To describe a case of atypical cerebrotendinous xanthomatosis and discuss diagnostic implications.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid metabolism disorder resulting from mutations in the CYP27A1 gene. Abnormal build-up of lipids in the brain and/or spinal cord may lead to ataxia, hyperreflexia, spasticity, and gait difficulty plus xanthomas, cognitive impairment, gastrointestinal issues, and premature cataracts. Classically, elevated serum cholestanol level (up to 4-5x the normal limit) has served as the primary biomarker for diagnosis. We present a case with phenotypic CTX findings and novel variants of unknown significance (VUS) but normal cholestanol levels.

A 61 year-old Colombian woman presented for evaluation of gait disorder. She had a history of bilateral Achilles tendon xanthomas since adolescence, hyperlipidemia, and bilateral cataracts. 2 of her 3 sisters also developed xanthomas in young adulthood. Exam was significant for appendicular ataxia plus tremor and mild choreiform movements at the hands. She was also noted to have hyperreflexia with bilateral non-sustained clonus, positive cross-adductors, and positive Hoffman’s sign. She had ataxic gait and was unable to tandem. MRI brain revealed pan-cerebellar atrophy, worse at the level of the vermis. MRI spine showed abnormal T2 signal at the anterolateral cord from C4-T1. Genetic testing was significant for novel autosomal recessive, homozygous VUS at the CYP27A gene (c.248 A>C p.Q83P). In silico analysis suggests pathogenicity. Cholestanol levels were unremarkable at 3.11mg/dL (normal range: 0.86-3.71) despite never receiving treatment.

Our case aligns with a series of reports describing individuals with a CTX phenotype and confirmed homozygous CYP27A1 variants despite normal cholestanol levels. Other biomarkers such as cholesterol precursors, chenodeoxycholic acid, and bile acid pathway intermediates may serve as more sensitive tools for diagnosis. It remains unclear whether standard treatment with chenodeoxycholic acid is beneficial for this subset.