Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of sterol 27-hydroxylase due to mutations in the CYP27A1 gene. It was first reported by Van Bogaert et al. in 1937.
Impaired bile acid synthesis leads to accumulation of cholestanol and bile alcohols in the brain, peripheral nerves, lens, tendons, bones, and other tissues, resulting in a variety of systemic symptoms.
The prevalence in the United States is estimated at 3–5 per 100,000 people. Approximately 400–425 cases have been reported worldwide, but underdiagnosis is likely. Among Moroccan Jews, the frequency is as high as 1 in 108. It is slightly more common in women.
About 259 mutations are known in the CYP27A1 gene, of which 85 are considered pathogenic or likely pathogenic4). Among the mutation types, splice site mutations are the most common at 29%, with mutations concentrated in exon 44).
In a large case series (49 cases), cataracts were found in 92%, pyramidal tract signs in 92%, cerebellar signs/peripheral neuropathy in 82%, tendon xanthomas in 78%, and cognitive impairment in 78%. The mean age at diagnosis was 35.5 years, with a delay of over 16 years from symptom onset to diagnosis.
Ma et al. (2021) reviewed 25 cases reported between 2016 and 2019 and found neurological symptoms in 92%, cataracts in 60%, tendon xanthomas in 68%, and chronic diarrhea in 20%5). The mean age was 36.6 years.
The onset and severity of symptoms are variable, and infantile diarrhea or juvenile cataracts are easily mistaken for other diseases. It is often overlooked until neurological symptoms appear, and CYP27A1 may not be included in initial gene panel testing1). Diagnostic delay can lead to irreversible neurological damage, so it is important to consider this disease when juvenile cataracts or unexplained diarrhea are present.
The clinical presentation of CTX varies depending on the age of onset.
The main clinical findings of CTX are broadly divided into ophthalmic findings, tendon xanthomas, and neurological findings.
Ophthalmic Findings
Juvenile cataract: The most frequent finding (92%). A morphology of posterior subcapsular cataract with cortical fleck-like opacities is considered characteristic of CTX 2).
Xanthelasma: Cholesterol deposition on the eyelids.
Optic atrophy: May be accompanied by afferent pupillary defect and central scotoma.
Tendon Xanthomas
Achilles tendon xanthoma: The most common site. Usually appears in the late teens to twenties.
Other sites: Also occur in the extensor tendons of the elbows and fingers, patellar tendon, and tendons of the neck.
When non-palpable: In some cases, xanthomas are not palpable and are first discovered on MRI 3).
Neurological Findings
Pyramidal tract signs: spastic paraplegia, hyperreflexia, positive Babinski sign.
Cerebellar signs: ataxia, dysarthria, nystagmus.
Cognitive impairment/dementia: progresses from the 20s, with more than half developing dementia.
Even among siblings with the same CYP27A1 mutation, phenotypes can differ. In one report, one of two brothers with the same homozygous mutation had dentate nucleus calcification and cerebellar atrophy, while the other had normal MRI findings6). A report of an Iranian family also showed differences in pes cavus, epilepsy, and xanthoma location among three siblings with the same mutation4).
A rare clinical manifestation is pulmonary involvement.
Zaizen et al. (2021) reported a 55-year-old CTX patient with diffuse micronodular shadows on chest CT, and transbronchial lung biopsy revealed foamy macrophages and lipid crystal clefts7). After two years of CDCA treatment, serum cholestanol decreased from 28 μg/mL to 5.9 μg/mL, and the lung lesions also shrank.
Posterior subcapsular cataract with cortical fleck-like opacities is considered characteristic of CTX 2). It is usually bilateral and develops between ages 4 and 18. Since cataract is the first symptom in 75% of CTX patients, the possibility of CTX should be considered when young bilateral cataracts are observed.
CTX is an autosomal recessive disorder caused by mutations in the CYP27A1 gene (chromosome 2q35).
CYP27A1 encodes mitochondrial sterol 27-hydroxylase, which converts cholesterol to chenodeoxycholic acid (CDCA). Deficiency of this enzyme leads to the following metabolic abnormalities.
Cholestanol deposits particularly in the brain, peripheral nerves, lens, tendons, and bones, causing organ damage.
More than 50 pathogenic variants have been reported, with missense mutations accounting for approximately 45% 6). Homozygous mutations are frequently observed in consanguineous families 4). Even with the same mutation, phenotypes can vary greatly, and genotype-phenotype correlation is poor 4).
CTX is an autosomal recessive disorder; if both parents are carriers, 25% of siblings may be affected. If a family member has been diagnosed with CTX, even asymptomatic individuals should consider CYP27A1 genetic testing and plasma cholestanol measurement after consulting a genetic counselor.
Diagnosis of CTX requires a comprehensive approach combining clinical suspicion, biochemical tests, imaging studies, and genetic analysis1).
CTX should be suspected when there is a combination of chronic diarrhea starting in infancy, juvenile bilateral cataracts, tendon xanthomas, and progressive neuropsychiatric symptoms. A “suspicion index” table has been proposed as a diagnostic aid, and a score of 100 or more should prompt measurement of serum cholestanol.
| Test Item | Characteristic |
|---|---|
| Plasma cholestanol | Elevated 5 to 10 times normal |
| Plasma cholesterol | Normal to low |
| Urinary bile alcohols | Markedly elevated |
Plasma cholestanol is the most accessible biomarker 2). Tendon xanthomas in patients with normal cholesterol levels should strongly suggest CTX.
