Cerebrotendinous Xanthomatosis (CTX) is a rare genetic metabolic disorder of cholesterol and bile acid metabolism results in systemic and neurological abnormalities. More than 300 patients have been diagnosed worldwide, with an estimated prevalence of 1 case per 50,000 individuals in white population.1
CTX is caused by mutations in the CYP27A1 gene, which provides instructions for producing sterol 27-hydroxylase, an enzyme that breaks down cholesterol into primary bile acids, cholic acid and chenodeoxycholic acid (CDCA). The lack of this enzyme causes a deficiency of primary bile acids, especially CDCA. CTX patients have high levels of cholestanol, which is an abnormal lipid that accumulates in the tissues and can be measured in the blood. Atypical bile alcohols can also be found in patients’ urine.
The typical CTX symptoms includes: infantile jaundice, infantile-onset diarrhea, childhood-onset cataract, adolescent- to adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures).
Chronic diarrhea from infancy may be the earliest clinical manifestation and cataracts are early finding, often appearing in the first decade of life. Xanthomas usually appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show cognitive impairment from childhood, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the 20s in more than 50 percent of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years.2 People with CTX are also at an increased risk of developing cardiovascular disease or respiratory failure because of lipid accumulation in the heart or lungs, respectively.3
The diagnosis of CTX is established in patients with the above clinical and biochemical findings and/or by the identification of balletic pathogenic variants in CYP27A1. Left untreated, CTX is a progressive and terminal disease, with signs and symptoms worsening over time, and life expectancy into the 40s or 50s, although confirmed deaths have been reported as early as 4 months of age.1
Long-term replacement with the deficient primary bile acid is reported to normalize the increased production of atypical metabolites. Although the presentation and course vary widely, treatment can dramatically alter the natural history, especially with early initiation.1