What Is Cerebrotendinous Xanthomatosis?

Overview

Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive gene disorder that affects the body’s ability to metabolise cholesterol.¹ As a result, patients with CTX cannot break down different forms of cholesterol, leading to their subsequent build-up in certain regions of the body.²

Understanding CTX is crucial for early detection and intervention to potentially improve the quality of life of affected individuals. Therefore, this article will provide a comprehensive explanation of the genetic basis, the clinical manifestations, diagnosis, treatment options, and prognosis.

Background

Cerebrotendinous Xanthomatosis is an autosomal recessive disorder, meaning that it results from mutations in both copies of a specific gene. CTX is caused by a mutation in the CYP27A1 gene, leading to an increased deposition of cholesterol and cholestanol in multiple tissues.³ This is due to the genetic mutation causing a deficiency in a vital enzyme in the bile acid production pathway, making CTX a bile acid synthesis disorder.⁴

Bile acids are fundamental for the effective functioning of the body as they are an important component of the bile and help the intestine absorb fats. As a result, CTX can also be classified as a lipid storage disorder due to its abnormal deposition or as a leukodystrophy due to the involvement of the white matter (the communication pathways in nerve cells - the myelinated axon) in the central nervous system (spinal cord and the brain).⁵

The onset of CTX varies widely, but symptoms typically become visible in late childhood or early adulthood. Due to this ambiguity of the age of onset and diagnosis, there is no consensus data on the prevalence of CTX. However, its estimated rate is 5:100,000 worldwide, but this varies with, country and ethnic group; for example, the rate of CTX in Spain is 1:800,000, whilst in Caucasians, it is approximately 1:50,000.⁶

Clinical features

Cerebrotendinous Xanthomatosis presents a diverse range of clinical symptoms that affect both the neurological and physical condition of the affected individual’s health.

Neuropsychiatry symptoms:

• Cognitive impairment: If CTX is untreated, it can lead to the development of progressive neurological problems like cognitive impairment, seizures, and ataxia (difficulties with coordination and balance).⁷
• Behavioural changes: Individuals with CTX may have hallucinations, become more agitated, have depression, and have suicidal tendencies.⁸

Physical symptoms: 

• Tendon Xanthomas: One of the most common features of CTX. Tendon xanthomas are cholesterol (fatty) deposits that accumulate in tendons throughout the body, commonly in the tendon of Achilles.⁹^,¹º These, once blood lipid levels are lowered, can go away by themselves, but if this doesn’t happen, they can be removed surgically.¹¹
• Ocular manifestations: Childhood-onset cataract is a typical sign of CTX. Cataracts and optic disk paleness are also common ocular features in adults.¹²
• Skeletal abnormalities: Other common clinical manifestations of patients with CTX are osteoporosis and repeated bone fractures. This results from having low bone mass along with severe gait disturbances as this would increase the risk of falling and, therefore, bone fractures.¹³

Systemic complications:

• Cardiovascular issues: Among the multiple clinical manifestations of CTX, there is also premature atherosclerosis (the thickening or hardening of the arteries due to the build-up of the deposits of fatty substances) and cardiovascular disease.¹⁴
• Pulmonary involvement: CTX may cause lung function to become compromised as it can cause accumulations of giant cells engorged with cholesterol in bronchoalveolar lavage fluids. However, patients with pulmonary involvement may have no clinical pulmonary symptoms such as shortness of breath or chest distress, and have normal pulmonary function tests.¹⁵
• Gastrointestinal problems: As a result of the accumulation of cholesterol in the liver, liver disease, such as cholestatic liver disease, may occur. This means that there is an interruption or suppression of the flow of bile from the liver (cholestasis). The features of this disease include jaundice (the yellowing of the skin, mucous membranes and whites of the eyes), growth deficiency, hepatomegaly (enlargement of the liver) and/or splenomegaly (enlargement of the spleen) may also occur.¹⁶

Diagnosis

Diagnosing Cerebrotendinous Xanthomatosis often begins with a thorough clinical evaluation. This consists of obtaining a detailed patient and family medical history, identifying characteristic clinical findings, and conducting specialised tests such as genetic testing and biochemical tests on blood and urine.¹⁷

Genetic testing permits the detection of the disease-causing variants (mutations) in the CYP27A1 gene, making it a vital test to confirm a diagnosis of CTX. Additionally, being an autosomal recessive disorder, two copies of the faulty gene are required for the onset of the disease. Genetic testing can also be useful for families of affected individuals when doing family planning, pregnancy management, etc., to find out if they have one or two copies of the faulty gene.¹⁸

Biochemical tests are also used to detect biochemical markers of CTX. An example is cholestanol levels.¹⁹ Cholestanol is an intermediate in the synthesis of bile acids from cholesterol, measured in the plasma.²⁰ Its concentrations can be used to determine if there is a disruption in the bile acid synthesis pathway.

