Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Charlevoix-Saguenay spastic ataxia. Core disease mechanisms, molecular and...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] Diplomyelia in a patient with a clinical suspicion of autosomal recessive spastic ataxia of Charlevoix-Saguenay type (ARSACS).

• Authors: D. Dziewulska
• Year: 2020
• Venue: Folia neuropathologica
• URL: https://www.semanticscholar.org/paper/2e075d2c247a016d6d0aea2cabce902befd25f83
• DOI: 10.5114/fn.2020.96646
• PMID: 32729297
• Citations: 1
• Summary: Diagnosis of diplomyelia does not exclude coexistence of ARSACS because of the occurrence of such clinical symptoms as dysarthria or nystagmus which cannot be explained by the presence of the spinal cord defect.
• Evidence snippets:
• Snippet 1 (score: 0.619) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a distinct form of early-onset cerebellar ataxia with progressive degeneration of cerebellum and spinal cord. The disorder was first described in the 1970s among inhabitants of the Charlevoix-Saguenay region in north-eastern Quebec in Canada [3]. ARSACS is related to mutations in the SACS gene on chromosome 13q12.12 encoding a large multidomain protein sacsin. Sacsin is involved in chaperon-mediated protein folding and regulation of the effects of other ataxia-associated proteins [11]. Although the molecular mechanism underlying ARSACS remains unknown, probably the disease is associated with a loss of sacsin function. The protein has a predominantly cytoplasmic distribution with a mitochondrial component and is most highly expressed in large neurons, particularly within brain motor systems, including cerebellar Purkinje cells. It is also present in fibroblasts, skeletal muscles and axons [11]. > More than 70 different mutations in the sacsin gene have been identified worldwide [2] causing phenotypic variability of ARSACS even within family members harbouring the same mutation. However, characteristic clinical features of the disease are cerebellar ataxia, spasticity, distal muscle wasting, axonal polyneuropathy, dysarthria, nystagmus, and finger or/and foot deformities. The presented case concerns a 32-year-old man with a clinical suspicion of ARSACS and unexpected finding in the autopsy examination -a spinal cord duplication.

[2] Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin

• Authors: D. Galatolo, S. Rocchiccioli, N. Di Giorgi, Flavio Dal Canto, Giovanni Signore et al.
• Year: 2024
• Venue: Frontiers in Neuroscience
• URL: https://www.semanticscholar.org/paper/ceb599ad093681b66afeebf7fa79bcfb2a5d8c04
• DOI: 10.3389/fnins.2024.1375299
• PMID: 38911600
• PMCID: 11191878
• Citations: 2
• Summary: Introduction Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the SACS gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking. However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early sta...
• Evidence snippets:
• Snippet 1 (score: 0.615) > Introduction: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the SACS gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking.However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early stages.

[3] Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

• Authors: Jaya Bagaria, Eva Bagyinszky, S. An
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/aacd6b03a4dfdf4a59a4ba3ed18b26b2b3cc976d
• DOI: 10.3390/ijms23010552
• PMID: 35008978
• PMCID: 8745260
• Citations: 32
• Summary: The genetic mutations discovered in the SACS gene are introduced, its pathomechanisms and its possible involvement in other neurodegenerative diseases are discussed and sacsin may also play a crucial role in regulating the mitochondrial functions.
• Evidence snippets:
• Snippet 1 (score: 0.610) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

[4] Integrative Organelle-Based Functional Proteomics: In Silico Prediction of Impaired Functional Annotations in SACS KO Cell Model

• Authors: F. Morani, S. Doccini, D. Galatolo, F. Pezzini, R. Soliymani et al.
• Year: 2022
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/3d4eda3d91878f3c02009b742fd16fd3654d6468
• DOI: 10.3390/biom12081024
• PMID: 35892334
• PMCID: 9331974
• Citations: 6
• Summary: The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure.
• Evidence snippets:
• Snippet 1 (score: 0.570) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS.

