The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders characterized by ataxia, dysarthria, dysmetria, and intention tremor. All ADCAs involve some degree of cerebellar dysfunction and a varying degree of signs from ... The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders characterized by ataxia, dysarthria, dysmetria, and intention tremor. All ADCAs involve some degree of cerebellar dysfunction and a varying degree of signs from other components of the nervous system. A commonly accepted clinical classification (Harding, 1993) divides ADCAs into 3 different groups based on the presence or absence of associated symptoms such as brainstem signs or retinopathy. The presence of pyramidal and extrapyramidal symptoms and ophthalmoplegia makes the diagnosis of ADCA I, the presence of retinopathy points to ADCA II, and the absence of associated signs to ADCA III. Genetic linkage and molecular analyses revealed that ADCAs are genetically heterogeneous even within the various subtypes.
Grewal et al. (1998) described a 4-generation mixed pedigree that segregated a distinct form of SCA. The clinical phenotypes were characterized by predominantly cerebellar symptoms and signs and thus fell within the ADCA III clinical classification. Two affected ... Grewal et al. (1998) described a 4-generation mixed pedigree that segregated a distinct form of SCA. The clinical phenotypes were characterized by predominantly cerebellar symptoms and signs and thus fell within the ADCA III clinical classification. Two affected individuals also had seizures, but it could not be determined whether these were caused by focal CNS lesions or were part of the degenerative phenotype. All known SCA loci, as well as mutations in the DRPLA gene (607462), were excluded by direct mutation or linkage analysis. Rasmussen et al. (2001) reported 18 affected individuals from 4 Mexican families who presented with gait ataxia, dysarthria, variable limb ataxia, and ocular movement abnormalities. Thirteen of the 18 had generalized motor seizures, 6 of whom also had partial seizures. Additional symptoms were mood disorders, pyramidal tract signs, EEG abnormalities, and sensorimotor polyneuropathy. Rasmussen et al. (2001) suggested that a wide range of tissues may be affected in SCA10. Grewal et al. (2002) presented a genotype-phenotype analysis of 2 large Mexican American families, originally reported by Grewal et al. (1998) and Matsuura et al. (1999), respectively, with genetically confirmed SCA10. Of 22 affected individuals, seizure disorders developed in 11, although the seizure frequency varied markedly between the 2 families (25% in family 1 had seizures vs 80% in family 2). Anticipation was present in both families, although stronger in family 1. Several individuals in family 1 showed mild personality changes, including flat affect and general disinterest. Grewal et al. (2002) concluded that seizure is an integral part of the SCA10 phenotype, but that family-dependent factors play a role in variability. Teive et al. (2004) reported 5 Brazilian families with SCA10 confirmed by genetic analysis (expanded alleles ranging from 1,350 to 2,400 ATTCT repeats). One of the families had multiple affected members spanning 6 generations. Age at onset in all the families ranged from 23 to 46 years, and genetic anticipation was observed. All patients had a cerebellar syndrome characterized by gait ataxia, dysarthria, dysmetria, dysdiadochokinesis, nystagmus, and cerebellar atrophy on brain imaging. In contrast to previous reports of SCA10, none of the Brazilian patients had seizures. Nerve conduction studies in all 10 patients tested were normal. Previous reports have suggested that Mexican SCA10 families show a complicated phenotype of progressive ataxia associated with seizures, polyneuropathy, pyramidal signs, and cognitive and neuropsychiatric impairment, whereas Brazilian SCA10 families tend to show a pure cerebellar ataxia. Gatto et al. (2007) reported an Argentinian family with Spanish and Amerindian ancestries in which several members had a complicated form of SCA10. The proband was a woman who developed progressive gait instability and incoordination at age 35 years. She also had seizures, mild cognitive impairment, urinary urgency, and depression. Her brother developed similar but more severe symptoms at age 35, with seizures, dysmetria, dysphagia, scanning speech, dementia, hyperreflexia, and extrapyramidal signs. Family history revealed that the father had seizures and progressive ataxia, and 2 of his maternal half-sibs had a similar disorder. The proband and her brother had 1,100 ATTCT repeats in the SCA10 gene.