Brain MRI is important in the diagnostic workup of CTX.
Brain MRI abnormalities were found in 84% (21/25) of reported cases, but CTX cannot be ruled out even if MRI is normal 5).
O’Keefe et al. (2025) reported a case of a 53-year-old woman who was presumed to have hereditary spastic paraplegia based on a 25-year history of spastic paraplegia. Achilles tendon MRI revealed xanthomas, and biochemical and genetic testing led to a diagnosis of CTX 1). The initial gene panel did not include CYP27A1, contributing to diagnostic delay.
Sequence analysis of the CYP27A1 gene is the gold standard. If a variant of uncertain significance (VUS) is detected, pathogenicity is determined by integrating clinical, biochemical, and imaging findings according to ACMG guidelines 1).
Fernandez-Eulate et al. (2022) prospectively performed cholestanol screening in 30 patients with juvenile bilateral cataract of unknown cause 2). One patient (3.3%) showed markedly elevated cholestanol (68 μmol/L, normal <10) and was diagnosed with CTX. This patient was a 19-year-old female with posterior capsular cataract accompanied by cortical fleck-like opacities.
The standard treatment for CTX is oral administration of chenodeoxycholic acid (CDCA).
The effectiveness of CDCA strongly depends on the age at treatment initiation.
A review by Ma et al. (2021) showed that patients who started treatment after age 25 had a poorer prognosis compared to the early treatment group, and improvement of advanced neurological impairment was difficult5).
O’Keefe et al. (2025) reported a case diagnosed at age 53 and started on CDCA 750 mg/day, achieving clinical stability and biochemical improvement (decreased serum cholestanol, normalized urinary bile alcohols) over 3 years, but without improvement of pre-existing neurological impairment1).
Surgery is considered for large tendon xanthomas that do not shrink with drug therapy.
Qi et al. (2023) resected bilateral Achilles tendon xanthomas (each 16 cm) and performed reconstruction using a vascularized iliotibial ligament 8). A good functional outcome was achieved with an AOFAS score of 100/100 at 9 years postoperatively.
Nakazawa et al. (2021) performed endoscopic resection of an olecranon tendon xanthoma in a 44-year-old CTX patient 9). There was no recurrence and no sensory disturbance at the surgical site at 2 years postoperatively.
Early treatment initiation as soon as possible is recommended. Patients who started treatment after age 25 have been shown to have a poorer prognosis compared to the early treatment group 5). Starting CDCA before the onset of symptoms can prevent the development of disease complications, and the significance of diagnosis and treatment initiation at the stage of juvenile cataract is extremely important.
The CYP27A1 gene is located on chromosome 2q35 and consists of 9 exons. The largest transcript is approximately 1895 bp in length and encodes a 531-amino acid sterol 27-hydroxylase 4). The mature enzyme consists of 498 amino acids and includes a 33-amino acid mitochondrial signal sequence 4).
Sterol 27-hydroxylase belongs to the mitochondrial cytochrome P450 family and catalyzes the side-chain oxidation of sterol intermediates. The adrenodoxin binding site (residues 351–365) and heme binding site (residues 435–464) are highly conserved 4). It is also involved in the hydroxylation of vitamin D3 at the C-1 and C-25 positions 4).
Normally, cholesterol is converted to CDCA by sterol 27-hydroxylase and excreted as bile acids. Enzyme deficiency leads to the following:
Accumulation of cholestanol in the brain is thought to activate apoptotic pathways, leading to neuronal cell death6). MRI signal changes in the dentate nucleus reflect demyelination and axonal degeneration secondary to lipid deposition5).
T2/FLAIR/SWI hypointensity in the dentate nucleus appears over time and reflects demyelination, hemosiderin deposition, microcalcification, necrosis, and cystic changes5). This change may serve as a biomarker of disease progression predicting clinical and MRI worsening despite CDCA treatment5).
Rashvand et al. (2021) reported that the c.1184+1G>A splicing mutation identified in an Iranian family generates three aberrant transcripts 4). All abnormal proteins lack the ferredoxin-binding domain and/or heme-binding domain, and enzyme activity was undetectable.
Development of a screening method for CTX using dried blood spots (DBS) from newborns is progressing. A highly sensitive detection method for accumulated ketosterol bile acid precursors has been reported, and DBS concentrations in CTX patients (120–214 ng/mL) were approximately 10 times higher than in unaffected infants (16.4±6.0 ng/mL).
In a prospective cohort study by Fernandez-Eulate et al. (2022), 1 out of 30 patients (3.3%) with juvenile bilateral cataract was diagnosed with CTX through cholestanol screening 2). This patient did not present other CTX symptoms, demonstrating the usefulness of early diagnosis based solely on cataract. The cataract cohort had a significantly higher rate of moderate cholestanol elevation compared to the control group (17.2% vs. 4.2%; p=0.014).
Cases have been reported where diagnosis was delayed because CYP27A1 was not included in the initial gene panel 1). When spastic paraplegia or progressive neurodegenerative disease is suspected, it is recommended to use a comprehensive gene panel including CYP27A1, or to perform whole exome sequencing.
