Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by mutations in either PCCA or PCCB. The products of these genes form the alpha and beta subunits of the enzyme propionyl-Co A carboxylase (PCC), a critically important mitochondrial enzyme involved in the catabolism of branched chain amino acids. NHGRI scientist have developed a new set of synthetic PCCA genes that can be used to treat PA caused by PCCA mutation(s). In brief, the amino acid sequence of PCCA was reverse translated, using a variety of algorithms and expert input, to generate novel DNA sequences encoding PCCA (synPCCA) having increased expression. The synPCCA sequences were cloned into a canonical adeno-associated virus (AAV) vector, pseudoserotyped with a serotype 9 capsid and used to rescue PCCA-1-knock-out mice from neonatal lethality and improve their clinical and metabolic phenotypes. Results of pre-clinical efficacy studies demonstrate a promising therapy for PA. Furthermore, because these genes are synthetic, specific nucleotide based-assays are possible for improved detection of the DNA and RNA expressed from these synPCCA genes.