In a multigenerational study, Matsuura et al. (2004) demonstrated that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission results in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal ... In a multigenerational study, Matsuura et al. (2004) demonstrated that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission results in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat. Matsuura et al. (2006) reported 2 SCA10 families showing distinct frequencies of seizures and correlations of repeat length with age at onset. One family displayed uninterrupted ATTCT expansions, whereas the other showed multiple interruptions of the repeat by nonconsensus repeat units, which differed both in the length and/or sequence of the repeat unit. Disease-causing microsatellite expansions had been assumed to be composed of uninterrupted pure repeats. The findings of Matsuura et al. (2006) challenged this convention and suggested that the purity of the expanded repeat element may be a disease modifier. McFarland et al. (2013) identified 3 different repeat interruptions at the 5- and 3-prime ends of the ATTCT ATXN10 expansion. Two heptanucleotide repeats were found at the 5-prime end and a pentanucleotide repeat was found at the 3-prime end. A specifically designed PCR assay showed that in some cells derived from SCA10 patients, stretches of the pure ATTCT pathogenic repeat were frequently interrupted by combinations of the 3 repeats; the interruptions thus occurred within the pathogenic SCA10-specific repeat. Among 31 SCA10 families tested, the ATXN10 expansion size was larger in patients with an interrupted allele. However, there was no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles showed anticipation but were accompanied by a paradoxical contraction in intergenerational repeat size, and there was evidence of a paternal effect. The findings suggested that SCA10 expansions with ATCCT interruptions differ from SCA10 expansions without detectable ATCCT interruptions in repeat size-instability dynamics and pathogenicity.
In all affected patients from 5 Mexican families with spinocerebellar ataxia-10, Matsuura et al. (2000) found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene (601150.0001).
In affected members of 4 ... In all affected patients from 5 Mexican families with spinocerebellar ataxia-10, Matsuura et al. (2000) found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene (601150.0001). In affected members of 4 Mexican families with SCA10, Rasmussen et al. (2001) identified expanded ATTCT repeats ranging from 920 to 4,140 repeats. Fang et al. (2002) reported a 19-year-old Hispanic woman from the U.S. with SCA10 who was found to have a 280-repeat expansion. Her asymptomatic mother had the same expansion. This was the smallest SCA10 expansion mutation identified to date. Alonso et al. (2006) reported a Brazilian family in which the proband had a 400 repeat expansion in the ATXN10 gene. She was a 59-year-old woman with gait ataxia since age 50 years. She also had mild limb ataxia, dysarthria, extensor plantar responses, and moderate axonal peripheral neuropathy. Two unaffected sibs and her unaffected father, aged 65, 56, and 90, had alleles of 370 and 360. In another Brazilian family, the affected son inherited an allele of 750 repeats from his affected mother who had 760 repeats. Alonso et al. (2006) noted that the first family lowered the threshold of repeat numbers for pathogenesis down to 400. Combined with the report of Fang et al. (2002), the findings suggested that there may be reduced penetrance for SCA10 alleles of 280 to 370 repeats. Raskin et al. (2007) reported a 28-year-old Brazilian women with early-onset SCA10 due to approximately 850 ATTCT repeats in the SCA10 gene. Similar 850-repeat expansions were found in 6 of 8 asymptomatic paternal relatives, including her unaffected 71-year-old father. The findings suggested stable transmission of this allele through 3 generations and incomplete penetrance. The patient had a severe form of the disorder with clear onset by age 14, severe and multiple seizures, deterioration of cognitive functions, and mutism. She was wheelchair-bound by age 24.
