Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy.

Cerebrotendinous xanthomatosis (CTX) is a rare treatable bile acid disorder caused by homozygous or compound heterozygous variants in CYP27A, a gene that encodes the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1). CYP27A1 facilitates the production of both cholic acid (CA) and chenodeoxycholic acid (CDCA). Deficiencies in CYP27A1 limit the production of both CA and CDCA, leading to multisystemic cholestanol deposition in membranes, including those of neurons, smooth muscle cells, tendons, and the eye. Because of increased concentrations of cholestanol, a byproduct of cholesterol metabolism, in the brain, cognitive decline develops as a hallmark of CTX. First-line treatment approaches for CTX include off-label prescribed CDCA to reduce serum cholestanol levels. Despite its effectiveness, the success of CDCA administration relies on early diagnosis and low disability scores at the time of initiation. Administration when neurological symptoms arise late in the diagnostic process can lead to worse outcomes, including higher mortality. US Food & Drug Administration-approved CA represents an alternative treatment for CTX. CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine. Importantly, outcomes with CA therapy are indistinguishable from those mediated by CDCA therapy and are associated with significantly fewer adverse effects. CA is used as an alternative therapy in patients who cannot tolerate CDCA due to its negative effects. Data from studies on CA strongly support the improvement of liver function, which is likely to be at the crux of secondary pathology, including neurological dysfunction. Because no consensus has been published on the treatment of CTX, Stelten et al (Orphanet J Rare Dis 16:353, 2021) a need exists for a direct comparison of the two approaches.