SACSIN-Related Autosomal Recessive Ataxia

Authors:

Isabelle Thiffault, Msc
Jean-Pierre Bouchard, MD
Jean Mathieu, MD
Bernard Brais, MD, PhD

About the Authors

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 nystagmus constitute the most frequent progressive neurologic signs. Yellow streaks of hypermyelinated fibers radiate from the edges of the retina. The retinal changes are uncommon in individuals with ARSACS of French, Italian, Tunisian, and Turkish heritage; they are described as less extensive in persons of Japanese descent. 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, with little extension into lateral cerebellar hemispheres. Dentate nuclei and pontine structures are spared. SACS is the only gene associated with ARSACS. About 96% of individuals with ARSACS from northeastern Quebec are homozygotes or compound heterozygotes for two founder mutations. Molecular genetic testing for these mutations is available on a clinical basis. Molecular genetic testing for mutations observed in other populations is available on a research basis only.

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; 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.

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 unaffected and not a carrier. Prenatal testing of at-risk pregnancies is not available.

Diagnosis

Clinical Diagnosis

The diagnosis of SACSIN-related autosomal recessive cerebellar ataxia (Autosomal recessive spastic ataxia of Charlevoix-Saguenay, or ARSACS) is established in individuals with the following:

• Age of onset between age 12-18 months
• Initial symptoms of cerebellar ataxia and/or dysarthria, spasticity, extensor plantar reflexes, distal muscle wasting, a distal sensorimotor neuropathy predominant in the legs, and horizontal gaze nystagmus constitute the most frequent progressive neurologic signs

Testing

Nerve conduction studies. Abnormal

Imaging. Always seen on MRI at the time of diagnosis: marked diffuse cerebellar atrophy.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work. Listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. --ED.

Gene. SACSIN is the only gene currently known to be associated with ARSACS.

Research testing

• DNA and cDNA Sequence analysis. Mutation detection is performed through sequence analysis of all exons and exon/intron junctions and cDNA sequencing. Large deletions are currently investing using Long-Range PCR.

Testing Strategy

To establish the diagnosis in a proband. Probands should initially undergo the following:

• Neurologic examination
• Brain MRI to evaluate the cerebellum
• Electrophysiologic studies
• Biochemical testing to rule out vitamin E deficiency (see Ataxia with Vitamin E Deficiency)
• Molecular genetic testing to rule out Friedreich ataxia Genetically

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in the SACSIN gene.

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 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. 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. A characteristic retinal finding is the presence of yellow streaks of hypermyelinated fibers radiating from the edges of the retina.

Subsequently, similar clinical phenotypes were identified in persons of French, Italian, Japanese, Tunisian, and Turkish heritage [Pulst & Filla 2000]. These individuals predominantly display spastic ataxia and most other neurologic features of the syndrome with late-infantile, juvenile, or adult onset, but most often without the retinal abnormalities. Japanese individuals have been described with cognitive impairment, but without spasticity or myelinated retinal fibers [Takiyama 2006].

The male-to-female ratio is nearly equal with slight male predominance.

Mitral valve prolapse may occasionally be observed. Cardiomyopathy does not occur.

Although IQ levels tend to be in the lower range of normal, in part as a result of the neurologic handicaps such as severe dysarthria, most affected individuals are able to cope well with daily living tasks. Cognitive skills tend to be preserved into late adult life.

Death commonly occurs in the sixth decade.

Prevalence

Nearly 325 individuals with ARSACS have been followed for many years in specialized ataxia clinics in Quebec.

The estimated carrier frequency of ARSACS 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 from France, Tunisia, Italy, Spain, Japan, and Turkey [Criscuolo et al 2004, Grieco et al 2004, Ogawa et al 2004, Criscuolo et al 2005, Takiyama 2006]. Its true worldwide incidence remains unknown as underdiagnosis is likely.

Genotype-Phenotype Correlations

In the French-Canadian population, more than eight mutations have been identified while several mutations still remain unknown.

Genotype-Phenotype correlation study of the mutations newly identified may lead to a specific phenotype.

