Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology

Abstract

Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-¹³C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.

Fig. 1. Neurocognitive outcomes in PA are associated with biomarkers linked to the mitochondrial dysfunction and the severity of PCC deficiency.

Biomarkers shown here as natural log-transformed values were linked via regression to the underlying severity of PA and mitochondrial dysfunction and showed similar associations with full scale IQ and Vineland Adaptive Behavior Composite scores. Red and blue lines illustrate an unadjusted linear regression for the outcomes (Y-axis) full scale IQ (blue) and Vineland Adaptive Behavior Composite (red). The log-transformed predictor variable for each panel is named in the header. The population-average standard score range (85–115) is shaded in gray. Parameter estimates corresponding to these lines are shown in Table 3 and test statistics in Supplementary Table S3. The distributions of untransformed continuous biomarkers are shown in Supplemental Figure S2. A Plasma propionylcarnitine (ln-transformed). B Plasma total 2-methylcitrate (ln-transformed). C In vivo whole body 1-¹³C-propionate oxidation (ln-transformed). D Plasma FGF21 (ln-transformed). E Plasma GDF15 (ln-transformed). F Plasma glycine (ln-transformed). G Plasma glutamine (ln-transformed). H Urinary concentration of glutamine normalized by creatinine (ln-transformed). I Serum erythropoietin (ln-transformed). J Affected gene, PCCA vs PCCB. K Comparison of neurocognitive outcomes in participants with two (biallelic) loss-of-function PCCA or PCCB alleles vs all other genotypes (e.g., two missense alleles or one missense plus one nonsense allele).