The important role of plasma cholestanol and 7α-hydroxycholesterol as biomarkers in cerebrotendinous xanthomatosis (CTX): long-term course in 5 patients

Background and Aims Cerebrotendinous xanthomatosis (CTX, OMIM #231700) is a rare autosomal-recessive bile acid disease due to defective mitochondrial sterol 27-hydroxylase CYP27A1, leading to tendon xanthomas, bilateral cataracts, diarrhea and progressive neurologic manifestations. Patients are usually diagnosed during adulthood. The combination of neurologic disturbances, cataracts, ataxia, diarrhea and tendon xanthomata mandates immediate determination of blood cholestanol and 7α-hydroxycholesterol levels. Oral therapy with CDCA, a bile acid, reverses symptoms, prolongs life span and can be continued throughout pregnancy.

Methods CTX patients were monitored in 6-month intervals with abdominal ultrasound, cMR imaging, ophthalmologic examinations and determination of biomarkers. Therapy with CDCA (10-15 mg/kg body wt.) was initiated plus individual lipid-lowering combination therapy and in one pregnant female patient, CDCA was continued throughout and monitoring intervals were shortened.

Results Three siblings, their mother and aunt from a consanginous family were diagnosed with CTX at ages of 38, 27, 18, 14, and 9 respectively. The aunt was diagnosed in 1997, the mother in 2003 and the siblings in 2005. At baseline, tendinous xanthomas were present in 4/5, diarrhea and ataxia in 1/5, hypercholesterolemia and hypertriglyceridemia in all patients. 3/5 patients suffered from cataracts requiring surgical therapy. Slight mental impairment was present in 4/5 patients. Mean follow-up in this cohort was 18±2 years. Ataxia and diarrhea subsided. At latest time point examined, total cholesterol (TC), LDL-C and HDL-C were with 195±7mg/dl, 115±12 mg/dl and 53 mg/dl± 6 mg/dl, respectively, in an acceptable range, although adherence to lipid-lowering drugs was suboptimal. Pretherapeutic cholestanol levels and 7α-hydroxycholesterol were 3,1±0,2 mg/dl (ref.0,2-0,7mg/dl) and 3857±802 ng/ml (ref.< 0,5ng/ml) and decreased to 0,3±0,02mg/dl and 76±10ng/dl. A clinically stable CTX female gave birth to a healthy boy in term after uncomplicated pregnancy. The child's development was age-appropriate and unremarkable so far.

Conclusion Oral CDCA therapy can help stabilize the control clinical symptoms of CTX and successfully be continued during pregnancy. Apart from Wilson’s disease, CTX should be suspected in adult dyslipidemic patients with heterogeneous neurologic manifestations, diarrhea and cataracts. Determination of cholestanol and 7α-hydroxycholesterol are crucial.

Publication History

Article published online:
19 August 2022