Skip Navigation
Skip to contents

JMD : Journal of Movement Disorders

OPEN ACCESS
SEARCH
Search

Articles

Page Path
HOME > J Mov Disord > Volume 18(1); 2025 > Article
Letter to the editor
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Masquerading as Charcot-Marie-Tooth Disease: A Case Study and Literature Review of Korean Patients
Yongmoo Kim1orcid, Seungbok Lee2,3orcid, Jae So Cho2,3orcid, Jihoon G Yoon2orcid, Sheehyun Kim2orcid, Man Jin Kim2orcid, Jong Hee Chae2,3orcid, Manho Kim1,4orcid, Jangsup Moon1,2corresp_iconorcid
Journal of Movement Disorders 2025;18(1):93-95.
DOI: https://doi.org/10.14802/jmd.24054
Published online: July 9, 2024

1Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

2Department of Genomic Medicine, Seoul National University Hospital, Seoul, Korea

3Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea

4Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Korea

Corresponding author: Jangsup Moon, MD, PhD Departments of Genomic Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea / Tel: +82-2-2072-4265 / Fax: +82-2-765-7920 / E-mail: jangsup.moon@gmail.com
• Received: March 3, 2024   • Revised: May 22, 2024   • Accepted: July 8, 2024

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.

prev next
  • 1,038 Views
  • 101 Download
Dear Editor,
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by the triad of cerebellar ataxia, progressive spasticity, and peripheral neuropathy, and a number of pathogenic mutations of the SACS gene have been reported in ARSACS patients [1]. The SACS gene encodes the multidomain protein sacsin, the highest expression of which occurs in the motor system, including the cerebellum, granular system, and Purkinje cells [1]. Literature reviews in recent decades revealed ARSACS cases outside of Quebec, where the initial cases were documented, and previous reports have revealed atypical clinical manifestations of ARSACS in East Asian countries [2]. Among the differential diagnoses for peripheral neuropathy, foot deformity and ataxia, Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disease, with multiple subtypes and associated genes [3]. However, a recent study revealed that the clinical profiles of ARSACS and CMT may overlap in multiple domains, and it is becoming increasingly difficult for clinicians to make diagnoses on the basis of clinical manifestations alone [4]. Here, we report a case that was initially suspected to be CMT with an atypical clinical manifestation and was rediagnosed with ARSACS according to a gene panel test and segregation analysis.
A 33-year-old female patient previously suspected of having unspecified CMT was referred to the outpatient clinic of the rare disease center of Seoul National University Hospital due to progressive gait disturbance. She reached the normal developmental milestones for early ages, except starting to walk at 15 months after birth. Other developmental milestones were intact, except difficulties running, which were revealed to be fallacious at age 12. At approximately age 16, her gait disturbance became prominent, and her symptoms were progressively aggravated. At another hospital, she received a clinical diagnosis of CMT despite negative genetic test results for Charcot-Marie-Tooth disease type 1A (CMT1A) and PMP22. Nerve conduction studies (NCSs) revealed findings consistent with mixed-type sensorimotor polyneuropathy (Supplementary Table 1 in the online-only Data Supplement). No cerebellar dysfunction or ataxia was noted at the time.
On physical and neurological examinations at outpatient clinics at age 33, she exhibited pes cavus (Figure 1A), and the Babinski signs of both feet were extensors, implying upper motor neuron involvement. She could not stand by herself without the aid of a cane, and she also exhibited gaze-evoked nystagmus without spontaneous nystagmus. Other cerebellar findings including finger-to-finger and rapid alternating movement tests were negative. She exhibited ataxic-paraparetic gait with some spasticity. Tandem gait could not be assessed due to gait disturbance. Due to abnormal reflexes in the lower extremity and a typical foot deformity, a NCS was performed. The results indicated a demyelinating type of sensorimotor polyneuropathy, supporting the possibility of CMT disease. However, genetic analysis of CMT-related genes yielded negative results for the duplication of PMP22 and for other mutations in MFN2, MPZ, and GJB1 [3].
