Cerebrotendinous Xanthomatosis

Abstract

Objectives

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder that may be underdiagnosed in Latin America (LatAm).

Methods

We describe 6 Mexican individuals with CTX from 2 unrelated families and review published LatAm cases. MEDLINE was searched (1966–October 2025) for CTX cases reported in LatAm in English, Portuguese, or Spanish. Twenty studies including 28 patients from 23 families were identified, and international CTX cohorts were selected for comparison.

Results

Individuals from one Mexican family carried compound heterozygous CYP27A1 variants (c.562C>T and c.1016C>T), whereas those from the other family harbored homozygous c.944_948del. Parkinsonism and dystonia were prominent among Mexican patients. Most LatAm cases were male, with childhood onset and a mean diagnostic age of 41.7 ± 16.17 years. Xanthomas, cataracts, diarrhea, and movement disorders were frequent. Elevated cholestanol levels were detected in 14 of 34 individuals. Genetic testing was performed in 24 of 34 individuals; all tested individuals had pathogenic CYP27A1 variants. Dentate nuclei abnormalities were the main brain MRI findings. Chenodeoxycholic acid was used in 13 of 34 cases.

Discussion

Besides classic CTX features, brownish dental enamel, hyperlordosis, and urinary incontinence were identified among some LatAm patients. Symptom onset was earlier in LatAm than in other regions. Diarrhea and neurologic symptoms with early-onset cataracts or xanthomas should prompt genetic testing for CTX.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by pathogenic variants in CYP27A1, leading to cholestanol deposition and progressive systemic and neurologic dysfunction.^1-3 CTX incidence in the Americas is estimated at approximately 1 per 72,000–150,000 individuals, with marked geographic variability worldwide (highest prevalence in Asia [1 per 44,407–93,084 individuals] and the lowest in Finland [1 per 3,388,767]).^4,5 Hallmark manifestations include early-onset cataracts, diarrhea, tendon xanthomas, and neuropsychiatric symptoms.⁴ Early diagnosis is essential because chenodeoxycholic acid (CDCA) may prevent irreversible neurologic impairment.^e1 We describe 2 Mexican families with CTX and compare LatAm individuals with international cohorts.

Methods and Cases

We described 6 Mexican individuals with CTX from 2 unrelated families and reviewed published LatAm cases. CYP27A1 testing was performed using whole-exome next-generation sequencing at a commercial laboratory. MEDLINE (1966–October 2025) was searched for “cerebrotendinous xanthomatosis,” “CTX,” and “CYP27A1” in English, Portuguese, or Spanish reports. Of 258 identified articles, 20 describing 28 patients who resided in LatAm were included. International CTX cohorts with detailed clinical characterization were selected for comparison. A Brailian cohort^e2 was excluded because individual-level data were unavailable, although its findings were used for comparisons. Approximate ages at symptom onset were assigned accordingly when developmental stages or decades were reported.³ Variants were annotated according to Human Genome Variation Society nomenclature using transcript NM_000784.3. Cholestanol levels were standardized to mg/dL when necessary. Statistical analysis is described in eMethods. Clinical features from the Mexican participants are summarized in the Supplementary Material (eAppendix 1). References for the published LatAm patients and international CTX cohorts are provided in eReferences.^e1-e28

Standard Protocol Approvals, Registrations, and Patient Consents

This study was approved by the ethics committees of participating hospitals. Written informed consent for video publication was obtained.

Data Availability

All data relevant to the study are included in this article and its supplementary material.

Results

Our analysis included 6 unpublished cases from Mexico (17.65%) and 28 previously published LatAm cases from 20 articles. Published cases were from Brazil (11 individuals, 32.35%),^e3-e10 Argentina (4 individuals, 11.76%),^e11-e13 Chile (5 individuals, 14.71%),^e14-e17 Colombia (5 individuals, 14.71%),^e18,e19 Peru (2 individuals, 5.88%),^e20,e21 and Ecuador (1 individual, 2.94%).^e22

eTable 1 provides clinicodemographic and genetic findings from LatAm patients. eTable 2 summarizes CTX cohorts reported worldwide. Brain MRI findings and pedigrees from the Mexican cases are shown in Figures 1 and 2, respectively. Video 1 and Video 2 illustrate the clinical features from both Mexican families.