[5] Diagnosis and management of progressive ataxia in adults

• Authors: R. de Silva, J. Vallortigara, J. Greenfield, Barry Hunt, P. Giunti et al.
• Year: 2019
• Venue: Practical Neurology
• URL: https://www.semanticscholar.org/paper/90fa1cd2b79d38ce9b63a144099ff70b13029286
• DOI: 10.1136/practneurol-2018-002096
• PMID: 31048364
• PMCID: 6585307
• Citations: 79
• Influential citations: 1
• Summary: Suggested diagnostic pathways for the general neurologist, based on Ataxia UK’s guidelines for professionals, are provided, which can no longer justify a nihilistic approach to the management of ataxia.
• Evidence snippets:
• Snippet 1 (score: 0.545) > Friedreich's ataxia is the most common inherited ataxia in Caucasian populations, with a prevalence of around 1 per 20 000-50 000. Spastic paraplegia 7 (SPG7), a classical cause of hereditary spastic paraparesis, is the next most common recessive ataxia in the UK. 8 Patients with SPG7 may have only minimal spasticity. Spastic ataxia is also a feature of autosomal recessive spastic ataxia of Charlevoix-Saguenay. In terms of frequency, Friedreich's ataxia and SPG7 are followed by ataxia with oculomotor apraxia type 2 and ataxia-telangiectasia (which presents less commonly in adulthood). MRI may provide useful clues on the genetic cause (table 2). Clues to ataxia-telangiectasia (and ataxia with oculomotor apraxias) include a high serum alpha-fetoprotein and creatine kinase, and a low serum albumin. Optical coherence tomography can provide support for a diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. > Despite the growing emphasis on next-generation sequencing in helping to diagnose inherited ataxia, 6 accurate clinical phenotyping (incorporating relevant laboratory data) remains important. This is especially so when there are 'variants of uncertain significance': knowledge and experience must then supplement the bioinformatics pipeline. 'Deep phenotyping' is an emerging field where promising biomarkers are used to target genetic testing (which is still expensive). For example, retinal fibre layer thickening (identified using optical coherence tomography) appears to be a sensitive and specific indicator of autosomal recessive spastic ataxia of Charlevoix-Saguenay. 9 Peripheral electrophysiology may also help define the cause of (recessive) ataxias. There are four categories (after eliminating Friedreich's ataxia) based on: > 1. The absence of neuropathy (mutations in SYNE1, ANO10 and ADCK3). Figure 7 shows data from two specialist ataxia centres in Sheffield and Dublin, giving an insight to the relative frequencies of the

[6] ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia

• Authors: S. Vermeer, R. Meijer, B. Pijl, J. Timmermans, J. Cruysberg et al.
• Year: 2008
• Venue: Neurogenetics
• URL: https://www.semanticscholar.org/paper/727e1df356bc6fd973784262d5d0edec04618d60
• DOI: 10.1007/s10048-008-0131-7
• PMID: 18465152
• PMCID: 2441586
• Citations: 88
• Influential citations: 4
• Summary: The high rate of mutations identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated and it is predicted that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARsACS phenotype will lead to the diagnosis of many additional patients.
• Evidence snippets:
• Snippet 1 (score: 0.543) > Autosomal recessive spinocerebellar ataxias constitute a heterogeneous group of neurodegenerative disorders characterized by ataxia mostly due to progressive degeneration of the cerebellum, spinal cord tracts, and associated structures. The clinical phenotype of these disorders is broad and quite variable. A number of recent reviews presented clinical diagnostic strategies to differentiate between the various types of recessive cerebellar ataxias [1][2][3]. Van de Warrenburg et al. grouped them into recognizable and more or less specific phenotypes: (a) ataxia with neuro(no)pathy, (b) spastic ataxia, (c) ataxia with oculomotor apraxia, and (d) Ramsay Hunt syndrome. The most common form, and representative of the first group, is Friedreich's ataxia (FRDA). Autosomal recessive spastic ataxia of Charlevoix-Saguenay (MIM 270550), ARSACS, is a distinct form of hereditary early-onset spastic ataxia. The disease was first described in the Charlevoix-Saguenay region of Northeastern Québec in Canada [4]. Two founder mutations were identified in this population [5]. Shortly after mutation analysis became available, patients outside Québec were molecularly characterized. To date, apart from the two Québec mutations, 27 different additional mutations have been found in ARSACS patients outside Quebec, namely from Turkey, Tunisia, Italy, Spain, Japan, and recently from Belgium [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The SACS gene is located on chromosome 13q12.12 and encodes the large protein sacsin [5]. Different transcripts of the gene have been identified, and in total, 11 different exons within the gene have been described. The large transcript NM_014363.4 reported recently (www.ncbi.nlm. nih.gov) comprises nine coding exons consisting of 13,737 base pairs which encode 4,579 amino acids [6].

