Novel SACS Variants not Recorded in ClinVar Identified in a Chinese Patient with Late-Onset Hereditary Neuropathy: a Case Report and Literature Review

Abstract

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder due to mutations in the SACS gene. While the typical phenotype is characterized by cerebellar ataxia, spasticity, and peripheral neuropathy, more reports are published of atypical and late-onset presentations, also lacking typical cerebellar signs of the disease, which can mimic Charcot-Marie-Tooth disease (CMT). We report a 58-year-old Chinese male with a 12-year history of progressive gait instability and lower limb weakness, who also exhibited retinal degeneration. Remarkably, in contrast to the majority of ARSACS patients, he had no significant spasticity, thus expanding the phenotypic spectrum. Genetic analysis identified a pathogenic compound heterozygous mutation in SACS: a novel frameshift variant (c.178del, p.Asp60ThrfsTer8) in exon 4, unreported in ClinVar, and a missense variant (c.4723 C > T, p.Arg1575Trp) in exon 10, documented in ClinVar with conflicting interpretations. The exceptionally late onset in this patient suggests that the c.178del frameshift may partially preserve sacsin function, thereby delaying disease manifestation. MLPA analysis excluded CMT1/HNPP-related rearrangements, confirming an ARSACS diagnosis. Familial segregation further supported autosomal recessive inheritance, emphasizing the importance of family screening. Given this, our case suggests a potential extended therapeutic window in late-onset ARSACS and may need to be included in future therapeutics efforts, emphasizing the importance of identifying such atypical forms. This observation highlights the importance of thorough genetic testing in achieving a correct diagnosis and providing treatment for patients with undiagnosed progressive ataxia.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12311-025-01909-9.

Introduction

ARSACS is an autosomal recessive neurodegenerative disease first reported in Quebec, Canada, characterized by mutations in the SACS gene which encodes the mitochondrial and cytoskeletal protein sacsin; its classic phenotype shows an early onset during childhood with cerebellar ataxia, spasticity, and peripheral neuropathy [5, 19]. In the last decades, a growing number of descriptions of patients with an atypical and even late-onset clinical picture, that diverges from the classical description, have been reported [3, 14, 18, 20]. In China, only a few genetically confirmed ARSACS cases have been described, and the clinical phenotype is not well-established so far [8, 15]. Herein, we report a case of an adult-onset ARSACS patient and we conduct an extensive review of the literature restricted to late-onset ARSACS, underlining its genetic and clinical variability.

Case Report

Patient Information

A 58-year-old man was brought in with a 12-year history of increasing lower limb weakness and unsteadiness in his gait, which started around age 46. His gait gradually deteriorated to the point where he needed full support and walking aids. The patient had retinal degeneration as well. Family history is significant for a sister with a history of gait instability (details unknown) and parental genetic testing is not available.

Clinical Examination

The patient had a clear consciousness, was oriented and cooperative. There were equal and round (approximately 3 mm in diameter), reactive to light, pupils in both eyes. There was coarse nystagmus bilaterally on horizontal gaze, but the other eye movements were normal. Bilateral hearing was reduced, consistent with a longstanding (> 10-year) sensorineural hearing loss (Rinne test: air conduction > bone conduction; Weber lateralized to the better ear). Facial structures were symmetrical and the tongue was in the midline position. Motor strength was 5/5 in the upper limbs and 4/5 in the lower limbs, with the lower-limb weakness being mild and distal-predominant; muscle mass was reduced in the lower extremities. Muscle tone was normal (Modified Ashworth Scale score 0, assessed independently by multiple examiners, indicating no spasticity). The deep tendon reflexes were absent in all 4 extremities. Pain was diminished bilaterally (greater in the lower limbs); the perception of vibration became diminished at the level of the iliac crest and missing at the ankles. Finger-to-nose testing revealed mild dysmetria on the left side (right side normal). The patient could not perform the heel-knee-shin test due to severe unsteadiness and refused further attempts. He also could not stand unaided (Romberg’s test was not possible), likely due to marked truncal ataxia combined with proprioceptive loss, despite relatively preserved strength and normal tone. There were bilateral positive Babinski signs. Furthermore, on physical examination, we found pes cavus (Fig. 1A). The presence of lower extremity weakness, atrophy, sensory loss, and pes cavus supported initial concern for Charcot-Marie-Tooth disease, particularly when follow-up EMG studies confirmed neuropathy.

Fig. 1.

