Herman-Bert et al. (2000) described a large French family in which 8 members were affected with autosomal dominant spinocerebellar ataxia. There were 7 affected women and an affected 4-year-old boy. Clinical features included slowly progressive childhood-onset cerebellar gait ... Herman-Bert et al. (2000) described a large French family in which 8 members were affected with autosomal dominant spinocerebellar ataxia. There were 7 affected women and an affected 4-year-old boy. Clinical features included slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ, 62-76), and mild developmental delay in motor acquisition. Nystagmus and pyramidal signs were also observed in some patients. Cerebral magnetic resonance imaging in 2 patients showed moderate cerebellar and pontine atrophy. Waters et al. (2005) reported a 3-generation Filipino family in which 11 members had autosomal dominant SCA. The 82-year-old proband was the oldest affected, with disease onset at age 60 years. Mean ages at onset in the second and third generations were 36.4 and 24.5 years, respectively. Clinical features included gait ataxia, limb ataxia/dysmetria, titubation, hypotonia, dysarthria, and nystagmus. Mental retardation was not a feature. Waters et al. (2005) noted that the phenotype in the Filipino family differed from that in the French family reported by Herman-Bert et al. (2000).
In affected members of a French family and a Filipino family with SCA13, Waters et al. (2006) identified 2 different heterozygous mutations in the KCNC3 gene (176264.0001; 176264.0002).
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. ...
DiagnosisClinical DiagnosisThe 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 TestingGene. KCNC3 (also known as Kv3.3) is the only gene in which mutations 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 mutations. Because data are limited, the proportion of mutations identified is not known. Note: As all known mutations cluster in exon 2, it is reasonable to begin by sequencing this exon. Table 1. Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type13View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityKCNC3 Sequence analysisSequence variants 2UnknownClinical1. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo 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 disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in KCNC3.
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....
Natural HistoryIn 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.
The known mutations in KCNC3 are associated with different phenotypes; however, data are too limited to make any genotype-phenotype correlations at this time....
Genotype-Phenotype CorrelationsThe known mutations in KCNC3 are associated with different phenotypes; however, data are too limited to make any genotype-phenotype correlations at this time.The p.Arg420His mutation was associated with adult-onset progressive ataxia in one family [Waters et al 2005]. The p.Phe448Leu mutation is associated with childhood onset ataxia and often intellectual disability and seizures. The p.Arg423His mutation has also been associated with mild cognitive impairment and seizures.
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). ...
Differential DiagnosisPersons with spinocerebellar ataxia type 13 (SCA13) may present with ataxia that is indistinguishable from other adult-onset inherited or acquired ataxias (see Ataxia Overview). 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).Childhood-onset SCA13Adult-onset SCA13
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 13 (SCA13), the following evaluations are recommended:...
ManagementEvaluations 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 ManifestationsEpileptic 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 ComplicationsNo 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. SurveillanceEvaluation 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 InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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. Spinocerebellar Ataxia Type 13: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKCNC319q13.33Potassium voltage-gated channel subfamily C member 3KCNC3 homepage - Mendelian genesKCNC3Data 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 Spinocerebellar Ataxia Type 13 (View All in OMIM) View in own window 176264POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 3; KCNC3 605259SPINOCEREBELLAR ATAXIA 13; SCA13Normal allelic variants. KCNC3 [reference sequence NM_004977.2] comprises four coding exons. The fifth exon encodes the majority of the relatively long 3' UTR. The substitution c.788G>A (p.Gly263Asp) appears to be a common benign variant [Figueroa et al 2011].Pathologic allelic variants. The c.1259G>A (p.Arg420His) and c.1268G>A (p.Arg423His) pathologic allelic variants are located in the S4 voltage-sensor domain and the c.1344C>A (p.Phe448Leu) mutation 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) mutation results in a dominant-negative affect [Waters et al 2006]. The c.1344C>A (p.Phe448Leu) mutation results in a gain of function.