ARSACS: Clinical Features, Pathophysiology and IPS-Derived Models

Overview

Journal Cerebellum

Publisher Springer

Specialty Neurology

Date 2025 Jan 3

PMID 39753868

Authors

Ikhlass Haj Salem

Mathieu Blais

Valeria M Zuluaga-Sanchez

Laurence Rouleau

Esther B E Becker

Nicolas Dupre

Affiliations

Soon will be listed here.

Abstract

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease caused by mutations in the SACS gene. The first two mutations were identified in French Canadian populations 20 years ago. The disease is now known as one of the most frequent recessive ataxias worldwide. Prominent features include cerebellar ataxia, pyramidal spasticity, and neuropathy. Neuropathological findings revealed cerebellar atrophy of the superior cerebellar vermis and the anterior vermis associated with Purkinje cell death, pyramidal degeneration, cortical atrophy, loss of motor neurons, and demyelinating neuropathy. No effective therapy is available for ARSACS patients but, in the last two decades, there have been significant advances in our understanding of the disease. New approaches in ARSACS, such as the reprogramming of induced pluripotent stem cells derived from patients, open exciting perspectives of discoveries. Several research questions are now emerging. Here, we review the clinical features of ARSACS as well as the cerebellar aspects of the disease, with an emphasis on recent fields of investigation.

References

Bouchard J, Barbeau A, Bouchard R, Bouchard R . Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci. 1978; 5(1):61-9. View

Synofzik M, Soehn A, Gburek-Augustat J, Schicks J, Karle K, Schule R . Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet J Rare Dis. 2013; 8:41. PMC: 3610264. DOI: 10.1186/1750-1172-8-41. View

Bouhlal Y, Jennewein D, Anderson B, Reynoldson J, Maamouri W, Hentati F . Computational analysis of a novel SACS gene mutation with BioExtract server. J Mol Neurosci. 2011; 44(1):53-8. DOI: 10.1007/s12031-011-9512-8. View

Pilliod J, Moutton S, Lavie J, Maurat E, Hubert C, Bellance N . New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Ann Neurol. 2015; 78(6):871-86. DOI: 10.1002/ana.24509. View

Anheim M . [Autosomal recessive cerebellar ataxias]. Rev Neurol (Paris). 2010; 167(5):372-84. DOI: 10.1016/j.neurol.2010.07.021. View

Anheim M, Chaigne D, Fleury M, Santorelli F, De Seze J, Durr A . [Autosomal recessive spastic ataxia of Charlevoix-Saguenay: study of a family and review of the literature]. Rev Neurol (Paris). 2008; 164(4):363-8. DOI: 10.1016/j.neurol.2008.02.001. View

Baets J, Deconinck T, Smets K, Goossens D, Van den Bergh P, Dahan K . Mutations in SACS cause atypical and late-onset forms of ARSACS. Neurology. 2010; 75(13):1181-8. DOI: 10.1212/WNL.0b013e3181f4d86c. View

Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V . A novel mutation in SACS gene in a family from southern Italy. Neurology. 2004; 62(1):100-2. DOI: 10.1212/wnl.62.1.100. View

Criscuolo C, Sacca F, De Michele G, Mancini P, Combarros O, Infante J . Novel mutation of SACS gene in a Spanish family with autosomal recessive spastic ataxia. Mov Disord. 2005; 20(10):1358-61. DOI: 10.1002/mds.20579. View

10.

El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung W . Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol. 2003; 60(7):982-8. DOI: 10.1001/archneur.60.7.982. View

11.

Gerwig M, Kruger S, Kreuz F, Kreis S, Gizewski E, Timmann D . Characteristic MRI and funduscopic findings help diagnose ARSACS outside Quebec. Neurology. 2010; 75(23):2133. DOI: 10.1212/WNL.0b013e318200d7f8. View

12.

Grieco G, Malandrini A, Comanducci G, Leuzzi V, Valoppi M, Tessa A . Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type. Neurology. 2004; 62(1):103-6. DOI: 10.1212/01.wnl.0000104491.66816.77. View

13.

Ogawa T, Takiyama Y, Sakoe K, Mori K, Namekawa M, Shimazaki H . Identification of a SACS gene missense mutation in ARSACS. Neurology. 2004; 62(1):107-9. DOI: 10.1212/01.wnl.0000099371.14478.73. View

14.

Ouyang Y, Segers K, Bouquiaux O, Wang F, Janin N, Andris C . Novel SACS mutation in a Belgian family with sacsin-related ataxia. J Neurol Sci. 2007; 264(1-2):73-6. DOI: 10.1016/j.jns.2007.07.022. View

15.

Richter A, Koksal Ozgul R, Poisson V, Topaloglu H . Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey. Neurogenetics. 2004; 5(3):165-70. DOI: 10.1007/s10048-004-0179-y. View

16.

Vermeer S, Meijer R, Pijl B, Timmermans J, Cruysberg J, Bos M . ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. Neurogenetics. 2008; 9(3):207-14. PMC: 2441586. DOI: 10.1007/s10048-008-0131-7. View

17.

Rezende Filho F, Parkinson M, Pedroso J, Poh R, Faber I, Lourenco C . Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS. Parkinsonism Relat Disord. 2019; 62:148-155. DOI: 10.1016/j.parkreldis.2018.12.024. View

18.

Kuchay R, Mir Y, Zeng X, Hassan A, Musarrat J, Parwez I . ARSACS as a Worldwide Disease: Novel SACS Mutations Identified in a Consanguineous Family from the Remote Tribal Jammu and Kashmir Region in India. Cerebellum. 2019; 18(4):807-812. DOI: 10.1007/s12311-019-01028-2. View

19.

De Braekeleer M, Giasson F, Mathieu J, Roy M, Bouchard J, Morgan K . Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec. Genet Epidemiol. 1993; 10(1):17-25. DOI: 10.1002/gepi.1370100103. View

20.

Engert J, Dore C, Mercier J, Ge B, Betard C, Rioux J . Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): high-resolution physical and transcript map of the candidate region in chromosome region 13q11. Genomics. 1999; 62(2):156-64. DOI: 10.1006/geno.1999.6003. View