Multimodal Evaluation of the Patient. A: Clinical photograph demonstrating bilateral pes cavus, a hallmark foot deformity. B: Optic nerve scan image showing no obvious abnormalities. C and D: Brain MRI T1-weighted image revealing cerebellar atrophy (C, arrowhead) and bilateral linear T2-FLAIR hypointensities in the paramedian region of the pons (D, arrows). E: Pedigree chart and SACS gene sequencing chromatograms of the patient and his son. The arrow in the pedigree marks the proband. Genetic analysis identified compound heterozygous mutations in the patient and his son is a heterozygous carrier of the SACS c.178del variant. FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging

Electromyography (EMG)

EMG showed symmetrical, multi-focal, motor-sensory peripheral neuropathy (length-dependent), primarily demyelinating with secondary axonal degenerations. (Supplementary Table S3 provides the original electrophysiology report.)

Ocular Examination

No fundoscopy and no OCT were undertaken. Figure 1B presents a regular optic nerve scan with no evident anomalies. The patient denied further ophthalmologic examination for personal reasons.

Neuroimaging Findings

Brain MRI showed cerebellar atrophy on T1-weighted images, and linear hypointensities on T2-weighted and FLAIR images in the bilateral paramedian pons (Fig. 1C and D)—a finding that has been described as typical MRI signs of ARSACS [12, 13].

Genetic Analysis (Fig. 1E)

Whole-exome sequencing identified compound heterozygous mutations in the SACS gene including a novel null frameshift mutation c.178del (p.Asp60ThrfsTer8) of exon 4 (classified as pathogenic, ACMG class V) and a missense mutation c.4723 C > T (p.Arg1575Trp) of exon 10 (classified as likely pathogenic, ACMG class IV, supported by multiple in silico predictions. In silico prediction results for both variants are summarized in Supplementary Table S2. The MLPA analysis, performed to check for a PMP22 duplication or deletion (the causes of CMT1A/HNPP) as well as large deletions/duplications in MPZ and GJB1, revealed no abnormalities. In addition, the substitution c.178del was identified in a heterozygous state in the patient’s son who is asymptomatic, thus confirming the autosomal recessive mode of inheritance.

Treatment and Follow-up

A diagnosis of ARSACS was made according to clinical, neuroimaging, and genetic criteria. The patient has been treated with pharmacological and physical rehabilitation. Pharmacological Therapy: Vitamin Bl, mecobalamin, coenzyme Q10, buspirone to improve neuronal metabolism and for neuroprotection. Physical Therapy: A formalized plan of care consisting of gait balance, and strength exercises was used to enhance motor coordination and function during activities of daily living. Six months post follow-up, the patient’s symptomatology and physical examination findings had not changed, indicating that the proposed therapeutic mixed intervention might preserve functional levels.

Literature Review>

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was first reported in the Charlevoix and Saguenay regions of Quebec, Canada, where a founder effect caused a high local prevalence [5]. Initial reports described ARSACS as a childhood-onset condition with a characteristic clinical triad: cerebellar ataxia, pyramidal signs, and a combined peripheral neuropathy (axonal + demyelinating) [6, 11]. Magnetic resonance imaging (MRI) findings, including atrophy of the superior cerebellar vermis and elongated linear hypointensities in the pons, have been widely described as diagnostic features [16, 23]. Epidemiological reports from different cohorts point out that ARSACS might be more prevalent in some populations than initially postulated [2, 9].

The evidence has continued to grow over the years, however, that ARSACS is not restricted to early childhood. For example, [3] described that out of 85 suspected patients, five developed symptoms after 20 years of age with the oldest person having the first symptoms at 40 years and thus defined the late-onset form of ARSACS [3]. Furthermore, in the study of a Russian individual, Russian investigators reported of a patient (37 years old) with symptoms starting at the age of 32 with moderate cognitive decline, again noted as surprising in view of the severe truncating mutations which are usually associated with early-onset disease [18]. Additionally, in addition to the confirmation of reports from different geographic regions including Japan, China, Tunisia, Italy, and Turkey, that have described the global presence of late-onset cases, there is a wide range of age of onset and phenotype [10, 21]. Molecularly, its gene, SACS, had been mapped to chromosome 13q12. 12) gene product referred to as sacsin, is characterized as a large multidomain protein that is implicated in mitochondrial dynamics, neurofilament assembly and protein quality control [4, 11]. Although the majority of SACS mutations (missense, nonsense, frameshift, and copy number variations) result in almost complete lack of sacsin function and tend to present a more severe ARSACS phenotype at younger age, the existence of mutations producing residual protein activity have been described that provide a milder, delayed ARSACS phenocopy [3, 18]. For example, mutations anterior to the extremely large exon or those to the contrary end of the disease of partial gene deletions might leave some sacsin expression, leading to delayed clinical presentation [3, 14]. Studies using homozygosity mapping in consanguineous families have expanded the known spectrum of SACS mutations, revealing complex genotype–phenotype correlations and underscoring the need for comprehensive genetic testing in ARSACS [20]. SACS gene mutations in our late onset ARSACS cohort are shown in Fig. 2 with our case mutations highlighted. Specific mutation details were listed in Supplementary Table S1.