[7] Identification of a novel SACS gene mutation leading to spastic ataxia Charlevoix-Saguenay type: a case report

• Authors: Víctor E Raggio, A. Rey, Camila Simoes, Florencia Birriel, S. Rodríguez et al.
• Year: 2025
• Venue: Journal of Medical Case Reports
• URL: https://www.semanticscholar.org/paper/d4bad4387670c4213a1975abc9bcaee4675003d9
• DOI: 10.1186/s13256-025-05480-z
• PMID: 40830897
• PMCID: 12363115
• Summary: The case of a 3-year-old Uruguayan girl with suspected autosomal recessive spastic ataxia of Charlevoix-Saguenay is presented, demonstrating the disease’s presence in previously unreported locations and highlighting the genomic heterogeneity of spastic ataxia Charlevoix-Saguenay.
• Evidence snippets:
• Snippet 1 (score: 0.540) > Spastic Ataxia Charlevoix-Saguenay (SACS) is a rare autosomal recessive neurodegenerative disorder characterized by a combination of spasticity, ataxia, and peripheral neuropathy [1]. Although a very rare disease, autosomal recessive SACS (ARSACS) is thought to be the second most common form of autosomal recessive cerebellar ataxia after Friedrich's ataxia [2]. ARSACS predominantly affects individuals of French-Canadian descent, with a higher prevalence in the Saguenay-Lac-Saint-Jean region of Quebec, as previously described here [3]. That study revealed a distinctive form of early-onset spastic ataxia, with a long course with little progression after age 20 years. Features additional to the ataxia include dysarthria, spasticity, distal muscle wasting, nystagmus, defect in conjugate pursuit ocular movements, retinal striation obscuring the retinal blood vessels in places, and the presence of mitral valve prolapse [3]. > The genetic alterations that cause ARSACS are biallelic loss of function mutations in the SACS gene. The high frequency in Saguenay-Lac-Saint-Jean region is owing to a founder effect of a couple that lived in Quebec City in 1650 [3]. > The SACS gene encodes the multidomain sacsin protein, which is expressed in the central nervous system, and plays a critical role in cellular homeostasis and neuronal function [4]. SACS protein has a functional DNAJ/ Hsp40 domain that would be relevant for the proper function of the Hsp70 chaperon machinery. > The Hsp70 chaperone machinery plays a key role in managing aggregation-prone mutant proteins linked to neurodegenerative diseases [5,6]. Small intefering RNA (siRNA)-mediated sacsin knockdowns do not affect the viability of wild-type (30Q) ataxin-1 transfected cells but increase toxicity in 82Q-transfected cells, suggesting that sacsin protects against polyglutamine-expanded ataxin-1 toxicity [4].

[8] In Vitro Characterization of Motor Neurons and Purkinje Cells Differentiated from Induced Pluripotent Stem Cells Generated from Patients with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

• Authors: Aurélie Louit, Marie-Josée Beaudet, M. Blais, F. Gros-Louis, N. Dupré et al.
• Year: 2023
• Venue: Stem Cells International
• URL: https://www.semanticscholar.org/paper/bd9110f13d0f247c122707cc759cc2741be2e01c
• DOI: 10.1155/2023/1496597
• PMID: 37096129
• PMCID: 10122584
• Citations: 6
• Summary: Results indicate that it is possible to recapitulate in vitro, at least in part, the ARSACS pathological signature in vitro using patient-derived motor neurons and Purkinje cells differentiated from iPSCs, which could be useful for the screening of new drugs for the treatment of ARsACS.
• Evidence snippets:
• Snippet 1 (score: 0.539) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset hereditary neurodegenerative disease. ARSACS is considered the second most frequent ataxia after the Friedreich ataxia [1]. Described for the first time in the 1970s [2] with a carrier prevalence of 1/22 in the Charlevoix-Saguenay region of the Quebec Province, ARSACS is now found in more than twenty countries worldwide [3,4]. Different causative mutations in the SACS gene are linked to the disease. To date, more than 200 mutations have been identified in this gene [5]. The SACS gene encodes the protein sacsin, highly expressed in Purkinje cells and motor neurons (MNs), which is involved in molecular chaperoning, mitochondrial transport and integrity, and neurofilament assembly [6]. Sacsin knockout mice recapitulated at least in part histopathological and neurological features of ARSACS, pointing out to a sacsin loss-of-function disease mechanism [7]. ARSACS is characterized by cerebellar, pyramidal, and neuropathic involvement and remains incurable [8]. Noteworthy, research on ARSACS patient fibroblasts and mice with decreased SACS gene expression showed mitochondrial abnormalities, with hyperfused mitochondria and a reduction in Drp1-mediated mitochondrial fission [9][10][11]. Mitochondria autophagy was studied on a commercial neuron-like cell line, and an alteration of this mechanism was discovered [12]. Studies conducted using ARSACS mouse models also indicated an alteration in the organization of the intermediate filament network with an accumulation of neurofilaments [7,13]. Although the actual ARSACS animal models are still valuable to investigate the role of sacsin in the pathology of the disease, more reliable humanderived cellular models need to be generated to better understand the underlying pathophysiology of ARSACS in specific cell types.

