Cerebrotendinous xanthomatotic (CTX)

 Cerebrotendinous xanthomatotic (CTX)

Cerebrotendinous xanthomatotic (CTX) is a rare condition that affects the body's ability to metabolize fats known as cholesterols. Patients with CTX are unable to break down different forms of cholesterol, which build up in certain areas of the body.

Overview

Cerebrotendinous xanthomatotic (CTX) is a rare condition that affects the body's ability to metabolize fats known as cholesterols. Patients with CTX are unable to break down different forms of cholesterol, which build up in certain areas of the body.

CTX is characterized by fatty yellow nodules (xanthomas) located in the connective tissues within the brain. These deposits can cause progressive damage to the brain and other areas of the body. Patients with CTX do not have elevated levels of cholesterol in their blood; however, they do have elevated levels in their tissues.

Symptoms

Symptoms of CTX vary depending on the age of the patient, and the severity of the condition.

For infants and children, symptoms may include: 

Chronic diarrhea during infancy

Cataracts in late childhood

Frequent bone fractures due to brittle bones

When a patient with CTX enters into adulthood, they may begin to notice the following neurological symptoms:

Dementia

Seizures

Hallucinations

Depression

Difficulty with coordination

Difficulty with speech

The fatty deposits can also result in cardiovascular disease or stroke if they limit or block the blood flow to the heart or brain.

Causes

CTX is caused by a disease-causing (pathogenic) variant in the CYP27A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic variant of a gene occurs, the protein product or enzyme may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. In CTX, the gene variant is inherited in an autosomal recessive manner.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Disease-causing variants in the CYP27A1 gene result in deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into the bile acid chenodeoxycholic acid. The block in synthesis of this bile acid causes accumulation of bile acid pathway intermediates and cholestanol in blood and tissues of affected individuals. Cholestanol deposits can accumulate in nerve cells and membranes and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries.

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of CTX. Comparisons may be useful for a differential diagnosis.

Sitosterolemia is a rare autosomal recessive genetic condition caused by an abnormality in the ABCG8 gene or the ABCG5 gene, resulting in an accumulation of cholesterol and other types of lipids called sterols in body tissues. Symptoms include clusters of fatty tumors in the skin of joints (tuberous xanthomas), on the tendons (tendon xanthomas), plaque deposits in the arteries (atherosclerosis), and coronary artery disease. Joint stiffness and pain can develop. In some cases affected individuals may have low levels of circulating red blood cells due to the premature destruction of red blood cells (hemolytic anemia). (For more information on this disorder, choose “sitosterolemia” as your search term in the Rare Disease Database.)

Familial hypercholesterolemia (FH) is characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol, often called the “bad” cholesterol. The levels of another blood lipid, triglycerides, are usually normal and the levels of high-density lipoprotein (HDL) cholesterol (the “good” cholesterol) are typically low or normal. The condition greatly increases the risk of atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions. Untreated men with FH often develop symptoms of coronary heart disease (CHD) in their early forties and women, in their early fifties. If one or more other major risk factors for CHD are present, especially cigarette smoking and diabetes mellitus, the risk of developing symptomatic CHD is greatly increased. Women without other major risk factors for CHD may survive to old age without developing symptomatic disease. Additional symptoms include the formation of fatty tumors of the tendons (tendinous xanthomas), cholesterol deposits on the eyelids (xanthelasmas), and a curved appearance of the corneas of the eyes (corneal arcus). (For more information on this disorder, choose “hypercholesterolemia” as your search term in the Rare Disease Database.)

Differential Diagnosis

Familial hypercholesterolemia and other forms of autosomal dominant hypercholesterolemias are potential causes of tendon xanthomas. With familial hypercholesterolemia, however, laboratory testing typically shows increased levels of total cholesterol and LDL cholesterol, which are not features of CTX.

Sitosterolemia is an inherited sterol storage disease characterized by tendon xanthomas and by strong predisposition to premature atherosclerosis. However, primary neurologic signs, diarrhea, and cataracts are not present in this disease.

Smith-Lemli-Optiz syndrome (SLOS) has many signs and symptoms of CTX, including juvenile cataract and xanthomas. SLOS is an autosomal recessive disorder associated with mutations in DHCR7 gene that reduces or eliminates the activity of 7-dehydrocholesterol reductase. This enzyme is responsible for the final step of cholesterol production. These patients have learning and behavioral dysfunction, however these patients often present with microcephaly, hypotonia, and hearing/speech problems. Unlike CTX, those with SLOS have hypocholesterolemia.

Diagnosis

The diagnosis of CTX is often delayed until the fourth decade of life. CTX should be suspected in patients with some combination of infantile onset diarrhea, juvenile onset bilateral cataracts, adolescent to young adult-onset tendon xanthoma, and adult-onset progressive neurologic dysfunction.

MRI studies of the brain are an important component of the diagnostic workup for CTX. It may show bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Other MRI findings may show signal alterations of the cerebral peduncle, corona radiate, and subcortical white matter. It should be known, however, that a normal MRI does not rule out CTX.

Biochemical testing can be performed which may show high plasma and tissue cholestanol concentration. A normal to low plasma cholesterol concentration is seen. Markedly decreased formation of chenodeoxycholic acid from impaired primary bile acid synthesis, and increased concentration of bile alcohols and their glycoconjugates in bile, urine, and plasma are features. Increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid from changes in the blood-brain barrier can be seen.

Molecular testing for mutations in the CYP27A1 gene using sequence analysis or deletion/duplication analysis can be performed. This is the gold standard for diagnosis. Genetic molecular testing in symptomatic suspected patients and in presymptomatic family members should be considered in consultation with a Geneticist and/or Genetics Counselor. More than 50 mutations in the CYP27A1 gene have been reported to be associated with CTX. The most frequent mutations of the CYP27A1 gene are distributed from exons 1 to 8. The majority of mutations are amino acid substitutions; splice site mutations have also been reported.

Enzyme assays for reduced activity of sterol 27-hydroxylase enzymatic activity can be performed as well.

There are proposed suspicion index tables that include family history, systemic symptoms, and neurologic factors that can be used to help aid in the diagnosis of CTX. Patients with a high suspicion index score (> or =100) should have assessment of serum cholestanol concentrations. Those with high plasma cholestanol concentrations should proceed to CYP27A1 gene sequencing.

There has been no suitable test to screen newborn dried bloodspots (DBS) for CTX, however development of a methodology to enable sensitive detection of ketosterol bile acid precursors that accumulate has been investigated and reported by DeBarber AE et al. In reports, Newborn DBS concentrations of this ketosterol (120–214 ng/ml) were about 10-fold higher than in unaffected newborn DBS (16.4 ± 6.0 ng/ml).

Treatment

Treatment for CTX is available in the form of oral chenodeoxycholic acid (CDCA). Berginer VM et al. published findings in 1984 showing that long-term treatment of CTX with chenodeoxycholic acid suppressed abnormal endogenous bile acid synthesis, lowered elevated plasma cholestanol levels, and exerted a beneficial effect on the course of neurologic diseases in the majority of the subjects they tested.

The Food and Drug Administration recently approved chenodeoxycholic acid.

Treatment of CTX in the preclinical stage can reportedly prevent the onset of disease complications. Because of this, the value of an early diagnosis for CTX is extremely important.

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