Behavioral Phenotyping of Propionic Acidemia: A Neurometabolic Disorder with Prominent Neurodevelopmental Sequelae

Background: Although neurometabolic disorders have been associated with neurodevelopmental problems, few natural history studies exist. Propionic acidemia (PA) is an autosomal recessive condition (OMIM# 606054), wherein mutations in the PCCA and PCCB genes cause propionyl-CoA carboxylase deficiency and accumulation of toxic propionate-related metabolites. While Intellectual Disability (ID) has been documented as a complication of PA, autism spectrum disorder (ASD) in PA has only been assessed recently. Recent reports suggest a potential relationship between PA and ASD, with two small studies indicating the rate of ASD in PA may be between 20-40% with ID and anxiety prominent in those diagnosed with ASD (de la Batie et al., 2017).

Objectives: The current study reports on 24 patients diagnosed with PA who received neurodevelopmental evaluations, including comprehensive ASD assessments, as part of a natural history protocol in order to characterize the sample and explore the relationship between PA and ASD.

Methods: In this observational case series, participants with PA received behavioral evaluations of cognitive and adaptive functioning, and autism symptoms. The appropriate Wechsler test for an individual’s age was attempted as a cognitive assessment; if the participant was unable to achieve basal, the Mullen Scales of Early Learning or Differential Ability Scales (DAS-II) was administered. Adaptive behavior was assessed with the Vineland Adaptive Behavior Scales-II. The autism assessment battery was administered by clinical psychologists with research reliability on the Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R). ASD assessments were administered to 16/24 participants; 3 did not complete extended testing due to fragile medical condition, 2 due to time constraints, and 3 did not present with clinical indications of ASD (i.e., SCQ scores ≤5, SRS-2 t-scores ≤56). In the ASD sample, 14 participants received both the ADOS-2 and ADI-R; 1 received only ADI-R and 1 only the ADOS-2.

Results: Participants were primarily female (n=13; 54%) with an age range from 3.5 to 34.4 years (mean =12.89, SD=8.03). Cognitive assessments were completed using a Wechsler scale (n=18), Mullen (n=5) or the DAS-II (n=1). Standard scores (IQ) were calculated, with developmental quotients (DQ) for children who received assessments out of age range. Mean cognitive IQ/DQ were 60.84±27.2. Adaptive skills were low with a mean Vineland-II ABC SS of 63.75±23 (range 20–100) and low range Communication (64.7±25.2), Daily Living (63.5±23) and Socialization (67.5±2523.4) scores.

ADOS-2 Modules 1 (n=3), 2 (n=2), 3 (n=9) and 4 (n=1) were administered. Across all modules, 9/15 children (60%) met for autism and 3/15 (20%) met for ASD. Mean ADOS severity score for the assessed sample was 6.58 (SD=3.3). The ADI-R was completed for 15 patients; 10 (67%) met ADI-R overall criteria for autism. Twelve of the 16 assessed participants were determined by clinical judgment to meet criteria for an ASD diagnosis.

Conclusions: A high rate of ASD was observed in the PA cohort, which approaches rates found in other genetic conditions traditionally associated with ASD (e.g. Fragile X). Further exploration of the neurometabolic effects of PA and related disorders and the underlying pathophysiology can help develop therapy approaches.