Genetics of Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is rare, autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in CYP27A1, which encodes sterile 27 hydroxylase, a key enzyme in bile acid biosynthesis. Enzyme deficiency results in reduced cholic and chenodeoxycholic acid synthesis with accumulation of cholestanol, bile acid intermediates, and bile alcohols, producing a progressive multisystem disorder characterized by chronic diarrhea, juvenile-onset cataracts, tendons xanthomas, and neurological dysfunction. Although CTX typically begins in childhood, diagnosis is frequently delayed until adulthood, limiting the benefit of effective disease modifying therapy with chenodeoxycholic acid. Since the identification of CYP27A1, more than 200 pathogenic variants have been reported, including canonical loss of function alleles and missense variants with variable residual enzyme activity. In this review, we summarize the medical genetics, population genetics and genotype phenotype relationships of CTX. We highlight insights from large population databases that refine global incidence estimates, revealing population-specific enrichment of pathogenic variants and persistent underdiagnosis. We further review functional and clinical data demonstrating that stratification of CYP27A1 variants by functional effect, complete loss of function versus hypomorph alleles, correlates with clinical severity and biochemical phenotype. Finally, we discuss emerging advances in biochemical testing and newborn screening strategies that offer the potential for presymptomatic diagnosis, enabling timely initiation of therapy and prevention of irreversible disease manifestations. Integrating molecular, functional, and population genetic data provides a framework for improved variant interpretation, earlier diagnosis, and optimized therapeutic intervention in CTX.