Computational MRI Analysis of Cerebellar Circuitry across Three Different Genetic Forms of Autism and Intellectual Disability

Background:

The genetic landscape of autism spectrum disorder (ASD) and intellectual disabiity (ID) is expanding to include a wide number of single-gene disorders, leading to increased efforts to study ASD and ID through the lens of specific genetic causes. The basis for this approach is that seemingly unrelated genetic disorders associated with ASD and ID may converge on final common pathways. Therefore, better understanding of mechanistic commonalities among distinct causes may shed light on the pathogenesis of ASD and ID, opening the door to potential targeted treatments.

Phelan-McDermid syndrome (PMS), PTEN hamartoma tumor syndrome (PHTS), and Tuberous sclerosis complex (TSC) are three examples of genetic disorders associated with a high prevalence of ASD and ID, with evidence for cerebellar dysfunction in all three. In PMS, cerebellar vermal hypoplasia is commonly reported as a finding on MRI. In PHTS, Purkinje cell-specific knockout of Ptenleads to autistic-like traits in mice. In TSC, there is overactivity of the mechanistic target of rapamycin (mTOR) pathway leading to Purkinje cell degeneration in the cerebellum.

Objectives:

In order to investigate whether defects in cerebellar circuits may be one of the final common pathways disrupted in ASD and ID, we performed computational volumetric analysis on brain MRIs of individuals with PMS, PHTS, and TSC, focusing on cerebellar regions of interest.

Methods:

Participants were part of the Developmental Synaptopathies Consortium, a multi-site, natural history study of PMS, PHTS, and TSC, collecting neurocognitive data as well as MRI brain data. We used an automated approach based on the PSTAPLE algorithm to carry out automatic MRI segmentation and generate relative volumes (structure volume divided by intracranial contents volume) of the following cerebellar structures: right/left cerebellar white matter, right/left cerebellar cortex, vermal lobules I-V, vermal lobules VI-VII, vermal lobules VIII-X. For each of the three syndromes, we compared relative volumes to different cognitive/adaptive measures depending on age/functioning of the participants using linear regression.

Results:

In this preliminary interim analysis, there were n=11 individuals with PMS (6 females, 5 males, mean age 9.24 [+/-5.29] years); n=15 individuals with PHTS (6 females, 9 males, mean age 9.42 [+/-5.77] years); and n=6 individuals with TSC (3 females, 3 males, mean age 9.49 [+/-1.93] years) who were part of the analysis.

For the PMS group, there was a trend for increasing Vineland Adaptive Behavior Scales (VABS) composite score with increasing relative volume of cerebellar vermal lobules I-V (p=0.074) and cerebellar vermal lobules VI-VII (p=0.068). For the PHTS group, there was a trend for increasing Stanford Binet-5 full scale IQ with increasing relative volume of left cerebellum white matter (p=0.095). For the TSC group, with increasing VABS composite score there was increasing relative volume of the cerebellar vermal lobules VI-VII (p=0.029).

Conclusions:

Based on volumetric analysis, the cerebellum may be affected in three different genetic causes of ASD and ID, warranting further investigation into cerebellar circuitry defects in the pathogenesis of ASD/ID.