• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

ARSACS

Synonyms: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay, Spastic Ataxia of Charlevoix-Saguenay

, MD, PhD, , MD, PhD, and , PhD.

Author Information
, MD, PhD
Radboud University Nijmegen Medical Center
Nijmegen, The Netherlands
, MD, PhD
Radboud University Nijmegen Medical Center
Nijmegen, The Netherlands
, PhD
Radboud University Nijmegen Medical Center
Nijmegen, The Netherlands

Initial Posting: ; Last Update: October 11, 2012.

Summary

Disease characteristics. ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is characterized in individuals born in Quebec Province by early-onset (age 12-18 months) difficulty in walking and gait unsteadiness. In individuals with ARSACS born outside the Province of Quebec, onset is often delayed until later childhood and even adulthood. Ataxia, dysarthria, spasticity, extensor plantar reflexes, distal muscle wasting, a distal sensorimotor neuropathy predominant in the legs, and horizontal gaze-evoked nystagmus constitute the most frequent progressive neurologic signs. Increased demarcation of the retinal nerve fibers located near the vessels close to the optic disc (formerly designated as yellow streaks of hypermyelinated fibers) is very common in individuals with ARSACS who originate from Quebec but may be absent in non-Quebec born individuals. Individuals with ARSACS born in the Province of Quebec become wheelchair bound at the average age of 41 years; cognitive skills are preserved in the long term as individuals remain able to perform daily living tasks late into adulthood. Death commonly occurs in the sixth decade.

Diagnosis/testing. Neuroimaging reveals atrophy of the superior vermis and cerebellar hemispheres next to linear hypointensities in the pons. SACS is the only gene in which mutations are known to cause ARSACS. More than 100 different pathogenic mutations have been identified in SACS. About 96% of individuals with ARSACS from northeastern Quebec are homozygotes or compound heterozygotes for two founder mutations.

Management. Treatment of manifestations: Physical therapy and oral medications such as baclofen to control spasticity in the early phase of the disease may prevent tendon shortening and joint contractures and, hence, may help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur; urinary urgency and incontinence may be controlled with low doses of amitryptiline or oxybutynin; custom-made leg braces may improve control of spasticity; during school years, speech therapy and psychological support may help enhance academic performance.

Surveillance: Annual neurologic examination, referral to neuro-rehabilitation unit.

Genetic counseling. ARSACS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing and prenatal testing for pregnancies at increased risk are possible if both disease-causing alleles of an affected family member have been identified.

Diagnosis

Clinical Diagnosis

ARSACS is clinically characterized by a progressive cerebellar syndrome, peripheral neuropathy, and spasticity. Disease onset is usually in early childhood, often leading to delayed walking because of gait unsteadiness in very young infants.

The clinical picture is fairly typical, consisting of the following triad of symptoms:

  • Progressive cerebellar ataxia
  • Peripheral neuropathy with distal wasting and weakness
  • Spasticity of the lower limbs

Ophthalmologic examination may show increased demarcation of retinal nerve fibers. However, absence of this finding does not exclude ARSACS.

Molecular Genetic Testing

Gene. SACS is the only gene in which mutations are known to cause autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in ARSACS

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SACSTargeted mutation analysis 6594delT and 5254C>T 495% 4
Sequence analysisSequence variants 5Unknown
Deletion/duplication analysis 6Partial- or whole-gene deletionsUnknown 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Founder mutations in individuals from northeastern Quebec [Mercier et al 2001]. 92.6% of individuals with ARSACS are homozygous for the 6594delT mutation; 3.7% of individuals with ARSACS are compound heterozygotes for the 6594delT deletion and a 5254C>T nonsense mutation [Richter et al 1999].