Imaging studies may also be used to supplement the diagnosis of CTX. Imaging techniques like computerized tomography (CT) scans, which use a computer and X-rays to create a film showing cross-sectional images of tissue structures, and magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce cross-sectional images. These tests can show cerebellar lesions and white matter damage in individuals with CTX.²¹

In addition, in the US, CTX has been nominated as a candidate disorder to add the recommended uniform screening panel of disorders (the RUSP) to screen for in newborns.²²

Treatment and management

Early diagnosis and treatment are fundamental to preventing disease complications. Inclusively, researchers have recently shown that CTX patients who started treatment later in life (after 25 years of age) had a worse outcome in comparison to their younger counterparts, as they were significantly more limited in ambulation (the ability to walk without the need for any kind of assistance) and more cognitively impaired.

A common treatment used for patients with Cerebrotendinous Xanthomatosis is using chenodeoxycholic acid, as it normalizes the production of cholestanol, which prevents symptoms in asymptomatic individuals and stops the progression of symptoms in affected individuals. 

In addition to chenodeoxycholic acid, it may also be effective to take a drug that inhibits HMG-CoA reductase (an enzyme that plays a role in the creation of cholesterol in the liver) in conjunction. These HMG-CoA reductase inhibitors, better known as statins, could boost the activity of the receptors for low-density lipoprotein cholesterol. As a consequence, this would increase cholesterol uptake and, therefore, potentially worsen CTX. 

Cholic acid, another bile acid, has also been used in the treatment of CTX but for young children, as it lacks the potential toxic effects on the liver sometimes associated with the usage of chenodeoxycholic acid.²³

Cataract extraction is typically required in at least one eye by the age of 50 years. Other symptoms like epilepsy, spasticity, and parkinsonism are treated symptomatically.

Along with these treatments, annual surveillance is also required to monitor cholestanol plasma concentrations, neurologic and neuropsychological evaluation, brain MRI scans, echocardiograms, and assessment of bone density.²⁴

Prognosis

The prognosis of individuals with Cerebrotendinous Xanthomatosis can vary widely due to the variety of factors that contribute; these include the age of onset, the severity of the symptoms, and the timing of the intervention.

As mentioned previously, the clinical course of CTX is progressive and potentially debilitating when untreated for a long time. Furthermore, CTX is often under-recognised and therefore not diagnosed for several years after clinical symptoms have emerged.²⁵

However, in an optimistic perspective where the condition is diagnosed early, appropriately managed and treated, individuals can expect to have a normal life expectancy and a good quality of life, but if that isn’t the case and individuals do not get the required treatment their life expectancy is 50 to 60 years.²⁶

Conclusion

To summarise, Cerebrotendinous Xanthomatosis is a rare recessive autosomal genetic disorder with profound implications for those affected. As a result of a mutation in the CYP27A1 gene, it disrupts the metabolism of cholesterol and cholestanol in various tissues in the body. This abnormal accumulation causes a wide range of clinical symptoms, affecting both the neurological and physical health of the affected individuals.

Diagnosis relies on a combination of clinical evaluation, genetic testing, and biochemical tests, where genetic testing, in particular, is crucial for confirming the presence of CTX and understanding its inheritance pattern.

Treatment and management strategies aim to mitigate symptoms and improve the quality of life. Medications like chenodeoxycholic acid, cholic acid and statins, along with surgical interventions for tendon xanthomas and cataracts, play a key role. Regular follow-up and monitoring are essential to assess treatment effectiveness and adjust interventions as needed.

The prognosis for individuals with CTX varies based on several factors, but early diagnosis and intervention offer the best chance for a normal life expectancy and improved quality of life. Continued research and awareness of CTX can aid in earlier detection and new treatments, offering a hopeful prospectus to those living and supporting individuals with this challenging condition.