Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications

Abstract.

Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the β subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to posttranscriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.