Plasma sterol profiling in autism spectrum disorder: insights from cerebrotendinous xanthomatosis screening and beyond.

Cerebrotendinous xanthomatosis (CTX) is a rare, treatable bile acid synthesis disorder characterized by increased levels of cholestanol. Studies indicate that autism spectrum disorder (ASD) may be an early manifestation of CTX. Independent of CTX, disturbances in sterol and bile acid metabolism are observed in ASD. Therefore, this study aimed to estimate the prevalence of CTX in a pediatric ASD cohort using cholestanol-based screening with reflex CYP27A1 sequencing and to compare plasma sterol profiles among children with ASD. We conducted a single-center, cross-sectional study including 103 patients with ASD and 70 age-matched, normally developed children. Fasting plasma cholestanol, campesterol, stigmasterol and sitosterol were quantified by gas chromatography/mass spectrometry. Participants with cholestanol ≥ 7 µg/ml underwent CYP27A1 sequencing, and five-day dietary recalls were analyzed in 75 ASD participants. Elevated cholestanol was observed in 27 of 103 patients with ASD (26.2%) but in none of the controls (p < 0.001). No participant had biallelic pathogenic CYP27A1 variants; one heterozygous variant of uncertain significance was detected. Median concentrations of cholestanol, campesterol, sitosterol and stigmasterol were significantly higher in patients with ASD than in controls (all p ≤ 0.001), and sterol fractions were strongly correlated (cholestanol–campesterol r = 0.74, p < 0.001). In summary, no cases of CTX were identified in this cohort, suggesting that cholestanol-based screening in unselected ASD populations may have limited yield, particularly in the absence of additional clinical features suggestive of CTX. Nevertheless, the elevated plasma sterol levels in ASD patients suggest dysregulated sterol and bile acid homeostasis, warranting further investigation.