Clinical Information

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis resulting from the deficiency of the mitochondrial enzyme, sterol 27-hydrolase. Sterol 27-hydrolase facilitates the first step of sterol degradation in the formation of bile acids; consequently, patients with CTX will experience increased storage of the sterol, cholestenol, and ketosterol bile acid precursors (7-alpha-hydroxy-4-cholesten-3-one [7a-C4] and 7-alpha,12 alpha–dihydroxycholest-4-en-3-one (7a12aC4)) in multiple tissues throughout the body with a resulting deficiency of the bile acid, chenodeoxycholic acid (CDCA). CTX is caused by variants in the CYP27A1 gene.

Patients with CTX can present with a constellation of findings, including infantile onset diarrhea, childhood onset cataracts, development of tendon/cerebral xanthomas in adolescence and early adulthood, early onset osteoporosis, as well as a broad array of neuropsychological manifestations, such as intellectual disability, dementia, psychiatric symptoms, ataxia, pyramidal signs, dystonia, and muscle weakness. Patients may occasionally present with cholestatic liver disease, which may present as jaundice, poor growth, and hepatosplenomegaly. Intrafamilial variability exists, and some heterozygous carriers may experience a higher incidence of cardiac disorders or gallstones. Treatment with CDCA normalizes bile acid synthesis and suppresses cholestenol biosynthesis, with improvement of clinical symptoms and arrest of disease progression. However, more recently, cholic acid has been proposed as an alternative treatment for adults with CTX. Supplementation with beta-hydroxy beta-methylglutaryl-CoA inhibitors and coenzyme Q10 has also been proposed. The availability of effective therapy makes early diagnosis and treatment of patients with CTX essential.

The estimated incidence of CTX is 1 in 50,000 individuals of Northern European ancestry and as high as 1 in 440 in the Druze population of Israel.

The diagnostic evaluation of patients with suspected CTX may reveal abnormalities on brain magnetic resonance imaging (eg, cerebellar atrophy, decrease in volume of grey and white matter, and abnormal white matter signal) in addition to the biochemical and clinical abnormalities. The biochemical diagnosis of CTX can be confirmed by molecular genetic analysis of the CYP27A1 gene (included in CHLGP / Cholestasis Gene Panel, Varies; or order CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies and indicate the gene to be assessed).