Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey.

BACKGROUND AND
PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the CYP27A1 gene resulting in sterol-27-hydroxylase deficiency. Current information about CTX is based mainly on case reports, with only few large series reported. Although perceived as a potentially treatable condition, efficacy of chenodeoxycholic acid plus statin therapy remains unclear. To perform a nationwide survey of confirmed cases, with a thorough analysis of genotype-phenotype data and prognostic factors.
METHODS: Retrospective review of the clinical and epidemiological aspects and mutations of all the patients diagnosed since 1992 in the main reference centers for genetic testing of CTX in Spain.
RESULTS: Twenty-five patients from 19 families were identified. An average delay of 19 years was observed between symptom onset and clinical diagnosis. Two main clinical subgroups were recognizable: a classic form (cerebellar and other supratentorial symptoms) and a spinal form (chronic myelopathy). Cholestanol levels did not correlate with clinical presentation, severity or response to therapy. Despite treatment, five patients died during follow-up, one to 4 years after diagnosis. Thirteen different mutations were identified, with a higher frequency of p.R395C in Northwestern Spain and p.R405W in Southern Spain. None of the mutations could be associated with a particular clinical feature combination or prognosis.
CONCLUSIONS: This is the first nationwide extensive series of CTX reported in Spain. The higher number of cases in some areas suggests a possible founder effect. Spinal forms had a less severe prognosis. A delayed diagnosis could contribute to the lack of significant response to treatment.