Evidence for Distinct Neural Endophenotypes of Executive Dysfunction in Autism and Phenylketonuria

Background: Phenylketonuria (PKU) is a neurodevelopmental disorder characterized by a deficient ability to metabolize the amino acid phenylanine, resulting in neurotransmitter dysregulation and white matter pathology. Similar to Autism Spectrum Disorder (ASD), the behavioral phenotype of PKU includes impairments in executive function and social communication (Baieli et al., 2003; Christ et al., 2010).  Furthermore, PKU has historically also been considered as one of the potential causes of ASD (Friedman, 1969). It remains unclear, however, to what extent these disorders (and their associated executive dysfunction) are characterized by similar versus distinct neural endophenotypes.

Objectives: Functional magnetic resonance imaging (fMRI) methodology was used in conjunction with a non-verbal working memory task to compare and contrast the neural endophenotype associated with ASD and PKU.

Methods: A sample of 22 individuals with ASD (mean age = 13.1 years), 11 individuals with PKU (mean age = 25.0 years), and a combined comparison group of 24 neurologically intact individuals without PKU or ASD (mean age = 18.2 years) participated. Scans were obtained on a 3T Siemens Trio scanner with a standard 8-channel head coil. Stimuli were displayed using an LCD projector, and responses were recorded using a fiber optic switch.  Neural activity was assessed while participants performed an n-back working memory task using novel face stimuli.  The n-back working memory task included two conditions: 2-back and 0-back. In the 2-back condition, participants were shown a series of novel face stimuli one at a time and were instructed to respond when the current stimulus was the same as the stimulus that appeared two items prior. For the 0-back condition, participants were again shown a series of face stimuli; however, in this instance, they were asked to simply respond when they saw a pre-specified target stimulus. Each participant completed two functional runs including 6-8 counterbalanced task epochs (3-4 per condition).

Results: Consistent with past studies (e.g., Koshino et al., 2008), we found ASD-related abnormalities in neural activation in prefrontal regions including anterior cingulate cortex (ACC) as well as left and right dorsolateral prefrontal cortex (DLPFC) [t(33) > 3.35, p < .005 in all instances].  PKU was also associated with atypical neural activation of left DLPFC [t(20) = 2.36, p = .03]; however, the pattern of activation differed from that observed in the ASD group. Specifically, ASD was associated with decreased activation of left DLPFC compared to the healthy comparison group whereas PKU was associated with increased activation. 

Conclusions: Although the general loci of the executive impairment (i.e., prefrontal cortex) are similar between the PKU and ASD, the precise pattern of activation differs.  Whereas these two disorders may share a similar behavioral phenotype, the underlying neural endophenotype is distinct for each disorder.