Clinical Diagnosis

The clinical diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) hinges on clinical symptoms and signs that are subdivided into major and minor criteria. At least two major criteria and one minor criterion are necessary to establish the clinical diagnosis.

Molecular Genetic Testing

Gene.   SACS is the only gene known to be associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).

Research testing

Direct DNA analysis.  Previously reported French, Tunisian, and Turkish individuals with ARSACS showed linkage to the 13q11 locus. Molecular genetic testing for other SACS mutations, identified in populations outside of northeastern Quebec, is available on a research basis only.

Table 1. Summary of Molecular Genetic Testing Used in ARSACS

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Test Method	Mutations Detected	Mutation Detection Frequency  1	Test Availability
Targeted mutation analysis	6594delT and 5254C>T mutations in SACS	95%  2	Clinical
Direct DNA  3	Other SACS sequence alterations	Unknown	Research only

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1.  Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
2. Individuals from northeastern Quebec
3. Direct DNA methods may include mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with ARSACS.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations of SACS.

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.

Ataxia

See Hereditary Ataxia Overview.

The classification of autosomal recessive ataxias was greatly expanded during the last few years (for review, see Robitaille et al 2003) with the inclusion of several new syndromes. Early-, juvenile-, and adult-onset types associated with diverse phenotypes from spastic paraplegia to mental retardation are to 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. 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 the FXN gene. 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 later. Age of onset was usually before 15 years; however, rarely persons first become symptomatic during early adulthood. A new locus, labeled fSAX2, 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.

Troyer syndrome (also called SPG20), is caused by mutations in the gene 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.

Retinal Streaks

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 this lesion in ARSACS.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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.  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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Literature Cited

1. Bouchard JP. Recessive spastic ataxia of Charlevoix-Saguenay. In: de Jong JMBV (ed) Handbook of Clinical Neurology, revised series. 1991;16
2. 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]
3. 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]
4. 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]
5. 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]
6. De Braekeleer M. Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). Hum Hered. 1991;41:141–6. [PubMed: 1937486]
7. 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]
8. 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]
9. El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung WY, Belal S, Siddique T, Hentati F. Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol. 2003;60:982–8. [PubMed: 12873855]
10. 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]
11. 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]
12. Gucuyener K, Ozgul K, Paternotte C, Erdem H, Prud'homme JF, Ozguc M, Topaloglu H. Autosomal recessive spastic ataxia of Charlevoix-Saguenay in two unrelated Turkish families. Neuropediatrics. 2001;32:142–6. [PubMed: 11521210]
13. 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]
14. Mrissa N, Belal S, Hamida CB, Amouri R, Turki I, Mrissa R, Hamida MB, Hentati F. Linkage to chromosome 13q11-12 of an autosomal recessive cerebellar ataxia in a Tunisian family. Neurology. 2000;54:1408–14. [PubMed: 10751248]
15. 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]
16. Ouyang Y, Takiyama Y, Sakoe K, Shimazaki H, Ogawa T, Nagano S, Yamamoto Y, Nakano I. Sacsin-related ataxia (ARSACS): expanding the genotype upstream from the gigantic exon. Neurology. 2006;66:1103–4. [PubMed: 16606928]
17. 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]
18. Pulst SM, Filla A. Ataxias on the march from Quebec to Tunisia. Neurology. 2000;54:1400–1. [PubMed: 10751244]
19. 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]
20. Richter AM, Ozgul RK, Poisson VC, Topaloglu H. Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey. Neurogenetics. 2004;5:165–70. [PubMed: 15156359]
21. Robitaille Y, Klockgether T, Lamarche JB. Friedrich's ataxia. In: Dickson D (ed) Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, ISN Neuropath Press, Basel, pp 257-68. 2003
22. 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]
23. Takiyama Y. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuropathology. 2006;26:368–75. [PubMed: 16961075]

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 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