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Breckpot et al [2008], Terracciano et al [2009], Baets et al [2010]

Testing Strategy

To confirm/establish the diagnosis in a proband. If an affected individual is clinically suspected of having ARSACS, sequence analysis of all coding exons and their flanking intronic sequences is performed. If only one heterozygous pathogenic mutation is identified, additional deletion/duplication analysis may be performed. Also, when one or more SACS exons fail to be amplified by PCR, deletion testing should be performed to determine if there is homozygosity for a deletion.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) defines a spastic ataxia usually of late-infantile onset in individuals born in Quebec, first described in 1978 among a cohort of about 325 French-Canadian individuals from 200 families born in the Saguenay-Lac-St-Jean area of northeastern Quebec [Bouchard et al 1978]. Little intra- and extrafamilial phenotypic variability has been observed among affected individuals born in Quebec.

The clinical phenotype in Quebec-born individuals is typically characterized by onset between age 12 and 18 months with difficulty in walking and gait unsteadiness [Bouchard 1991]. Spastic ataxia and dysarthria tend to worsen slowly but relentlessly in the preteen and teen years. A childhood-onset mixed sensorimotor peripheral neuropathy with both axonal and demyelinating features is observed in most affected individuals. This leads to distal muscle atrophy and weakness, foot deformities, impaired tactile and vibration sense and (eventually) to a decrease or loss of tendon reflexes in the legs [Vermeer et al 2008]. Electrophysiology often confirms a mixed demyelinating and axonal neuropathy [Bouchard et al 1978, García et al 2008, Baets et al 2010]. Distal amyotrophy, which leads to loss of ankle reflexes and sometimes bilateral foot drop, is found in most individuals after age 21 years. Other deep tendon reflexes remain brisk. Oculomotor disturbances, dysarthria, and upper limb ataxia usually progress much slower than gait ataxia, spasticity, and neuropathy.

A characteristic retinal finding is the presence of yellow streaks of hypermyelinated fibers radiating from the edges of the retina. Retinal nerve fiber hypertrophy as demonstrated on ocular coherence tomography (OCT) has been reported in several individuals with ARSACS [Pablo et al 2011].

Superior vermis atrophy, linear hypointensities in the pons, and atrophy of the cerebellar hemispheres and spinal cord can be seen on brain MRI [Martin et al 2007].

Mitral valve prolapse, a frequent feature among individuals with ARSACS from Quebec [Bouchard et al 1978], has to date been reported in only one affected individual not of Quebec origin [Baets et al 2010].

Since mutation analysis became available, many affected individuals outside Quebec have been molecularly characterized. Almost all affected individuals show the highly characteristic triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs.

Disease onset is typically in early childhood, although adult onset has also been described [Ogawa et al 2004, Baets et al 2010]. The first signs of the disease are a slowly progressive cerebellar ataxia (which can lead to delayed walking because of gait unsteadiness in very young infants [Bouchard et al 1978]) usually with subsequent lower limb spasticity, followed by features of peripheral neuropathy. However, pronounced peripheral neuropathy as a first sign of ARSACS, followed by pyramidal and cerebellar signs, has also been observed. Often, this leads to significant and severe lower-limb and gait impairment.

To date, three mutation-proven individuals with ARSACS and an unusual phenotype (lacking either spasticity or peripheral neuropathy) have been described [Shimazaki et al 2005, Baets et al 2010]. However, the two affected individuals described by Shimazaki et al with absence of lower-limb spasticity both displayed bilateral Babinski signs indicating pyramidal involvement; here, the spasticity was likely masked by the severe neuropathy. In the third individual, from a Belgian cohort, clinical or electrophysiologic signs of peripheral neuropathy were lacking. Disease onset in this individual was unusually late (age 40 yrs); it may be that peripheral neuropathy has not yet developed.

Although IQ levels tend to be in the lower range of normal, in part as a result of the neurologic handicaps (e.g., severe dysarthria), most affected individuals are able to cope well with daily living tasks. Cognitive skills tend to be preserved into late adult life, although this is queried by recent observations. Detailed neuropsychiatric and neurophysiologic assessment was performed in two individuals with ARSACS. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunction were present indicating that the cerebellum may also play a functional role in human cognition and affect [Verhoeven et al 2012].

