DiagnosisClinical DiagnosisARSACS 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 ataxiaPeripheral neuropathy with distal wasting and weaknessSpasticity of the lower limbsOphthalmologic examination may show increased demarcation of retinal nerve fibers. However, absence of this finding does not exclude ARSACS. Molecular Genetic TestingGene. 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 ARSACSView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilitySACSTargeted mutation analysis 6594delT and 5254C>T 295% 2ClinicalSequence analysisSequence variants 3UnknownDeletion / duplication analysis 4Partial- or whole-gene deletionsUnknown 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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]. 3. 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.4. 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.5. Breckpot et al [2008], Terracciano et al [2009], Baets et al [2010]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo 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.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations of SACS.}

Natural HistoryARSACS (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 CorrelationsIndividuals 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].

Differential DiagnosisAtaxia. 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 consultationTreatment of ManifestationsCurative 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. SurveillanceSurveillance should include annual neurologic examination.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationGene 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSACS13q12​.12SacsinSACSIN Gene Database
SACS homepage - Mendelian genesSACSData 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) View in own window 270550SPASTIC ATAXIA, CHARLEVOIX-SAGUENAY TYPE; SACS 604490SACSIN; SACSNormal allelic variants. The reference sequence NM_014363.4 has ten (of which nine are coding) exons.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 heterozygous for the common deletion and a missense 5254C>T mutation [Richter et al 1999].A founder mutation (p.Arg3636Gln) associated with ARSACS has been identified in the Belgian population [Baets et al 2010].The p.Gln4054X mutation is a common mutation among Dutch persons with ARSACS [Vermeer et al 2008].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.