Definitions

Cerebro - Relates to the brain

Tendinous - Relates to tendons

Xanthomatosis - A condition where yellowish cholesterol-rich bumps appear on the body¹

Cerebrotendinous xanthomatosis

Cerebrotendinous Xanthomatosis (CTX), also known as Cerebral Cholesterosis, is a rare inherited condition known as a lipid storage disease, a disorder that is characterised by harmful fatty material (lipid) buildup in cells and tissues in the body.

This buildup occurs due to a lack of or faulty enzymes that are needed to metabolise lipids, which can damage cells and tissues over time, especially within the heart, eyes, nervous system, liver, spleen, bone marrow and brain.³

CTX is caused by mutations in the CYP27A1 gene, which affects the mitochondrial enzyme sterol 27-hydroxylase, which helps maintain normal cholesterol levels in the body by converting cholesterol into bile acids, which then helps with digesting fat.⁴

Because the enzyme needed to convert cholesterol into bile acids isn’t there, the unconverted cholesterol and by-product cholestanol will accumulate in deposits within the nerve cells and membranes, which can cause significant damage in the affected areas.⁵

Symptoms

Symptoms include

• Diarrhoea (in infancy)
• Cataracts (childhood)
• Brittle bones (childhood)
• Xanthomas (adolescent - young adult)

In adulthood, symptoms present more neurological conditions, such as:

• Dementia
• Seizures
• Hallucinations
• Depression
• Coordination issues
• Speech issues

Adulthood symptoms typically appear if CTX is left untreated.

A more formal way to describe CTX is “rare autosomal-recessive inborn bile acid metabolism disorder caused by mutations in the CYP27A1 gene”.

What does this mean?

When something is autosomal, it means that you inherit a mutated gene, so if you have an autosomal disorder, it means that it was passed down to you from either one or both of your parents who carry the mutated gene.⁷

Autosomal disorders can be dominant or recessive. Autosomal dominant disorders require only one copy of the mutated gene from one parent, whereas autosomal recessive disorders need two copies of the mutated gene, one copy from each parent.⁷

In the case of CTX, which is related to mutations in the CYP27A1 gene, a CTX patient has it as a result of both of their parents passing down one copy of the mutated CYP27A1 gene. It is important to note that just because a parent is a carrier, it doesn’t mean they suffer from the disease themselves. Additionally, if one child suffers from an autosomal disorder, it doesn’t necessarily mean that their siblings will also suffer from the disease.

Diagnosis

Along with the previously stated symptoms, CTX is typically diagnosed through clinical evaluation, which involves looking at the medical history of the patient as well as their family history. This is to recognise any common symptoms and/or signs, as well as standard urine and blood tests. It may also involve using CT and MRI scans to check for deposits in the tissues and, most importantly, any damage to the brain.⁶

Mental health disorders

Mental health disorders and psychiatric conditions are conditions that affect your behaviour, thoughts and/or emotions. They are incredibly common and affect approximately 1 in 8 people globally.⁸

There are many different types of mental health disorders, the most common include:⁸

• Anxiety disorders - Post-Traumatic Stress Disorder, Obsessive Compulsive Disorder and anxiety
• Mood disorders - depression and bipolar disorder (extreme mood swings)
• Neurodevelopmental disorders - Attention Deficit Hyperactivity Disorder and autism
• Behaviour disorders - defiance and aggression
• Eating disorders - anorexia, bulimia, and overeating
• Personality disorders - borderline, antisocial, and narcissistic traits
• Psychotic disorders - schizophrenia
• Addiction disorders - drug or alcohol dependence

Because mental health disorders are so complex, there could be a wide range of causes or a combination of causes based on your family history, lifestyle etc.⁹

Causes-genetics

If you have an immediate family member with a mental illness, it’s quite likely that you more likely to develop one yourself. However, just because a family member has a mental health problem doesn't mean you or others in the family will have it too.

