Cerebrotendinous Xanthomatosis (CTX)

What is Cerebrotendinous Xanthomatosis (CTX)? 

Cerebrotendinous xanthomatosis (CTX) is a rare genetic condition that affects the body's ability to metabolize cholesterol. This leads to a buildup of cholesterol in various tissues, including the brain, tendons and eyes.    

Symptoms of CTX can vary widely and often progress over time. Some common symptoms include diarrhea in infancy, childhood cataracts in both eyes and later development of neurological problems.  Diagnosis of the condition can be done by a genetic test to detect pathogenic variants or “spelling changes” in both copies of the CYP27A1 gene. Individuals may also have abnormal blood and urine tests that show elevated levels of cholestanol (a metabolite of cholesterol) and bile alcohols, and differences seen on an MRI of the brain.  

While CTX is a serious condition, early diagnosis and treatment can help manage symptoms and improve quality of life. Treatment often involves dietary changes, medications and sometimes surgery. There are also medications (chenodeoxycholic acid, or CDCA, and cholic acid) that if administered early in life, generally prevent symptoms from worsening and new symptoms from developing.

What Causes CTX in Kids?

CTX is an autosomal recessive genetic condition. It occurs when a person has a pathogenic variant or “spelling change” in both of their two copies of the CYP27A1 gene. This gene provides instructions for the body to produce an enzyme called sterol 27-hydroxylase, which plays a crucial role in breaking down cholesterol. People with CTX are unable to make enough of this enzyme to break down cholesterol. This leads to an accumulation of cholesterol in various tissues throughout the body.

Autosomal recessive conditions are typically inherited from parents who are carriers of the condition. Carriers have one working copy of the gene and one copy with a pathogenic variant. Carriers are not expected to have signs or symptoms of the condition. However, when two biological parents are both carriers of CTX, they have a 25% (1/4) risk with each pregnancy to have a child with CTX.

What Are the Symptoms of CTX? 

Symptoms of cerebrotendinous xanthomatosis (CTX) can vary depending on age and individual severity. Here are the common symptoms:    

• Infantile Diarrhea: Persistent, watery diarrhea.  
• Childhood Cataracts: Clouding of the lens of the eye, affecting vision.    
• Tendon Xanthomas: Yellowish nodules or bumps on tendons, especially in the Achilles tendon and hands. These may not be visible on the outside of the body and instead may be detected by medical imaging, like an MRI, when a person is experiencing pain or swelling of a joint.   
• Neurological symptoms that worsen over time: 
  
  • Seizures 
  • Movement disorders, including ataxia, dystonia or parkinsonism
  • Peripheral neuropathy, which may present with tingling, numbness, burning sensation, muscle weakness or loss of balance  
  • Cognitive impairment 
  • Dementia or difficulties with memory 
  • Behavioral changes 
  • Psychiatric symptoms, such as depression and anxiety 
• Other Possible Symptoms:
  • Cholestatic jaundice: Yellowing of the skin and eyes due to impaired bile flow.    
  • Osteoporosis: Weak and brittle bones that may lead to more frequent bone fractures.   
  • Cardiovascular disease: Increased risk of heart disease due to cholesterol buildup in blood vessels.    

How is CTX Treated? 

There is currently no cure for cerebrotendinous xanthomatosis (CTX), but treatment can help manage symptoms and slow disease progression, especially when started at a young age. The primary treatment for CTX is: 

• Chenodeoxycholic Acid (CDCA) Replacement Therapy: This prescription medication helps replace the bile acids that the body is unable to produce on its own. CDCA can help reduce cholesterol levels and improve liver function.

In addition to medication, other treatment approaches may include:

• Dietary Changes: Limiting dietary cholesterol intake can help manage the condition. 
• Surgery: In some cases, surgery may be necessary to remove cholesterol deposits or treat complications, such as cataracts or tendon xanthomas.    
• Symptomatic Treatment: This may involve managing specific symptoms like pain, neurological issues or psychiatric disorders.    

Early diagnosis and consistent treatment are crucial for managing CTX and improving the quality of life for individuals with CTX.

How is CTX Diagnosed?

Diagnosing cerebrotendinous xanthomatosis (CTX) typically involves a combination of clinical evaluation and testing, and genetic testing.  

Clinical evaluation and testing: 

• Physical Examination: A doctor will look for physical signs such as tendon xanthomas, cataracts and other visible symptoms.    
• Medical History: A detailed medical history, including family history, can help identify potential risk factors and symptoms.    
• Cholesterol Tests: Measuring levels of cholesterol, especially cholestanol, in the blood. Elevated levels of cholestanol are a strong indicator of CTX.    
• Bile Acid Analysis: Analyzing bile acids in the blood or urine can help confirm the diagnosis.

Genetic Testing: 

• CYP27A1 Gene Sequencing: This test directly analyzes the CYP27A1 gene for specific pathogenic variants or “spelling changes” associated with CTX. 

What is the Long-Term Outlook for Children with CTX? 

The long-term outlook for children with cerebrotendinous xanthomatosis (CTX) has improved significantly with early diagnosis and treatment. Early intervention with chenodeoxycholic acid (CDCA) therapy can help manage symptoms, prevent disease progression and improve quality of life.    

Key factors influencing the long-term outlook include: 

• Early Diagnosis: Early diagnosis allows for timely initiation of treatment, which can significantly reduce the risk of neurological complications.    
• Adherence to Treatment: Consistent adherence to CDCA therapy and dietary recommendations is crucial for managing the condition. 
• Individual Variability: The severity of symptoms and the rate of disease progression can vary widely among individuals.    

While CTX is a lifelong condition, with proper management, many individuals with CTX live full lives. However, it's important to monitor for potential complications and adjust treatment as needed.