Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis is an autosomal recessive bile acid synthesis disorder (CYP27A1) that causes cholestanol accumulation, with chronic diarrhoea in childhood, juvenile cataracts, tendon xanthomas, and progressive neurological disease. It is treatable, and diagnosis is often delayed by 15 to 20 years. Prevalence is about 1 in 50,000 to 1 in 100,000.

Pathophysiology. Deficient sterol 27-hydroxylase prevents production of chenodeoxycholic acid, so there is no negative feedback and toxic bile alcohol and cholestanol accumulate in tendons, brain and lens.

Infantile cholestasis or chronic diarrhoea, bilateral juvenile cataracts, tendon xanthomas (Achilles, extensor tendons of hands), premature atherosclerosis and osteoporosis. Neurology: cerebellar ataxia, spastic paraparesis, cognitive decline or intellectual disability, seizures, parkinsonism, psychiatric disease and peripheral neuropathy. Neurological features appear from the second to third decade.

Red flags.

• Unexplained juvenile cataracts or chronic diarrhoea with ataxia.
• Tendon swellings with neurological decline.

Serum cholestanol raised (key test), with normal or low cholesterol, and raised urinary bile alcohols. Genetic testing of CYP27A1 confirms the diagnosis. MRI shows T2 hyperintensity of dentate nuclei and cerebellar white matter, cerebral atrophy and spinal cord lesions. Tendon imaging, bone density, lipid profile, ophthalmology and nerve conduction studies.

Differential diagnosis.

• Familial hypercholesterolaemia and sitosterolaemia (xanthomas).
• Hereditary spastic paraplegia, spinocerebellar ataxia and Friedreich ataxia.
• Multiple sclerosis, adrenoleukodystrophy and mitochondrial disease.

Start early, since treatment can prevent or stabilise the neurological disease.

Chenodeoxycholic acid. Adults 250 mg orally three times daily (750 mg daily); children 5 mg/kg three times daily. Monitor liver function tests, cholestanol and bile alcohols. Hepatotoxicity is a risk.

Additional. Statins (such as atorvastatin 20 to 40 mg daily) may be combined with chenodeoxycholic acid for cholestanol reduction, with monitoring of muscle and liver function.

Cataract surgery and ophthalmology. Treat cataracts.

Neurological symptoms. Spasticity (baclofen), seizures (levetiracetam), parkinsonism and rehabilitation.

Bone health. Calcium, vitamin D and assessment for osteoporosis.

Cardiovascular risk. Manage lipids and vascular risk factors.

Monitoring. Cholestanol, liver tests, neurological examination and imaging yearly.

Referral and escalation. Refer to metabolic and neurology services and genetics.

Special groups. Chenodeoxycholic acid is avoided in pregnancy unless clearly needed. Offer genetic counselling to siblings.