In two reported sibs with ARSACS from Quebec, death occurred in the sixth decade.

Genotype-Phenotype Correlations

Individuals with a microdeletion of 13q12.12 that encompasses SACS (and a mutation on the other allele) have a slightly different phenotype consisting of hearing loss and learning difficulties in addition to the typical features of ARSACS [Breckpot et al 2008, Terracciano et al 2009].

Prevalence

The exact prevalence of ARSACS is unknown. Nearly 325 individuals with ARSACS have been followed for many years in specialized ataxia clinics in Quebec. The male-to-female ratio is nearly equal.

The estimated carrier frequency of SACS mutations in the Saguenay-Lac-St-Jean (SLSJ) region of Quebec, northeast of Quebec City, Canada is 1:21, based on data gathered between 1941 and 1985 [De Braekeleer 1991, De Braekeleer et al 1993, Dupre et al 2006]. The birth incidence of ARSACS was 1:1,932. Consanguinity was slightly increased (13%) within affected kindreds. A founder effect is largely suspected as the root cause of the high regional prevalence of ARSACS, which could date back to 1650, a date consistent with the arrival of the first carrier family from France. The geographic isolation of the SLSJ region from large urban areas during the 18th and 19th centuries played a role in the sustained high levels of hereditary transmission and local incidence of ARSACS.

Although initially confined to Quebec, genetically confirmed ARSACS has now been reported in individuals all over Europe, Tunisia, Japan, and Turkey [Criscuolo et al 2004, Grieco et al 2004, Ogawa et al 2004, Criscuolo et al 2005, Takiyama 2006, Vermeer et al 2008, Baets et al 2010]. In a Belgian cohort of individuals with cerebellar ataxia suggestive of ARSACS, a relative prevalence of 13% was identified [Baets et al 2010]. In another cohort of 232 (index) individuals with cerebellar ataxia, a comparable prevalence of 12% was found [Vermeer et al, unpublished data].

The true worldwide incidence of ARSACS remains unknown; it is likely underdiagnosed.

Differential Diagnosis

Ataxia. See Hereditary Ataxia Overview.

  • The classification of autosomal recessive ataxias has been greatly expanded (for review, see Robitaille et al [2003] and de Bot et al [2012]) with the inclusion of several new syndromes. Early-, juvenile-, and adult-onset types associated with diverse phenotypes from spastic paraplegia to intellectual disability may be excluded.
  • Friedreich ataxia, the autosomal recessive ataxic disorder with the highest worldwide prevalence, may overlap with ARSACS. Friedreich ataxia is characterized by slowly progressive ataxia with onset usually before age 25 years. It is typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration sense. A discriminating feature of Friedreich ataxia is the absence of the early-onset spasticity seen in ARSACS. MRI often does not show cerebellar atrophy until late in the disease; atrophy of the dentate nuclei is common. About 25% of individuals have an atypical presentation with onset after age 25 years, retained tendon reflexes, or unusually slow progression of disease. About two thirds of individuals have cardiomyopathy. Diabetes mellitus occurs in 10% of individuals. The far earlier onset of ARSACS, the absence of cardiomyopathy in ARSACS and the presence of hypermyelinated retinal fibers in Quebec-born persons with ARSACS help distinguish the two disorders. The vast majority of individuals with Friedreich ataxia have identifiable mutations in FXN. The most common mutation, seen in more than 95% of individuals, is a GAA triplet-repeat expansion in intron 1, which leads to transcription of mutated frataxin, an iron transporter localized in the mitochondria.
  • Autosomal recessive ataxia with vitamin E deficiency (AVED) (and more rarely, abetalipoproteinemia) may need to be excluded on the basis of clinical phenotypes and relevant laboratory tests. Malabsorption syndromes of various causes may also cause ataxia late in the disease course.
  • An autosomal recessive spastic ataxia involved 15 out of 34 candidate families in Morocco not linked to the SACS locus on chromosome 13 [Bouslam et al 2007]. Dysarthria appeared first, followed by gait abnormalities. Age of onset was usually before 15 years; however, rarely persons first become symptomatic during early adulthood. A new locus, labeled SAX2, was found on chromosome 17p13.