[9] Deciphering Spastic Ataxia

• Authors: J. Damásio, Mariana Santos, Sara Costa, J. Moura, Ana Sardoeira et al.
• Year: 2025
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/206c0ec660765307c464544d9381380c74722064
• DOI: 10.1212/NXG.0000000000200331
• PMID: 41357347
• PMCID: 12681266
• Summary: Spastic ataxia represented a clinically and genetically distinct subgroup within HCA, marked by recessive inheritance, large genetic heterogeneity, and more severe motor impairment.
• Evidence snippets:
• Snippet 1 (score: 0.517) > Hereditary cerebellar ataxia (HCA) and spastic paraplegia (HSP) are rare neurologic diseases, characterized by degeneration of the cerebellum/cerebellar pathways or corticospinal tracts. 1 Both conditions are highly heterogeneous, presenting either as pure forms-ataxia or spastic paraplegia-or complex phenotypes with additional clinical features, such as intellectual disability, dementia, epilepsy, movement disorders, or neuropathy. 2 A significant diversity of genetic etiologies and disease mechanisms has been described, accelerated since the introduction of new genetic diagnostic techniques in clinical practice. It is important to note that the widespread use of next-generation sequencing (NGS), based on whole-exome sequencing (WES), has revealed genes classically associated with HSP as the underlying genetic cause of HCA, and vice versa. 1,3 The genetic overlap observed in HCA/ HSP, as well as in other hereditary movement disorders, prompted the Task Force for the Nomenclature of Genetic Movement Disorders of the Movement Disorder Society (MDS) to incorporate combined phenotypes into its classification system. 5][6] HCA and HSP are often viewed as 2 ends of a clinical continuum, 1 with pyramidal signs widely recognized as frequent among patients with HCA, as cerebellar signs are in patients with HSP. Nevertheless, the term spastic ataxia (Human Phenotype Ontology [HPO]: 0002497) is reserved for the coexistence of a cerebellar syndrome with overt spasticity and classically linked to a more restricted number of genetic causes. 1,7,8 ecessive inheritance is the most frequent pattern among spastic ataxia cases, with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS, also known as SPAX6 or ATX/HSP-SACS), late-onset Friedreich ataxia, HSP/ATX-PGN 7, and cerebrotendinous xanthomatosis being the most common. 1,7,8

[10] Analyzing Gene Expression Profiles from Ataxia and Spasticity Phenotypes to Reveal Spastic Ataxia Related Pathways

