examination at age 10 years showed generalized muscle weakness and wasting, ataxic gait, hepatomegaly, and lactic acidemia. He was treated with riboflavin, coenzyme Q, biotin, and carnitine. Six years later, he was functioning well at a normal school, but had slight ataxia and intention tremor. Two additional patients, both of Ashkenazi Jewish descent, had a severe form of E3 deficiency and the G194C mutation. One had repeated episodes of hypoglycemia and was in a persistent vegetative state at age 4 years; he died soon after. A girl had recurrent episodes of repeated vomiting and acidosis since infancy; she died of hepatic failure at age 5 years. All patients had decreased levels of the E3 protein (range, 35-68% of controls) and decreased E3 activity (8-33% of controls). Hong et al. (2003) emphasized the favorable outcome in the 1 child treated with riboflavin and additional supplements. By in vitro functional expression studies, Ambrus et al. (2011) found that the G194C mutant protein caused no significant changes in LADH activity but did result in significantly increased generation of reactive oxygen species. (less)