Worth et al. (1999) identified 2 British families with a relatively pure form of autosomal dominant cerebellar ataxia in which affected individuals did not have the CAG expansion in the CACNA1A gene (601011), excluding a diagnosis of SCA6 ... Worth et al. (1999) identified 2 British families with a relatively pure form of autosomal dominant cerebellar ataxia in which affected individuals did not have the CAG expansion in the CACNA1A gene (601011), excluding a diagnosis of SCA6 (183086), and in which the disease was not linked to the SCA5 (600224) or SCA10 (603516) loci. Houlden et al. (2007) described an affected family from Devon, on the southwest coast of England, which stretched over 8 generations. Affected individuals had progressive cerebellar ataxia, abnormal eye signs and pyramidal features, as well as cerebellar atrophy visible upon magnetic resonance imaging.
After screening 54 genes in the linked region identified on chromosome 15q15-q21, none of which had a pathogenic mutation, Houlden et al. (2007) analyzed the gene encoding tau tubulin kinase-2 (TTBK2; 611695) and found a 1-base insertion of ... After screening 54 genes in the linked region identified on chromosome 15q15-q21, none of which had a pathogenic mutation, Houlden et al. (2007) analyzed the gene encoding tau tubulin kinase-2 (TTBK2; 611695) and found a 1-base insertion of an adenosine in exon 13 at nucleotide 1329, codon 444 (611695.0001). In a second family with pure ataxia, they found a frameshift deletion of 2 bases (GA) in exon 13 of TTBK2 (611695.0002).
Spinocerebellar ataxia type 11 (SCA11) is characterized by the following:...
DiagnosisClinical DiagnosisSpinocerebellar ataxia type 11 (SCA11) is characterized by the following:Progressive cerebellar ataxiaAbnormal eye signs (jerky pursuit, horizontal and vertical nystagmus)Rare findings in SCA11:Pyramidal featuresPeripheral neuropathyDystoniaThe diagnosis can only be established by molecular genetic testing [Houlden et al 2007].Molecular Genetic TestingGene. TTBK2, the gene encoding tau-tubulin kinase 2, is the only gene in which mutations are known to cause SCA11.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in SCA11View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTTBK2Sequence analysisSequence variantsSequence variants, including c.1329dupA, c.1284_1285delAG 2 ClinicalTargeted mutation analysisc.1329dupA, c.1284_1285delAG 2Unknown 3 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Houlden et al [2007]; see Molecular Genetics.3. TTBK2 mutations have been identified in four families to date [Houlden et al 2007, Bauer 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 Strategy The diagnosis of a pure SCA is based on the clinical assessment; the molecular diagnosis of SCA11 is based on molecular genetic test results identifying a TTBK2 disease-causing mutation.Because SCA11 is rare, it is recommended that individuals with autosomal dominant pure SCA be tested first for mutations associated with more common types of autosomal dominant SCA (e.g., SCA1, 2, 3, 6, 7, 12, and 17).To confirm/establish the diagnosis in a proband requires identification of a TTBK2 mutation on molecular genetic testing.Targeted mutation or sequence analysis can be used to detect mutations in TTBK2. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TTBK2.
In the four families described with spinocerebellar ataxia type 11 (SCA11) the mean age of onset ranged from the early teens in the family of Pakistani origin to between 40 and 50 years of age in the families from France and Germany. The ataxia was clinically similar in all four families, presenting with difficulty walking and balance, is slowly progressive with abnormal eye signs (jerky pursuit and horizontal and vertical nystagmus) and pyramidal features. Dysarthria and swallowing difficulties are common in SCA11. The severity ranged from very mild balance problems, usually at disease onset, to severe speech and swallowing problems and ataxia requiring the use of a wheelchair....
Natural HistoryIn the four families described with spinocerebellar ataxia type 11 (SCA11) the mean age of onset ranged from the early teens in the family of Pakistani origin to between 40 and 50 years of age in the families from France and Germany. The ataxia was clinically similar in all four families, presenting with difficulty walking and balance, is slowly progressive with abnormal eye signs (jerky pursuit and horizontal and vertical nystagmus) and pyramidal features. Dysarthria and swallowing difficulties are common in SCA11. The severity ranged from very mild balance problems, usually at disease onset, to severe speech and swallowing problems and ataxia requiring the use of a wheelchair.Peripheral neuropathy and dystonia have only been seen in two individuals and thus are considered rare findings.Life span is normal for northern Europe; many affected individuals live beyond age 75 years.Neuroimaging. Brain MRI shows mild to severe cerebellar atrophy.Neuropathology. Neuropathologic examination of the brain of one affected individual showed marked cerebellar and brain stem loss with Purkinje cell degeneration and abnormal tau deposition in the brain stem and cortex [Houlden et al 2007].