Spastic paraplegia. See Hereditary Spastic Paraplegia.

  • Most individuals with ARSACS first reported by Bouchard et al [1978] had been diagnosed as having cerebral palsy with spastic diplegia. Confusion with cerebral palsy and secondary spastic diplegia may in part explain the apparent low incidence of ARSACS in many parts of the world.
  • SPG30 is characterized by early-onset unsteady spastic gait and hyperreflexia of lower limbs. Mildly impaired sensation and cerebellar involvement have been described [Klebe et al 2006]. Mutations in KIF1A have been associated with SPG30 [Erlich et al 2011].
  • Troyer syndrome (also called SPG20), is caused by mutations in SPG20 [Patel et al 2002]. Troyer syndrome is characterized by spastic paraplegia with distal arm and leg amyotrophy, dysarthria, and mild cerebellar signs. It has a higher frequency in the Amish population than elsewhere in the world.
  • Autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL, spastic ataxia 3, SPAX3), is characterized by spastic ataxia and brain white matter changes [Thiffault et al 2006]. Mutations in MARS2 have recently been associated with ARSAL [Bayat et al 2012].

Retinal streaks may be observed in individuals without spastic ataxia or other neurodegenerative abnormalities. Recent ultrastructural observations have not corroborated the hypothesis that hypermyelinated fibers constitute the basic pathophysiology of retinal streaks in ARSACS.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay), the following evaluations are recommended:

  • Neurologic examination
  • Brain MRI
  • Retinal examination
  • EMG
  • Medical genetics consultation

Treatment of Manifestations

Curative therapy is not available.

Physical therapy and use of oral medications such as baclofen to control spasticity in the early phase of the disease may prevent tendon shortening and joint contractures. These measures may help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur.

Urinary urgency and incontinence may be controlled with low doses of amitryptiline or oxybutynin.

During school years, speech therapy and psychological support may help enhance academic performance.

Surveillance

Surveillance should include annual neurologic examination.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Gene therapy may possibly be considered in the long term once transgenic models provide more specific clues on the molecular cascades of partially deleted or truncated sacsin and their effects on neuronal survival and functions that lead to the ARSACS phenotype.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are usually obligate heterozygotes and therefore carry one mutant allele. A report of uniparental isodisomy of the paternal chromosome 13 resulting in a homozygous p.Arg4378Ter mutation in an affected individual suggests that not all parents are heterozygous [Anesi et al 2011].
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband. The offspring of an individual with ARSACS are obligate heterozygotes for a disease-causing mutation in SACS.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier detection is possible if the disease-causing mutations have been identified in an affected family member.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Population screening. In the Saguenay-Lac-St-Jean (Quebec, Canada) population, the high carrier frequency (1:21) could warrant population screening for reproductive purposes. In this population, molecular genetic testing of the two founder mutations (6594delT and 5254C>T) detects 92.6% of carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. ARSACS: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SACS13q12​.12SacsinSACS homepage - Mendelian genes
SACSIN Gene Database
SACS

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for ARSACS (View All in OMIM)

270550SPASTIC ATAXIA, CHARLEVOIX-SAGUENAY TYPE; SACS
604490SACSIN; SACS

Normal allelic variants. The reference sequence NM_014363.4 has ten (of which nine are coding) exons.

