Cerebellar volume as an imaging marker of development in infants with tuberous sclerosis complex

Objective In this cohort analysis, we studied 1-year-old infants with tuberous sclerosis complex (TSC), correlating volumes of cerebellar structures with neurodevelopmental measures. Methods We analyzed data from a prospective biomarker study in infants with TSC (ClinicalTrials.gov NCT01780441). We included participants aged 12 months with an identified mutation of TSC1 or TSC2. Using MRI segmentation performed with the PSTAPLE algorithm, we measured relative volumes (structure volume divided by intracranial contents volume) of the following structures: right/left cerebellar white matter, right/left cerebellar exterior, vermal lobules I-V, vermal lobules VI-VII, and vermal lobules VIII-X. We correlated relative volumes to Mullen Scales of Early Learning (MSEL) scores. Results There were 70 participants (mean age 1.03 [0.11] years): n = 11 had a TSC1 mutation; n = 59 had a TSC2 mutation. For patients with TSC2 mutation, for every percentage increase in total cerebellar volume, there was an approximate 10-point increase in MSEL composite score (beta = 10.47 [95% confidence interval 5.67, 15.27], p < 0.001). For patients with TSC1 mutation, the relationship between cerebellar volume and MSEL composite score was not statistically significant (beta = -10.88 [95% confidence interval -22.16, 0.41], p = 0.06). For patients with TSC2 mutation, there were positive slopes when regressing expressive language and visual reception skills with volumes of nearly all cerebellar structures (p <= 0.29); there were also positive slopes when regressing receptive language skills, gross motor skills, and fine motor skills with volumes of cerebellar right/left exterior (p <= 0.014). Conclusions Cerebellar volume loss-perhaps reflecting Purkinje cell degeneration-may predict neurodevelopmental severity in patients with TSC2 mutations.