• Authors: Andrea C. Kakouri, Christina Votsi, Marios Tomazou, G. Minadakis, E. Karatzas et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/80f6c58080446277d5f3f70957b5fa42a7069b9a
• DOI: 10.3390/ijms21186722
• PMID: 32937819
• PMCID: 7555177
• Citations: 5
• Summary: Examination of publicly available human gene expression datasets of diseases presented with ‘ataxia’ or ‘spasticity’ in their clinical phenotype and pathway analysis demonstrate consistent differential expression of genes that participate in the sphingolipid pathways and highlight alterations in the pathway level that might be associated with the disease phenotype.
• Evidence snippets:
• Snippet 1 (score: 0.516) > Spastic ataxia (SA) is a group of rare neurodegenerative diseases, characterized by mixed features of generalized ataxia and spasticity. The pathogenetic mechanisms that drive the development of the majority of these diseases remain unclear, although a number of studies have highlighted the involvement of mitochondrial and lipid metabolism, as well as calcium signaling. Our group has previously published the GBA2 c.1780G > C (p.Asp594His) missense variant as the cause of spastic ataxia in a Cypriot consanguineous family, and more recently the biochemical characterization of this variant in patients’ lymphoblastoid cell lines. GBA2 is a crucial enzyme of sphingolipid metabolism. However, it is unknown if GBA2 has additional functions and therefore additional pathways may be involved in the disease development. The current study introduces bioinformatics approaches to better understand the pathogenetic mechanisms of the disease. We analyzed publicly available human gene expression datasets of diseases presented with ‘ataxia’ or ‘spasticity’ in their clinical phenotype and we performed pathway analysis in order to: (a) search for candidate perturbed pathways of SA; and (b) evaluate the role of sphingolipid signaling pathway and sphingolipid metabolism in the disease development, through the identification of differentially expressed genes in patients compared to controls. Our results demonstrate consistent differential expression of genes that participate in the sphingolipid pathways and highlight alterations in the pathway level that might be associated with the disease phenotype. Through enrichment analysis, we discuss additional pathways that are connected to sphingolipid pathways, such as PI3K-Akt signaling, MAPK signaling, calcium signaling, and lipid and carbohydrate metabolism as the most enriched for ataxia and spasticity phenotypes.

[11] Spastic Ataxia Composite (SPAXCOM): A Scale to Evaluate the Progression of Subjects with Spasticity and Ataxia

• Authors: Cécile Di Folco, Charlotte Dubec-Fleury, A. Traschütz, Christoph Kessler, S. Reich et al.
• Year: 2025
• Venue: Movement Disorders
• URL: https://www.semanticscholar.org/paper/3629ac6b478cc983efff4f49eeec0abfb06ebf27
• DOI: 10.1002/mds.70006
• PMID: 40832806
• PMCID: 12661626
• Citations: 1
• Summary: Current clinical scales that track disease progression are more tailored to spasticity or ataxia, with limited sensitivity to change.
• Evidence snippets:
• Snippet 1 (score: 0.513) > The SPAXCOM is more sensitive to change and homogeneous across genotypes than the reference scales, allowing a reduction of the required sample size in future clinical trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Key Words: ataxia; disease progression; spastic ataxia; spastic ataxia Charlevoix-Saguenay type; SPG7 Spastic ataxia (SPAX) is a clinical phenotype defined by the coexistence of cerebellar ataxia and spastic paraplegia comprising a heterogeneous group of >100 predominantly hereditary conditions. 1,2 Among these, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spastic paraplegia type 7 (SPG7) are amongst the most common genetic forms of SPAXs worldwide. 2,3 These diseases are multisystemic, neurodegenerative, and characterized by progressive cerebellar ataxia, spasticity. 4 ith continuous progress in the understanding of the molecular pathogenesis of these and related disorders, novel targeted disease-modifying therapies are on the horizon and will need to be evaluated in clinical trials. Conducting such trials in these diseases is, however, challenging due to their rarity, heterogeneity, and slow progression. Sensitive outcome measures that capture change in relatively short frames are thus crucial to successful drug development. > Several scales have been published to measure ataxia 5 and spasticity. 6 Among those, spasticity and ataxia are often measured by two different scales, the Spastic Paraplegia Rating Scale (SPRS) 7 and the Scale for the Assessment and Rating of Ataxia (SARA). 8 As a result, none of the scales are designed for the conditions in which both symptoms are present in combination. SARA showed a low sensitivity to change in SPG7, 3,9,10 other hereditary spastic paraplegias, 11 and ARSACS. 3,9,12,13 5][16] However, their sensitivity to change has not been systematically assessed and compared against each other in genotypes such as SPG7 and ARSACS.