Pathogenic allelic variants. In a study of 164 alleles, 92.6% of individuals with ARSACS born in Quebec were homozygous for the deletion 6594delT and 3.7% of individuals were compound heterozygous for the common deletion and a missense 5254C>T mutation [Richter et al 1999].

Normal gene product. Sacsin is an 11.7-kb protein of yet-unknown function [Engert et al 2000]. The sacsin isoform NP_055178.3, encoded by the transcript NM_014363.4, has 4579 amino acid residues. The carboxy-terminus domain harbors a 'DnaJ' motif that has the potential to interact with members of the HSP70 family of heat shock proteins and a ubiquitin-like domain suggesting that sacsin may play a specific cellular role linking the ubiquitin-proteosome pathway to the heat shock protein 70 machinery [Parfitt et al 2009]. The N-terminus has extensive homology for HSP90, a subtype of heat shock protein that can act as a chaperone molecule important in the regulation of protein folding. Wild-type sacsin is expressed throughout the CNS, in skeletal muscles, and in skin fibroblasts. However, no knock-out transgenic models of ARSACS are yet available to assess the potential lethality of mutated sacsin.

Studies in sacsin knockout mice have shown that sacsin localizes to mitochondria in non-neuronal cells and primary neurons and that it interacts with dynamin-related protein 1, which participates in mitochondrial fission. Furthermore, it is likely that sacsin plays a role in the regulation of mitochondrial dynamics and that mitochondrial dysfunction/mislocalization is the cellular basis for ARSACS [Girard et al 2012].

