Propionic acidemia in Mexico: Clinical and genotypic spectrum

Propionic acidemia (PA) is conditioned by a deficiency of propionyl-CoA carboxylase, whose subunits are coded by the PCCA and PCCB genes. In the Mexican population, little is known about the clinical presentation of PA and the underlying genotypic PCCA and PCCB spectrum. PA is not currently assessed in the mandatory Mexican newborn screening (NBS) program. We aimed to characterize the clinical and genotypic spectrum in 51 Mexican patients with PA seen at a national reference center in Mexico. Most of the patients (92.1%) showed an early symptom onset (mean 21 days of life), delayed diagnosis (mean 5.1 months of life), considerable diagnostic odyssey (mean 4.4 months), and a high early mortality rate (66.7%). Feeding difficulties, hyperammonemia, and metabolic acidosis predominated as early PA signs occurring within the first month of life. At the last follow-up, 60% (N = 18/30) of patients exhibited profound intellectual and motor impairment. Next-generation sequencing revealed that 46.66% (N = 14/30) of cases were PCCA-related and 53.3% (N = 16/30) were PCCB-related. We identified four clinically relevant novel variants in PCCA [c.-10_105 + 11del, p.(Gly226Arg), c.1643 + 3 A > G, p.(Ser245*)] and one in PCCB [p.(Met463Arg)]. Protein in silico modeling of the PCCA p.(Gly226Arg) and PCCB p.(Met463Arg) variants predicted structural disturbances supporting their pathogenicity. The c.2041-1G > T [rs1367867218] and c.1309G > A or p.(Gly437Ser) [rs1349202366] variants were the most frequent pathogenic ones in PCCA (N = 5/28 alleles, 17.9%) and PCCB (N = 7/32 alleles, 21.9%), respectively. Predominance of neonatal onset, severe neurological sequelae, and high mortality rate emphasize that PA should be considered for inclusion in the Mexican NBS program. Until PA screening is routinely performed at birth in Mexico, efforts are needed to increase pediatricians' awareness of the clinical picture, to support early detection and prompt management.