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Spinocerebellar Ataxia Type 13

Synonym: SCA13
, MD
Department of Neurology
University of Utah
Salt Lake City, Utah

Initial Posting: ; Last Update: March 1, 2012.

Summary

Clinical characteristics.

In the families described to date, the phenotype of spinocerebellar ataxia type 13 (SCA13) has ranged from slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria and often accompanied by mild intellectual disability and occasional seizures to adult-onset progressive ataxia. Life span is not shortened and many persons live beyond age 70 years, but assistance with gait may be required as the disease progresses.

Diagnosis/testing.

Diagnosis is based on clinical findings and molecular genetic testing of KCNC3 (also known as Kv3.3), the only gene known to be associated with SCA13.

Management.

Treatment of manifestations: Antiepileptic drugs for seizures; canes, walkers and other adaptive devices to help prevent falls; speech therapy and communication devices; feeding assessment if dysphagia is present.

Prevention of secondary complications: Weight control.

Surveillance: Evaluation by a neurologist at least annually, and more often in the event of acute exacerbation.

Agents/circumstances to avoid: Alcohol and sedating drugs because they can exacerbate ataxia.

Genetic counseling.

SCA13 is inherited in an autosomal dominant manner. Too little data are available to estimate the proportion of cases resulting from a new pathogenic variant. Each child of an individual with SCA13 has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for SCA13 is possible if the pathogenic variant in the family is known.

Diagnosis

Clinical Diagnosis

The phenotype of spinocerebellar ataxia type 13 (SCA13) overlaps with that of other infantile or adult-onset ataxias. The correct diagnosis can only be established by molecular genetic testing of KCNC3.

Molecular Genetic Testing

Gene. KCNC3 (also known as Kv3.3) is the only gene in which pathogenic variants are known to cause SCA13.

Clinical testing

  • Sequence analysis. Direct sequencing of all four coding exons and flanking splice sites of KCNC3 is the most sensitive approach for identifying pathogenic variants. Because data are limited, the proportion of pathogenic variants identified is not known. Note: As all known pathogenic variants cluster in exon 2, it is reasonable to begin by sequencing this exon.

Table 1.

Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 13

Gene 1Test MethodAllelic Variants Detected 2Variant Detection Frequency by Test Method 3
KCNC3Sequence analysis 4Sequence variantsUnknown
1.
2.

See Molecular Genetics for information on allelic variants.

3.

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

4.

Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. The testing strategy for hereditary cerebellar ataxias is discussed in the Hereditary Ataxia Overview.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

In the families described to date, the spinocerebellar ataxia type 13 (SCA13) phenotype has ranged from early-onset ataxia with little progression, often accompanied by mild intellectual disability and occasional seizures [Herman-Bert et al 2000, Figueroa et al 2011], to adult-onset progressive ataxia [Waters et al 2005, Waters & Pulst 2008, Figueroa et al 2010]. Onset has ranged from infancy to 60 years.

In the family described by Herman-Bert et al [2000], seven women and a four-year-old boy exhibited slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate intellectual disability (IQ 62-76), and mild developmental delays in motor acquisition. Nystagmus and pyramidal signs were also observed in some.

Life span is not shortened and many persons live beyond age 70 years; assistance with gait may be required as the disease progresses.

Brain MRI in all affected persons has shown mild to moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years. Atrophy of the brain stem or cerebral cortex is not observed.

Genotype-Phenotype Correlations

The known pathogenic variants in KCNC3 are associated with different phenotypes; however, data are too limited to make any genotype-phenotype correlations at this time.

  • The p.Arg420His variant was associated with adult-onset progressive ataxia in one family [Waters et al 2005].
  • The p.Phe448Leu variant is associated with childhood onset ataxia and often intellectual disability and seizures.
  • The p.Arg423His variant has also been associated with mild cognitive impairment and seizures.

Penetrance

KCNC3 pathogenic variants appear to be fully penetrant in the families described.

Anticipation

Anticipation is not observed.

Prevalence

The prevalence of SCA13 is not known. Only one person with SCA13 was identified in a cohort of 327 probands with ataxia [Figueroa et al 2011].

Differential Diagnosis

Persons with spinocerebellar ataxia type 13 (SCA13) may present with ataxia that is indistinguishable from other adult-onset inherited or acquired ataxias (see Ataxia Overview).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 13 (SCA13), the following evaluations are recommended:

  • Medical history
  • Neurologic examination
  • EEG
  • Formal neuropsychological tests for individuals with problems in learning and social adaptation
  • Speech pathology evaluation if dysarthria is atypical or severe enough to cause communication problems. For individuals with frequent choking or severe dysphagia, speech pathology evaluation may be important in assessing aspiration risks.

Treatment of Manifestations

Epileptic seizures can be improved by treatment with anticonvulsive medications.

Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.

Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary. Weighted eating utensils and dressing hooks help maintain a sense of independence.

Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.

When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.

Note: Tremor-controlling drugs are not effective for cerebellar tremors.

Prevention of Secondary Complications

No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.

Weight control is important because obesity can exacerbate difficulties with ambulation.

Surveillance

Evaluation by a neurologist is indicated annually, or more often in the event of an acute exacerbation.

Agents/Circumstances to Avoid

Alcohol and sedating drugs can exacerbate ataxia.

Evaluation of Relatives at Risk

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

Pregnancy Management

Weight gain during pregnancy can further impair gait ataxia.

Therapies Under Investigation

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. —ED.

Mode of Inheritance

Spinocerebellar ataxia type 13 (SCA13) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Only two families with SCA13 have been described; the individuals diagnosed with SCA13 had an affected parent.
  • As the KCNC3 pathogenic variants identified to date are private (i.e., occurring in only a single family), de novo pathogenic variants may arise in this gene. Too few unselected cases have been studied to derive a reliable estimate of the proportion of cases that result from de novo mutation.
  • It is recommended that both parents of a proband with an apparent de novo pathogenic variant be evaluated using molecular genetic testing.
  • Note: The family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance; therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and a pathogenic variant cannot be detected in the DNA of either parent, the risk to the sibs of a proband is probably low; however, no such cases have been studied to date. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with SCA13 has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband

  • The risk to other family members depends on the genetic status of the proband's parents.
  • If a parent is affected or has a pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the pathogenic variant, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk 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 or at risk.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the KCNC3 pathogenic variant has been identified in the family, prenatal diagnosis for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: smillman@ataxia.org.uk
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: sanfordresearch@sanfordhealth.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spinocerebellar Ataxia Type 13: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Spinocerebellar Ataxia Type 13 (View All in OMIM)

176264POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 3; KCNC3
605259SPINOCEREBELLAR ATAXIA 13; SCA13

Gene structure. KCNC3 (reference sequence NM_004977.2) comprises four coding exons. The fifth exon encodes the majority of the relatively long 3' UTR. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. The substitution c.788G>A (p.Gly263Asp) appears to be a common benign variant [Figueroa et al 2011].

Pathogenic allelic variants. The c.1259G>A (p.Arg420His) and c.1268G>A (p.Arg423His) pathogenic variants are located in the S4 voltage-sensor domain and the c.1344C>A (p.Phe448Leu) pathogenic variant in the S5 domain, which forms the ion pore.

Normal gene product. KCNC3 (NP_004968.2) encodes a protein of 757 amino acid residues. It is a voltage-gated potassium channel with six membrane-spanning domains. Because this channel opens late during depolarization and is rapidly deactivated, it is important in regulation of the action potential and properties of bursting neurons [Joho & Hurlock 2009].

Abnormal gene product. The c.1259G>A (p.Arg420His) pathogenic variant results in a dominant-negative effect [Waters et al 2006]. The c.1344C>A (p.Phe448Leu) pathogenic variant results in a gain of function.

References

Literature Cited

  • Figueroa KP, Minassian NA, Stevanin G, Waters M, Garibyan V, Forlani S, Strzelczyk A, Bürk K, Brice A, Dürr A, Papazian DM, Pulst SM. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients. Hum Mutat. 2010;31:191–6. [PMC free article: PMC2814913] [PubMed: 19953606]
  • Figueroa KP, Waters MF, Garibyan V, Bird TD, Gomez CM, Ranum LP, Minassian NA, Papazian DM, Pulst SM. Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13). PLoS One. 2011;6:e17811. [PMC free article: PMC3066194] [PubMed: 21479265]
  • Herman-Bert A, Stevanin G, Netter JC, Rascol O, Brassat D, Calvas P, Camuzat A, Yuan Q, Schalling M, Durr A, Brice A. Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation. Am J Hum Genet. 2000;67:229–35. [PMC free article: PMC1287081] [PubMed: 10820125]
  • Joho RH, Hurlock EC. The role of Kv3-type potassium channels in cerebellar physiology and behavior. Cerebellum. 2009;8:323–33. [PubMed: 19247732]
  • Waters MF, Fee D, Figueroa KP, Nolte D, Muller U, Advincula J, Coon H, Evidente VG, Pulst SM. An autosomal dominant ataxia maps to 19q13: Allelic heterogeneity of SCA13 or novel locus? Neurology. 2005;65:1111–3. [PubMed: 16135769]
  • Waters MF, Pulst SM. SCA13. Cerebellum. 2008;7:165–9. [PubMed: 18592334]
  • Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D, Mock AF, Evidente VG, Fee DB, Muller U, Durr A, Brice A, Papazian DM, Pulst SM. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet. 2006;38:447–51. [PubMed: 16501573]

Chapter Notes

Revision History

  • 1 March 2012 (me) Comprehensive update posted live
  • 9 November 2006 (me) Review posted to live Web site
  • 19 September 2006 (smp) Original submission
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