Abnormal gene product. Individuals homozygous for the 6594delT deletion have complete loss of sacsin expression in skin fibroblasts as determined by immunocytochemical and western blot analyses. It is then likely that major deletions result in complete suppression of sacsin expression, including in the CNS. It is postulated that SACS mutations may interfere with protein folding and lead to significant loss of function in key signaling pathways even at an embryonic stage. Compound heterozygosity for less extensive deletions or point mutations will result in the synthesis of a truncated sacsin molecule that may not be able to interact normally with other proteins.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Anesi L, de Gemmis P, Pandolfo M, Hladnik U. Two novel homozygous SACS mutations in unrelated patients including the first reported case of paternal UPD as an etiologic cause of ARSACS. J Mol Neurosci. 2011;43:346–9. [PubMed: 20852969]
  2. Baets J, Deconinck T, Smets K, Goossens D, Van den Bergh P, Dahan K, Schmedding E, Santens P, Rasic VM, Van Damme P, Robberecht W, De Meirleir L, Michielsens B, Del-Favero J, Jordanova A, De Jonghe P. Mutations in SACS cause atypical and late-onset forms of ARSACS. Neurology. 2010;75:1181–8. [PubMed: 20876471]
  3. Bayat V, Thiffault I, Jaiswal M, Tétreault M, Donti T, Sasarman F, Bernard G, Demers-Lamarche J, Dicaire MJ, Mathieu J, Vanasse M, Bouchard JP, Rioux MF, Lourenco CM, Li Z, Haueter C, Shoubridge EA, Graham BH, Brais B, Bellen HJ. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol. 2012;10:e1001288. [PMC free article: PMC3308940] [PubMed: 22448145]
  4. Bouchard JP. Recessive spastic ataxia of Charlevoix-Saguenay. In: de Jong JMBV, ed. Handbook of Clinical Neurology 16: Hereditary Neuropathies and Spinocerebellar Degenerations. Vol 60. Amsterdam, Netherlands: Elsevier; 1991:451-9.
  5. Bouchard JP, Barbeau A, Bouchard R, Bouchard RW. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci. 1978;5:61–9. [PubMed: 647499]
  6. Bouslam N, Bouhouche A, Benomar A, Hanein S, Klebe S, Azzedine H, Giandomenico SD, Boland-Auge A, Santorelli FM, Durr A, Brice A, Yahyaoui M, Stevanin G. A novel locus for autosomal recessive spastic ataxia on chromosome 17p. Hum Genet. 2007;121:413–20. [PubMed: 17273843]
  7. Breckpot J, Takiyama Y, Thienpont B, Van Vooren S, Vermeesch JR, Ortibus E, Devriendt K. A novel genomic disorder: a deletion of the SACS gene leading to spastic ataxia of Charlevoix-Saguenay. Eur J Hum Genet. 2008;16:1050–4. [PubMed: 18398442]
  8. Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V, Santorelli FM, Perretti A, Santoro L, De Michele G, Filla A. A novel mutation in SACS gene in a family from southern Italy. Neurology. 2004;62:100–2. [PubMed: 14718706]
  9. Criscuolo C, Sacca F, De Michele G, Mancini P, Combarros O, Infante J, Garcia A, Banfi S, Filla A, Berciano J. Novel mutation of SACS gene in a Spanish family with autosomal recessive spastic ataxia. Mov Disord. 2005;20:1358–61. [PubMed: 16007637]
  10. de Bot ST, Willemsen MA, Vermeer S, Kremer HP, van de Warrenburg BP. Reviewing the genetic causes of spastic-ataxias. Neurology. 2012;79:1507–14. [PubMed: 23033504]
  11. De Braekeleer M. Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). Hum Hered. 1991;41:141–6. [PubMed: 1937486]
  12. De Braekeleer M, Giasson F, Mathieu J, Roy M, Bouchard JP, Morgan K. Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec. Genet Epidemiol. 1993;10:17–25. [PubMed: 8472930]
  13. Dupre N, Bouchard JP, Brais B, Rouleau GA. Hereditary ataxia, spastic paraparesis and neuropathy in the French-Canadian population. Can J Neurol Sci. 2006;33:149–57. [PubMed: 16736723]
  14. Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res. 2011;21:658–64. [PMC free article: PMC3083082] [PubMed: 21487076]
  15. Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melancon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A. ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet. 2000;24:120–5. [PubMed: 10655055]
  16. García A, Criscuolo C, de Michele G, Berciano J. Neurophysiological study in a Spanish family with recessive spastic ataxia of Charlevoix-Saguenay. Muscle Nerve. 2008;37:107–10. [PubMed: 17683082]
  17. Girard M, Larivière R, Parfitt DA, Deane EC, Gaudet R, Nossova N, Blondeau F, Prenosil G, Vermeulen EG, Duchen MR, Richter A, Shoubridge EA, Gehring K, McKinney RA, Brais B, Chapple JP, McPherson PS. Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Proc Natl Acad Sci U S A. 2012;109:1661–6. [PMC free article: PMC3277168] [PubMed: 22307627]