Nomenclature

ARSACS has also been referred to as autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with mean age of onset between ten and 15 years and usually before age 25 years. FRDA is typically associated with depressed tendon reflexes, dysarthria, muscle weakness, spasticity in the lower limbs, optic nerve atrophy, scoliosis, bladder dysfunction, and loss of position and vibration senses. About two-thirds of individuals with FRDA have cardiomyopathy, 30% have diabetes mellitus, and about 25% have an "atypical" presentation with later onset, retained tendon reflexes, or unusually slow progression of disease. Individuals with FRDA have identifiable mutations in the FXN gene.

Ataxia with vitamin E deficiency (AVED). Most individuals with AVED present at puberty; common characteristics of the disease include progressive ataxia, clumsiness of the hands, loss of proprioception (especially of vibration and joint position sense), and areflexia. The principal criterion for diagnosis is a Friedreich ataxia-like neurologic phenotype associated with markedly reduced plasma vitamin E (alpha-tocopherol) concentration in the absence of known causes of malabsorption. In most cases, molecular analysis of TTPA, the gene encoding alpha-tocopherol transfer protein and the only gene known to be associated with AVED, allows confirmation of the diagnosis by demonstrating the presence of pathogenic mutations.

Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe axonal motor neuropathy. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. Chorea and upper-limb dystonia are common. Cerebellar atrophy is visible on MRI in all affected individuals. EMG reveals axonal neuropathy in 100% of individuals with AOA1. APTX is the only gene associated with AOA1.

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between ages ten and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP). AOA2 is associated with mutations in the gene SETX.

16q-ADCA is characterized by onset after age 55 years and sensorineural hearing impairment [Ishikawa et al 2005]. It is a relatively pure cerebellar syndrome caused by mutations in PLEKHG4.

Spinocerebellar ataxia type 5 (SCA5) is characterized by a slowly progressive cerebellar syndrome beginning mostly in the third decade [Burk et al 2004]. The most consistent clinical feature is downbeat nystagmus. Other common features include gait, stance, and limb ataxia; dysarthria; intention tremor and resting tremor; impaired smooth pursuit; and gaze-evoked nystagmus. Symptom progression is slow, and all affected individuals remain ambulatory despite disease duration of up to 30 years. MRI shows atrophy of the cerebellar vermis and hemispheres. SCA5 is caused by mutations in SPTBN2.

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Age of onset is between 19 and 71 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance in about 90% of individuals; the remainder present with dysarthria. Symptoms progress slowly, and eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. CACNA1A is the only gene known to be associated with SCA6.

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in males who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor. (See FMR1-Related Disorders.)

Other acquired causes of late-onset ataxia include [Fogel & Perlman 2006]: neurosyphilis, subacute combined degeneration, vitamin E deficiency, subcortical vascular disease, multiple sclerosis, normal-pressure hydrocephalus, copper myelopathy, gluten-sensitive enteropathy, paraneoplastic cerebellar ataxia, and brain tumors and metastases.

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

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.

Technical support for daily living tasks, such as driving a car, may be achieved through the wearing of custom-made leg braces to improve control of spasticity.

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

Surveillance

Surveillance should include annual neurologic examination.

Testing 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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —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 child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) 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 (carriers) for a disease-causing mutation in the SACS gene.

• Other family members of a proband. 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 availability of prenatal testing is before pregnancy.

• 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. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Molecular Genetics of SACSIN-Related AUTOSOMAL RECESSIVE SPASTIC ATAXIA CHARLEVOIX-SAGUENAY TYPE; SACSIN

Gene Symbol	Chromosomal Locus	Protein Name
SACS	13q12	SACSIN
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

OMIM Entries for SACSIN-Related AUTOSOMAL RECESSIVE SPASTIC ATAXIA CHARLEVOIX-SAGUENAY TYPE; SACSIN

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

Genomic Databases for SACSIN-Related AUTOSOMAL RECESSIVE SPASTIC ATAXIA CHARLEVOIX-SAGUENAY TYPE; SACSIN

Gene Symbol	Entrez Gene	GeneCards	GDB	GenAtlas
SACS	26278	SACS	9954724	SACSIN
For a description of the genomic databases listed, click here.

