Cerebrotendinous Xanthomatosis (CTX) Clinical Presentation

Updated: Jul 07, 2017
  • Author: Robert D Steiner, MD; Chief Editor: Maria Descartes, MD  more...
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Presentation

History

Typically, untreated cerebrotendinous xanthomatosis (CTX) follows a progressive course. Mignarri et al recently proposed a suspicion index for earlier diagnosis of cerebrotendinous xanthomatosis with weighted scores assigned to indicators of disease. [21] Four clinical criteria are used in diagnosis; the presence of any 2 of the criteria warrants testing for cerebrotendinous xanthomatosis, although because this is a treatable disorder, testing when only 1 criterion is present is reasonable. The criteria include intractable diarrhea, presenile cataracts, tendinous xanthomas, and neurologic abnormalities. The symptoms usually manifest themselves in that order, although atypical cases have been reported and the disease spectrum widely varies, even among families. To date, no genotype-phenotype correlation has been reported.

Common findings

Chronic, sometimes intractable diarrhea occurs, with onset typically in infancy. The diarrhea continues through adulthood if left untreated. [22] Neonatal or infantile hepatitis and prolonged jaundice have been described. [8, 23]

The typical onset of ocular symptoms is in the first decade of life, rarely earlier than age 5 years. The following ocular findings are noted:

  • Bilateral, presenile cataracts that may be corticonuclear, anterior pole, or dense posterior opacities [24, 25, 26, 27]
  • Optic disk pallor
  • Premature retinal senescence with retinal vessel sclerosis
  • Cholesterol-like deposits along vascular arcade
  • Myelinated retinal nerve fibers [28]
  • Rarely, palpebral xanthelasma, proptosis (described once), and optic nerve atrophy
  • Unique bilateral fleck lenticular deposits have been described in affected children prior to development of capsular opacities [29]

Juvenile cataracts may be a presenting sign. [27] Xanthomas are rarely seen before age 20 years, although an exaggerated phenotype may be observed in patients with heterozygous familial hypercholesterolemia and cerebrotendinous xanthomatosis. [30] They are usually found on the Achilles tendon but may also be found on the patella, elbow, hand, and neck tendons. They have also been reported on the parenchyma of the lungs and brain, as well as in the bones. See the images below for examples.

Sixteen-year-old male with cerebrotendinous xantho Sixteen-year-old male with cerebrotendinous xanthomatosis. Note the xanthomas on his knuckles.
Sixteen-year-old male with cerebrotendinous xantho Sixteen-year-old male with cerebrotendinous xanthomatosis.
Xanthomas of the Achilles tendon. Photo courtesy o Xanthomas of the Achilles tendon. Photo courtesy of William Connor, MD, Oregon Health and Science University.
Xanthomas on the knees in a patient with cerebrote Xanthomas on the knees in a patient with cerebrotendinous xanthomatosis. Photo courtesy of William Connor, MD, Oregon Health and Science University.

Neurologic symptoms tend to manifest in the third decade of life; however, children and young adults may have below-average intelligence, occasionally severe mental retardation, with worsening and deterioration in the third decade of life. In one study, neurologic symptoms were broken down into extrapyramidal (81%), low intelligence (66%), and cerebellar signs (56%). [21] Polyneuropathy was present in 31% of patients, and only 16% of patients had seizures, although seizures can be the presenting symptom. [31] The latter is a lower estimate in relation to other reports. Other symptoms include the following:

  • Fronto-temporal dementia [10, 28]
  • Spasticity (both periventricular white matter and isolated spinal cord disease)
  • Cerebellar symptoms and ataxia (with other neurologic signs or isolated) [32]
  • Extrapyramidal symptoms, including dystonia and oromandibular dyskinesia [33]
  • Early-onset Parkinson disease [34]
  • Seizures
  • Peripheral neuropathy

Muscular symptoms may include myopathic facies and generalized feelings of weakness. [35]

Less common findings

Cerebrotendinous xanthomatosis has been associated with marked cardiovascular findings, including coronary and carotid vascular disease [20, 36] and atrial septal hypertrophy [37, 38]

Granulomatous bone lesions, osteopenia, osteoporosis, and pathologic fractures have been well described. The granulomas are typically in the femur and lumbar vertebrae; thoracic kyphosis has been described. [39]

Granulomatous lung disease has been reported based on bronchoalveolar lavage findings. [40] These patients did not have correlating clinical symptoms. Pulmonary xanthomas have also been described.

Although hypothyroidism is not a common manifestation, it appears to be one of the few endocrinologic complications. In one particular series, the proband case had an ectopic thyroid gland and typical neurologic changes associated with cerebrotendinous xanthomatosis; 4 patients in this study had cerebrotendinous xanthomatosis and hypothyroidism. [41]

A single case report described a case of "minimal change" nephrotic syndrome and cerebrotendinous xanthomatosis in a Japanese adult. [42]

Osteoporosis, tooth loss, cataracts, dementia and parkinsonism, and heart disease can mimic signs of aging at an earlier age. [43]

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Physical

See History.

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Causes

Cerebrotendinous xanthomatosis is a defect in bile acid synthesis, with subsequent overproduction and accumulation of cholestanol in multiple tissues of the body. It is caused by a defect in the CYP27A1 gene that codes for sterol 27-hydoxylase. The gene is located at 2q33-qter. It is an autosomal recessive disorder.

A recent review and update by Gallus et al identified mutations in exons 1-8 of the CYP27A1 gene but none in exon 9. [9] More than 50 mutations have been identified. Half of these are found in exons 6-8, and many have effects on enzyme heme-binding and adrenodoxin-binding sites. In one study, mutation analysis revealed mutations of all types, including missense (45%), nonsense (20%), splice site (18%), deletion (14%), and insertion (2%). [9]

Typically, affected individuals have mutations in both alleles; although sometimes homozygous, a substantial number of compound heterozygote patients have been described. Two heterozygous patients with clinical disease and decreased enzyme function have been reported, but no second mutation was identified despite an extensive search. [10, 44]

CYP27A1 was recently identified as a candidate gene for sporadic amyotrophic lateral sclerosis (ALS). [45] This is of interest as cerebrotendinous xanthomatosis can present as a clinical mimic of ALS with progressive upper motor neuron loss.

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