Causes-substance abuse

Using drugs or abusing alcohol can also trigger mental health issues, such as a manic episode in bipolar disorder or episodes of psychosis. Drugs like cocaine, marijuana, and amphetamines can cause feelings of paranoia.

Physical causes

Some physical health problems or changes in hormones can also affect mental health, such as experiencing a head injury or a neurological condition that could affect your mood.

Causes-trauma

Difficult experiences during childhood, like abuse or neglect, can increase the chances of developing mental health issues later on.

Stressful or traumatic events in adulthood, such as feeling lonely, experiencing violence at home, relationship problems, or financial difficulties, can raise the risk of mental health problems. Living in a war zone or experiencing other traumatic events can lead to conditions like post-traumatic stress disorder (PTSD).

Causes-personality traits

Certain personality traits, like being a perfectionist or having low self-esteem, can also make someone more prone to depression or anxiety.

Psychiatric manifestations in CTX

Whilst psychiatric and behavioural manifestations in CTX are rare, within an already rare disorder, they still do occur.

Psychiatric abnormalities include:¹⁰

• Behavioural changes
• Hallucinations
• Agitation
• Agression
• Depression
• Suicidal ideation

Psychiatric disorders and neurological/cerebral disorders can sometimes be difficult to tell if one disorder is responsible for the other. For example, if someone has a tumour that presses on their brain, which could affect their mood, but has a previous diagnosis of depression, how do we know for sure that the depression is because of the tumour, or not?

However, there is also an increased likelihood that living with a disorder that affects your body in such a significant way decreases your quality of life, which could contribute to symptoms of mental health disorders.¹¹

Because of the cholesterol build-up that favours depositing itself around the brain, it is likely that it affects the mood-related areas of the brain and contributes to psychiatric abnormalities, as it interferes with emotional regulation.¹²

Studies show he earlier someone with CTX starts showing psychiatric symptoms, the less severe they tend to be. For people under 25, signs such as personality changes, moodiness, and aggressive behaviour happen more often. Sometimes, problems like being irritable, overly active, having difficulty paying attention, or acting out in children or teenagers can be wrongly viewed as normal teenage behaviour or influence from friends. Because of this, it's important to get a thorough neurological exam, including physical and eye check-ups, especially if family members have had similar issues, which could indicate it runs in the family.¹⁰

Treatment

There is currently no cure for CTX, but if the condition is caught and treated early, its progress can be slowed down or stopped.

The usual first treatment is taking a medicine called chenodeoxycholic acid (CDCA), which is a bile acid that can help the body process cholesterol properly by dissolving it when the body cannot naturally do to those with CTX. CDCA has also been shown to help with early-onset psychiatric symptoms as well¹⁰. Doctors might also prescribe other medicines which help lower cholesterol by blocking the cholesterol-synthesising enzyme, known as HMG-CoA reductase.⁶

Summary

Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited lipid storage disorder caused by CYP27A1 gene mutations, leading to defective bile acid processing. It results in harmful cholesterol and cholestanol deposits in tissues, damaging the nervous system, heart, eyes, liver, spleen, and bones.

Symptoms include:

• Early: diarrhoea, cataracts, brittle bones, xanthomas
• Late: dementia, seizures, hallucinations, depression, coordination and speech issues

Diagnosis involves clinical evaluation, genetic testing, blood/urine analysis, and imaging (CT/MRI).

CTX is an autosomal recessive disorder, where both parents are carriers of the mutated gene. It stems from an enzyme deficiency affecting cholesterol conversion to bile acids, causing accumulation and tissue damage.

Mental health issues, including anxiety, depression, and psychosis, can occur due to cholesterol deposits in the brain and the psychological impact of the disease. Psychiatric symptoms are often subtle early on but can include agitation, hallucinations, and mood changes.

Currently, there is no cure. Fortunately, early treatment with chenodeoxycholic acid (CDCA) can slow progression and alleviate symptoms, alongside cholesterol-lowering medications.