Normal allelic variants: Full intron-exon mapping of the SACS gene is still ongoing.

Pathologic 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 heterozygotes for the common deletion and a missense 5254C>T mutation. Additional French-Canadian mutations have been recently uncovered (data unpublished). Several novel mutations have now been reported in individuals with ARSACS from Tunisia, Turkey, Italy, and Japan. Criscuolo et al (2004) described two affected sisters (one mentally retarded) born to consanguineous parents from southern Italy with a homozygous 1859insC mutation at the N terminal domain of the SACS gene that causes a frameshift mutation at codon 597 leading to transcription of truncated sacsin. None of the previously described SACS mutations was found among 22 index persons with an ARSACS-like phenotype from a series of 85 persons with early-onset ataxia.

Criscuolo et al (2005) reported a new missense SACS mutation (7848C>T) in a Spanish family whose phenotype was similar to the earliest presentations associated with ARSACS, thus emphasizing the widespread occurrence of ARSACS-causing mutations around the world, with the highest incidence around the Mediterranean basin.

Grieco et al (2004) described three new SACS mutations in two of the original six Italian families. All three were novel mutations not found in the chromosomes of 190 healthy Italian individuals. The phenotype of the two affected individuals was similar to that reported in Quebec-born individuals with ARSACS except for the absence of retinal striations.

• Patient 1 of Grieco et al (2004) was 32 years old, born to healthy consanguineous parents. He was able to walk at age two years. He was homozygous for an out-of-frame deletion of five bases at codon 4999 (5del4999CAGAA5003), which removes an MboII restriction enzyme site in SACS. This mutation causes a frameshift with an early stop codon at residue 1679 with transcription of a truncated sacsin lacking about 55% of the wild type sequence. Both parents and the older of two brothers were heterozygous for the five base-pair deletion.
• Patient 2 of Grieco et al (2004), age 21 years, was born to healthy unrelated parents. He was able to walk at age 17 months, despite frequent falls. He was compound heterozygous for a C>T transition at nucleotide position (np) 1858 and a maternally inherited single adenosine insertion at np 4585 (4585insA). The insertion causes an abnormal stop codon at amino acid residue 1540.

Ogawa et al (2004) found a previously undescribed mutation in two siblings born to healthy unrelated parents. Both had early onset of spastic ataxia, slurred speech, and retinal striations. They were homozygous for a missense mutation (Thr7492Cys) with substitution of an arginine for tryptophan at amino acid residue 2498 (Trp2498Arg). The mutation results in partial loss of Nla III restriction enzyme site. A healthy sister and 200 healthy Japanese individuals did not have this novel mutation.

• Patient 1 of Ogawa et al (2004), age 37 years, had walked at age 18 months, with slow gait during the first decade. At age six years, he had a slowly progressive gait disturbance with deformed toes. At age 20 years, he required assistance with walking and speech was slowed and dysarthric. At age 28 years, he had spasticity and mild distal weakness of lower limbs with gaze-evoked nystagmus. Some retinal striations were present.
• Patient 2 of Ogawa et al (2004) was the 43-year-old sister of Patient 1. She displayed gait unsteadiness and leg spasticity, first noticed at age 26 years. Retinal striations were less extensive than her brother's.

Shimazaki et al (2005) described two Japanese siblings without spasticity, who harbored a novel homozygous missense mutation (Thr987Cys) in the SACS gene. A similar phenotype was documented as linked to yet another new SACS mutation (c.5988-9delCT). The latter phenotype was complicated by a severe peripheral neuropathy.

