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Letter to the editor
Diagnosing Cerebrotendinous Xanthomatosis in a Middle-Aged Woman With Cervical Dystonia -
Wei-Sheng Wang1
, Yu-Ping Chiu1, Meng-Han Tsai2,3, Shey-Lin Wu4,5
, Yen-Chung Chen1,6,7 -
Journal of Movement Disorders 2025;18(2):182-184.
DOI: https://doi.org/10.14802/jmd.24202
Published online: January 20, 2025
1Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
2Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
3School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
4Department of Neurology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan
5Department of Electrical Engineering, National Changhua University of Education, Changhua, Taiwan
6Department of Public Health, Chung Shan Medical University, Taichung, Taiwan
7Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, Taiwan
- Corresponding author: Yen-Chung Chen, MD, PhD Department of Neurology, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua city, Changhua 50006, Taiwan / Tel: +886-4-7238595 # 7891 / E-mail: 180300@cch.org.tw
- Corresponding author: Shey-Lin Wu, MD, PhD Department of Neurology, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 50544, Taiwan / Tel: +886-4-7813888 / E-mail: wusheylin@gmail.com
• Received: September 28, 2024 • Revised: November 27, 2024 • Accepted: January 17, 2025
Copyright © 2025 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Dear Editor,
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder caused by mutations in the CYP27A1 gene. Biallelic pathogenic variants in CYP27A1 contribute to a deficiency in sterol 27-hydroxylase [1], disrupting bile acid synthesis and cholesterol metabolism pathways and ultimately leading to the formation and deposition of abnormal lipid contents in various tissues, particularly the brain, tendons, lenses, and peripheral nerves.
Owing to its multisystemic involvement, CTX presents with a wide and heterogeneous clinical spectrum, including neonatal cholestatic jaundice, juvenile cataracts, chronic diarrhea, osteoporosis, cerebellar ataxia, peripheral neuropathy, epilepsy, movement disorders, pyramidal signs, cognitive decline, neuropsychiatric problems, and characteristic xanthomas [2]. These diverse clinical symptoms make prompt and accurate diagnosis challenging, often leading to underdiagnosis.
In this article, we present the case of a middle-aged woman who visited the neurology clinic with the troubling complaint of involuntary cervical movements. Detailed neurological examinations revealed cerebellar ataxia, to which the patient had likely adapted and did not perceive as serious. Due to the presence of xanthomas and distinctive abnormalities on brain magnetic resonance imaging (MRI), the patient was promptly referred for CYP27A1 gene sequencing to confirm the diagnosis of CTX.
A 52-year-old woman visited the neurology clinic due to involuntary movements in the cervical region that had developed over the past month. She described her head intermittently tilting backward and turning to the side without conscious control. Her medical history included urolithiasis, breast cancer, uterine myoma, and cataracts. She denied any long-term medication usage or exposure to occupational toxins. No other family members exhibited similar symptoms. She self-reported normal developmental milestones and completed her education at a vocational high school.
Further detailed neurological examination revealed cervical dystonia, characterized by a combination of torticollis and retrocollis. Other findings included smooth pursuit with mild hypermetric saccades, mild dysdiadochokinesia, mild dysmetria in finger-nose-finger and heel-knee-shin tests, bilateral extensor plantar reflex, failed tandem gait, and a positive retropulsive pull test (Supplementary Video 1 in the online-only Data Supplement). Additionally, bilateral enlarged subcutaneous nodules over the Achilles tendons were observed (Supplementary Figure 1 in the online-only Data Supplement). These subcutaneous nodules could be traced back to her adolescence. Her husband reported observing subtle cognitive decline in recent years, such as easily forgetting recent conversations and occasionally miscalculating amounts while shopping.
Laboratory examinations were conducted to assess nutrient levels, metabolic function, and endocrinological parameters. The results revealed only a mild elevation in lipid profiles (Supplementary Table 1 in the online-only Data Supplement). Subsequent brain MRI revealed symmetric hyperintensities affecting the bilateral dentate nucleus (Figure 1). Given these findings, CTX was highly suspected. After obtaining informed consent, Sanger sequencing was performed, and two pathogenic variants were identified in the CYP27A1 gene: c.409C>T (R137W) and c.1435C>T (R479C) (Supplementary Figure 2 in the online-only Data Supplement). Both of these variants are well-documented pathogenic variants of CTX.
Although the clinical presentations of CTX are highly heterogeneous, there are diagnostic criteria and suspicion indices that can aid clinicians in the timely diagnosis of this elusive disease in clinical practice. The Mignarri suspicion index assigns different weights to family history, systemic symptoms, and neurological involvement, categorizing these factors as very strong, strong, or moderate indicators (Supplementary Table 2 in the online-only Data Supplement) [3]. A suspicion index score of 200 or greater warrants direct sequencing of the CYP27A1 gene, whereas a score of 100 or higher justifies plasma analysis of the cholestanol levels. Elevated cholestanol levels indicate the need for CYP27A1 gene sequencing. Additionally, diagnostic criteria have been proposed on the basis of the studies by Sekijima et al. [4] and Stelten et al. [5] (Supplementary Table 3 in the online-only Data Supplement). In our case, the suspicion index score was 200, indicating that direct referral of the patient for Sanger sequencing of the CYP27A1 gene was both prudent and efficient, leading to a prompt diagnosis. The patient was subsequently confirmed to have definite CTX.
