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Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by biallelic pathogenic variants in CYP27A1, encoding mitochondrial sterol 27-hydroxylase. Affected individuals exhibit progressive neurological dysfunction, premature atherosclerosis, tendon xanthomas, chronic diarrhea, and juvenile cataracts. Early molecular diagnosis enables presymptomatic detection and treatment, significantly altering clinical outcomes.
Genetic evidence for the CYP27A1–CTX association includes over 50 distinct alleles reported across diverse populations, comprising missense, nonsense, frameshift, splice-site, and deep-intronic variants. Founder mutations such as c.355del (p.Arg119fs) in Druze families and c.379C>T (p.Arg127Trp) in Moroccan Jews underlie multiple pedigrees (PMID:7977352, PMID:8014582). In a Japanese family, the variant c.410G>C (p.Arg137Pro) was homozygous in two siblings with CTX and absent in unaffected heterozygotes, confirming its pathogenicity (PMID:8006521).
Segregation analysis across unrelated pedigrees demonstrates that homozygosity or compound heterozygosity for CYP27A1 variants co-segregates with CTX, while heterozygous carriers remain asymptomatic or exhibit only mild hypercholesterolemia. In the Druze cohort, 10 homozygotes and 28 heterozygotes were identified, with clinical progression correlating with age and genotype (PMID:7977352).
Functional studies of CYP27A1 variants reveal severe loss of enzyme activity. Expression of p.Arg137Pro and other missense mutants in COS-1 or HEK293 cells results in <5% residual 27-hydroxylase activity and alternative splicing at cryptic sites for splice-region mutations. Mouse knockout models and cellular assays further confirm that deficient CYP27A1 leads to cholestanol accumulation and impaired bile acid synthesis (PMID:9790667, PMID:8728324).
Clinically, CTX patients present with tendon xanthomas (HP:0010874), juvenile cataracts (HP:0000518), progressive ataxia (HP:0001251), peripheral neuropathy (HP:0009830), EEG abnormalities (HP:0002353), and premature atherosclerosis (HP:0002621). Magnetic resonance imaging shows diffuse white matter changes and dentate nucleus hyperintensities. Biochemical hallmarks include elevated plasma cholestanol and bile alcohols with reduced 27-hydroxycholesterol.
Integration of genetic and functional data supports a Strong gene–disease validity by ClinGen criteria, with a Strong genetic evidence score and Moderate functional evidence. Early diagnosis and chenodeoxycholic acid therapy can normalize biochemical markers, prevent neurological deterioration, and improve cognitive and motor function. Key take-home: CYP27A1 testing should be considered in any child or adult with xanthomas, cataracts, or neurodegeneration given the treatable nature of CTX.
Gene–Disease AssociationStrongMultiple probands (>10) across diverse families with consistent segregation and functional concordance Genetic EvidenceStrongBiallelic pathogenic variants in >50 patients, including >20 missense/LoF alleles, reaching genetic cap Functional EvidenceModerateFunctional assays demonstrate <5% residual enzyme activity in mutant CYP27A1 and lipid accumulation in cellular models |