Clinical characteristics: Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young 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 and/or neonatal cholestasis may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas 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 early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the third decade in more than 50% 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.
The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased chenodeoxycholic acid (CDCA), increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid.
Diagnosis/testing: The diagnosis of CTX is established in a proband with suggestive findings and biallelic pathogenic variants in CYP27A1 identified on molecular genetic testing.
Management: Treatment of manifestations: Long-term treatment with CDCA normalizes plasma and CSF concentration of cholestanol and improves neurophysiologic findings. Inhibitors of HMG-CoA reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle damage. Cholic acid treatment decreases cholestanol levels and improves neurologic symptoms in the few individuals in whom it has been tried and may be useful in those who experience side effects with CDCA treatments. Cataract extraction is typically required in at least one eye by age 50 years. Epilepsy, spasticity, and parkinsonism are treated symptomatically.
Prevention of primary manifestations: Early treatment with CDCA in presymptomatic individuals appears to prevent clinical manifestations.
Surveillance: Annual cholestanol plasma concentration, neurologic and neuropsychological evaluation, brain MRI, echocardiogram, and assessment of bone density.
Agents/circumstances to avoid: Caution has been suggested with statins.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of CDCA treatment and surveillance.
Pregnancy management: Treatment with CDCA should not be interrupted during pregnancy.
Genetic counseling: CTX is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CYP27A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible if both CYP27A1 pathogenic variants in the family are known.
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