[12] Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

• Authors: V. Naef, Serena Mero, G. Fichi, Angelica D’Amore, A. Ogi et al.
• Year: 2019
• Venue: Frontiers in Neuroscience
• URL: https://www.semanticscholar.org/paper/88f1c9cc6cece9b31e03e629cda8c271c873f3e0
• DOI: 10.3389/fnins.2019.01311
• PMID: 31920481
• PMCID: 6914767
• Citations: 22
• Summary: The zebrafish, a vertebrate model widely used in biomedical research, is found to be very useful for demonstrating the causal relationship between defect and mutation and offers a useful platform to exploit for the development of therapies.
• Evidence snippets:
• Snippet 1 (score: 0.501) > The identification of other HSP causative genes, together with the discovery of the function of the related proteins, has made it possible to hypothesize at least 10 functional "modes of action" that could play a role in HSP pathogenesis, and also appear to be involved in other neurological disorders: namely, dysfunction of axonal transport, abnormal membrane trafficking and organelle shaping, abnormal endosome membrane trafficking and vesicle formation, oxidative stress, abnormal lipid metabolism, abnormal DNA repair, dysregulation of myelination, autophagy, impairment of axonal development, and abnormal cellular signaling in protein morphogenesis (Lo Giudice et al., 2014;Boutry et al., 2019b). The various forms of HSP, as well as the groups of similar neurodegenerative diseases, such as hereditary ataxia (HA), spinocerebellar ataxia (SCA), autosomal-recessive spinocerebellar ataxia (SCAR), and spastic paraplegia, can be due to mutations in either the spastic paraplegia gene (SPG) or the spastic ataxia genes (SPAX). Clinically, they can present as pure or complicated phenotypes (Synofzik and Schüle, 2017). Formally, HSP and HA are characterized, respectively, by progressive dysfunction or degeneration of the pyramidal tracts (HSP) and of the Purkinje cells and spinocerebellar tracts (HA) (Synofzik and Schüle, 2017). In recent years, genes that cause both cerebellar and pyramidal phenotypes have been discovered, and some genes classified among the HA causative genes have been found to cause HSP phenotypes, too, and vice versa (Galatolo et al., 2018). Furthermore, it is possible that HSP and HA could also share certain pathological mechanisms and cellular pathways. For all these reasons, a new classification of ataxia-spasticity spectrum (ASS) genes has recently been proposed (Synofzik and Schüle, 2017).

[13] Recent advances in understanding hereditary spastic paraplegias and emerging therapies

• Authors: P. Lallemant-Dudek, F. Darios, A. Durr
• Year: 2021
• Venue: Faculty Reviews
• URL: https://www.semanticscholar.org/paper/f952ac77f7cc9c1c221fd5c2589bb8a1b2173184
• DOI: 10.12703/r/10-27
• PMID: 33817696
• PMCID: 8009193
• Citations: 16
• Summary: The focus is on the HSP with cerebellar ataxias since this is a frequent association described for several genes and this overlap leads to an intermediary group of spastic ataxia which is actively genetically and clinically studied.
• Evidence snippets:
• Snippet 1 (score: 0.501) > Hereditary spastic paraplegias (HSPs) are a group of rare, inherited, neurological diseases characterized by broad clinical and genetic heterogeneity. Lower-limb spasticity with first motoneuron involvement is the core symptom of all HSPs. As spasticity is a syndrome and not a disease, it develops on top of other neurological signs (ataxia, dystonia, and parkinsonism). Indeed, the definition of genes responsible for HSPs goes beyond the 79 identified SPG genes. In order to avoid making a catalog of the different genes involved in HSP in any way, we have chosen to focus on the HSP with cerebellar ataxias since this is a frequent association described for several genes. This overlap leads to an intermediary group of spastic ataxias which is actively genetically and clinically studied. The most striking example is SPG7, which is responsible for HSP or cerebellar ataxia or both. There are no specific therapies against HSPs, and there is a dearth of randomized trials in patients with HSP, especially on spasticity when it likely results from other mechanisms. Thus far, no gene-specific therapy has been developed for HSP, but emerging therapies in animal models and neurons derived from induced pluripotent stem cells are potential treatments for patients.

[14] Clinical and genetic characterization of a Taiwanese cohort with spastic paraparesis combined with cerebellar involvement

