Cerebrotendinous Xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid

Abstract

Background Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurometabolic disorder of lipid storage and bile acid synthesis. Whilst CTX is said to present with the classic triad of juvenile onset cataracts, tendon xanthomata and progressive ataxia, the diversity of presentation can be such that the diagnosis may be substantially delayed resulting in permanent neurological disability. Methods A retrospective review of the clinical characteristics and imaging findings of 4 patients with CTX presenting to the Sheffield Ataxia Centre over a period of 25 years. Results Although CTX-related symptoms were present from childhood, the median age at diagnosis was 39 years. Only 1 of the 4 cases had tendon xanthomata, only 2 cases had juvenile onset cataracts and 3 had progressive ataxia with one patient presenting with spastic paraparesis. Serum cholestanol was elevated in all 4 patients, proving to be a reliable diagnostic tool. In addition, cholestanol was raised in the CSF of 2 patients who underwent lumbar puncture. Despite treatment with chenodeoxycholic acid (CDCA) and normalization of serum cholestanol, CSF cholestanol remained high in one patient, necessitating increase in the dose of CDCA. Further adjustments to the dose of CDCA in the patient with raised CSF cholestanol resulted in slowing of progression. Two of the patients who have had the disease for the longest continued to progress, one subsequently dying from pneumonia. Conclusion A high index of suspicion for CTX, even in the absence of the classical triad is essential in reaching such diagnosis. The earlier the diagnosis and treatment, the better the outcome.

First case series of Polish patients with cerebrotendinous xanthomatosis and systematic review of cases from the 21st century

“…87 MRI of the spinal cord was performed (or reported) in only 26 cases, with 18/27 of them showing T2-weighted hyperintense lesions. 28,34,38,41,42,46,50,51,57,58,70,71,72,96,144,171 Additionally, Patient 6, reported by us, presented multiple hyperintense T2-weighted changes in the posterior spinal cord C-Th regions. Furthermore, multiple nodular thickening of the nerve roots and trunks of the lumbosacral plexus was described on MRI neurography.…”

Cerebrotendinous Xanthomatosis: Report of Two Siblings With the Same Mutation but Variable Presentation

“…The actual cause of CTX-induced brain injury is unknown. A high quantity of cholestanol in brain tissue is considered to activate apoptotic pathways, resulting in neuronal death [ 6 ].…”

Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment

“…Plasma cholestanol level assessment is indicated in patients with Mignarri scores ≥100. With previous high levels of plasma cholestanol or a Mignarri score ≥200 (including at least 1 "very strong indicator" or 4 "strong indicator"), there is a formal indication for genetic analysis of CYP27A1 gene (2,37,39,40). The clinical use of the Mignarri score should not limit the early investigation of patients with clinical features highly suggestive of CTX diagnosis (i.e., juvenile cataracts, childhoodonset chronic diarrhea), even in the absence of score values higher than 100 or 200 points or other clinical signs.…”

“…CTX is caused by bi-allelic pathogenic variants in CYP27A1 (2q35), which codes sterol 27-hydroxylase, a mitochondrial enzyme of cytochrome P450 oxidase system. Reduction of the activity of this enzyme leads to increased formation and storage of abnormal lipid content in several tissues, especially tendons, lenses and peripheral, and central nervous system (2).…”