Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Masquerading as Charcot-Marie-Tooth Disease: A Case Study and Literature Review of Korean Patients

Article information

J Mov Disord. 2025;18(1):93-95

Publication date (electronic) : 2024 July 9

doi : https://doi.org/10.14802/jmd.24054

Yongmoo Kim¹, Seungbok Lee^2,3, Jae So Cho^2,3, Jihoon G Yoon², Sheehyun Kim², Man Jin Kim², Jong Hee Chae^2,3, Manho Kim^1,4, Jangsup Moon^1,2,

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 2024 March 3; Revised 2024 May 22; Accepted 2024 July 8.

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].

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.

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.