• Authors: M. Lan, C. Lu, Shey‐Lin Wu, Ying-Fa Chen, Y. Sung et al.
• Year: 2022
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/92844d9538211bed6e1de41fb82dab9215edf8e6
• DOI: 10.3389/fneur.2022.1005670
• PMID: 36247768
• PMCID: 9563621
• Citations: 3
• Influential citations: 1
• Summary: This study revealed the genetic complexity of HSP combined with cerebellar involvement, withCausative mutations in up to 10 genes traditionally related to HSP, HCA and other neurogenetic diseases detected in 16 of the 22 pedigrees.
• Evidence snippets:
• Snippet 1 (score: 0.500) > Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower-limb spasticity. Cerebellar ataxia commonly co-occurs with complicated HSPs. HSP with concurrent cerebellar ataxia has significant clinical and genetic overlaps with hereditary cerebellar ataxia (HCA) and other inherited neurological diseases, adding to the challenge of planning genetic testing for the disease. In this study, we characterized clinical features of a cohort of 24 patients (male/female: 15/9) from 22 families who presented spastic paraparesis combined with cerebellar involvement, with a median disease onset age 20.5 (range 5–53) years. Aside from the core phenotype, 18 (75%) patients had additional neuropsychiatric and systemic manifestations. A stepwise genetic testing strategy stratified by mode of inheritance, distinct neuroimaging features (e.g., thin corpus callosum), population-specific prevalence and whole-exome sequencing was utilized to investigate the genetic etiology. Causative mutations in up to 10 genes traditionally related to HSP, HCA and other neurogenetic diseases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, neurodegeneration with brain iron accumulation, and progressive encephalopathy with brain atrophy and thin corpus callosum) were detected in 16 (73%) of the 22 pedigrees. Our study revealed the genetic complexity of HSP combined with cerebellar involvement. In contrast to the marked genetic diversity, the functions of the causative genes are restricted to a limited number of physiological themes. The functional overlap might reflect common underlying pathogenic mechanisms, to which the corticospinal tract and cerebellar neuron circuits may be especially vulnerable.

[15] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
• DOI: 10.29245/2572.942X/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 9
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.496) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[16] Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a family report from South Brazil

• Authors: Daniela Burguêz, C. M. Oliveira, M. Rockenbach, H. Fussiger, L. Vedolin et al.
• Year: 2016
• Venue: Arquivos de Neuro-Psiquiatria
• URL: https://www.semanticscholar.org/paper/7d43b0732b93a0237db8c98cd1a379f8762eeec5
• DOI: 10.1590/0004-282X20170044
• PMID: 28658401
• Citations: 10
• Influential citations: 1
• Summary: Clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil are described.
• Evidence snippets:
• Snippet 1 (score: 0.490) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay has rarely been addressed in population studies outside Quebec, in the context of autosomal recessive ataxias, spastic ataxias and hereditary spastic paraplegias. The relative frequency of ARSACS varied from 0.3% of hereditary spastic paraplegia patients to 5% of early onset ataxia patients from Germany 24,26 ; and to 8% of spastic ataxia or congenital ataxia patients from multiple origins 25 . The ARSACS frequency among ataxic or hereditary spastic paraplegia families from Brazil is unknown. > The two individuals in the present report presented with clinical, neuroimaging, electrophysiological and ophthalmological findings resembling the characteristics of the Quebec patients, which led to the suspicion of ARSACS. Before them, three Brazilian siblings presenting with a clinical diagnosis of typical ARSACS, without molecular confirmation, were reported 27 . Therefore, there is reason to expect other cases, typical or atypical, in our population. > In conclusion, ARSACS is a spastic ataxic disorder, with worldwide distribution, being the second or third most common cause of autosomal recessive ataxias in some series outside Quebec 24 . Brain MRI is a mandatory complementary investigation for ataxic disorders of unknown diagnosis 28 and ARSACS is one of the diseases where a specific MRI pattern may give rise to a correct diagnosis. Both ophthalmological evaluation and nerve conduction studies should be routinely ordered for patients with ataxia for a better phenotypic characterization. The suspicion of persistent myelination of the retina in an ataxic patient should be confirmed by optical coherence tomography; prominent myelinated retinal nerve fibers on fundoscopy should lead to SACS sequencing. A demyelinating or axonal-demyelinating sensorimotor polyneuropathy in an ataxic patient should also raise ARSACS suspicion. Finally, atypical ARSACS cases with Charcot-Marie-Tooth-like, or other complex phenotypes, might lack both MRI and fundoscopy abnormalities. Their diagnosis may be made with a next-generation sequencing panel or whole exome sequencing analysis 24,25 .

[17] Functional Network Profiles in ARSACS Disclosed by Aptamer-Based Proteomic Technology

• Authors: F. Morani, S. Doccini, G. Chiorino, F. Fattori, D. Galatolo et al.
• Year: 2021
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/223b7db1faa4f65bdb9f512fd8bf65d96236bab9
• DOI: 10.3389/fneur.2020.603774
• PMID: 33584503
• PMCID: 7873355
• Citations: 11
• Summary: Proteomics data obtained using the SomaLogic technology identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls, suggesting that common dysfunctional networks could be therapeutic targets for future investigations.
• Evidence snippets:
• Snippet 1 (score: 0.488) > Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations.
• Snippet 2 (score: 0.487) > Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations.