With the advent of next-generation sequencing (NGS), gene panel analysis has become more affordable and accessible. In this context, a comprehensive ataxia gene panel consisting of 41 genes (Supplementary Material in the online-only Data Supplement) was performed to investigate the cause of her ataxia. Genetic analysis of the SACS gene revealed one pathogenic variant (P) and one variant of unknown significance (VUS): c.2439_2440del, p.Val815Glyfs*4, heterozygote (P), and c.10897T>G, p.Phe3633Val, heterozygote (VUS). Segregation analysis was performed on the patient’s parents, who were found to be heterozygous carriers, and the patient was compound heterozygous for the SACS variants (Figure 1B). Therefore, we reclassified the VUS (c.10897T>G, p.Phe3633Val) as likely pathogenic variant (LP) and genetically diagnosed the patient with ARSACS.
For reverse phenotyping, we retrospectively reviewed the patient’s symptoms and observed several clinical features, including gaze-evoked nystagmus and an extensor Babinski sign, which are unusual for CMT disease. Optical coherence tomography (OCT) conducted on both eyes of the patient revealed thickening of the peripapillary retinal nerve fiber layer beyond the 95th percentile. This finding supports the diagnosis of ARSACS rather than other genetic disorders presenting with ataxia, such as Friedreich ataxia and spinocerebellar ataxia (Figure 1C) [5]. Brain magnetic resonance imaging (MRI) also revealed characteristic findings of ARSACS, including cerebellar atrophy (Figure 1D) and linear T2-hypointensities in the bilateral paramedian pons (Figure 1E and F).
ARSACS is a rare autosomal recessive form of ataxia, and a limited number of cases have been previously reported in Korea, particularly genetically confirmed cases (Supplementary Table 2 in the online-only Data Supplement). In this case report, we present an instance of a young female initially presumed to have CMT disease, which was later revealed to be ARSACS. For patients in whom CMT disease is suspected but genetic irregularities are not identified, if there are clinical indications such as gaze-evoked nystagmus suggestive of cerebellar ataxia, it becomes crucial to also consider the possibility of ARSACS.
The sacsin gene (SACS) is located on chromosome 13, spanning 10 exons and encoding the 520-kDa protein sacsin, which is prominently expressed in the Purkinje cells of the cerebellum. Mutations in SACS lead to early-onset cerebellar ataxia [1]. Consequently, early-onset cerebellar ataxia, along with gaze-evoked nystagmus, is a significant distinguishing factor between CMT disease and ARSACS.
Compared with the first ARSACS patients, who exhibited all three clinical features, several East Asian patients did not exhibit spasticity, one of the upper motor neuron signs [6]. Notably, the presence of upper motor neuron signs has also been reported in CMT disease [7]. Considering the clinical variations, if an extensor toe sign is present, we recommend conducting brain MRI and ophthalmic examinations, including OCT. This case highlights the importance of using NGS panels in patients with previously negative genetic tests when there is clinical suspicion. Notably, in autosomal recessive disorders, VUSs can be reclassified as LP variants through additional family testing, as observed in the present case. To summarize, in cases where CMT disease is suspected and genetic abnormalities are not identified, genetic testing including the SACS gene should be conducted.
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24054.
SUPPLEMENTARY MATERIAL
jmd-24054-Supplementary-Material.pdf
Supplementary Table 1.
Comprehensive motor and sensory NCS data for the left limb
jmd-24054-Supplementary-Table-1.pdf
Supplementary Table 2.
Clinical manifestations of reported cases of ARSACS in South Korea
jmd-24054-Supplementary-Table-2.pdf

Ethics Statement

This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Seoul National University Hospital (2410-147-1579). The participant provided informed consent.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Jangsup Moon. Data curation: Yongmoo Kim. Formal analysis: Man Jin Kim. Investigation: Yongmoo Kim, Jangsup Moon. Methodology: Jangsup Moon, Manho Kim. Project administration: Yongmoo Kim, Jangsup Moon. Resources: Jangsup Moon. Software: Man Jin Kim. Supervision: Jangsup Moon. Validation: Yongmoo Kim, Jangsup Moon. Visualization: Yongmoo Kim, Jangsup Moon, Man Jin Kim. Writing—original draft: Yongmoo Kim. Writing—review & editing: all authors.

