Cerebrotendinous Xanthomatosis (CTX) Clinical Presentation

Updated: Dec 08, 2021
  • Author: Austin Larson, MD; Chief Editor: Maria Descartes, MD  more...
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Untreated CTX usually follows a progressive course. Mignarri and colleagues proposed a suspicion index for earlier diagnosis of CTX with weighted scores assigned to indicators of disease. [24] Four clinical criteria are used in diagnosis; the presence of any two of the criteria warrants testing for CTX, although because this is a treatable disorder, testing when only one 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 within families. To date, no genotype-phenotype correlation has been reported.

Common findings

Chronic diarrhea occurs in a significant portion of patients and the onset may be in infancy. The diarrhea may continue through adulthood if left untreated. Neonatal or infantile hepatitis and prolonged jaundice have been described. [9, 25, 26]

Juvenile cataracts are often the presenting sign of CTX. [27, 22]  A recent study found that the prevalence of CTX in a cohort of 170 patients presenting with juvenile cataracts was 1.8%. [28]  

The typical onset of ocular symptoms is in the first decade of life, though 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 [29, 30, 31, 27]
  • Optic disc pallor
  • Premature retinal senescence with retinal vessel sclerosis
  • Cholesterol-like deposits along vascular arcade
  • Myelinated retinal nerve fibers [32]
  • Rarely, palpebral xanthelasma and optic nerve atrophy
  • Unique bilateral fleck lenticular deposits have been described in affected children prior to development of capsular opacities [33]

Tendon xanthomas are rarely seen before age 20 years, although an early onset phenotype may be observed in patients with concurrent heterozygous familial hypercholesterolemia and CTX. [34] 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. 

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 intellectual disability, with worsening and deterioration in the third decade of life. In one study, neurologic symptoms were broken down into extrapyramidal (81%), cognitive impairment (66%), and cerebellar signs (56%). [24] Peripheral neuropathy was present in 31% of patients, and 16% of patients had seizures, although seizures can be the presenting symptom in rare cases. [35]  Importantly, all of these symptoms are progressive and age-dependent, so the cumulative incidence by age of each symptom is an informative way to understand the natural history of CTX. [22]

Other symptoms include the following:

  • Fronto-temporal dementia [11, 32]
  • Spasticity (both periventricular white matter and isolated spinal cord disease)
  • Cerebellar symptoms and ataxia (with other neurologic signs or isolated) [36]
  • Extrapyramidal symptoms, including dystonia and oromandibular dyskinesia [37]
  • Early-onset  Parkinson disease  [38]
  • Seizures
  • Peripheral neuropathy

Muscular symptoms may include myopathic facies and generalized feelings of weakness. [39]

Less common findings

Neonatal cholestasis has been observed repeatedly. [40] Cerebrotendinous xanthomatosis has been associated with marked cardiovascular findings, including coronary and carotid vascular disease [23, 41] and atrial septal hypertrophy [42, 43]

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. [44]

Granulomatous lung disease has been reported based on bronchoalveolar lavage findings. [45] 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 CTX; four patients in this study had CTX and hypothyroidism. [46]

A single case report described a case of "minimal change" nephrotic syndrome and CTX in a Japanese adult. [47]

Osteoporosis, tooth loss, cataracts, dementia and parkinsonism, and heart disease can mimic signs of aging at an earlier age. [48]




See History.



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. 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. [10] More than 50 different mutations have been identified. Half of these are found in exons 6 to 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%). [10]

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. [11, 49]

CYP27A1 was recently identified as a candidate gene for sporadic amyotrophic lateral sclerosis (ALS). [50] This is of interest as CTX can present as a clinical mimic of ALS with progressive upper motor neuron loss.