What is Cerebrotendinous Xanthomatosis (CTX)
CTX is a very rare disorder (with an incidence estimated to be 1 per million individuals worldwide) characterized by abnormal storage of fats (lipids) in many areas of the body. People with this disorder cannot break down certain lipids effectively, specifically different forms of cholesterol, so these fats (cholestenol) accumulate in the body in the form of fatty yellow nodules called xanthomas. These xanthomas are most commonly found in the brain and in connective tissue called tendons that attach muscle to bone, which is reflected in the condition name (cerebro- meaning brain and -tendinous referring to tendons).
Left untreated, CTX is a progressive and terminal disease, with signs and symptoms worsening over time, and life expectancy reduced to the 40s, although confirmed deaths have been reported as early as 4 months of age.
What are the Symptoms of CTX?
Symptoms and age of onset vary widely depending on when and where these deposits form, but can include:
- Chronic diarrhea (infancy)
- Cataracts (early childhood)
- Impaired speech (dysarthria)
- Loss of sensation in the arms and legs (peripheral neuropathy)
- Xanthomas (early adulthood)
- Dementia with deterioration in intellectual abilities (Starting in infancy)
- Spasticity (early adulthood)
- Cerebellar signs such as
- Intention tremor
- Difficulty with fast hand movements
- Truncal ataxia
- Brittle bones that are prone to fracture (osteoporosis) (early adulthood)
- Increased risk of developing heart or lung failure because of lipid buildup (early adulthood)
- Behavioral changes (puberty or early adulthood)
- Hallucinations (early adulthood)
- Agitation (early adulthood)
- Aggression (early adulthood)
- Depression (early adulthood)
- Suicide attempt (early adulthood)
What is the Cause?
Mutations in the CYP27A1 gene cause Cerebrotendinous Xanthomatosis. The CYP27A1 gene provides instructions for producing an enzyme called sterol 27-hydroxylase. This enzyme works in the pathway that breaks down cholesterol to form acids used in the digestion of fats (bile acids), specifically a bile acid called chenodeoxycholic acid.
How is CTX Diagnosed?
Though an increase in the use of genetic testing has recently increased the number of known patients, patients with CTX still have an average age of 35 years at the time of diagnosis and a diagnostic delay of approximately 16 years. The sometimes vague and broad range of symptoms make it very hard to diagnose in a timely manner.
What is the Treatment for CTX?
CTX is one of the few leukodystrophies with an available treatment! Once a patient is diagnosed, they will typically obtain baseline testing of their cholestenol levels and start receiving treatment with CDCA (chenodeoxycholic acid).
In 2009, the U.S. Food and Drug Administration (FDA) re-approved an artificially made (synthetic) form of chenodeoxycholic acid (CDCA) known as Chenodal® and received an orphan drug designation from the FDA for the treatment of CTX in the U.S. Chenodal is manufactured by Retrophin.
Cholic acid, another bile acid, has also been used to treat young children with CTX. However, cholic acid is generally not as effective as chenodeoxycholic acid, but does lack the potential toxic effects on the liver (hepatotoxicity) sometimes associated with chenodeoxycholic acid.
Early diagnosis and treatment of CTX is critical for those affected by the disorder. In general, the later the onset of treatment, the less benefit there is to treatment. Because of this, and the large delay in diagnosis, many involved with CTX believe strongly in newborn screening and are currently working hard to pursue CTX’s addition to the RUSP.