None
Figure 1.
Clinical and genetic profile of the patient. A: The patient exhibited high arches in both feet, a condition known as pes cavus. B: Segregation analysis confirmed that the patient had compound mutations in the SACS gene. C: OCT of both eyes revealed a thickened RNFL above the 95th percentile. D, E, and F: Brain MRI revealed cerebellar atrophy (D, arrowhead) and pontine linear T2-hypointensities in the bilateral paramedian area (E and F, arrows) (D, sagittal T1; E, axial T2; F, axial T2-FLAIR). RNFL, retinal nerve fiber layer; TMP, temporal; SUP, superior; NAS, nasal; INF, inferior; OCT, optical coherence tomography; MRI, magnetic resonance imaging; FLAIR, fluid attenuated inversion recovery.
jmd-24054f1.jpg
  • 1. Parfitt DA, Michael GJ, Vermeulen EG, Prodromou NV, Webb TR, Gallo JM, et al. The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum Mol Genet 2009;18:1556–1565.ArticlePubMedPMC
  • 2. Synofzik M, Soehn AS, Gburek-Augustat J, Schicks J, Karle KN, Schüle R, et al. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet J Rare Dis 2013;8:41.ArticlePubMedPMC
  • 3. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009;8:654–667.ArticlePubMed
  • 4. Zaman Q, Khan MA, Sahar K, Rehman G, Khan H, Rehman M, et al. Novel variants in MPV17, PRX, GJB1, and SACS cause Charcot-MarieTooth and spastic ataxia of Charlevoix-Saguenay type diseases. Genes (Basel) 2023;14:328.ArticlePubMedPMC
  • 5. Parkinson MH, Bartmann AP, Clayton LMS, Nethisinghe S, Pfundt R, Chapple JP, et al. Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay. Brain 2018;141:989–999.ArticlePubMed
  • 6. Shimazaki H, Takiyama Y, Honda J, Sakoe K, Namekawa M, Tsugawa J, et al. Middle cerebellar peduncles and pontine T2 hypointensities in ARSACS. J Neuroimaging 2013;23:82–85.ArticlePubMed
  • 7. Xu YS, Zhang S, Liu XX, Sun AP, Fan DS. [Assessment of upper motor neuron dysfunction by triple stimulation technique in patients with Charcot-Marie-Tooth disease]. Zhonghua Yi Xue Za Zhi 2016;96:1660–1663.Chinese. PubMed

Figure & Data

References

    Citations

    Citations to this article as recorded by  

      Comments on this article

      Add a comment
      Figure
      • 0
      Related articles
      Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Masquerading as Charcot-Marie-Tooth Disease: A Case Study and Literature Review of Korean Patients
      Image
      Figure 1. Clinical and genetic profile of the patient. A: The patient exhibited high arches in both feet, a condition known as pes cavus. B: Segregation analysis confirmed that the patient had compound mutations in the SACS gene. C: OCT of both eyes revealed a thickened RNFL above the 95th percentile. D, E, and F: Brain MRI revealed cerebellar atrophy (D, arrowhead) and pontine linear T2-hypointensities in the bilateral paramedian area (E and F, arrows) (D, sagittal T1; E, axial T2; F, axial T2-FLAIR). RNFL, retinal nerve fiber layer; TMP, temporal; SUP, superior; NAS, nasal; INF, inferior; OCT, optical coherence tomography; MRI, magnetic resonance imaging; FLAIR, fluid attenuated inversion recovery.
      Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Masquerading as Charcot-Marie-Tooth Disease: A Case Study and Literature Review of Korean Patients

      JMD : Journal of Movement Disorders Twitter
      Close layer
      TOP