What is Cerebrotendinous Xanthomatosis?
Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder that interferes with the body’s ability to metabolize fats, leading to abnormally high levels of a fat-related substance, called cholestanol, in the blood. This substance accumulates in different parts of the body, including the nervous system, brain, tendons, eyes, and arteries, causing a wide range of health problems.
They may begin during infancy with chronic diarrhea or in adolescence with blurred vision due to cataracts. As people with CTX get older, fatty deposits can form in their tendons, leading to noticeable lumps (tendon xanthomas), and they can start to experience difficulties with movement and cognition.
People with CTX may develop issues such as poor coordination, muscle stiffness, seizures, learning disabilities, memory decline, nerve damage in the hands and feet, and symptoms resembling Parkinson’s disease. Because symptoms can vary significantly and can show up at different ages, CTX is often not diagnosed promptly. On average, there’s a delay of 16 years between when symptoms first appear and when the diagnosis is confirmed.
Early treatment is crucial for the best outcome. A medication called chenodeoxycholic acid (CDCA) is used to manage the condition and can slow down its progression. Therefore, it’s critical for doctors to recognize and start treating CTX as early as possible.
What Causes Cerebrotendinous Xanthomatosis?
Cerebrotendinous xanthomatosis, often abbreviated as CTX, is caused by a specific mutation or change in the CYP27A1 gene. This gene is responsible for producing a particular enzyme within the mitochondria (the ‘powerhouses’ of cells) that helps make bile acid, a substance that is important for digestion.
When this gene is mutated, it affects the body’s ability to create certain types of bile acid. As a result, the body starts to make too much of a different substance, known as cholestanol, which is normally converted from cholesterol. When the body can’t convert cholesterol into bile acids because of the gene mutation, it leads to an excess of cholestanol.
This surplus of cholestanol can build up and get deposited in different tissues and organs in the body, causing a variety of health issues that can affect multiple organs.
Studies have shown that during this process, as the protective barrier around the brain gets damaged, cholestanol finds its way into the brain. This can lead to long-lasting cognitive impairments, or problems with how the brain thinks and learns. Shrinking of the brain, or brain atrophy, is often observed in CTX patients, which raises questions about whether cholestanol might contribute to pathways that lead to cell death.
Cholestanol can also build up in bones, leading to early onset of osteoporosis (a condition that weakens bones) and a higher risk of fractures.
Risk Factors and Frequency for Cerebrotendinous Xanthomatosis
CTX, or cerebrotendinous xanthomatosis, is seen as a rare disease because only a few hundred cases have been reported globally. However, because its symptoms can vary and diagnosis is often delayed, the true number of CTX cases is likely higher than recorded. Based on older research estimates, roughly 3 to 5 in every 100,000 individuals of European heritage in the United States might have this disease. The chance of an American having CTX is estimated at 1 in 72,000 to 1 in 150,000. Given the United States’ population of over 320 million, the predicted number of CTX cases in the country itself could be greater than the number of confirmed cases throughout the world. Researchers studying CYP27A1 gene variants in a group of 60,000 unrelated adults from around the globe found that CTX was most prevalent among South and East Asians, followed by North Americans, Europeans, and Africans. It’s also worth noting that more CTX cases have been reported in women than men.
- CTX is a rare disease, but the actual number of cases is probably higher than reported.
- It might affect 3 to 5 in every 100,000 individuals of European heritage in the US.
- The chances of an American having CTX are estimated between 1 in 72,000 and 1 in 150,000.
- The suspected number of CTX cases in the US could be more than confirmed cases worldwide.
- A study found CTX was most common among South and East Asians, followed by North Americans, Europeans, and Africans.
- More CTX cases have been reported in women than in men.
Signs and Symptoms of Cerebrotendinous Xanthomatosis
People with CTX, a genetic disorder, often show a range of symptoms that can begin during infancy and continue throughout adulthood. It’s common for the first signs to be general health issues and not specific CTX indicators. Infants might deal with unmanageable diarrhea or liver-related symptoms like jaundice or cholestasis. As they grow, they might continue to have chronic diarrhea and could also start experiencing problems with their vision due to early-onset cataracts. In their teens or twenties, they could also develop tendon xanthomas, which are clumps of fat in tendons in regions like the Achilles, elbow, and knee. Other possible non-neurologic symptoms include osteoporosis, early atherosclerosis, hypothyroidism, and various psychiatric conditions.