In Tunisia, a total of five affected families have been reported, nine individuals by Mrissa et al (2000) and 18 by El Euch-Fayache et al (2003). In all, two missense and two nonsense mutations were identified:

• A 10046G>C transversion resulting in an Ala3324Pro substitution
• A 3662T>C transition resulting in a Trp1196Arg substitution
• A 1-bp insertion (1155insA), producing a truncated peptide of 360 amino acids
• A 1-bp deletion (1411delT), yielding a premature stop codon that forms a truncated sacsin peptide of 456 amino acids

The phenotype observed in persons of Tunisian heritage differs from that observed in Quebec-born individuals in the very low incidence of retinal networks of myelinated fibers and the later age of onset (mean of 4.5 years). In addition, progressive ataxia with spastic paresis was more common in older individuals and absent ankle reflexes and peripheral neuropathy, both axonal and demyelinating, remained stereotyped, albeit punctuated by heterogeneous course within and in between kindreds. Age of onset across all individuals from the five Turkish families ranged from 1.5 to 3.5 years. Thus once more, a trend towards later age of onset in non-Quebec-born individuals within the juvenile range was emphasized. Clinical phenotypes were otherwise stereotyped and characterized by slow evolution and even stationary course.

In four of five ARSACS consanguineous families from Turkey, four new private homozygous SACS mutations were found [Richter et al 2004], which brought to 12 the total number of mutations in individuals born in countries located around the Mediterranean basin:

• A homozygous T>C point mutation at position 2018 of NM_014363 (2018T>C), which changes cysteine 648 to arginine (Cys648Arg) without impairment of secondary protein structure
• An A>G mutation at residue 11471 (11471A>G), which changes asparagine 3799 to aspartic acid (Asn3799Asp). A 28% homology of the sacsin molecular segment in which this human mutation occurred was documented in the genome of a lower vertebrate (fugu), which indicated that this segment of the protein is highly conserved.
• A homozygous four-base deletion at residue 9655 (9655_9658delAGTT), leading to an ORF change that involves a stop codon at residue 9676. The deletion allows transcription of a truncated sacsin, which lacks key carboxy and amino terminus domains.
• A homozygous deletion of C at residue 8124 (8124delC) that changes the ORF to include a stop codon at residue 8203 and encodes a truncated sacsin protein
• A Japanese individual has been reported with compound heterozygous mutations in an exon upstream from the gigantic exon [Ouyang et al 2006]. This study introduced the long-suspected notion that additional exons (besides the previously documented larger exon) could be part of the sacsin locus.

Normal gene product: Sacsin was first described as an 11.7-kb protein of yet unknown function [Engert et al 2000]. In 2003, Sacsin was described has a protein coded by single exons [Richter 2003, personal communication]. 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 stimulate its ATPase activity. 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. Different transcripts of the gene have been identified, and a total of 11 exons within the gene have been described. The large transcript reported in NCBI (NM_014363.4) comprises 9 coding exons consisting of 13,737 bp which encode 4.579 amino acids.

Abnormal gene product: : Individuals homozygous for the 6594delT deletion have complete loss of sacsin immunocytochemical and western blot expression in skin fibroblasts. It is then likely that major deletions result in complete suppression of sacsin expression, including 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 heterozygotes for less extensive deletions or point mutations will result in the synthesis of a truncated sacsin molecule that may not able to interact normally with other proteins.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

• Ataxia of Charlevoix-Saguenay Foundation Research that heals
  Ataxia of Charlevoix-Saguenay Foundation
  1, Place Ville-Marie, 39th floor
  Montreal (Quebec) H3B 4M7
  Phone: (514) 878-8851
  Fax: (514) 866-2241
  Email : ataxia@arsacs.com
  http://www.arsacs.com/
  
  


• Euro-ataxia (European Federation of Hereditary Ataxias)
  Boherboy Dunlavin
  Co Wicklow
  Ireland
  Phone: 045 401218
  Fax: 045 401371
  Email: mary.kearneyl@euro-ataxia.org
  www.euro-ataxia.org
  
  
• International Network of Ataxia Friends (INTERNAF)
  www.internaf.org
  
  
• National Ataxia Foundation
  2600 Fernbrook Lane Suite 119
  Minneapolis MN 55447
  Phone: 763-553-0020
  Fax: 763-553-0167
  Email: naf@ataxia.org
  www.ataxia.org

References

1. Kamada S, Okawa S, Imota T, Sugawara M, Toyoshima I.
   Title: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) : Novel compound heterozygous mutations in the SACS gene.
   J Neurol. 2008 May 19. [Epub ahead of print]
   PMID: 18484239 [PubMed - as supplied by publisher]
   


