Cerebrotendinous xanthomatosis (NORD)
Definitions & Key takeaways
Cerebrotendinous xanthomatosis (CTX) is a rare genetic lipid storage disease that is characterized by abnormally high cholestanol levels in the blood. It causes cholesterol to accumulate in the brain, tendons, eyes, arteries, and other organs, causing health problems. Symptoms of CTX depend on affected organs, but usually include progressive neurologic deterioration, seizures, intellectual disability, decreased muscle strength, joint pain and swelling (arthritis), yellowing of the skin and whites of the eyes (xanthomas), and cataracts.
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.
Infants with CTX may develop cholestatic liver disease where bile can stagnate in the liver, causing symptoms such as jaundice, and liver enlargement.
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.
Genetic testing identifies pathogenic variants in the CYP27A1 gene and biochemical testing confirms a lack of sterol 27-hydroxylase activity.
The biochemical testing typically shows normal to low blood cholesterol levels and little to no chenodeoxycholic acid and cholic acid.
BiIle alcohols are also present at high concentrations in the urine. Imaging tests may also be used to determine disease progression and can include computerized tomography, CT, or magnetic resonance imaging, MRI, of the brain.Effective treatment for CTX optimally requires early diagnosis and treatment to prevent lasting complications.
Treatment at any stage can be helpful to stop disease progression but it generally cannot reverse any existing neurological damage.
Treatment involves oral bile acid replacement therapy. Chenodeoxycholic acid is the first-line therapy as it helps normalize the levels of cholestanol, bile acid intermediates and bile alcohols.Cholic acid may also be considered for children as it can be less toxic for the liver than chenodeoxycholic acid.
Genetic counseling is recommended to help families understand the genetics and natural history of CTX and to provide psychosocial support.As a quick recap, cerebrotendinous xanthomatosis, or CTX, is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27A1 gene.
Symptoms and disease progression vary greatly, and can present as chronic diarrhea, cholestatic liver disease or infantile spasms in infants, developmental delay and cataracts in childhood, and cognitive impairment, seizures, tremors, spasticity, xanthomas, atherosclerosis, osteoporosis, and hypothyroidism later in life.
CTX affects the conversion of cholesterol into bile acids, resulting in little to no bile acids and high levels of cholestanol, bile acid intermediates and bile alcohols.
Diagnosis involves a thorough clinical examination, and genetic and biochemical confirmation of disease. A CT scan or MRI of the brain may be necessary to determine disease progression.
Effective treatment for CTX optimally requires early diagnosis and treatment to prevent lasting complications. Treatment at any stage can be helpful to stop disease progression although it generally cannot reverse any existing neurological damage.Treatment includes long-term oral bile acid replacement therapy, with chenodeoxycholic acid as the first-line therapy.
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