  18. Grieco GS, Malandrini A, Comanducci G, Leuzzi V, Valoppi M, Tessa A, Palmeri S, Benedetti L, Pierallini A, Gambelli S, Federico A, Pierelli F, Bertini E, Casali C, Santorelli FM. Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type. Neurology. 2004;62:103–6. [PubMed: 14718707]
  19. Klebe S, Azzedine H, Durr A, Bastien P, Bouslam N, Elleuch N, Forlani S, Charon C, Koenig M, Melki J, Brice A, Stevanin G. Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain. 2006;129:1456–62. [PubMed: 16434418]
  20. Martin MH, Bouchard JP, Sylvain M, St-Onge O, Truchon S. Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a report of MR imaging in 5 patients. AJNR Am J Neuroradiol. 2007;28:1606–8. [PubMed: 17846221]
  21. Mercier J, Prevost C, Engert JC, Bouchard JP, Mathieu J, Richter A. Rapid detection of the sacsin mutations causing autosomal recessive spastic ataxia of Charlevoix-Saguenay. Genet Test. 2001;5:255–9. [PubMed: 11788093]
  22. Ogawa T, Takiyama Y, Sakoe K, Mori K, Namekawa M, Shimazaki H, Nakano I, Nishizawa M. Identification of a SACS gene missense mutation in ARSACS. Neurology. 2004;62:107–9. [PubMed: 14718708]
  23. Pablo LE, Garcia-Martin E, Gazulla J, Larrosa JM, Ferreras A, Santorelli FM, Benavente I, Vela A, Marin MA. Retinal nerve fiber hypertrophy in ataxia of Charlevoix-Saguenay patients. Mol Vis. 2011;17:1871–6. [PMC free article: PMC3144729] [PubMed: 21850161]
  24. Parfitt DA, Michael GJ, Vermeulen EG, Prodromou NV, Webb TR, Gallo JM, Cheetham ME, Nicoll WS, Blatch GL, Chapple JP. The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum Mol Genet. 2009;18:1556–65. [PMC free article: PMC2667285] [PubMed: 19208651]
  25. Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet. 2002;31:347–8. [PubMed: 12134148]
  26. Richter A, Rioux JD, Bouchard JP, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, Weissenbach J, Hudson TJ, Melancon SB, Morgan K. Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11. Am J Hum Genet. 1999;64:768–75. [PMC free article: PMC1377794] [PubMed: 10053011]
  27. Robitaille Y, Klockgether T, Lamarche JB. Friedrich's ataxia. In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Basel, Switzerland: ISN Neuropath Press; 2003:257-68.
  28. Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I. A phenotype without spasticity in sacsin-related ataxia. Neurology. 2005;64:2129–31. [PubMed: 15985586]
  29. Takiyama Y. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuropathology. 2006;26:368–75. [PubMed: 16961075]
  30. Terracciano A, Casali C, Grieco GS, Orteschi D, Di Giandomenico S, Seminara L, Di Fabio R, Carrozzo R, Simonati A, Stevanin G, Zollino M, Santorelli FM. An inherited large-scale rearrangement in SACS associated with spastic ataxia and hearing loss. Neurogenetics. 2009;10:151–5. [PubMed: 19031088]
  31. Thiffault I, Rioux MF, Tetreault M, Jarry J, Loiselle L, Poirier J, Gros-Louis F, Mathieu J, Vanasse M, Rouleau GA, Bouchard JP, Lesage J, Brais B. A new autosomal recessive spastic ataxia associated with frequent white matter changes maps to 2q33-34. Brain. 2006;129:2332–40. [PubMed: 16672289]
  32. Verhoeven WM, Egger JI, Ahmed AI, Kremer BP, Vermeer S, van de Warrenburg BP. Cerebellar cognitive affective syndrome and autosomal recessive spastic ataxia of charlevoix-saguenay: a report of two male sibs. Psychopathology. 2012;45:193–9. [PubMed: 22441213]
  33. Vermeer S, Meijer RP, Pijl BJ, Timmermans J, Cruysberg JR, Bos MM, Schelhaas HJ, van de Warrenburg BP, Knoers NV, Scheffer H, Kremer B. ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. Neurogenetics. 2008;9:207–14. [PMC free article: PMC2441586] [PubMed: 18465152]

Chapter Notes

Author History

Jean-Pierre Bouchard, MD; Laval University (2003-2012)
Erik-Jan Kamsteeg, PhD (2012-present)
Jean Mathieu, MD, FRCPC; Complexe Hospitalier de la Sagamie (2003-2012)
Andrea Richter, PhD; University of Montreal (2003-2012)
Yves Robitaille, MD, FCAP; University of Montreal (2003-2012)
Bart P van de Warrenburg, MD, PhD (2012-present)
Sascha Vermeer, MD, PhD (2012-present)

Revision History

  • 11 October 2012 (me) Comprehensive update posted live
  • 11 April 2007 (me) Comprehensive update posted to live Web site
  • 3 January 2005 (me) Comprehensive update posted to live Web site
  • 9 December 2003 (me) Review posted to live Web site
  • 2 July 2003 (yr) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1255PMID: 20301432
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...