2. Vermeer S, Meijer RP, Pijl BJ, Timmermans J, Cruysberg JR, Bos MM, Schelhaas HJ, van de Warrenburg BP, Knoers NV, Scheffer H, Kremer B.
   Title: ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia.
   Neurogenetics. 2008 May 9. [Epub ahead of print]
   PMID: 18465152 [PubMed - as supplied by publisher]
   


3. Anheim M, Chaigne D, Fleury M, Santorelli FM, De Sèze J, Durr A, Brice A, Koenig M, Tranchant C.
   Title: [Autosomal recessive spastic ataxia of Charlevoix-Saguenay: Study of a family and review of the literature.]
   Rev Neurol (Paris). 2008 Apr;164(4):363-368. Epub 2008 Mar 25. French.
   PMID: 18439928 [PubMed - as supplied by publisher]
   


4. Breckpot J, Takiyama Y, Thienpont B, Van Vooren S, Vermeesch JR, Ortibus E, Devriendt K.
   Title: A novel genomic disorder: a deletion of the SACS gene leading to Spastic Ataxia of Charlevoix-Saguenay.
   Eur J Hum Genet. 2008 Apr 9. [Epub ahead of print]
   PMID: 18398442 [PubMed - as supplied by publisher]
   


5. Dupré N, Chrestian N, Thiffault I, Brais B, Rouleau GA, Bouchard JP.
   Title: [Hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada]
   Rev Neurol (Paris). 2008 Jan;164(1):12-21. Epub 2008 Jan 25. Review. French.
   PMID: 18342054 [PubMed - indexed for MEDLINE]
   


6. Takiyama Y.
   Title: Sacsinopathies: sacsin-related ataxia.
   Cerebellum. 2007 Feb 28:1-7. [Epub ahead of print]
   PMID: 17853117 [PubMed - as supplied by publisher]
   


7. Martin MH, Bouchard JP, Sylvain M, St-Onge O, Truchon S.
   Title: Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a report of MR imaging in 5 patients.
   AJNR Am J Neuroradiol. 2007 Sep;28(8):1606-8. Review.
   PMID: 17846221 [PubMed - indexed for MEDLINE]
   


8. Ouyang Y, Segers K, Bouquiaux O, Wang FC, Janin N, Andris C, Shimazaki H, Sakoe K, Nakano I, Takiyama Y.
   Title: Novel SACS mutation in a Belgian family with sacsin-related ataxia.
   J Neurol Sci. 2008 Jan 15;264(1-2):73-6. Epub 2007 Aug 22.
   PMID: 17716690 [PubMed - indexed for MEDLINE]
   


9. García A, Criscuolo C, de Michele G, Berciano J.
   Title: Neurophysiological study in a Spanish family with recessive spastic ataxia of Charlevoix-Saguenay.
   Muscle Nerve. 2008 Jan;37(1):107-10.
   PMID: 17683082 [PubMed - indexed for MEDLINE]
   


10. Shimazaki H, Sakoe K, Niijima K, Nakano I, Takiyama Y.
    Title: An unusual case of a spasticity-lacking phenotype with a novel SACS mutation.
    J Neurol Sci. 2007 Apr 15;255(1-2):87-9. Epub 2007 Mar 8.
    PMID: 17349660 [PubMed - indexed for MEDLINE]
    


11. Bouslam N, Bouhouche A, Benomar A, Hanein S, Klebe S, Azzedine H, Di Giandomenico S, Boland-Augé A, Santorelli FM, Durr A, Brice A, Yahyaoui M, Stevanin G.
    Title: A novel locus for autosomal recessive spastic ataxia on chromosome 17p.
    Hum Genet. 2007 May;121(3-4):413-20. Epub 2007 Feb 2.
    PMID: 17273843 [PubMed - indexed for MEDLINE]
    


12. Takiyama Y.
    Title: Autosomal recessive spastic ataxia of Charlevoix-Saguenay.
    Neuropathology. 2006 Aug;26(4):368-75.
    PMID: 16961075 [PubMed - indexed for MEDLINE]
    


