Cerebrotendinous Xanthomatosis (CTX)

What happens in Cerebrotendinous Xanthomatosis?

Cerebrotendinous xanthomatosis (CTX) is a rare inherited  disorder that causes the body to not be able to break down cholesterol. This leads to a buildup of cholesterol and a related product, cholestanol, in the nervous system and other organ systems. CTX has many clinical symptoms.

CTX is caused by a mutation (change) in the CYP27A1 gene. The CYP27A1 gene modifies an enzyme that is responsible for bile acid synthesis. This enzyme coverts cholesterol into bile acids. The mutation caused by CTX leads to decreased conversion of cholesterol into bile acids. The cholesterol becomes cholestanol, which builds up in the body , especially in the brain, tendons, eyes, and arteries. 
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What are the Symptoms of CTX?

CTX symptoms can be very different between people with CTX and can appear at any age:

  • Infants
  • Chronic diarrhea
  • Neonatal cholestasis (poor flow of bile at any point from the liver cells into the intestine of a newborn)
  • Children
  • Premature cataracts
  • Thickening of tendons, especially the Achilles tendon, called xanthomata
  • Developmental delays, cognitive impairment, intellectual disability, and learning difficulties
  • Adults
  • The abnormal accumulation of fat in the brain leads to progressive problems with the nervous system, resulting in seizures, abnormal muscle movements, trouble maintaining balance, difficulty speaking clearly, loss of feeling in the arms and legs, dementia, hallucinations, and depression.
  • Other symptoms include an increased risk of bone fractures, due to loss of calcium, and an increased risk of developing heart or lung failure at an early age.


What causes CTX?

Individuals with CTX are unable to make bile acids correctly. Bile acids are produced in the body to help break down fats, allowing for normal daily activities and good health. Because the body lacks proper amounts of bile acid in those with CTX, there is a buildup of fat in many organs, including the brain, which causes problems with normal function and may lead to organ failure. In addition, there is often a buildup of other chemicals that can damage the body’s organs.

How can you tell if someone has CTX?

CTX is often suspected in someone when typical signs and symptoms are present. Symptoms, which are often present in infants, usually start during the first and second decades of life. A blood test can detect the presence of abnormal bile acids and fats. Scans, such as with an MRI scan, may show typical changes of CTX in the brain. Genetic tests can be done to confirm that a person is affected by CTX, as well as to identify carriers of the CTX gene. Although they are not affected by the condition themselves, finding carriers of the CTX gene can help parents make decisions about future pregnancies.

How Do I Get CTX?

CTX is an inherited condition. Although neither the child’s mother nor father is affected, the condition is passed down when the child receives one affected copy of the gene causing CTX from each parent. Genes help determine everything from the color of our eyes to how our body’s work. The presence of 2 affected copies of the CTX gene (one from the mother and the other from the father) causes the child to have CTX at birth.

How Common is CTX?

It is thought that between 1 in 72,000 to 1 in 150,000 Americans have CTX. When both parents are carriers of the CTX gene, the risk of having an affected child is 25% (a 1 in 4 chance)  each time these parents decide to have a child.

How is CTX Diagnosed?


CTX is usually diagnosed based on clinical symptoms, biochemical tests showing elevated levels of cholestanol, and confirmed through genetic testing for mutations in the CYP27A1 gene.

1.     Clinical Presentation: The main clinical features of CTX are infantile-onset diarrhea, childhood-onset cataract, presence of tendon xanthomas, and progressive neurologic function. 

2.     Biochemical Tests: Blood tests to measure cholesterol and cholestanol levels can provide diagnostic clues. The most common biochemical abnormality in patients suspected to have CTX is elevated cholestanol levels (5-10 times above normal limits), with low or normal cholesterol levels. 

3.     Genetic Testing: Identifying mutations in the CYP27A1 gene confirms the diagnosis. 

Treatment Options

  • Chenodeoxycholic Acid (CDCA): Long-term treatment with the oral bile acid replacement therapy, chenodeoxycholic acid (CDCA,) has been effective in helping to reduce cholestanol levels and manage symptoms. Early treatment in young people without symptoms appears to prevent development of clinical signs and symptoms. Early treatment in symptomatic patients has also been shown to limit progression and to reverse neurologic deficits in some cases. The recommended dose of CDCA for adults is 250 mg three times a day and 15 mg/kg per day divided into three doses for children.
  • Symptomatic Treatment: This includes treating symptoms, which may include offering cataract surgery for vision issues or providing physical therapy for problems with movement. Neurologic complications of epilepsy, spasticity, and parkinsonism are treated symptomatically by a neurologist. Xanthomas may be surgically removed for cosmetic reasons. 


Lifestyle Recommendations

Patients with CTX can benefit from: 

  • Low Cholesterol Diet: Avoiding foods high in cholesterol. 
  • Regular Exercise: Promotes overall health and may help manage symptoms. 
  • Regular Monitoring: Regular check-ups to measure cholestanol levels, screen for complications, and monitor overall health. 


Finding a Specialist

Consulting with a medical geneticist, neurologist, or metabolic specialist experienced in treating rare genetic disorders like CTX is recommended. Organizations like the National Institutes of Health (NIH) or patient advocacy groups can provide referrals. To find a lipid specialist in your area, use the  “find a clinician” tool on learnyourlipids.com.

Clinical Trials

Participation in clinical trials can provide access to experimental treatments and contribute to advancing research on CTX. Information on ongoing trials can be found through clinical trial registries ( https://clinicaltrials.gov/) or research institutions specializing in metabolic disorders. 

Summary

Cerebrotendinous xanthomatosis (CTX) is a complex disorder with significant implications for patients and families. Through early diagnosis, appropriate management strategies, and ongoing research, individuals affected by CTX can improve their quality of life and contribute to broader scientific understanding of rare genetic conditions.