DiagnosisClinical DiagnosisThe diagnosis of SYNE1-related autosomal recessive cerebellar ataxia (also known as autosomal recessive cerebellar ataxia type 1 or ARCA1) is established in individuals with the following: Age of onset between late teens and early forties Initial symptoms of cerebellar ataxia and/or dysarthria "Pure" cerebellar ataxia phenotype with few associated features other than dysmetria, brisk lower-extremity tendon reflexes, and minor abnormalities in ocular saccades and smooth ocular pursuits TestingNerve conduction studies. Always normal Imaging. Always seen on MRI at the time of diagnosis: marked diffuse cerebellar atrophy (Figure 1) with no other abnormalitiesFigureFigure 1. MRI of a 29-year-old female with ARCA1. Sagittal T₁ shows marked diffuse cerebellar atrophy with no atrophy of the cerebral cortex, midbrain, pons, or medulla. Molecular Genetic TestingGene. SYNE1 is the only gene in which mutations are known to cause ARCA1. Clinical testingSequence analysis. Mutation detection is performed through sequence analysis of all exons and exon/intron junctions [Gros-Louis et al 2007]. The mutation detection frequency of variants approaches 100% in the regions of the gene that are sequenced.Targeted mutation analysis. Testing for a panel of mutations identified in affected individuals of French Canadian ancestry; see Table 1.Mutation scanning of select exons. The mutation detection frequency is not known.Deletion/duplication analysis. The usefulness of such testing has not been demonstrated, as no deletions or duplications of SYNE1 have been reported to result in ARCA1.Table 1. Summary of Molecular Genetic Testing Used in SYNE1-Related Autosomal Recessive Cerebellar Ataxia (ARCA1)View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency ¹ Test AvailabilitySYNE1Sequence analysis of coding region and exon/intron junctions Sequence variants ² including those in a targeted mutation panel(s)~100% of variants in the regions sequencedClinicalTargeted mutation analysis ^{3Mutations found in French Canadian population, p.Arg2906X, c.15705-12A>G, c.16177-2A>G, p.Asp5868Alafs*13 4100% of targeted mutationsMutation scanning of select exonsExons 56, 71, 81, 84, 93, 118, 126 5Unknown Deletion / duplication analysis 6Deletion/duplication of one or more exons or the whole gene 7Unknown; none reported to date1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Targeted mutation analysis refers to testing for specific mutation(s). The panel of mutations may vary among testing laboratories.4. Some laboratories may offer testing for the mutations found in the French Canadian population: p.Gln7640X, p.Gln7386X, and c.281100-281101delTG.5. Exons analyzed may vary by laboratory.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.7. No deletions or duplications of SYNE1 have been reported to cause ARCA1. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)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 and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Probands should initially undergo the following: 1.Neurologic examination 2.Brain MRI to evaluate the cerebellum 3.Electrophysiologic studies to rule out a polyneuropathy 4.Biochemical testing to rule out vitamin E deficiency (see Ataxia with Vitamin E Deficiency) 5.Molecular genetic testing to rule out Friedreich ataxia and spinocerebellar ataxia type 66.Molecular genetic testing of SYNE1 by sequence analysis. If the proband is of French Canadian ancestry, testing as follows:a.Targeted mutation analysis for mutations in this population b.If only one or neither mutation is identified, sequence analysis 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.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.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) DisordersAutosomal recessive arthrogryposis is also caused by mutations in SYNE1 [Attali et al 2009].}

Natural HistoryOverall, the SYNE1-related autosomal recessive cerebellar ataxia (ARCA1) phenotype consists of a middle-age onset disease (mean age: 31.60 years [SD 7.81]; range: 17-46 years) that presents with either cerebellar ataxia (62.5%) or dysarthria (12.5%) or both coincidentally (25%). Over time, all affected individuals develop significant dysarthria and ataxia, with other associated features such as dysmetria (90.6%), brisk lower-extremity tendon reflexes (32.8%), and minor abnormalities in ocular saccades (31.2%) and smooth pursuit (43.8%). Individuals with ARCA1 showed significant deficits in attention (attention span, speed of information processing, sustained attention), verbal working memory, and visuospatial/visuoconstructional skills (3-D drawings, copy of a complex figure) [LaForce et al 2010].No individuals with ARCA1 have shown extrapyramidal signs, retinopathy, cardiomyopathy, sensory abnormalities, or autonomic disturbances. The disease progresses slowly, resulting in a moderate degree of disability. Life expectancy is normal [Gros-Louis et al 2007].

Differential DiagnosisFriedreich 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 FXN. 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 (α-tocopherol) concentration in the absence of known causes of malabsorption. In most cases, molecular analysis of TTPA, the gene encoding α-tocopherol transfer protein and the only gene in which mutation is known to cause 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 in which mutations are known to cause 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 caused by mutations in 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 in which mutations are known to cause 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. 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 SYNE1-related autosomal recessive cerebellar ataxia (ARCA1):Brain MRI to assess for cerebellar atrophy Nerve conduction studies to rule out a peripheral neuropathy Treatment of ManifestationsIndividuals with ARCA1 should be followed by a neurologist and eventually a physiatrist as well.As the disease progresses, individuals need walking aids such as a cane, a walker, and ultimately a wheelchair. SurveillanceYearly evaluation by a neurologist or physiatrist to prescribe walking aids is appropriate. Agents/Circumstances to AvoidPeople with ARCA1 should be advised to avoid employment that may put them at risk of falls or that may require a high degree of physical dexterity.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementNo pregnancy complications have been reported.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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. SYNE1-Related Autosomal Recessive Cerebellar Ataxia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSYNE16q25​.1-q25.2Nesprin-1SYNE1 homepage - Leiden Muscular Dystrophy pagesSYNE1Data 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 SYNE1-Related Autosomal Recessive Cerebellar Ataxia (View All in OMIM) View in own window 608441SYNAPTIC NUCLEAR ENVELOPE PROTEIN 1; SYNE1 610743SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8; SCAR8Molecular Genetic PathogenesisAlthough SYNE1 is expressed in multiple tissues, its greatest level in the central nervous system of mice is in the cell bodies of the Purkinje cells and in neurons of the olivary region of the brain stem, while in humans it is also expressed predominantly in the cerebellum; it is not expressed in glial cells [Gros-Louis et al 2007]. SYNE1 is part of the spectrin family of structural proteins that share a common function of linking the plasma membrane to the actin cytoskeleton, which is thought to have an important role in Purkinje cells. In the peripheral nervous system, SYNE1 is involved in anchoring specialized myonuclei underneath the neuromuscular junctions. Muscle biopsy of an individual with SYNE1-related autosomal recessive cerebellar ataxia (ARCA1) revealed that fewer myonuclei come to lie beneath the neuromuscular junction, although this finding has no clinical, electrophysiologic, or ultrastructural consequences. Normal allelic variants. SYNE1, one of the largest genes in the human genome (0.5 Mb of genomic DNA), comprises 147 exons. Pathologic allelic variants. Known ARCA1-causing mutations are listed in Table 1 and its footnotes.Normal gene product. SYNE1 encodes a 27652-bp mRNA and an 8797-amino acid protein (>1,000 kd) [Gros-Louis et al 2007]. The protein contains two N-terminal actin-binding regions that comprise tandem paired calponin-homology domains, a transmembrane domain, multiple spectrin repeats, and a C-terminal KASH domain. Abnormal gene product. All detected mutations lead to premature termination of the protein [Gros-Louis et al 2007]. A common feature of all detected mutations is the absence of the C-terminal KASH domain.