Figure 1. Brain MRI Findings From Mexican Individuals With CTX.

T2-weighted images are shown on the left, and FLAIR images are shown on the right in each panel. (A) Axial T2 and FLAIR images at the lower pontine level showing moderate cerebellum atrophy with bilateral hyperintense lesions surrounding the dentate nuclei. (B) Axial T2 and FLAIR images at the lower pontine level demonstrating mild-to-moderate cerebellum atrophy with a right cystic degeneration lesion with hyperintense halo involving the dentate nuclei, a characteristic finding frequently reported in CTX. (C, D, and E) Axial T2 and FLAIR sections at the level of the cerebellar peduncles showing bilateral hyperintense lesions involving the dentate nuclei, respectively. FLAIR = fluid-attenuated inversion recovery.

Figure 2. Pedigrees of Mexican Individuals Affected by CTX.

(A) Individuals F1-III-3 and F1-III-4 had genetically confirmed CTX, carrying compound heterozygous CYP27A1 variants c.562C>T and c.1016C>T. (B) Individuals F2-III-3, F2-III-4, and F2-III-5 carried the homozygous CYP27A1 variant c.944_948del, confirming the diagnosis. In generations I and II, individuals were not clinically or genetically evaluated for CTX; symbols denote relevant comorbidities reported as family history, including chronic obstructive pulmonary disease, obstructive sleep apnea, hypertension, type 2 diabetes mellitus, cerebrovascular disease, dementia, breast cancer, and gastric carcinoma. d. = deceased; E1+ = physical examination; E2+ = MoCA; E3+ = brain MRI; E4+ = whole-exome sequencing; MRI: magnetic resonance imaging; MoCA = Montreal Cognitive Assessment; y = years.

Video 1

Family 1. Family 1 shows 2 siblings (out of 6) manifesting a parkinsonian syndrome mixed with cerebellar, dystonic, and pyramidal signs. Xanthomas are evident in the knees of both patients.Download Supplementary Video 1 ^{(38.4MB, mp4)} via http://dx.doi.org/10.1212/200443_Video_1

Video 2

Family 2. Family 2 shows 3 siblings (out of 5) with a mixture of cognitive decline, parkinsonism, and dystonia. Mild unstable gait is also found in case F2-III-5. Xanthomas are easily seen at different joint levels in all patients.Download Supplementary Video 2 ^{(31.7MB, mp4)} via http://dx.doi.org/10.1212/200443_Video_2

Among 34 participants, 14 of 34 (41.2%) were female and 11 of 34 (32.4%) showed consanguinity. The mean age at onset was 9.2 ± 8.1 years, whereas the mean age at diagnosis was 41.7 ± 16.17 years, resulting in a mean diagnostic delay of 31.59 ± 14.77 years, with no gender differences in any of these comparisons. The most frequent systemic manifestations were juvenile cataracts (24/34 [70.59%]), xanthomas (21/34 [61.76%]), and diarrhea (13/34 [38.24%]). Achilles tendon enlargement or edema was noted in 9 of 34 cases (26.47%).

Cognitive decline (23/34 [67.65%]), pyramidal signs (20/34 [58.82%]), and movement disorders (24/34 [70.59%]) were common neurologic manifestations. Cerebellar syndrome occurred in 15 of 34 cases (44.12%), whereas tremor and parkinsonism were each observed in 9 of 34 (26.47%). Psychiatric symptoms, polyneuropathy, dystonia, seizures, and cranial nerve involvement were less frequent.

Cholestanol levels were available in 14 of 34 individuals, with a mean level of 2.79 ± 3.03 mg/dL, without significant differences among countries. One value was excluded because of a possible reporting error.^e14 Brain MRI was performed in 24 of 34 participants, showing cerebellar involvement in 17 of 24 (70.8%) and dentate nuclei abnormalities in 9 of 17 (52.94%). Treatment was described in 19 of 34 individuals. CDCA was used in 13 of 34 cases, either alone (11/34) or combined with vitamin D or simvastatin (1/34 each). Other treatments included levodopa, statins, ezetimibe, psychiatric medications, and dietary interventions.

