Juvenile-Onset Cerebrotendinous Xanthomatosis with Novel Compound Heterozygous CYP27A1 Mutations: Case Series and...

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disorder characterized by multisystem involvement and marked clinical heterogeneity. Pathogenic variants in the CYP27A1 gene, encoding mitochondrial sterol-27-hydroxylase, disrupt bile acid synthesis, leading to pathological accumulation of cholestanol in neural tissues, tendons, and other organs. This study aimed to characterize two novel CTX cases with compound heterozygous variants in the CYP27A1 gene through integrated clinical-genetic analysis, and to systematically synthesize current evidence on CTX through a literature review. Molecular investigations employed a tiered sequencing strategy: whole-exome sequencing (WES) for variant discovery, third-generation sequencing for variant screening of WES-negative samples, and Sanger sequencing for familial segregation validation. We present two Chinese juvenile-onset CTX cases demonstrating characteristic multisystem involvement, including both extraneural manifestations and progressive neurological deterioration. Genetic investigations revealed three CYP27A1 variants: the previously unreported c.845 - 46_881del83, the splicing variant c.1477-2 A > C, and a novel nonsense variant c.487 C > T in exon 3. Both probands exhibited compound heterozygosity, sharing the c.845 - 46_881del83 variant alongside distinct second alleles (c.1477-2 A > C and c.487 C > T, respectively). Then, a literature review synthesizes current evidence on clinical manifestations, genotypic patterns, and therapeutic approaches in CTX. This study expands the CYP27A1 mutational spectrum with two novel variants and validates the diagnostic utility of long-read sequencing (LRS) in resolving complex autosomal recessive cerebellar ataxia (ARCA) cases. The synthesis of clinical and literature evidence underscores the need for early recognition of CTX's heterogeneous presentations.