Neurological symptoms usually start appearing in their thirties and progressively get worse. Most commonly, these include symptoms related to motor function and coordination, such as dystonia, oromandibular dyskinesia, spasticity, hyperreflexia, ataxia, nystagmus, and dysarthria. They might also see peripheral neuropathy symptoms. Sometimes, these neurological symptoms can appear earlier in life, such as developmental delays, cognitive impairment, intellectual disability, and learning difficulties. Less common neurologic symptoms can include dementia, epilepsy, and parkinsonism.
- Diarrhea or liver-related issues in infancy
- Chronic diarrhea
- Early-onset cataracts
- Tendon xanthomas in Achilles, elbow, and knee tendons
- Osteoporosis, early atherosclerosis and hypothyroidism
- Psychiatric conditions
- Motor function and coordination issues
- Peripheral neuropathy
- Developmental delays, cognitive impairment and learning difficulties
- Dementia, epilepsy, and parkinsonism
Testing for Cerebrotendinous Xanthomatosis
If you exhibit at least two out of four specific symptoms, your doctor might suspect a medical condition called cerebrotendinous xanthomatosis (CTX). The symptoms important for diagnosing CTX are: diarrhea beginning in infancy, cataracts developing in childhood, lumps beneath the skin (tendon xanthomas) appearing during adolescence or young adulthood, and deterioration of neurological function starting in adulthood.
To confirm these suspicions, your doctor may conduct biochemical tests. These tests typically reveal high serum plasma cholestanol levels – a type of fat – in your blood. This level can be 5 to 10 times above normal, while your cholesterol concentration may be normal or low. Other biochemical signs of CTX include increased bile alcohols in your blood, urine, and plasma. There might also be a decrease in a certain type of bile acid in your bile, an increased plasma lactate concentration, and an increased amount of cholestanol and apolipoprotein B in your spinal fluid.
Because the symptoms of CTX can vary widely between individuals, neuroimaging (scans of the brain) and genetic testing are needed to confirm the diagnosis. Genetic testing is used to look for mutations in the CYP27A1 gene which is linked to CTX. Scans, such as a CT scan of your head or an MRI of your brain, can show changes in the brain that are typical of CTX. These can include certain kinds of degeneration or brain lesions that are specific to CTX.
Electrophysiological studies, which measure the electrical activity of your nerves, can also aid in diagnosing CTX. In this condition, the speed at which your nerves conduct electrical signals might be decreased, and there could be abnormal activity when examining sensory, motor, visual, and brainstem responses.
All of these diagnostic tools can help doctors make a diagnosis at an earlier stage than previous methods, potentially reducing the average age of diagnosis from 35 years to around 10 to 20 years.
Treatment Options for Cerebrotendinous Xanthomatosis
Long-term treatment for Cerebrotendinous xanthomatosis (CTX), a rare genetic disorder, often comes in the form of a medication called Chenodeoxycholic acid (CDCA). CTX is linked to the body’s inability to create CDCA. Hence, this medication helps to balance the production of bile acids in the body, preventing an excessive build-up of a substance called cholestanol. This build-up can be harmful as it can lead to a variety of symptoms and complications in the body.
When treatment begins before symptoms appear, it can often prevent the effects of CTX from developing. Beginning treatment early in individuals already showing symptoms can slow down the progression of the disease and, in some cases, even reverse some of the neurological problems linked to CTX. Besides CDCA, some patients may also take statin medications, which can help reduce the level of cholestanol in the body and improve neurological symptoms. Because statins can sometimes cause muscle weakness, a supplement called Coenzyme Q10 is often taken alongside these medications to counteract this side effect.
The treatment for CTX also includes addressing individual symptoms of the disease, both neurological and non-neurological. If a patient has cataracts, a common complication with CTX, they may undergo a procedure for their removal. If they experience neurological issues like epilepsy, muscle stiffness (spasticity), and symptoms similar to Parkinson’s disease, they will receive medications accordingly. Individuals with CTX often have weakened bones (osteoporosis), so supplements with calcium and vitamin D can help strengthen them. CTX can lead to the formation of fatty deposits under the skin called xanthomas, which can be surgically removed if they are a cosmetic concern.
