Genet Med. 2025 Apr 25:101449. doi: 10.1016/j.gim.2025.101449. Online ahead of print.
ABSTRACT
BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in CYP27A1 resulting in sterol 27-hydroxylase deficiency and accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, diarrhea, cataracts, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The effects of CDCA withdrawal on CTX biomarkers and safety in adult patients were evaluated.
MATERIALS AND METHODS: Patients (≥16 years) received CDCA 750 mg/day for two 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for two 4-week periods. Key endpoints included changes from baseline in CTX biomarkers (23S-pentol, cholestanol, 7αC4, 7α12αC4) and the proportion of patients requiring CDCA rescue during DB periods.
RESULTS: CDCA withdrawal resulted in a 20-fold increase in 23S-pentol, and increases in cholestanol (2.8-fold), 7αC4 (50-fold) and 7α12αC4 (14-fold). During the DB withdrawal periods, 61% of participants on placebo required rescue medication. CDCA treatment was well tolerated; the most common treatment-emergent adverse events were diarrhea and headache, most mild/moderate in severity and not considered treatment-related.
CONCLUSIONS: CDCA withdrawal caused statistically significant increases in CTX biomarkers and necessitated rescue therapy in most participants. CDCA treatment is critical for control of biochemical abnormalities and helps avoid disease progression.
PMID:40297984 | DOI:10.1016/j.gim.2025.101449