Fig. 2.

Distribution of SACS Gene Mutations in Late-Onset ARSACS Patients

In clinical practice, the symptomatology of adult-onset ARSACS can be atypical with respect to the triad. Patients with onset after 10 years of age may have less spasticity—occasionally even only brisk reflexes, without hypertonia—and initial manifestations may be dominated by peripheral neuropathy, also resulting in misdiagnosis (e.g., as Charcot–Marie–Tooth disease); as such, onset in the third decade appears to be common [3, 22]. In a number of cases, late-onset forms of the disease can also manifest with more variable degree of cerebellar ataxia and, in some cases, mild cognitive or psychiatric symptoms [1, 18]. The cerebellar and pontine changes continue to be detectable by MRI in these patients, but the changes may be milder at the onset and throughout the disease, likely corresponding to a more indolent disease course [18, 23]. Recent research that takes into account patient-reported outcomes has drawn attention to wider effects on everyday life including fatigue, problems with balance, and decreased social participation which are not entirely reflected by traditional neurological examination [1].

The high-throughput sequencing, copy number variation analysis, and establishment of induced pluripotent stem cell (iPSC) models have deepened our understanding of ARSACS pathogenesis [4, 17]. These reports imply that a minor loss of sacsin function is sufficient to disturb mitochondrial distribution and neurofilament dynamics, which may in turn lead to Purkinje cells degeneration [7, 14].

In conclusion, the recent literature indicates that ARSACS is a genetically and clinically diverse disease. The classical early-onset disease is still the most known, but a relevant proportion of patients come to medical attention at later stages of life with atypical features which may lead to a diagnostic delay. A comprehensive knowledge of all types of SACS mutations and their phenotypic consequence is crucial for more accurate diagnosis and identifying potential therapeutic targets. Again, as the research landscape continues to develop, the unison between molecular understanding and comprehensive clinical evaluation will facilitate addressing the complexities of this disorder.

Discussion

From a molecular perspective, late-onset ARSACS cases may be due to mutations that allow retention of some sacsin function. From a genetic standpoint, the new mutation is a novel frameshift c.178del (p.Asp60ThrfsTer8), which enlarges the mutational spectrum of the SACS gene, since thus far it has not been previously reported in ClinVar. Of interest, while c.178del is a frameshift mutation in an 5’ exon, the fact that the observed onset is rather late in our patient hints that this variant might be a hypomorph that contributes to a protective allele. In other words, the mutation may spare some minimal residual sacsin function, thus limiting the neurodegenerative course. This hypothesis is consistent with what has been observed in type I, late-onset ARSACS individuals in which at least one mutation results in some residual protein activity ​ [3]. For example, [3] described adult-onset ARSACS patients carrying one truncating SACS mutation together with a non-truncating or partially overlapping deletion; based on these cases, a partial loss-of-function mechanism was postulated. Conversely, knock-in mice carrying an N-terminal missense mutation (p.Arg272C) in SACS had a moderate ataxia phenotype, suggesting that specific N-terminal mutations could cause reduced, late-onset disease​ [14]. To our knowledge, no other ARSACS cases harboring a similar early truncating mutation (close to the N-terminus of the SACS protein) have been described in the literature, possibly due to rarity of these mutations and/or failure to recognize late–onset presentations. Conversely, the missense mutation c.4723 C > T (p.Arg1575Trp) was reported in ClinVar (Variation ID: 1709385) but its pathogenicity is unclear with conflicting interpretations. This particular arginine at position 1575 is indeed a hotspot for mutations – the neighbouring variant c.4724G > A (p.Arg1575Gln) is designated with conflicting interpretations of pathogenicity(Variation ID: 930257), whereas c.4724G > C (p.Arg1575Pro) has a definitive pathogenic annotation (Variation ID: 989207). MLPA for MPZ, PMP22, and GJB1 (genomic coordinates as per UCSC hg19) ruled out large genomic rearrangements as frequently observed in CMT1/HNPP, further supporting the ARSACS diagnosis. In addition, the finding of a heterozygous mutation c.178del in the asymptomatic son of patient further supports autosomal recessive inheritance. This identification has several important genetic counseling implications. First, the family we describe supports the occurrence of late penetrance in ARSACS—biallelic mild mutations carriers can remain asymptomatic until mid-adulthood as in the proband presented here​ [3]. The takeaway is that family members at risk should not conclude they are unaffected based on the absence of symptoms in childhood or young adulthood. Second, the patient’s son, who is a c.178del carrier, would not experience any symptoms other than the likelihood of having fewer children than expected. He should be told that he has a 50% chance of inheriting the mutation from his father. Their offspring having both mutations could potentially present with ARSACS, even if late in life, if his future wife is also a carrier. So proactive screening of family members — and counseling around the results for those who test positive, as was the case with the son, who also received counseling related to future family planning and about the symptoms of ARSACS, even if the symptoms might not present early in life — is necessary. This observation emphasizes the need for extensive family testing in ARSACS and demonstrates that even late-onset phenotypes follows the classical autosomal recessive pattern of inheritance. Apart from diagnosis and counseling, identification of late-onset ARSACS has important therapeutic implications. Particularly, the very late-onset presentation in our patient indicates some degree of partial sacsin function conserved by the c.178del mutation, leading to delayed disease manifestation. This indicates that some of the genotypes lead to longer subclinical disease duration, potentially extending the pre-symptomatic phase and creating opportunities for early intervention. Discovering such disease modifiers may shed light on the pathophysiology of ARSACS and help in selecting the patients who would benefit most from future treatments. Second, individuals who develop ARSACS in mid and late adult life will have a longer preclinical and early phase of the disease duration and hence may have more prolonged therapeutic window for intervention. Indeed new treatments, such as gene therapy intending to reinstate sacsin expression, could benefit especially to this category. [3] underscored that ARSACS patients are more common than previously thought and often underdiagnosed due to atypical presentations​ [3], implying that identifying these patients earlier could open the door for treatment. Patients with late-onset disease, having relatively preserved neuronal function leading into adult years, would be ideal targets for such interventions, as they potentially have more to gain from interventions implemented before the severe disability has occurred. Therefore, early identification and correct diagnosis of late-onset ARSACS is crucial not only for the understanding the patient’s disease but also in order to maximize his or her chances to be involved in future disease-modifying trials.

Conclusion

This report expands the phenotypic spectrum of ARSACS by presenting a non-spastic, adult onset case in a Chinese patient who was initially misdiagnosed as having Charcot–Marie–Tooth disease. Novel SACS frameshift (c.178del) and missense (c.4723 C > T) variants further extends the necessity for detailed genetic screening of progressive ataxia. The late-onset phenotype in this case indicates that some genotypes may confer partial sacsin function and affect disease progression. Late-onset patients also preserve more “neurological reserve” at time of diagnosis, possibly eligible for next-generation therapies like gene therapy. Identification and accurate diagnosis of such cases does not only improve patient care, but also offer valuable information for disease-modifying therapies.

Study Limitations

A number of limitations must be noted. Firstly, the observed genotype-phenotype correlation is not generalizable due to the single-patient design. Secondly, pathogenicity interpretations are based mainly on in silico predictions and database annotations; experimental validation (such as sacsin expression assays) was not carried out to directly confirm the functional impact of the *SACS* variants. The third limitation of the familial segregation analysis was that only the proband’s son was tested; the parents and siblings were not available because of privacy concerns, which limited the confirmation of inheritance. Finally, this study is unable to establish causal relationships because it is an observational case report. These drawbacks emphasize the necessity of more research with bigger sample sizes and functional characterization.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

M.C.: Data curation, Formal analysis, Software, Investigation, Writing – Original Draft; X.W.: Writing – Review & Editing, Project administration; J.W.: Supervision, Writing – Review & Editing;X.Y., H.F., Z.W.: Data curation, Investigation, Formal analysis; J.Y., W.W.: Formal analysis.All authors have read and approved the final manuscript.

Funding

This work was supported by the Hangzhou Medical and Health Technology Project (grant number: A20210513), the Hangzhou Science and Technology Development Plan (grant number: 20241203A12), and the Construction Fund of Key Medical Disciplines of Hangzhou (No. 2025HZGF02).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval

 This study was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Hangzhou Normal University.

Consent to Participate

This study was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Hangzhou Normal University. Written informed consent to participate was obtained from all individual participants prior to inclusion in the study, in accordance with institutional requirements and the Declaration of Helsinki.

Consent to Publish

Written informed consent for publication of clinical details and clinical images were obtained from all individual participants (or their parent/legal guardian/next of kin, as appropriate). A copy of the signed consent form, based on the journal’s template, is available for review by the Editor.

Competing Interests

The authors declare no competing interests.