Cerebrotendinous xanthomatosis (NORD)

Cerebro refers to the brain, tendinous refers to the tendons, and xanthoma refers to fatty deposits.

Cerebrotendinous xanthomatosis, also called CTX, is a rare genetic disorder caused by alterations in the CYP27A1 gene that adversely affect the body’s ability to convert cholesterol to the bile acids chenodeoxycholic acid and cholic acid.

This results in the accumulation of abnormal disease-causing compounds and leads to fatty deposits, or xanthomas, in the brain and tendons as well as other parts of the body.

The symptoms and progression of CTX may differ greatly from person-to-person with symptoms that can range from mild to severe and that can appear from infancy through adulthood.

Among infants, the disease may first present as chronic diarrhea that remains unchanged despite treatment, or as seizures, often called infantile spasms.

Infants with CTX may develop cholestatic liver disease where bile can stagnate in the liver, causing symptoms such as jaundice, and liver enlargement.

Another symptom in children may include juvenile cataracts that can manifest as difficulty following objects with the eyes, eyes pointing in different directions, or cloudiness over the eye’s lens.

Neurological symptoms can appear in childhood or later in life and may include cognitive impairment such as difficulty with memory, concentration, and reasoning.

Other symptoms may include epilepsy and spasticity, causing difficulties in movement and speech.

Adolescents may display behavioral changes such as agitation, aggression, and depression and may also experience hallucinations and suicidal thoughts.

In early adulthood, tendinous xanthomas may appear where fatty bumps or nodules form around the elbows, hands, knees, and heels.

If the disease remains untreated and continues to progress, affected individuals may become wheelchair bound and continued neurological decline may lead to early dementia.

CTX is also linked to atherosclerosis, osteoporosis, and hypothyroidism which present as fatigue, sensitivity to cold, weight gain, and thinning hair.

CTX is a genetic disorder caused by disease-causing genetic alterations, or pathogenic variants, in the CYP27A1 gene.

This results in a lack of sterol 27-hydroxylase, an enzyme that facilitates the removal of cholesterol from the body through its conversion into the bile acids, chenodeoxycholic and cholic acid.

The substances formed from cholesterol in the production of bile acids, known as bile acid pathway intermediates, remain unused in patients with CTX and accumulate, along with compounds called cholestanol and bile alcohols.

CTX is inherited in an autosomal recessive pattern so a child must inherit a pathogenic variant in the CYP27A1 gene from both parents, who are carriers, in order to be affected.

Parents who are carriers have one normal CYP27A1 gene and one pathogenic CYP27A1 gene variant, and have a 25% chance to have an affected child with another carrier, regardless of whether the child is male or female.

Diagnosis begins with an assessment of the individual’s medical history and includes genetic and biochemical testing for confirmation of disease.