13. Dupré N, Bouchard JP, Brais B, Rouleau GA.
    Title: Hereditary ataxia, spastic paraparesis and neuropathy in the French-Canadian population.
    Can J Neurol Sci. 2006 May;33(2):149-57. Review.
    PMID: 16736723 [PubMed - indexed for MEDLINE]
    


14. Ouyang Y, Takiyama Y, Sakoe K, Shimazaki H, Ogawa T, Nagano S, Yamamoto Y, Nakano I.
    Title: Sacsin-related ataxia (ARSACS): expanding the genotype upstream from the gigantic exon.
    Neurology. 2006 Apr 11;66(7):1103-4.
    PMID: 16606928 [PubMed - indexed for MEDLINE]
    


15. Criscuolo C, Saccà F, De Michele G, Mancini P, Combarros O, Infante J, Garcia A, Banfi S, Filla A, Berciano J.
    Title: Novel mutation of SACS gene in a Spanish family with autosomal recessive spastic ataxia.
    Mov Disord. 2005 Oct;20(10):1358-61.
    PMID: 16007637 [PubMed - indexed for MEDLINE]
    


16. Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I.
    Title: A phenotype without spasticity in sacsin-related ataxia.
    Neurology. 2005 Jun 28;64(12):2129-31.
    PMID: 15985586 [PubMed - indexed for MEDLINE]
    


17. Hara K, Onodera O, Endo M, Kondo H, Shiota H, Miki K, Tanimoto N, Kimura T, Nishizawa M.
    Title: Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan.
    Mov Disord. 2005 Mar;20(3):380-2.
    PMID: 15486997 [PubMed - indexed for MEDLINE]
    


18. Gagnon C, Desrosiers J, Mathieu J.
    Title: Autosomal recessive spastic ataxia of Charlevoix-Saguenay: upper extremity aptitudes, functional independence and social participation.
    Int J Rehabil Res. 2004 Sep;27(3):253-6.
    PMID: 15319698 [PubMed - indexed for MEDLINE]
    


19. Richter AM, Ozgul RK, Poisson VC, Topaloglu H.
    Title: Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey.
    Neurogenetics. 2004 Sep;5(3):165-70. Epub 2004 May 20.
    PMID: 15156359 [PubMed - indexed for MEDLINE]
    


20. Ogawa T, Takiyama Y, Sakoe K, Mori K, Namekawa M, Shimazaki H, Nakano I, Nishizawa M.
    Title: Identification of a SACS gene missense mutation in ARSACS.
    Neurology. 2004 Jan 13;62(1):107-9.
    PMID: 14718708 [PubMed - indexed for MEDLINE]
    


21. 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.
    Title: Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type.
    Neurology. 2004 Jan 13;62(1):103-6.
    PMID: 14718707 [PubMed - indexed for MEDLINE]
    


22. Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V, Santorelli FM, Perretti A, Santoro L, De Michele G, Filla A.
    Title: A novel mutation in SACS gene in a family from southern Italy.
    Neurology. 2004 Jan 13;62(1):100-2.
    PMID: 14718706 [PubMed - indexed for MEDLINE]
    


23. Gomez CM.
    Title: ARSACS goes global.
    Neurology. 2004 Jan 13;62(1):10-1. No abstract available.
    PMID: 14718687 [PubMed - indexed for MEDLINE]
    


24. El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung WY, Belal S, Siddique T, Hentati F.
    Title: Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia.
    Arch Neurol. 2003 Jul;60(7):982-8.
    PMID: 12873855 [PubMed - indexed for MEDLINE]
    


25. Mercier J, Prévost C, Engert JC, Bouchard JP, Mathieu J, Richter A.
    Title: Rapid detection of the sacsin mutations causing autosomal recessive spastic ataxia of Charlevoix-Saguenay.
    Genet Test. 2001 Fall;5(3):255-9.
    PMID: 11788093 [PubMed - indexed for MEDLINE]
    


26. Mrissa N, Belal S, Hamida CB, Amouri R, Turki I, Mrissa R, Hamida MB, Hentati F.
    Title: Linkage to chromosome 13q11-12 of an autosomal recessive cerebellar ataxia in a Tunisian family.
    Neurology. 2000 Apr 11;54(7):1408-14.
    PMID: 10751248 [PubMed - indexed for MEDLINE]
    