CTX is a rare but treatable disease. Chenodeoxycholic acid has been shown to be an effective replacement therapy that can restore bile acid synthesis and terminate abnormal lipid content deposition. In addition to normalizing plasma cholestanol levels, chenodeoxycholic acid also helps stabilize systemic symptoms and neurological manifestations. Nevertheless, prognosis largely depends on how early treatment begins. Older age at diagnosis, characteristic imaging changes in the dentate nucleus on brain MRI, and existing neuropsychiatric involvement are associated with a poorer prognosis [2]. Therefore, to facilitate early diagnosis and management, experts have suggested the implementation of a national newborn screening program. However, this proposal requires careful consideration, as it may lead to the detection of mild variants that might not cause any pathological symptoms during a person’s lifetime [1].
No concrete genotype‒phenotype correlation has been established for the various CYP27A1 gene variants, although some specific features have been sporadically documented. Notable associations include c.1421G>A (R474Q) with classical CTX, c.1214G>A (R405Q) with spinal CTX, and c.435G>T (G145G) with nonneurological CTX [1]. According to a case series with a brief review by Lee and colleagues [6], CTX patients in Taiwan often exhibit compound heterozygous mutations, with hotspots at exon 2, exon 8, and intron 7, and no evidence of a founder effect. Our case represents an example of classical CTX. Among movement disorders, parkinsonism is the most frequently reported disorder, followed by dystonia, myoclonus, and postural tremor [7]. Although movement disorders are a rare clinical feature of CTX, the condition should still be considered in the differential diagnosis, particularly in patients presenting with cognitive impairment, cerebellar signs, chronic diarrhea, young-onset cataracts, and especially tendon xanthomas.
In conclusion, CTX is a rare but treatable autosomal recessive disorder caused by variants in the CYP27A1 gene. Owing to the multisystem involvement, timely and accurate diagnosis of CTX is challenging. However, the earlier the treatment is initiated, the less neurological burden the patient will experience, and the slower the disease will progress. Although no definite genotype‒phenotype correlation has been established, attention should be given to the rare but significant presentation of movement disorders, including parkinsonism and dystonia. As shown in this patient, the presence of cervical dystonia should raise suspicion for CTX, especially when accompanied by cognitive impairment, cerebellar signs, chronic diarrhea, young-onset cataracts, and tendon xanthomas. Addressing the challenges of delayed diagnosis and underrecognition of CTX is crucial, and recognizing cervical dystonia as a potential symptom highlights the need for heightened clinical awareness.
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24202.
Supplementary Fig 1.
Xanthomas over the Achilles tendons since the patient’s adolescence.
Supplementary Fig 2.
Sanger sequencing for the CYP27A1 gene identified two pathogenic variants: c.409C>T (R137W) and c.1435C>T (R479C).
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Ethics Statement
Written informed consent was obtained from the participant for the publication of this case report.
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
None
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Acknowledgments
None
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Author Contributions
Conceptualization: Shey-Lin Wu, Yen-Chung Chen. Data curation: Wei-Sheng Wang, Yu-Ping Chiu, Meng-Han Tsai. Investigation: Wei-Sheng Wang, Yu-Ping Chiu, Meng-Han Tsai. Methodology: Wei-Sheng Wang, Yu-Ping Chiu. Project administration: Shey-Lin Wu, Yen-Chung Chen. Resources: Shey-Lin Wu, Yen-Chung Chen. Supervision: Shey-Lin Wu. Validation: Wei-Sheng Wang, Yu-Ping Chiu. Visualization: Wei-Sheng Wang, Yu-Ping Chiu. Writing—original draft: Wei-Sheng Wang. Writing—review & editing: Shey-Lin Wu, Yen-Chung Chen.
Notes
Figure 1.
Brain MRI demonstrated symmetric hyperintensity affecting the bilateral dentate nucleus, with highly suspicion of CTX. T2 FLAIR, T2-weighted-fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; CTX, cerebrotendinous xanthomatosis.
- 1. Nóbrega PR, Bernardes AM, Ribeiro RM, Vasconcelos SC, Araújo DABS, Gama VCV, et al. Cerebrotendinous xanthomatosis: a practice review of pathophysiology, diagnosis, and treatment. Front Neurol 2022;13:1049850.PubMedPMC
- 2. Koyama S, Sekijima Y, Ogura M, Hori M, Matsuki K, Miida T, et al. Cerebrotendinous xanthomatosis: molecular pathogenesis, clinical spectrum, diagnosis, and disease-modifying treatments. J Atheroscler Thromb 2021;28:905–925.ArticlePubMedPMC
- 3. Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis 2014;37:421–429.Article
- 4. Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y. Nationwide survey on cerebrotendinous xanthomatosis in Japan. J Hum Genet 2018;63:271–280.ArticlePubMedPDF
- 5. Stelten BML, Dotti MT, Verrips A, Elibol B, Falik-Zaccai TC, Hanman K, et al. Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study. Orphanet J Rare Dis 2021;16:353.ArticlePubMedPMCPDF
- 6. Lee CW, Lee JJ, Lee YF, Wang PW, Pan TL, Chang WN, et al. Clinical and molecular genetic features of cerebrotendinous xanthomatosis in Taiwan: report of a novel CYP27A1 mutation and literature review. J Clin Lipidol 2019;13:954–959.e1.ArticlePubMed
- 7. Stelten BML, van de Warrenburg BPC, Wevers RA, Verrips A. Movement disorders in cerebrotendinous xanthomatosis. Parkinsonism Relat Disord 2019;58:12–16.ArticlePubMed
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XML DownloadDiagnosing Cerebrotendinous Xanthomatosis in a Middle-Aged Woman With Cervical Dystonia
Figure 1. Brain MRI demonstrated symmetric hyperintensity affecting the bilateral dentate nucleus, with highly suspicion of CTX. T2 FLAIR, T2-weighted-fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; CTX, cerebrotendinous xanthomatosis.
Figure 1.
Diagnosing Cerebrotendinous Xanthomatosis in a Middle-Aged Woman With Cervical Dystonia
