Cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder caused by mutations in the CYP27A1 gene, leading to a deficiency of the enzyme sterol 27-hydroxylase. This deficiency results in the accumulation of cholestanol in various body tissues, including the brain, spinal cord, and tendons, which can cause significant neurological and physical impairments. Symptoms typically begin in infancy with chronic diarrhea, followed by the development of cataracts in early childhood and tendon xanthomas in adolescence. As the disease progresses, individuals may experience ataxia, dementia, seizures, and other motor disturbances, along with an increased risk of osteoporosis and coronary artery disease.
CTX is inherited in an autosomal recessive pattern, meaning both parents must carry the defective gene for their child to be affected. Diagnosis can be challenging due to the variability in symptoms, but it can be confirmed through biochemical testing and genetic analysis. Although CTX is progressive and can be fatal if untreated, early diagnosis and treatment with chenodeoxycholic acid (CDCA) can significantly improve outcomes by normalizing bile acid production and stabilizing neurological function. Awareness and access to genetic testing are crucial for better management of this condition.
Cerebrotendinous xanthomatosis
ALSO KNOWN AS: Van Bogaert-Scherer-Epstein disease; xanthomatosis, cerebrotendinous; cerebral cholesterinosis; CTX
DEFINITION Cerebrotendinous xanthomatosis (CTX) is a slowly progressive genetic disorder caused by mutations in the CYP27A1gene, resulting in deficiency of the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1) and deposition of cholestanol (5-alpha-dihydro derivative of cholesterol) in nerve cells and body tissues. Excess cholestanol eventually damages the brain, spinal cord, tendons, lens of the eye, and arteries, leading to paralysis, ataxia, dementia, and/or coronary heart disease by adulthood.
Risk Factors
According to the US National Library of Medicine's Genetic Home Reference in 2014, CTX is rare, occurring in only an estimated 3 to 5 per 100,000 births worldwide, though the incidence is much higher in the Moroccan Jewish population, occurring in 1 per 108 births. More than three hundred patients have been diagnosed with CTX. Most experts believe that the is higher; however, no epidemiological studies exist to verify this.
CTX is an autosomal recessive disorder and can be inherited only if the parents each carry the defective CYP27A1 gene. For every pregnancy, the risk of the child inheriting both genes and being affected is 25 percent and the risk of the child inheriting one gene and being a carrier is 50 percent. Prenatal testing is available for at-risk populations and for those with a family history of CTX.
Etiology and Genetics
CTX is caused by defects in the CYP27A1 gene located on the long arm of chromosome 2 (2q33-qter). CYP27A1 belongs to the Cytochrome P450 superfamily, contains nine exons and eight introns, and consists of 33,515 bases spanning 18.6 kilobase pairs (kpb) of DNA. Mutations of the gene result in deficient CYP27A1, causing truncated versions of the enzyme, and involve mainly adrenodoxin-binding or heme-binding sites. Most alleles are point mutations (for example, amino acid substitution, frameshift, splice-junction variants). More than fifty mutations of the CYP27A1 gene have been identified, but no genotype-phenotype relationship has been established.
CTX is a lipid storage disease of bile acid synthesis. Bile acids play a major role in the body’s homeostasis, are necessary for the absorption of fats and fat-soluble vitamins, and serve as the main catabolic pathway for cholesterol. Cholesterol is the precursor for the synthesis of bile acids, and CYP27A1 is the initiating the first step in oxidizing the side chain of the sterol which metabolizes it to the primary bile acids, cholic acid, and chenodeoxycholic acid (CDCA).
In affected individuals who have the faulty CYP27A1 gene and lack the CYP27A1 enzyme, cholesterol is impaired, bile acid production is disrupted, and little or virtually no CDCA is formed. Instead, large amounts of bile alcohols are produced and excreted in urine, and the cholesterol-to-cholestanol ratio is altered, causing pathological storage of cholestanol in tissues and plasma, and eventually in the circulation and brain. Cholestanol is usually present in minute amounts but increases manyfold in the absence of CDCA and becomes toxic. Over time, as cholestanol deposits accumulate, lipid-filled nodules called xanthomas form, first in the Achilles and other tendons and then in the brain, most often in the cerebellar hemispheres and cerebellum. These lesions contain cholesterol and cholestanol in the form of lipid crystals and foamy cell granulomata, respectively, and are responsible for the characteristic ataxia and neurodegeneration associated with CTX.
Symptoms
CTX is characterized by these hallmark conditions: chronic, often intractable, diarrhea in infancy; cataracts in early childhood; and tendon xanthomas in adolescence, with progressive neurologic dysfunction occurring simultaneously or in early adulthood. Such symptoms include dementia and seizures, ataxia and motor disturbances, and peripheral neuropathy. Patients with CTX are also at greater risk for osteoporosis and coronary artery disease.
Screening and Diagnosis
CTX can be diagnosed by clinical features and biochemical testing. Despite the hallmark signs of the disorder, CTX can be difficult to diagnose; clinical presentation and time of onset can vary considerably, and tendon xanthomas may or may not be present. CTX should be suspected whenever there are complaints of chronic diarrhea and evidence of cataracts in the same patient. High cholestanol levels in tissues, plasma, and cerebrospinal fluid; increased concentrations of bile alcohols in urine; and greatly reduced or absent CDCA are diagnostic for CTX. Magnetic resonance imaging (MRI) can detect evidence of cerebral and cerebellar atrophy and xanthomatous lesions in the brain of affected patients. The definitive diagnosis is made by mutation analysis of the CYP27A1 gene coding for the CYP27A1 enzyme.
Treatment and Therapy
Unlike most genetic diseases, CTX is a treatable disorder, provided that it is diagnosed before irreversible damage to the nervous system occurs. First-line treatment for CTX is long-term administration of CDCA, which helps prevent further neurological degeneration. In most cases, treatment with exogenous CDCA normalizes cholestanol levels and bile acid synthesis, compensating for the lack of enzyme activity.
Prevention and Outcomes
Left untreated, CTX is a slowly progressive and fatal disease. Greater awareness and early diagnosis is crucial since treatment with CDCA can resolve the metabolic abnormalities, stabilize neurologic function, and stop progression of the disease. With genetic testing and a known treatment available, the prognosis for CTX is becoming less grim.
Bibliography
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Federico, Antonio, Maria Teresa Dotti, and Gian Nicola Gallus. "GeneReviews: Cerebrotendinous Xanthomatosis." NCBI. NCBI/NLM, 16 July 2023, www.ncbi.nlm.nih.gov/books/NBK1409/. Accessed 5 Sept. 2024.
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Moore, David, and James Jefferson. “Cerebrotendinous Xanthomatosis.” Moore and Jefferson: Handbook of Medical Psychiatry. 2d ed. Philadelphia: Elsevier, 2004. Print.
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