Understanding CTX: A Rare but Treatable Genetic Disorder

Isabella Lazzareschi

Nov 6, 2024

Cerebrotendinous xanthomatosis (CTX) is a rare, inherited lipid storage and metabolic disorder that can severely impact a patient’s quality of life from infancy. Though it is a progressive condition, early diagnosis and treatment can significantly improve outcomes – the earlier you’re able to identify CTX, the better you can treat or even prevent more severe symptoms.

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It’s estimated that CTX affects 1 in every 72,000 to 150,000 Americans¹, but due to its rarity and the broad range of symptoms, CTX is often misdiagnosed or overlooked, allowing irreversible damage to occur. This article will discuss the causes, symptoms, and diagnostic challenges of CTX, along with the importance of genetic testing and counseling for patients and their families.

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What Causes CTX?

CTX is caused by changes (or mutations) in a gene called CYP27A1, which is important for how our bodies break down cholesterol. Normally, this gene makes a protein that helps turn cholesterol into bile acids, which our bodies use to digest fat. But in people with CTX, the gene isn’t able to produce the protein properly. This causes cholesterol to build up in different parts of the body, like the brain, tendons, and other organs, leading to the symptoms of the disease.

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These cholesterol build-ups can then create xanthomas—cholesterol-rich deposits that can be found in the tendons, brain, and spinal cord—which can lead to a range of neurological, physical, and cognitive symptoms. Xanthomas typically appear as yellowish or orange-colored bumps or lumps. Their size can vary from small, pinhead-sized spots to larger nodules, and they can be soft or firm to the touch. Without treatment, this buildup progresses, causing more severe complications with age.

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Symptoms of CTX Across the Lifespan

CTX symptoms manifest at different stages of life, often starting in infancy and becoming more pronounced as the disease progresses. Recognizing these symptoms early is crucial to preventing irreversible damage.

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Infancy and Early Childhood

In infancy, the symptoms of CTX are typically subtle and hard to recognize. It typically presents through the following symptoms:

Chronic diarrhea: This often persists for months or even years.
Delayed developmental milestones: Children with CTX will often begin sitting, walking, and talking much later than expected.
Idiopathic bilateral cataracts: These are cataracts in both eyes, which cloud the lens due to cholesterol build-up, making it difficult to see. Cataracts are a significant early warning sign of CTX, which might be more recognizable as they tend to be rare in young children. These present in roughly 85% of CTX patients².
Neonatal cholestasis: Reduction or blockage of bile flow from the liver to the intestines. The most noticeable signs of neonatal cholestasis is prolonged jaundice (yellowing of the skin or eyes), pale-colored stools, and dark urine

Due to the rarity of CTX, these symptoms are often mistaken for more common conditions like gastrointestinal disorders or general developmental delays. While diarrhea, jaundice, and even delayed milestones can be common in infancy due to a number of health conditions, bilateral cataracts are relatively rare. Unless they are very clearly attributed to another health condition, bilateral cataracts can be a significant reason to seek out genetic testing to determine if the patient has the genetic variant connected with CTX.

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Adolescence and Early Adulthood

As children with CTX grow older, they usually develop additional symptoms that are more noticeable, but still often misdiagnosed as psychiatric disorders, epilepsy, or neurodegenerative diseases like multiple sclerosis (MS). As CTX develops, adolescent patients begin showing the following symptoms:

Continuing diarrhea and idiopathic bilateral cataracts: While these symptoms often develop in infancy, they will commonly persist through childhood and young adulthood.
Xanthomas: Cholesterol deposits that appear as yellowish growths on the tendons, especially the Achilles tendons, impacting nearly 70% of CTX patients³. These deposits become noticeable during adolescence and can affect mobility and cause discomfort.
Neurological symptoms: Caretakers might notice cognitive decline, behavioral changes and peripheral neuropathy (nerve damage that causes pain, numbness, and weakness, particularly in the hands and feet).

Some children with CTX might also start having seizures or develop early-onset osteoporosis, which increases the risk of bone fractures. Without an accurate diagnosis and care plan, the symptoms will continue to worsen.