All four families had frameshift mutations and remarkably similar phenotypes. The same mutation was found in two unrelated families from France and Germany, suggesting that they could be related; this, however, is unlikely as they live more than 600 km apart [Bauer et al 2010]....
Genotype-Phenotype CorrelationsAll four families had frameshift mutations and remarkably similar phenotypes. The same mutation was found in two unrelated families from France and Germany, suggesting that they could be related; this, however, is unlikely as they live more than 600 km apart [Bauer et al 2010].
According to Harding’s classification, spinocerebellar ataxia type 11 (SCA11) is included in the pure autosomal dominant cerebellar ataxias (ADCA III) [Worth et al 1999], the most common group of inherited ataxias. SCA11 accounts for approximately 2% of ADCA III....
Differential DiagnosisAccording to Harding’s classification, spinocerebellar ataxia type 11 (SCA11) is included in the pure autosomal dominant cerebellar ataxias (ADCA III) [Worth et al 1999], the most common group of inherited ataxias. SCA11 accounts for approximately 2% of ADCA III.Significant overlap is observed between SCA11 and SCA5, SCA6, SCA15, and SCA20, all of which are distinguished by molecular genetic testing.See Hereditary 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).
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 11 (SCA11), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 11 (SCA11), the following evaluations are recommended:Medical historyGeneral and neurologic examinationHead MRINerve conduction studiesNeuropsychological tests for individuals with problems in learning and social adaptationMedical genetics or neurogenetics consultationTreatment of ManifestationsThe following are appropriate: Speech and language therapy to address dysarthria and swallowing problems and to teach patients strategies to improve their articulation and to avoid aspirationOccupational therapy, including home adaptationsPhysiotherapy and assessment for cane and wheelchairAnkle-foot orthotics (AFOs) for those with neuropathyOphthalmology consultation is often helpful for individuals with nystagmus as prism glasses can help double visionPrevention of Secondary ComplicationsWeight control can help to facilitate ambulation.SurveillanceAnnual evaluation by a neurologist is indicated to monitor the ataxia and to identify any new findings that may occur over time.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.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.
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 11: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTTBK215q15.2Tau-tubulin kinase 2TTBK2 homepage - Mendelian genesTTBK2Data 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 11 (View All in OMIM) View in own window 604432SPINOCEREBELLAR ATAXIA 11; SCA11 611695TAU TUBULIN KINASE 2; TTBK2Normal allelic variants. No normal variants or polymorphisms have been detected in the coding exons.Pathologic allelic variants. All mutations to date have been frameshift mutations that predict loss of function. The mutation in the original family from Devon, England with 36 affected members from eight generations was c.1329dupA. Onset of ataxia was in the mid-20s.The mutation in the family from Pakistan with four affected individuals from three generations was c.1287_1288delAG. Onset of ataxia was in the early teen years.The mutation identified in two unrelated families from France and Germany was c.1306_1307delGA.Table 2. Selected TTBK2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.1329dupA (1329insA)p.Arg444Thrfs*7NM_173500.3 NP_775771.3c.1287_1288delAG (1284_1285delAG)p.Glu429Aspfs*21c.1306_1307delGAp.Asp436Tyrfs*14See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. Tau-tubulin kinase 2 (TTBK2) comprises 1244 amino acids. The function of the gene is the modification of specific targets to initiate ciliogenesis [Goetz et al 2012]. TTBK2 phosphorylates the tau protein at positions 208 and 210 (numbered according to a 441-residue human tau isoform; Kitano-Takahashi et al [2007]). This also indicates that TTBK2 may interact with the inositol/IP3 pathway and stabilize cells (in particular, Purkinje cells) against calcium-induced cell death [Houlden et al 2007, van de Leemput et al 2007].Abnormal gene product. The mutations truncate the protein and cause nonsense decay leading to haploinsufficiency of the TTBK2 protein. Loss of function affects normal phosphorylation of tau and leads to tau deposition and effected calcium-induced cell death, particularly in Purkinje cells.