Genetic testing was performed in 24 of 34 individuals (18 individuals from LatAm and 6 from Mexico), all confirming a pathogenic CYP27A1 variant. Fourteen participants carried homozygous variants and 10 compound heterozygous variants. The most frequent variant was c.1183C>T in exon 6, identified in either homozygous or compound heterozygous state. Other reported variants included c.1183_1184insT,^{e5,e11,e13,e15-e18} c.1213C>T,^e12 c.1185-1G>A,^e15 c.1435C>G, and c.1435C>T^e8 (eTable 1). Individuals from Mexican Family I carried compound heterozygous c.562C>T and c.1016C>T variants, resulting in p.[Arg188*]; [Thr339Met], whereas those from Family II harbored c.944_948del p.(Leu315Glnfs*15).

Discussion

This report describes 2 Mexican families with genetically confirmed CTX and expands the available data from LatAm.

Symptom onset was earlier in the LatAm cohort compared with other regions, whereas diagnostic age remained relatively delayed. Juvenile cataracts, xanthomas, diarrhea, pyramidal signs, cognitive decline, and movement disorders were among the most frequent CTX manifestations in LatAm individuals, consistent with international cohorts (eTable 2). Movement disorders commonly included ataxia, tremor, parkinsonism, dystonia, and gait disturbances, including early-onset parkinsonism,^e15 as previously reported.⁶ Neuropsychiatric symptoms and epileptic seizures were less frequent, whereas rare findings included brownish dental enamel, hyperlordosis, urinary incontinence, bilateral facial palsy, akathisia, and spasmodic dysphonia-like symptoms.^{e5,e11-e14,e18} Dentate nuclei abnormalities were the predominant neuroimaging finding, while cortical/cerebellar atrophy, spinal cord hyperintensities, intracranial calcifications, and metabolic or perfusion abnormalities were also observed.^e3,e4,e9,e16 Elevated cholestanol levels were consistently observed in genetically confirmed cases.

The most frequent variant identified in LatAm individuals was c.1183_1184insT, previously reported in Spanish and Brazilian cohorts.^e2,e24 Mexican individuals carried distinct pathogenic variants, including compound heterozygous c.562C>T and c.1016C>T variants in Family I and c.944_948del p.(Leu315Glnfs*15) in Family II, broadening the genetic spectrum of CTX in LatAm in accordance with previous international reports.^7-9

CDCA remains the main treatment and was associated with clinical improvement in 69% (9/13) of LatAm participants treated. Early treatment is particularly important because delayed therapy is associated with worse outcomes.¹⁰

Compared with the reported Brazilian cohort,^e2 our series showed earlier symptom onset and longer diagnostic delay, supporting underrecognition of CTX in LatAm.

This study expands the clinical and genetic characterization of CTX in LatAm by including 6 genetically confirmed Mexican individuals and comparison with international cohorts. Limitations include the absence of individualized data from the reported Brazilian cohort,^e2 which reduced the number of analyzable participants, and missing clinical information in some retrospective reports.

Conclusion

Nearly 70 individuals with CTX have been reported in LatAm, although the disease likely remains underdiagnosed. Neurologic symptoms associated with early-onset cataracts, diarrhea, or xanthomas should prompt consideration of CTX, particularly in patients with movement disorder. Early CDCA treatment may improve outcomes and quality of life.

Author Contributions

H.R. Martínez-Hernández: major role in the acquisition of data; study concept or design; analysis or interpretation of data. L. Villa-Villegas: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. C.E. Piña-Avilés: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. R. Leal-Ortega: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. M. Sáenz-Farret: drafting/revision of the manuscript for content, including medical writing for content; study concept or design A. Camacho-Molina: major role in the acquisition of data; analysis or interpretation of data. C. Zúñiga-Ramírez: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data.

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures.