RARE DISEASE
Autosomal recessive spastic ataxia of Charlevoix-Saguenay
Autosomal recessive spastic ataxia of Charlevoix-Saguenay
Autosomal recessive spastic ataxia of Charlevoix-Saguenay
Synonyms: ARSACS, Autosomal recessive spastic ataxia type 6, SPAX6
Synonyms: ARSACS, Autosomal recessive spastic ataxia type 6, SPAX6
Synonyms: ARSACS, Autosomal recessive spastic ataxia type 6, SPAX6
Drug discovery
0
drugs
With orphan designations
Overview
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by SACS gene mutations, characterized by early-onset cerebellar ataxia (12-24 months), progressive spasticity, axonal neuropathy, and retinal hypermyelination. Disease progression leads to wheelchair dependence by age 30-40, with life expectancy typically extending to the sixth decade. Diagnosis combines clinical triad (ataxia, spasticity, neuropathy), neuroimaging (cerebellar/pontine atrophy), and genetic confirmation [1][6][11].
Burden
Functional decline: 100% require wheelchairs by mid-adulthood; 50% develop academic struggles despite normal cognition [3][12].
Economic impact: Requires lifelong specialized care, adaptive devices, and caregiver support [16][17].
Mortality: Median survival ~60 years, with complications from immobility contributing to morbidity [3][6].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
50 drug discovery papers about Autosomal recessive spastic ataxia of Charlevoix-Saguenay, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
50 drug discovery papers about Autosomal recessive spastic ataxia of Charlevoix-Saguenay, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-15 | Loss of SARM1 Improves Phenotypes in a Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by pathogenic variants in SACS. ARSACS is characterized by mitochondrial abnormalities and disruptions of the neurofilament cytoskeleton. In other conditions, these features have been linked to activation of Sterile Alpha and TIR Motif Containing 1 (SARM1), an enzyme that can trigger axon degeneration and neuronal death. Inhibition of SARM1 is an attractive therapeutic strategy because SARM1 is inactive in healthy cells and knockout of SARM1 has little or no deleterious effects. We therefore asked whether SARM1 activity contributed to Purkinje cell degeneration and motor defects present in a Sacs -/- mouse model of ARSACS. We studied 4 cohorts of mice: (1) Sacs -/- ; Sarm1 +/+ ; (2) Sacs +/+ ; Sarm1 +/- ; (3) Sacs -/- ; Sarm1 +/- ; and (4) Sacs -/- ; Sarm1 -/- . In 9-month-old mice, we analyzed protein markers of Purkinje cells (n = 3-4 mice per genotype) and counted surviving Purkinje cells in folia III, IV, and VIII of cerebellar sections (n = 3 mice per genotype, 6 sections per mouse), and tested motor function at 3, 6, and 9 months by quantifying parameters of gait (Digigait) and coordination and balance (Rotarod) (8 male, 8 female mice of each genotype). Probing of cerebellar extracts showed that the Purkinje cell protein markers Calbindin-1, RGS8, and PCP2 were decreased in Sacs -/- mice but restored to normal levels in Sacs -/- ; Sarm1 -/- mice. Purkinje cell loss in Sacs -/- mice was most prominent in anterior folia, as previously noted. Sarm1 loss partially mitigated the Purkinje cell death in folium III of 9-month-old Sacs -/- mice. Similarly, longitudinal behavioral assessment of motor functions showed that disturbances in gait pattern (slower cadence, prolonged swing, and stance phases) were partially alleviated. Rotarod tests gave more ambivalent results, as the homozygous loss of Sarm1 was less effective than heterozygous loss in ameliorating the Sacs -/- phenotype. We conclude that SARM1 contributes to neurodegeneration in ARSACS, and its downregulation or inhibition could constitute a significant therapeutical strategy in the treatment of the disease.
2025-08-05 | A Pharmacometrics-Informed Trial Simulation Framework for Optimizing Study Designs for Disease-Modifying Treatments in Rare Neurological Disorders.
The development of new treatments for rare neurological diseases (RNDs) may be very challenging due to limited natural history data, lack of relevant biomarkers and clinical endpoints, small and heterogeneous patient populations, and other complexities. A systematic approach is needed for comparing various design and analysis strategies to identify "optimal" approaches for a clinical trial in a chosen RND with the given resource constraints. For this purpose, we propose a pharmacometrics-informed clinical scenario evaluation framework (CSE-PMx), which includes some important research hallmarks relevant to RND clinical trials: a disease progression model for simulating individual longitudinal outcomes, the choice of a suitable randomization method for trial design, and an option to perform subsequent statistical analysis with randomization tests. We illustrate the utility of CSE-PMx for an exemplary randomized trial to compare the disease-modifying effect of an experimental treatment versus control in patients with Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). In the considered example, our simulation evidence suggests that a nonlinear mixed-effects model (NLMEM) with a population-based likelihood ratio test analysis is valid, robust, and more powerful than some conventional methods such as two-sample t-test, analysis of covariance (ANCOVA), or a mixed model with repeated measurements (MMRM). Our proposed framework is very flexible and generalizable to clinical research in other rare disease indications.
2025-04-16 | Long-Term Benefits of TUDCA Supplement in ARSACS Zebrafish Model
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodevelopmental and neurodegenerative disorder characterized by ataxia, spasticity, and peripheral neuropathy. However, several studies have highlighted that some patients also experience cognitive, emotional and social deficits, suggesting a more complex clinical picture that extends beyond motor symptoms. Building on these findings, this study aimed to: i) investigate locomotor, social and cognitive deficits in adult sacs-/- zebrafish versus wild-type (WT) controls through behavioural tests; ii) identify molecular patterns associated with the adult disease phenotype using transcriptomic and proteomic analyses of sacs-/- and WT brains; iii) evaluate the effectiveness of long-term treatment with tauroursodeoxycholic acid (TUDCA) on behavioural outcomes and omics profiles in the zebrafish sacs-/- model. Our findings indicate impairments in cognitive, social, and emotional behaviors in aged sacs-/- zebrafish, which resemble some deficits observed in human patients. Transcriptomic and proteomic analyses of adult brains identified alterations in genes related to circadian rhythms and neuroinflammation. Notably, disruptions in sleep and circadian rhythms are frequently reported in individuals with cerebellar ataxia and may contribute to cognitive and behavioral changes. Long-term treatment with TUDCA, a neuroprotective molecule, was associated with partial improvements in social and cognitive behaviors and modifications in omics profiles in the zebrafish model. These results support the potential of further exploring TUDCA in future preclinical and clinical studies, while also emphasizing the need for additional investigations to better understand its mechanisms of action.
2024-09-01 | F032 Towards digital-motor outcomes for limb movements in spastic ataxia: a comparative validation of Q-motor in ataxia and hereditary spastic paraplegia – lessons learnt for HD
Q-Motor assessments, widely used in HD, capture upper-limb ataxia with digital-motor outcomes that are patient-meaningful and sensitive to change. Whether Q-Motor also captures damage to the pyramidal tract – an ideal prerequisite for trial outcomes in spastic ataxias –, and how this interferes with digital measures for cerebellar ataxia is unknown. This cross-sectional single-center study validated digital upper-limb measures of finger-tapping, diadochokinesia, grip-lift, spiral-drawing and target-reaching, together with lower limb measures of foot-tapping, in 41 patients with hereditary spastic paraplegia (HSP; age: 48±14 ; Spastic Paraplegia Rating Scale [SPRS]: 19±9) as compared to 46 cross-genotype ataxia patients (age: 50±18; SARA: 12±6). Validation criteria comprised discrimination from 48 matched controls, and significant correlations to each disease severity (SPRS or SARA), activities of daily living (FARS-ADL), and the 9-hole-peg-test (9HPT). Speed measures of finger-tapping and diadochokinesia, but no other movement feature or task, captured HSP motor impairment in the upper-limbs. These measures better reflected impaired fine motor function in HSP than in ataxia (|rho9HPT|=0.7–0.8 vs. 0.5–0.6), comparable to smoothness of target-reaching as most sensitive measure for upper-limb ataxia (|rho9HPT|=0.8). Correlations of finger-tapping to disease severity were limited to the dominant hand in HSP ((|rhoSPRS|=0.3–0.4), while upper-limb ataxia was better captured in the non-dominant hand. In In the lower-limb, speed of foot-tapping captured both ataxia (|rhoSARA|=0.4–0.7) and spastic paraplegia (|rhoSPRS|= 0.4–0-6), with strong discrimination of HSP from controls (AUC=0.96), while variability measures of tap duration were specific for ataxia. Discussion: Digital tapping speed measures capture cerebellar ataxia and pyramidal tract involvement, while variability measures appear specific for ataxia. Sensitivity for the interaction of both systems in spastic ataxias is being validated in ARSACS and SPG7. Q-Motor presents a promising digital-motor outcome for spastic ataxias. This study demonstrates that Q-Motor can be applied in other movement disorders beyond HD.
2024-08-17 | HDAC inhibitor SAHA resolved intermediate filament bundling and defective autophagy caused by the lack of sacsin in ARSACS.
Autosomal recessive spastic ataxia of the Charlevoix-Saguenay (ARSACS) is a progressive childhood-onset neurological disease caused by loss-of-function mutations in the SACS gene. This condition is characterized by cerebellar ataxia, peripheral neuropathy, and spastic plasticity. ARSACS patient-derived fibroblasts and mouse models lacking sacsin exhibit altered mitochondrial networks, intermediate filament bundling, dysregulated autophagic flux, and aberrant protein/organelle localization. Sacsin, a large multidomain protein, plays a critical role in chaperoning and protein homeostasis, particularly in neurons. Dysregulation of autophagy in ARSACS is evidenced by increased LC3 levels and defective lysosome-autophagosome fusion in the absence of sacsin. Recent omics approaches suggest sacsin’s involvement in cytoskeleton regulation, intracellular transport, calcium homeostasis, synaptic organization, and mitochondrial maintenance. This study aimed to explore the effects of histone deacetylase (HDAC) inhibitors on neurofilament (NF) protein acetylation and autophagic flux in ARSACS. NF proteins from Sacs-/- mice showed no significant acetylation differences compared to controls, though HDAC inhibitor SAHA resolved NF bundling. Purification and analysis of NF proteins confirmed high purity and minor acetylation differences at specific lysines (K214). Treatment with SAHA reduced NF bundling in Sacs-/- motor neurons and promoted lysosomal recruitment to autophagosomes in ARSACS patient-derived fibroblasts, indicating restored autophagic flux. These findings highlight the potential of HDAC inhibitors in resolving cytoskeletal abnormalities and improving autophagic processes in ARSACS, offering promising therapeutic avenues for this debilitating disorder. Further research is needed to elucidate the precise mechanisms underlying these effects and their implications for NF homeostasis and autophagy regulation in ARSACS.
proteins
2025-09-29 | Novel SACS Variants not Recorded in ClinVar Identified in a Chinese Patient with Late-Onset Hereditary Neuropathy: a Case Report and Literature Review.
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.
2024-09-24 | Sacsin levels in PBMCs: A diagnostic assay for SACS variants in peripheral blood cells - A PROSPAX study.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a common recessive ataxia that is still underdiagnosed worldwide. An easily accessible diagnostic biomarker might help to diagnostically confirm patients presenting SACS variants of unknown significance (VUS) or atypical phenotypes. To detect sacsin in peripheral blood mononuclear cells (PBMCs) and to validate its diagnostic biomarker quality to discriminate biallelic SACS patients (including patients with VUS and/or atypical phenotypes) against healthy controls, non-ARSACS spastic ataxia patients, and heterozygous SACS carriers. Sacsin protein levels in PBMCs were assessed in patients versus controls and validated in skin-derived fibroblasts. Patients with biallelic SACS variants - including patients with VUS and/or atypical phenotypes - showed loss of sacsin in PBMCs, with discriminative performance against healthy, heterozygous, and non-ARSACS controls. This included all investigated SACS missense variants. Also, C-terminal variants escaping nonsense-mediated decay, while not differing from controls in expression level, showed lower molecular weight in this assay. Assessing sacsin levels using PBMCs offers an easy, peripherally accessible diagnostic biomarker for ARSACS, with PBMCs being much less invasive and easier to handle than fibroblasts. Additionally, this might be a potential target-engagement blood biomarker for sacsin-increasing therapies.
2024-01-09 | Interactors of sacsin’s DNAJ domain identify function in organellar transport and membrane composition relevant to ARSACS pathogenesis
Abstract Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by loss of function mutations in the SACS gene encoding sacsin, a 520kDa protein with multiple functional domains. The goal of this study was to identify client proteins interacting with the J domain, a cochaperone domain interacting with Hsp70 chaperones, to gain insights into sacsin’s function and its disruption in experimental models of ARSACS. Pull downs from mouse brain identified Rabs and Rab-associated proteins including Rab1b, ARF5 and endophilin B2, involved in organelle trafficking. In cell and mouse models of ARSACS, higher molecular weight species of Rab1b were identified on SDS-PAGE in addition to the normal 25kDa band and Rab1was retained in the soma along with membranous organelles ( i.e. , ER, Golgi and ATG9 autophagic vesicles). These changes were reversed by expression of the DNAJ domain or the Ubl domain of sacsin and occurred independent of the formation of abnormal bundles of intermediate filaments, a key feature of ARSACS. Although Rab1b was associated with both Golgi and ER in both Sacs +/+ and Sacs -/- cells, expression of the DNAJ domain or the Ubl domain of sacsin increased Rab1b association with ER and restored normal electrophoretic mobility. Finally, subcellular distribution of another membrane protein, neuroplastin, a key receptor for synapse formation and plasticity, also was impaired, pointing to a general problem in Rab-dependent membrane trafficking in the absence of sacsin.
2023-01-04 | The J Domain of Sacsin Disrupts Intermediate Filament Assembly.
Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured Sacs-/- neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured Sacs-/- motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured Sacs+/+ fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.
2019-09-30 | Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.
Loss of sacsin, a large 520 kDa multidomain protein, causes autosomal recessive spastic ataxia of the Charlevoix-Saguenay, one of the most common childhood-onset recessive ataxias. A prominent feature is abnormal bundling of neurofilaments in many neuronal populations. This study shows the direct involvement of sacsin domains in regulating intermediate filament assembly and dynamics and identifies important domains for alleviating neurofilament bundles in neurons lacking sacsin. Peptides encoding sacsin internal repeat (SIRPT) 1, J-domains, and ubiquitin-like domain modified neurofilament assembly in vivo. The domains with chaperone homology, the SIRPT and the J-domain, had opposite effects, promoting and preventing filament assembly, respectively. In cultured Sacs-/- motor neurons, both the SIRPT1 and J-domain resolved preexisting neurofilament bundles. Increasing expression of heat shock proteins also resolved neurofilament bundles, indicating that this endogenous chaperone system can compensate to some extent for sacsin deficiency.-Gentil, B. J., Lai, G.-T., Menade, M., Larivière, R., Minotti, S., Gehring, K., Chapple, J.-P., Brais, B., Durham, H. D. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.
gene therapies
2025-12-07 | Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay in Two Half-Siblings.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by biallelic pathogenic variants in the SACS gene. We report the clinical, radiologic and neurophysiologic features of a pair of half-siblings who presented with progressive cerebellar ataxia, peripheral neuropathy and upper motor neuron signs. After significant diagnostic delay, genetic testing revealed both harboured a shared, paternally inherited microdeletion encompassing the SACS gene, and each harboured a different single nucleotide variant in SACS, each likely maternally inherited. Recognition of the clinical and radiologic phenotype of ARSACS may facilitate early diagnosis of this disorder even in the face of uncommon inheritance patterns.
2025-05-04 | Genetic analysis of three patients from two unrelated Chinese families with autosomal recessive spastic ataxia of Charlevoix-Saguenay.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity, and sensorimotor peripheral neuropathy. This disorder is caused by homozygous or compound heterozygous variants in the sacsin (SACS) gene on chromosome 13q12.12. Three patients with ARSACS from two unrelated Chinese families were recruited for this study. Patient #1 was an 18-year-old male who had been walking unstably for 12 years. Patient #2, the younger sister of Patient #1, was a 5-year-old girl who had been walking unstably for 2 years. Patient #3 was a 19-year-old female who had been walking unstably and a tendency to fall for 17 years. For Patient #1, whole-exome sequencing (WES) identified a hemizygous variant c.8310_8313delAGAT (p.Asp2771fs4*) in SACS (NM_014363.6), with the father being heterozygous, the mother wild-type, and Patient #2 hemizygous, as verified by Sanger sequencing. Additional copy number variant analysis of the WES data indicated that Patient #1 had a heterozygous gross deletion of chr13q12.12 (chr13:23,808,732 - 24,890,322). Low-coverage whole-genome sequencing results revealed that Patient #2 carried a chr13q12.12 deletion (chr13:23,520,000-24,940,000). Together with Sanger sequencing results, this gross deletion was speculated to have been inherited from the mother, further explaining the hemizygous state of c.8310_8313delAGAT (p.Asp2771fs4*) in Patients #1 and #2. Through WES, Patient #3 was identified as having suspected compound heterozygous variants of c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*), inherited from the father and mother, respectively, as confirmed by Sanger sequencing. This study identified three variants in SACS. The c.8310_8313delAGAT (p.Asp2771fs4*) is novel, whereas c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*) have been reported previously. Moreover, this study highlights the growing trend that ARSACS has become increasingly prevalent worldwide rather than being localized to a specific region or race. As an increasing number of patients with ARSACS are diagnosed, the genetic spectrum of ARSACS will gradually broaden, providing an accurate genetic basis for prenatal diagnosis of mothers in the years ahead, if possible.
2024-04-10 | Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay
Abstract Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion ( B β 2 KO) nor fission ( Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.
2022-09-17 | Insights into SACS pathological attributes in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)☆
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disease caused by mutations in the SACS gene, encoding Sacsin. Initial functional annotation of Sacsin was based on sequence homology, with subsequent experiments revealing the Sacsin requirement for regulating mitochondrial dynamics, along with its domains involved in promoting neurofilament assembly or resolving their bundling accumulations. ARSACS phenotypes associated with SACS loss-of-function are discussed, and how advancements in ARSACS disease models and quantitative omics approaches can improve our understanding of ARSACS pathological attributes. Lastly in the perspectives section, we address gene correction strategies for monogenic disorders such as ARSACS, along with their common delivery methods, representing a hopeful area for ARSACS therapeutics development.
small molecules
2026-06-15 | Loss of SARM1 Improves Phenotypes in a Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by pathogenic variants in SACS. ARSACS is characterized by mitochondrial abnormalities and disruptions of the neurofilament cytoskeleton. In other conditions, these features have been linked to activation of Sterile Alpha and TIR Motif Containing 1 (SARM1), an enzyme that can trigger axon degeneration and neuronal death. Inhibition of SARM1 is an attractive therapeutic strategy because SARM1 is inactive in healthy cells and knockout of SARM1 has little or no deleterious effects. We therefore asked whether SARM1 activity contributed to Purkinje cell degeneration and motor defects present in a Sacs -/- mouse model of ARSACS. We studied 4 cohorts of mice: (1) Sacs -/- ; Sarm1 +/+ ; (2) Sacs +/+ ; Sarm1 +/- ; (3) Sacs -/- ; Sarm1 +/- ; and (4) Sacs -/- ; Sarm1 -/- . In 9-month-old mice, we analyzed protein markers of Purkinje cells (n = 3-4 mice per genotype) and counted surviving Purkinje cells in folia III, IV, and VIII of cerebellar sections (n = 3 mice per genotype, 6 sections per mouse), and tested motor function at 3, 6, and 9 months by quantifying parameters of gait (Digigait) and coordination and balance (Rotarod) (8 male, 8 female mice of each genotype). Probing of cerebellar extracts showed that the Purkinje cell protein markers Calbindin-1, RGS8, and PCP2 were decreased in Sacs -/- mice but restored to normal levels in Sacs -/- ; Sarm1 -/- mice. Purkinje cell loss in Sacs -/- mice was most prominent in anterior folia, as previously noted. Sarm1 loss partially mitigated the Purkinje cell death in folium III of 9-month-old Sacs -/- mice. Similarly, longitudinal behavioral assessment of motor functions showed that disturbances in gait pattern (slower cadence, prolonged swing, and stance phases) were partially alleviated. Rotarod tests gave more ambivalent results, as the homozygous loss of Sarm1 was less effective than heterozygous loss in ameliorating the Sacs -/- phenotype. We conclude that SARM1 contributes to neurodegeneration in ARSACS, and its downregulation or inhibition could constitute a significant therapeutical strategy in the treatment of the disease.
2025-08-05 | A Pharmacometrics-Informed Trial Simulation Framework for Optimizing Study Designs for Disease-Modifying Treatments in Rare Neurological Disorders.
The development of new treatments for rare neurological diseases (RNDs) may be very challenging due to limited natural history data, lack of relevant biomarkers and clinical endpoints, small and heterogeneous patient populations, and other complexities. A systematic approach is needed for comparing various design and analysis strategies to identify "optimal" approaches for a clinical trial in a chosen RND with the given resource constraints. For this purpose, we propose a pharmacometrics-informed clinical scenario evaluation framework (CSE-PMx), which includes some important research hallmarks relevant to RND clinical trials: a disease progression model for simulating individual longitudinal outcomes, the choice of a suitable randomization method for trial design, and an option to perform subsequent statistical analysis with randomization tests. We illustrate the utility of CSE-PMx for an exemplary randomized trial to compare the disease-modifying effect of an experimental treatment versus control in patients with Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). In the considered example, our simulation evidence suggests that a nonlinear mixed-effects model (NLMEM) with a population-based likelihood ratio test analysis is valid, robust, and more powerful than some conventional methods such as two-sample t-test, analysis of covariance (ANCOVA), or a mixed model with repeated measurements (MMRM). Our proposed framework is very flexible and generalizable to clinical research in other rare disease indications.
2025-04-16 | Long-Term Benefits of TUDCA Supplement in ARSACS Zebrafish Model
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodevelopmental and neurodegenerative disorder characterized by ataxia, spasticity, and peripheral neuropathy. However, several studies have highlighted that some patients also experience cognitive, emotional and social deficits, suggesting a more complex clinical picture that extends beyond motor symptoms. Building on these findings, this study aimed to: i) investigate locomotor, social and cognitive deficits in adult sacs-/- zebrafish versus wild-type (WT) controls through behavioural tests; ii) identify molecular patterns associated with the adult disease phenotype using transcriptomic and proteomic analyses of sacs-/- and WT brains; iii) evaluate the effectiveness of long-term treatment with tauroursodeoxycholic acid (TUDCA) on behavioural outcomes and omics profiles in the zebrafish sacs-/- model. Our findings indicate impairments in cognitive, social, and emotional behaviors in aged sacs-/- zebrafish, which resemble some deficits observed in human patients. Transcriptomic and proteomic analyses of adult brains identified alterations in genes related to circadian rhythms and neuroinflammation. Notably, disruptions in sleep and circadian rhythms are frequently reported in individuals with cerebellar ataxia and may contribute to cognitive and behavioral changes. Long-term treatment with TUDCA, a neuroprotective molecule, was associated with partial improvements in social and cognitive behaviors and modifications in omics profiles in the zebrafish model. These results support the potential of further exploring TUDCA in future preclinical and clinical studies, while also emphasizing the need for additional investigations to better understand its mechanisms of action.
2024-09-01 | F032 Towards digital-motor outcomes for limb movements in spastic ataxia: a comparative validation of Q-motor in ataxia and hereditary spastic paraplegia – lessons learnt for HD
Q-Motor assessments, widely used in HD, capture upper-limb ataxia with digital-motor outcomes that are patient-meaningful and sensitive to change. Whether Q-Motor also captures damage to the pyramidal tract – an ideal prerequisite for trial outcomes in spastic ataxias –, and how this interferes with digital measures for cerebellar ataxia is unknown. This cross-sectional single-center study validated digital upper-limb measures of finger-tapping, diadochokinesia, grip-lift, spiral-drawing and target-reaching, together with lower limb measures of foot-tapping, in 41 patients with hereditary spastic paraplegia (HSP; age: 48±14 ; Spastic Paraplegia Rating Scale [SPRS]: 19±9) as compared to 46 cross-genotype ataxia patients (age: 50±18; SARA: 12±6). Validation criteria comprised discrimination from 48 matched controls, and significant correlations to each disease severity (SPRS or SARA), activities of daily living (FARS-ADL), and the 9-hole-peg-test (9HPT). Speed measures of finger-tapping and diadochokinesia, but no other movement feature or task, captured HSP motor impairment in the upper-limbs. These measures better reflected impaired fine motor function in HSP than in ataxia (|rho9HPT|=0.7–0.8 vs. 0.5–0.6), comparable to smoothness of target-reaching as most sensitive measure for upper-limb ataxia (|rho9HPT|=0.8). Correlations of finger-tapping to disease severity were limited to the dominant hand in HSP ((|rhoSPRS|=0.3–0.4), while upper-limb ataxia was better captured in the non-dominant hand. In In the lower-limb, speed of foot-tapping captured both ataxia (|rhoSARA|=0.4–0.7) and spastic paraplegia (|rhoSPRS|= 0.4–0-6), with strong discrimination of HSP from controls (AUC=0.96), while variability measures of tap duration were specific for ataxia. Discussion: Digital tapping speed measures capture cerebellar ataxia and pyramidal tract involvement, while variability measures appear specific for ataxia. Sensitivity for the interaction of both systems in spastic ataxias is being validated in ARSACS and SPG7. Q-Motor presents a promising digital-motor outcome for spastic ataxias. This study demonstrates that Q-Motor can be applied in other movement disorders beyond HD.
2024-08-17 | HDAC inhibitor SAHA resolved intermediate filament bundling and defective autophagy caused by the lack of sacsin in ARSACS.
Autosomal recessive spastic ataxia of the Charlevoix-Saguenay (ARSACS) is a progressive childhood-onset neurological disease caused by loss-of-function mutations in the SACS gene. This condition is characterized by cerebellar ataxia, peripheral neuropathy, and spastic plasticity. ARSACS patient-derived fibroblasts and mouse models lacking sacsin exhibit altered mitochondrial networks, intermediate filament bundling, dysregulated autophagic flux, and aberrant protein/organelle localization. Sacsin, a large multidomain protein, plays a critical role in chaperoning and protein homeostasis, particularly in neurons. Dysregulation of autophagy in ARSACS is evidenced by increased LC3 levels and defective lysosome-autophagosome fusion in the absence of sacsin. Recent omics approaches suggest sacsin’s involvement in cytoskeleton regulation, intracellular transport, calcium homeostasis, synaptic organization, and mitochondrial maintenance. This study aimed to explore the effects of histone deacetylase (HDAC) inhibitors on neurofilament (NF) protein acetylation and autophagic flux in ARSACS. NF proteins from Sacs-/- mice showed no significant acetylation differences compared to controls, though HDAC inhibitor SAHA resolved NF bundling. Purification and analysis of NF proteins confirmed high purity and minor acetylation differences at specific lysines (K214). Treatment with SAHA reduced NF bundling in Sacs-/- motor neurons and promoted lysosomal recruitment to autophagosomes in ARSACS patient-derived fibroblasts, indicating restored autophagic flux. These findings highlight the potential of HDAC inhibitors in resolving cytoskeletal abnormalities and improving autophagic processes in ARSACS, offering promising therapeutic avenues for this debilitating disorder. Further research is needed to elucidate the precise mechanisms underlying these effects and their implications for NF homeostasis and autophagy regulation in ARSACS.
proteins
2025-09-29 | Novel SACS Variants not Recorded in ClinVar Identified in a Chinese Patient with Late-Onset Hereditary Neuropathy: a Case Report and Literature Review.
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.
2024-09-24 | Sacsin levels in PBMCs: A diagnostic assay for SACS variants in peripheral blood cells - A PROSPAX study.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a common recessive ataxia that is still underdiagnosed worldwide. An easily accessible diagnostic biomarker might help to diagnostically confirm patients presenting SACS variants of unknown significance (VUS) or atypical phenotypes. To detect sacsin in peripheral blood mononuclear cells (PBMCs) and to validate its diagnostic biomarker quality to discriminate biallelic SACS patients (including patients with VUS and/or atypical phenotypes) against healthy controls, non-ARSACS spastic ataxia patients, and heterozygous SACS carriers. Sacsin protein levels in PBMCs were assessed in patients versus controls and validated in skin-derived fibroblasts. Patients with biallelic SACS variants - including patients with VUS and/or atypical phenotypes - showed loss of sacsin in PBMCs, with discriminative performance against healthy, heterozygous, and non-ARSACS controls. This included all investigated SACS missense variants. Also, C-terminal variants escaping nonsense-mediated decay, while not differing from controls in expression level, showed lower molecular weight in this assay. Assessing sacsin levels using PBMCs offers an easy, peripherally accessible diagnostic biomarker for ARSACS, with PBMCs being much less invasive and easier to handle than fibroblasts. Additionally, this might be a potential target-engagement blood biomarker for sacsin-increasing therapies.
2024-01-09 | Interactors of sacsin’s DNAJ domain identify function in organellar transport and membrane composition relevant to ARSACS pathogenesis
Abstract Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by loss of function mutations in the SACS gene encoding sacsin, a 520kDa protein with multiple functional domains. The goal of this study was to identify client proteins interacting with the J domain, a cochaperone domain interacting with Hsp70 chaperones, to gain insights into sacsin’s function and its disruption in experimental models of ARSACS. Pull downs from mouse brain identified Rabs and Rab-associated proteins including Rab1b, ARF5 and endophilin B2, involved in organelle trafficking. In cell and mouse models of ARSACS, higher molecular weight species of Rab1b were identified on SDS-PAGE in addition to the normal 25kDa band and Rab1was retained in the soma along with membranous organelles ( i.e. , ER, Golgi and ATG9 autophagic vesicles). These changes were reversed by expression of the DNAJ domain or the Ubl domain of sacsin and occurred independent of the formation of abnormal bundles of intermediate filaments, a key feature of ARSACS. Although Rab1b was associated with both Golgi and ER in both Sacs +/+ and Sacs -/- cells, expression of the DNAJ domain or the Ubl domain of sacsin increased Rab1b association with ER and restored normal electrophoretic mobility. Finally, subcellular distribution of another membrane protein, neuroplastin, a key receptor for synapse formation and plasticity, also was impaired, pointing to a general problem in Rab-dependent membrane trafficking in the absence of sacsin.
2023-01-04 | The J Domain of Sacsin Disrupts Intermediate Filament Assembly.
Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured Sacs-/- neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured Sacs-/- motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured Sacs+/+ fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.
2019-09-30 | Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.
Loss of sacsin, a large 520 kDa multidomain protein, causes autosomal recessive spastic ataxia of the Charlevoix-Saguenay, one of the most common childhood-onset recessive ataxias. A prominent feature is abnormal bundling of neurofilaments in many neuronal populations. This study shows the direct involvement of sacsin domains in regulating intermediate filament assembly and dynamics and identifies important domains for alleviating neurofilament bundles in neurons lacking sacsin. Peptides encoding sacsin internal repeat (SIRPT) 1, J-domains, and ubiquitin-like domain modified neurofilament assembly in vivo. The domains with chaperone homology, the SIRPT and the J-domain, had opposite effects, promoting and preventing filament assembly, respectively. In cultured Sacs-/- motor neurons, both the SIRPT1 and J-domain resolved preexisting neurofilament bundles. Increasing expression of heat shock proteins also resolved neurofilament bundles, indicating that this endogenous chaperone system can compensate to some extent for sacsin deficiency.-Gentil, B. J., Lai, G.-T., Menade, M., Larivière, R., Minotti, S., Gehring, K., Chapple, J.-P., Brais, B., Durham, H. D. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.
gene therapies
2025-12-07 | Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay in Two Half-Siblings.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by biallelic pathogenic variants in the SACS gene. We report the clinical, radiologic and neurophysiologic features of a pair of half-siblings who presented with progressive cerebellar ataxia, peripheral neuropathy and upper motor neuron signs. After significant diagnostic delay, genetic testing revealed both harboured a shared, paternally inherited microdeletion encompassing the SACS gene, and each harboured a different single nucleotide variant in SACS, each likely maternally inherited. Recognition of the clinical and radiologic phenotype of ARSACS may facilitate early diagnosis of this disorder even in the face of uncommon inheritance patterns.
2025-05-04 | Genetic analysis of three patients from two unrelated Chinese families with autosomal recessive spastic ataxia of Charlevoix-Saguenay.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity, and sensorimotor peripheral neuropathy. This disorder is caused by homozygous or compound heterozygous variants in the sacsin (SACS) gene on chromosome 13q12.12. Three patients with ARSACS from two unrelated Chinese families were recruited for this study. Patient #1 was an 18-year-old male who had been walking unstably for 12 years. Patient #2, the younger sister of Patient #1, was a 5-year-old girl who had been walking unstably for 2 years. Patient #3 was a 19-year-old female who had been walking unstably and a tendency to fall for 17 years. For Patient #1, whole-exome sequencing (WES) identified a hemizygous variant c.8310_8313delAGAT (p.Asp2771fs4*) in SACS (NM_014363.6), with the father being heterozygous, the mother wild-type, and Patient #2 hemizygous, as verified by Sanger sequencing. Additional copy number variant analysis of the WES data indicated that Patient #1 had a heterozygous gross deletion of chr13q12.12 (chr13:23,808,732 - 24,890,322). Low-coverage whole-genome sequencing results revealed that Patient #2 carried a chr13q12.12 deletion (chr13:23,520,000-24,940,000). Together with Sanger sequencing results, this gross deletion was speculated to have been inherited from the mother, further explaining the hemizygous state of c.8310_8313delAGAT (p.Asp2771fs4*) in Patients #1 and #2. Through WES, Patient #3 was identified as having suspected compound heterozygous variants of c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*), inherited from the father and mother, respectively, as confirmed by Sanger sequencing. This study identified three variants in SACS. The c.8310_8313delAGAT (p.Asp2771fs4*) is novel, whereas c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*) have been reported previously. Moreover, this study highlights the growing trend that ARSACS has become increasingly prevalent worldwide rather than being localized to a specific region or race. As an increasing number of patients with ARSACS are diagnosed, the genetic spectrum of ARSACS will gradually broaden, providing an accurate genetic basis for prenatal diagnosis of mothers in the years ahead, if possible.
2024-04-10 | Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay
Abstract Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion ( B β 2 KO) nor fission ( Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.
2022-09-17 | Insights into SACS pathological attributes in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)☆
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disease caused by mutations in the SACS gene, encoding Sacsin. Initial functional annotation of Sacsin was based on sequence homology, with subsequent experiments revealing the Sacsin requirement for regulating mitochondrial dynamics, along with its domains involved in promoting neurofilament assembly or resolving their bundling accumulations. ARSACS phenotypes associated with SACS loss-of-function are discussed, and how advancements in ARSACS disease models and quantitative omics approaches can improve our understanding of ARSACS pathological attributes. Lastly in the perspectives section, we address gene correction strategies for monogenic disorders such as ARSACS, along with their common delivery methods, representing a hopeful area for ARSACS therapeutics development.
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