27. Engert JC, Bérubé P, Mercier J, Doré C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melançon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A.
    Title: ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF.
    Nat Genet. 2000 Feb;24(2):120-5.
    PMID: 10655055 [PubMed - indexed for MEDLINE]
    


28. Engert JC, Doré C, Mercier J, Ge B, Bétard C, Rioux JD, Owen C, Bérubé P, Devon K, Birren B, Melançon SB, Morgan K, Hudson TJ, Richter A.
    Title: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): high-resolution physical and transcript map of the candidate region in chromosome region 13q11.
    Genomics. 1999 Dec 1;62(2):156-64.
    PMID: 10610707 [PubMed - indexed for MEDLINE]
    


29. Bouchard M, Langlois G.
    Title: Orthopedic management in autosomal recessive spastic ataxia of Charlevoix-Saguenay.
    Can J Surg. 1999 Dec;42(6):440-4.
    PMID: 10593245 [PubMed - indexed for MEDLINE]
    


30. Richter A, Rioux JD, Bouchard JP, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, Weissenbach J, Hudson TJ, Melançon SB, Morgan K.
    Title: 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 Mar;64(3):768-75. Erratum in: Am J Hum Genet 1999 Apr;64(4):1257.
    PMID: 10053011 [PubMed - indexed for MEDLINE]
    


31. De Braekeleer M, Giasson F, Mathieu J, Roy M, Bouchard JP, Morgan K.
    Title: Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec.
    Genet Epidemiol. 1993;10(1):17-25.
    PMID: 8472930 [PubMed - indexed for MEDLINE]
    


32. Richter A, Morgan K, Bouchard JP, Poirier J, Mercier J, Gosselin F, Melançon SB.
    Title: Clinical and molecular genetic studies on autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).
    Adv Neurol. 1993;61:97-103. Review. No abstract available.
    PMID: 8421971 [PubMed - indexed for MEDLINE]
    


33. Richards C, Bouchard JP, Bouchard R, Barbeau H.
    Title: A preliminary study of dynamic muscle function in hereditary ataxia.
    Can J Neurol Sci. 1980 Nov;7(4):367-77.
    PMID: 7214252 [PubMed - indexed for MEDLINE]
    


34. Langelier R, Bouchard JP, Bouchard R.
    Title: Computed tomography of posterior fossa in hereditary ataxias.
    Can J Neurol Sci. 1979 May;6(2):195-8.
    PMID: 487310 [PubMed - indexed for MEDLINE]
    


35. Bouchard RW, Bouchard JP, Bouchard R, Barbeau A.
    Title: Electroencephalographic findings in Friedreich's ataxia and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).
    Can J Neurol Sci. 1979 May;6(2):191-4.
    PMID: 487309 [PubMed - indexed for MEDLINE]
    


36. Bouchard JP, Barbeau A, Bouchard R, Bouchard RW.
    Title: Electromyography and nerve conduction studies in Friedreich's ataxia and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).
    Can J Neurol Sci. 1979 May;6(2):185-9.
    PMID: 487308 [PubMed - indexed for MEDLINE]
    

Author Information

Isabelle Thiffault, Msc

Neuromics Center for Excellence of Universite de Montreal
CRCHUM Notre-Dame Hospital
Neurogenetics Lab. (M4211-L)
1560 Sherbrooke East
Montreal, QC, H2L 4M1
Email:isabelle.thiffault@elf.mcgill.ca

Jean-Pierre Bouchard, MD

Faculty of Medicine, Laval University
Department of Neurological Sciences
CHAUQ - Enfant-Jésus
Quebec City, Canada

Jean Mathieu, MD, FRCPC

Department of Neurology Complexe Hospitalier de la Sagamie Chicoutimi
Email:jmathieu@saglac.qc.ca

Bernard Brais, MD, PHD

Neurogenetics Lab. (M4211-L)
Center for the Study of Brain Diseases
CHUM Notre-Dame Hospital
Email:bernard.brais@umontreal.ca