What else can Cerebrotendinous Xanthomatosis be?
Marinesco-Sjogren syndrome is a genetic disease that also features symptoms like poor coordination (cerebellar ataxia), childhood-onset clouding of the lens in the eyes (congenital cataract), and intellectual disabilities. It might seem similar to a condition called CTX, but it doesn’t come with chronic diarrhea or a high amount of a molecule called cholestanol. One might not usually find fatty lumps in tendons (tendon xanthomas) in people with Marinesco-Sjogren syndrome, although there are exceptions. More typical symptoms include:
- Being shorter than average
- Having weak muscle tone (muscular hypotonia)
- Delayed or absent puberty (hypogonadism)
- Nerve diseases that affect the limbs (peripheral neuropathy)
- Deformed bones
Doctors might suspect Marinesco-Sjogren syndrome when a patient shows these symptoms and has higher-than-normal levels of creatinine kinase, an enzyme associated with muscle breakdown. They would look for changes in muscle tissue and fat buildup while examining muscle through a microscope. An MRI of the brain might reveal a shrunken part called the cerebellum, especially in the central part of it more than the outer parts. The syndrome can be confirmed by finding alterations in a particular gene called SIL1.
Sitosterolemia is another rare disease where fat accumulates in places it shouldn’t, causing symptoms like tendon xanthomas, early onset of artery-hardening disease (atherosclerosis), and blood disorders such as easily broken down red blood cells (hemolytic anemia) or low platelet count (thrombocytopenic purpura). People with this condition don’t develop cataracts or nerve-related issues, which distinguishes it from CTX. Treatment with a drug called ezetimibe and a diet low in plant-derived sterols can improve heart and blood health, and shrink xanthomas.
A genetic disease called familial hypercholesterolemia is characterized by high cholesterol levels that run in families, also features tendon xanthomas, and a history of relatives getting atherosclerosis early in life. Diagnosis involves finding high levels of certain cholesterol particles in the blood. However, unlike CTX, familial hypercholesterolemia doesn’t come with chronic diarrhea, cataract formation, or nerve-related symptoms.
What to expect with Cerebrotendinous Xanthomatosis
CTX, also known as Cerebrotendinous xanthomatosis, is a condition that worsens over time. If it’s not treated, people with this disease often live into their 50s or 60s. However, early treatment can make a big difference, especially before any neural symptoms like muscle weakness or coordination problems appear. With timely and proper treatment, it is expected that someone with CTX can live an average lifespan.
Possible Complications When Diagnosed with Cerebrotendinous Xanthomatosis
If not treated, CTX or Cerebrotendinous xanthomatosis can lead to many serious health problems. Neurologic complications can progress over time, including conditions like seizures, peripheral neuropathy (nerve damage typically affecting the hands and feet), ataxia (loss of full control of bodily movements), and dementia. Mental health issues may also arise, such as paranoid delusions, seeing or hearing things that aren’t there, restless behavior, depression, and these can all increase the risk of attempting suicide.
Other than neurological and mental health issues, physical health can also be impacted. These non-neurologic complications include compression fractures, early onset of arterial diseases which could potentially result in a heart attack, and premature aging.
- Neurologic complications such as seizures, peripheral neuropathy, ataxia, and dementia
- Psychiatric complications such as paranoid delusions, hallucinations, restlessness, depression which potentially escalate to suicide attempts
- Physical health complications like compression fractures
- Early onset of diseases of arteries leading to heart attacks
- Premature aging
Preventing Cerebrotendinous Xanthomatosis
The condition known as Cerebrotendinous xanthomatosis (CTX) tends to get worse over time and can cause severe health problems if it’s not treated. CTX comes with a range of different symptoms and can start at any age, making it often overlooked and not diagnosed until many years after symptoms have begun. Hence, it’s crucial that patients, their families, and their healthcare providers are aware of the signs to spot it early and start the right treatment as soon as possible.
Another important point to make clear is how the disease can be inherited. CTX is classified as an autosomal recessive disorder. This means that both parents need to be carriers of the disease gene. If so, there’s a 25% chance that their child will inherit two copies of the rare gene variant (one from each parent), and thus develop the disease. This information is vital for couples planning to have children, as it can help them understand the risks involved.
