Clinical Diagnosis

The 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

Testing

Nerve conduction studies. Always normal

Imaging. Always seen on MRI at the time of diagnosis: marked diffuse cerebellar atrophy (Figure 1) with no other abnormalities

Figure

Figure 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 Testing

Gene. SYNE1 is the only gene in which mutations are known to cause ARCA1.

Clinical testing

• Sequence 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 is available (Table 1).
• Mutation scanning of select exons is available clinically; the mutation detection frequency is not known.
• Deletion/duplication analysis is available clinically; however, 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)

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
SYNE1	Sequence 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 sequenced	Clinical
	Targeted mutation analysis 3	Mutations found in French Canadian population, p.Arg2906X, c.15705-12A>G, c.16177-2A>G, p.Asp5868AlafsX13 4	100% of targeted mutations
	Mutation scanning of select exons	Exons 56, 71, 81, 84, 93, 118, 126 5	Unknown
	Deletion / duplication analysis 6	Deletion/duplication of one or more exons or the whole gene 7	Unknown; none reported to date

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

2. 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. See array GH.

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 Strategy

To 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 6

6.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Autosomal recessive arthrogryposis is also caused by mutations in SYNE1 [Attali et al 2009].

Natural History

Overall, 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].

Genotype-Phenotype Correlations

In the French-Canadian population, none of the mutations identified so far leads to a specific phenotype.

Nomenclature

ARCA1 has also been referred to as recessive ataxia of the Beauce.

Prevalence

To date, more than 100 individuals with ARCA1 have been identified mainly in the Beauce and Bas St-Laurent regions of the Province of Quebec (Canada). The exact prevalence is unknown, but ARCA1 is the third most common hereditary ataxia in Quebec, after ARSACS and Friedreich ataxia.

ARCA1 has not been reported outside Quebec.

Evaluations Following Initial Diagnosis

To 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 Manifestations

Individuals 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.

Surveillance

Yearly evaluation by a neurologist or physiatrist to prescribe walking aids is appropriate.

Agents/Circumstances to Avoid

People 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.

Testing of Relatives at Risk

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

Pregnancy Management

No pregnancy complications have been reported.

Therapies Under Investigation

Search 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.

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.

Mode of Inheritance

SYNE1-related autosomal recessive cerebellar ataxia (ARCA1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual 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 unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with ARCA1 are obligate heterozygotes (carriers) for a disease-causing mutation.

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 testing for at-risk family members is available once the mutations have been identified in the family.

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.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been 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 the family. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Although 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.

Literature Cited

1. Attali R, Warwar N, Israel A, Gurt I, McNally E, Puckelwartz M, Glick B, Nevo Y, Ben-Neriah Z, Melki J. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet. 2009;18:3462–9. [PubMed: 19542096]
2. Burk K, Zuhlke C, Konig IR, Ziegler A, Schwinger E, Globas C, Dichgans J, Hellenbroich Y. Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred. Neurology. 2004;62:327–9. [PubMed: 14745083]
3. Fogel BL, Perlman S. An approach to the patient with late-onset cerebellar ataxia. Nat Clin Pract Neurol. 2006;2:629–35. [PubMed: 17057750]
4. Gros-Louis F, Dupre N, Dion P, Fox MA, Laurent S, Verreault S, Sanes JR, Bouchard JP, Rouleau GA. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet. 2007;39:80–5. [PubMed: 17159980]
5. Ishikawa K, Toru S, Tsunemi T, Li M, Kobayashi K, Yokota T, Amino T, Owada K, Fujigasaki H, Sakamoto M, Tomimitsu H, Takashima M, Kumagai J, Noguchi Y, Kawashima Y, Ohkoshi N, Ishida G, Gomyoda M, Yoshida M, Hashizume Y, Saito Y, Murayama S, Yamanouchi H, Mizutani T, Kondo I, Toda T, Mizusawa H. An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains. Am J Hum Genet. 2005;77:280–96. [PMC free article: PMC1224530] [PubMed: 16001362]
6. Laforce R Jr, Buteau JP, Bouchard JP, Rouleau GA, Bouchard RW, Dupré N. Cerebellum. 2010;9:443–53. [PubMed: 20559786]

Revision History

• 13 October 2011 (cd) Revision: cognitive changes associated with this disorder as reported by Laforce et al 2010
• 18 August 2011 (cd) Revision: mutation scanning of select exons and prenatal testing clinically available
• 14 July 2011 (me) Comprehensive update posted live
• 15 September 2009 (cd) Revision: sequence analysis and targeted mutation analysis available clinically
• 23 February 2007 (me) Review posted to live Web site
• 6 February 2007 (nd) Original submission