[18] Genetic analysis of three patients from two unrelated Chinese families with autosomal recessive spastic ataxia of Charlevoix-Saguenay

• Authors: Hui Liu, Ranran Li, Chen Chen, Lin Shang, Ying Bai et al.
• Year: 2025
• Venue: BMC Medical Genomics
• URL: https://www.semanticscholar.org/paper/fc2f9b6a2f1cabff71938900d513c456221f1b5c
• DOI: 10.1186/s12920-025-02151-2
• PMID: 40319245
• PMCID: 12049771
• Summary: 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.
• Evidence snippets:
• Snippet 1 (score: 0.487) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS, online Mendelian inheritance in man [OMIM]: #270550), a rare early-onset progressive neurodegenerative disease, was originally identified in the 1970s in a French Canadian population from Charlevoix-Saguenay in Quebec [1]. Since then, ARSACS cases outside Quebec populations, such as Italy [2], Japan [3], Spain [4], Turkey [5], and China [6], have also been reported. The clinical phenotypes of ARSACS are highly diverse owing to the increasing number of patients worldwide. ARSACS is characterized by three main clinical phenotypes, including early-onset cerebellar ataxia, spasticity, and sensorimotor peripheral neuropathy, accompanied by other atypical clinical phenotypes, for instance, weakness of limbs, skeletal abnormalities, flexion deformity of fingers, dental abnormalities, hearing loss, and mental retardation [7]. > ARSACS is caused by homozygous or compound heterozygous variants in the sacsin (SACS, OMIM: #604490) gene mapping on chromosome 13q12.12. SACS consists of 10 exons. The last exon, spanning exactly 12.8 kb, is the largest exon found in vertebrates [8]. To date, more than 600 SACS variants have been registered as likely pathogenic or pathogenic in the public databases of Clin-Var ( h t t p s : / / w w w . n c b i . n l m . n i h . g o v / c l i n v a r /) and OMIM (https://www.omim.org/), with most of the variants located in exon 10 [9]. The vast majority of SACS variants are single nucleotide variants (SNVs) or small insertions and deletions (indels), although copy number variants (CNVs) have also been reported.

[19] A Novel SACS Variant Identified in a Chinese Patient: Case Report and Review of the Literature

• Authors: Yu-Chou Chen, Xiao-dong Lu, Yi Jin, Dan Li, Xiaojun Ye et al.
• Year: 2022
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/4bcaae1ddf228a407da67e73b987a9b7e2aee6d3
• DOI: 10.3389/fneur.2022.845318
• PMID: 35386405
• PMCID: 8978317
• Citations: 4
• Summary: A 35-year-old Chinese patient carrying a novel variant in SACS (c.11486C>T) presenting with progressive ataxia and demyelinating peripheral neuropathy is described and contributes to the evaluation of genotype-phenotype correlations.
• Evidence snippets:
• Snippet 1 (score: 0.484) > Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is one of the most common autosomal recessive ataxia caused by biallelic mutations within the SACS (OMIM: 270550) gene (1). The majority of patients with ARSACS present three core typical phenotypes of early-onset cerebellar ataxia, spasticity, peripheral neuropathy, and other atypical manifestations, including cognition disability, lacking spasticity, epileptic seizures, and hearing loss (2,3). Brain magnetic resonance imaging (MRI) often revealed remarkable findings of cerebellum atrophy and linear T2 hypointensities in the pons. The optical coherence tomography (OCT) presented a remarkable abnormality in the retinal nerve fiber layer (RNFL) hypertrophy. However, in clinical practice, the absence of remarkable finds in brain MRI or retinal OCT were also present in some ARSACS cases (4,5). > Genetically, over 200 mutations have been described in the SACS gene, most of which have been detected in the gigantic exon 10. The majority of the mutation's types were missense mutation and small deletions subsequently. The identical same mutation leading to different clinical features were described, even in siblings (6). These findings suggested that ARSACS is a clinically and genetically heterogeneous disease and it usually confuses us to make a precise diagnosis. Here, we describe the case of a Chinese patient carrying a novel variant in SACS presented with progressive ataxia and demyelinating peripheral neuropathy.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.