The genetic characterisation of propionic acidemia and trimethylaminuria patients in the South African population

Abstract

The two inborn errors prop10mc acidemia and trimethylaminuria of propionic acid metabolism and trimethylamine metabolism respectively are some of the organic acidurias in South Africa with the highest occurrence in the population. Propionic acidemia is a disorder of branched-chain amino acid metabolism and is characterised by the accumulation of propionic acid resulting in episodes of vomiting, lethargy, dehydration, and severe metabolic acidosis. It is caused by a genetic defect in one of the two subunits of the enzyme propionyl-CoA carboxylase that carboxylates propionic acid in the metabolism. The mutation responsible for the genetic defect is unknown in the South African population and a common ancestor is thought to exist. Trimethylaminuria is an inherited metabolic disorder in which the affected individuals excrete markedly increased amounts of the simple tertiary aliphatic amine trimethylamine in the urine, sweat and breath making them smell like rotten fish. This trimethylamine is a product of intestinal bacterial metabolism and converted by the liver enzyme flavin containing monooxygenase-3 (FMO3) to the odourless trimethylamine N-oxide in unaffected individuals, but not oxidised in trimethylaminuria patients. Recent evidence suggests that the condition is much more common than first thought and causes severe psychological disturbances in affected individuals. Because the mutations or polymorphisms responsible for these disorders are unknown in South African populations, the author undertook a study to identify and characterise on a molecular level the defective genes of those inherited metabolic diseases. The mutation responsible for the propionic acidemia could not be elucidated in this study because of the failer to successfully amplify the target sequence by RT-PCR techniques. A family with a trimethylaminuria sibling was, however, shown to be carriers of two known polymorphisms El58K in exon 4 and E308G in exon 7 of the FMO3 gene. The sibling is a homozygote for polymorphism E308G, but also heteroallelic for these two polymorphisms. The mother was shown to be a carrier of the defect by a trimethylaminuria load test and in this study confirmed to exhibit the E308G polymorphism. The father on the other hand did not seem to be a carrier with the load test, but was also shown in this study to be a carrier for the E308G polymorphism. Because of these results it was speculated that the mother must also be a heterozygous carrier of the E 158K polymorphism. This could however not be substantiated by mutational analysis because of the failure to sequence exon 4 of the parents.