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Adulthood

In adults, untreated CTX leads to more severe neurological and physical deterioration, often presenting as the following symptoms:

Dementia: As cognitive decline worsens, CTX can progress into dementia at an early age.
Spasticity: Stiff muscles, causing pain and difficulty moving.
Ataxia: Noticeable lack of coordination or balance.
Premature atherosclerosis: Hardening of the arteries, which increases the risk of heart disease and stroke.
Additional xanthomas: Xanthomas often develop in adolescents, but continue to be one of the cardinal symptoms of CTX through adulthood, particularly on the Achilles tendon.
Osteoporosis: This symptom can become much more severe into adulthood, increasing the risk of bone fractures.

Without intervention, individuals with CTX often face a significantly reduced quality of life and a shortened lifespan. Due to spasticity and ataxia, some patients will begin needing wheelchairs to reduce risk of falling and breaking bones.

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Diagnostic Challenges: CTX’s Hidden Nature

Diagnosing CTX is notoriously challenging due to its rarity and the variability of symptoms across different stages of life. Often, patients with CTX undergo a lengthy diagnostic odyssey, seeing multiple specialists and receiving one or more incorrect diagnoses before the true underlying cause is identified.

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In infancy, symptoms like chronic diarrhea or delayed milestones may be misattributed to more common pediatric issues. As children grow older and neurological symptoms arise, they may be diagnosed with psychiatric conditions, epilepsy, or even multiple sclerosis, depending on which symptoms are most prominent. These misdiagnoses are particularly dangerous because they delay appropriate treatment, which is crucial for slowing the disease's progression.

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The most reliable way CTX can be definitively diagnosed is through genetic testing. By analyzing the CYP27A1 gene for variants, healthcare providers can confirm the disorder and develop the right treatment plans to prevent further damage.

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How CTX Is Treated

Once diagnosed, CTX can be treated with chenodeoxycholic acid (CDCA), a bile acid replacement therapy that helps reduce the buildup of cholesterol and its byproducts in the body. While CDCA therapy can’t reverse damage, it can significantly improve symptoms and slow disease progression, particularly if started early. Other treatments may include medications to manage seizures, osteoporosis, or other complications.

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The Importance of Genetic Testing and Counseling

Testing for the CYP27A1 gene mutation can provide a definitive diagnosis, eliminating the uncertainty that many patients experience as they navigate their symptoms. For individuals experiencing chronic diarrhea, neurological symptoms, cataracts, or xanthomas, genetic testing can be a crucial step toward getting the answers they need.

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At Probably Genetic, we offer no-cost genetic testing for individuals who have been experiencing multiple CTX symptoms. After testing, patients receive a free session with a licensed genetic counselor, who can help interpret the results and create a personalized care plan. This support helps patients and families navigate their treatment options and make informed decisions about their care. Click here to check your eligibility through our short online assessment.

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Category:

Rare Disease

References

Appadurai V, DeBarber A, Chiang PW, et al. Apparent underdiagnosis of cerebrotendinous xanthomatosis revealed by analysis of ~60,000 human exomes. Mol Genet Metab. 2015;116(4): 298-304.
Gallus GN, Dotti M, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci. 2006;27(2):143-149.
Mignarri, A., Gallus, G. N., Dotti, M. T., & Federico, A. (2014). Cerebrotendinous xanthomatosis, clinical and neuroradiological findings in a long series of patients. Journal of Inherited Metabolic Disease, 37(3), 421-429; 473-480.
Verrips, A., van Engelen, B. G., Wevers, R. A., van Geel, B. M., Saijo, T., Kaji, M., ... & Gabreëls, F. J. (2000). Cerebrotendinous xanthomatosis: diagnosis, clinical findings, treatment, and follow-up. Journal of Neurology Neurosurgery & Psychiatry, 68(6), 745-752.
European Association for the Study of the Liver. (2009). EASL Clinical Practice Guidelines for the management of cholestatic liver diseases. Journal of Hepatology, 51(2), 237-267.
Grisch-Chan, H. M., Bachmann, L. M., Gemperle-Britschgi, C., Colombo, R., Smit, L., & Ballhausen, D. (2017). Diagnostic odyssey in CTX: a case of delay in diagnosis and how it could be shortened. Molecular Genetics and Metabolism Reports, 11, 63-67.