Cerebrotendinous xanthomatosis

Overview

Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder affecting how the body processes cholesterol and produces bile acids [PMID:31548177]. It's classified as an inborn error of metabolism, meaning there's a problem with a specific chemical reaction in the body. In CTX, a particular enzyme isn't working correctly, leading to an accumulation of cholesterol and related substances in various tissues, including the brain, tendons, and eyes. This build-up forms fatty deposits called xanthomas, which can interfere with normal organ function.

While CTX is present from birth, its symptoms often develop gradually and become noticeable in childhood or early adulthood. Without treatment, the condition typically progresses, leading to increasing health problems over time. Early diagnosis and intervention can significantly alter the disease's course and improve outcomes for affected individuals.

Symptoms & clinical features

The symptoms of CTX can vary widely between individuals but generally become more pronounced with age. Neurological problems are a common feature and may include progressive spasticity (muscle stiffness), ataxia (problems with coordination and balance), and intellectual disability [PMID:31548177]. Some individuals may also experience seizures, dementia, and psychiatric symptoms like behavioural changes.

Another characteristic sign of CTX is the development of xanthomas, which are fatty deposits under the skin or in tendons. These are often seen in the Achilles tendons, but can also appear in other tendons or elsewhere. Eye problems, such as cataracts, are frequent and can develop early in life, sometimes even in infancy. Other possible symptoms include chronic diarrhoea, early-onset atherosclerosis (hardening of the arteries), and bone fragility.

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Affected organs

CTX affects multiple organ systems throughout the body due to the widespread accumulation of cholesterol and its metabolites. The brain is significantly impacted, leading to a range of neurological and cognitive difficulties. The tendons, particularly the Achilles tendons, are commonly affected by xanthoma formation. The eyes are also vulnerable, with cataracts being a frequent finding.

Less commonly, other organs can be involved. The gastrointestinal system may experience chronic diarrhoea. The cardiovascular system can be affected by premature atherosclerosis, and bone abnormalities such as low bone density have also been reported. The systemic nature of cholesterol metabolism means that various tissues and organs are susceptible to the effects of CTX.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

CTX is a progressive disorder, meaning that symptoms typically worsen over time if left untreated. The severity of the condition can vary, even within the same family. Untreated individuals often experience significant neurological decline, including worsening ataxia, spasticity, and cognitive impairment, potentially leading to a significantly reduced quality of life [PMID:32766327]. Without intervention, psychiatric symptoms and seizures may also become more problematic.

The age of symptom onset is variable, but symptoms often begin in childhood or adolescence. Cataracts might appear in childhood, while neurological symptoms and tendon xanthomas typically emerge in late childhood or adulthood. The exact prevalence of CTX is estimated to be between 1 in 50,000 and 1 in 70,000 in the general population, although it may be underdiagnosed.

Genetic causes

Cerebrotendinous xanthomatosis is caused by pathogenic variants in the *CYP27A1* gene [PMID:32766327]. This gene provides instructions for making an enzyme called sterol 27-hydroxylase. This enzyme plays a crucial role in the body's normal cholesterol metabolism, specifically in the pathway that converts cholesterol into bile acids in the liver.

Bile acids are essential for digesting dietary fats and removing excess cholesterol from the body. When pathogenic variants occur in *CYP27A1*, the sterol 27-hydroxylase enzyme is either dysfunctional or absent. This leads to a disruption in the normal bile acid synthesis pathway, causing cholesterol and its precursors, such as cholestanol, to build up in various tissues and organs instead of being properly processed and eliminated.

• CYP27A1
  cytochrome P450 family 27 subfamily A member 1
  The CYP27A1 gene provides instructions for an enzyme called sterol 27-hydroxylase, which is vital for the breakdown of cholesterol and the production of bile acids in the body.

Inheritance pattern

CTX is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the *CYP27A1* gene - one from each parent - to develop the condition. Individuals who inherit only one altered copy of the gene are called carriers. Carriers typically do not show symptoms of CTX because their one working copy of the gene is sufficient to produce enough functional enzyme.

If both parents are carriers of a pathogenic *CYP27A1* variant, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and develop CTX. There is a 50% chance that the child will be a carrier, and a 25% chance that the child will inherit two working copies of the gene and not be a carrier.

Diagnosis & testing

Diagnosing CTX typically involves a combination of clinical evaluation, imaging studies, and specific biochemical and genetic tests. Clinical signs such as chronic diarrhoea, early-onset cataracts, and slowly progressive neurological symptoms or tendon xanthomas may prompt suspicion of CTX [PMID:31548177]. Blood tests showing elevated levels of cholestanol are a key indicator of the condition.

Definitive diagnosis is confirmed through genetic testing, which identifies pathogenic variants in the *CYP27A1* gene. In the UK, individuals suspected of having CTX based on clinical and biochemical findings can be referred to Clinical Genetics services within the NHS for assessment and genetic testing. This testing would generally fall under NHS Genomic Medicine Service (GMS) pathways, with specific R-codes for inherited metabolic disorders.

Management & lifestyle

While there is currently no cure for CTX, effective management strategies can significantly slow down or halt disease progression, particularly if started early. The primary treatment involves lifelong oral chenodeoxycholic acid (CDCA) supplementation. CDCA replaces the missing bile acid, which helps to normalise bile acid production and reduce the accumulation of cholestanol and other cholesterol metabolites in the body. This treatment has been shown to improve neurological symptoms and prevent further disease progression in many individuals [PMID:32766327].

Management also involves regular monitoring by a team of specialists, including neurologists, ophthalmologists, and gastroenterologists, to address specific symptoms and complications. Physical therapy, occupational therapy, and speech therapy can help manage neurological symptoms. Genetic counsellors can provide support and information to individuals with CTX and their families about the inheritance pattern and implications for family planning. The NHS offers comprehensive multidisciplinary care for rare metabolic conditions, typically coordinated through specialist metabolic centres.

UK care pathway

In the UK, if CTX is suspected, a referral to a Clinical Genetics service or a specialist metabolic centre within the NHS is the usual next step. These services can confirm the diagnosis through genetic testing, often funded through the NHS Genomic Medicine Service (GMS). Genetic tests for inherited metabolic disorders are covered by specific R-codes and are performed in NHS Genomic Laboratory Hubs.

Once a diagnosis is made, care is typically coordinated by a multidisciplinary team. Access to genetic counselling is also an integral part of the pathway, offering information about the condition, its inheritance, and support for family planning.

Related conditions

Several conditions can present with overlapping symptoms or similar types of deposits, making differential diagnosis important. These include other forms of xanthomatosis or metabolic disorders that affect cholesterol transport or lipid metabolism. For example, some forms of familial hypercholesterolaemia can cause xanthomas, though these typically affect different sites and are not associated with progressive neurological decline in the same way as CTX. Conditions causing progressive neurological dysfunction, such as multiple sclerosis or spinocerebellar ataxias, may also initially be considered before the specific metabolic nature of CTX is identified.

Frequently asked questions

References

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