In support of a founder mutation in the Mexican population, Rasmussen and Alonso (2002) noted that many SCA10 affected Mexican families carry a common haplotype, and that the SCA10 mutation accounts for almost 15% of autosomal dominant ataxia ... In support of a founder mutation in the Mexican population, Rasmussen and Alonso (2002) noted that many SCA10 affected Mexican families carry a common haplotype, and that the SCA10 mutation accounts for almost 15% of autosomal dominant ataxia in Mexicans, second to SCA2. Fujigasaki et al. (2002) found no SCA10 repeat expansions in 123 French families with autosomal dominant ataxia. Matsuura et al. (2002) genotyped 478 patients with cerebellar ataxia from multiple ethnic groups (not including Mexican) and found no ATTCT expansions. They suggested that the expansion mutation originated in the New World and questioned the use of SCA10 genetic testing in populations other than Mexican. Among 114 Brazilian families with autosomal dominant SCA, Trott et al. (2006) found that 2 (1.8%) had SCA10.
The major findings of SCA10 include the following:...
DiagnosisClinical DiagnosisThe major findings of SCA10 include the following:Slowly progressive cerebellar ataxia starting as poor balance and unsteady gait Scanning dysarthria, dysphagia, and upper-limb ataxia following the gait ataxia Family history consistent with autosomal dominant inheritance, often with Mexican American, Mexican, or Brazilian ethnicity [Matsuura et al 2002, Matsuura et al 2006]. Generalized motor seizures and/or complex partial seizures, frequently found in individuals of Mexican descent [Rasmussen et al 2001, Grewal et al 2002] Other suggestive findings: MRI. Progressive pan cerebellar atrophy with preservation of the cerebrum and brain stem EEG. Evidence of cortical dysfunction with or without focal epileptiform discharges on interictal electroencephalography in some affected individuals Neurophysiology. Polyneuropathy Molecular Genetic TestingGene. ATXN10 is the only gene in which mutations are known to cause spinocerebellar ataxia type 10. An ATTCT pentanucleotide repeat-expansion mutation is associated with SCA10. Allele sizes Normal alleles. 10-32 ATTCT repeats; standard nomenclature c.1430+54822_54826ATTCT(10_32) [Matsuura et al 2000, Wang et al 2010]82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range. 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range. Mutable normal alleles. None identified Reduced-penetrance alleles. Further investigation is needed to determine what range of expanded allele sizes between 33 and 850 ATTCT repeats results in reduced penetrance. Alleles between 33 and 280 ATTCT repeats have not been observed but could in some cases show reduced penetrance. Alleles between 400 and 760 found in Brazilian individuals with SCA10 were reported as full-penetrance but are likely to have reduced penetrance [Alonso et al 2006].280 ATTCT repeats; standard nomenclature c.1430+54822_54826ATTCT[280]. Identified in an individual with ataxia whose asymptomatic mother has the same size expansion, probably representing reduced penetrance [Matsuura et al 2006]. Alleles of 360 and 370 ATTCT repeats; standard nomenclature c.1430+54822_54826ATTCT(360_370). May be intermediate alleles with reduced or no penetrance [Alonso et al 2006]. Overlap of full and reduced penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature c.1430+54822_54826ATTCT(850). May be intermediate alleles with reduced penetrance [Raskin et al 2007].Full-penetrance alleles. 800 to 4,500 ATTCT repeats; standard nomenclature c.1430+54822_54826ATTCT(800_4500). The lower end of the full-penetrance allele range of 800 is not well defined; overlap with reduced penetrance alleles exists. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in SCA10View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityATXN10Targeted mutation analysis and Southern blot analysis 2ATTCT pentanucleotide repeat expansion in intron 9 100%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Southern blot analysis of both genomic DNA and amplicons from ATTCT-repeat primed PCR may be useful (see Testing Strategy).Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of SCA10 should be considered in symptomatic or at-risk members of families in which the molecular diagnosis of SCA10 has been established. The diagnosis may also be considered in individuals with cerebellar ataxia, especially those from a family with autosomal dominant cerebellar ataxia with a Latin American ethnicity and Amerindian admixture. To date most (if not all) individuals with SCA10 have shown this ethnic/racial background [Ashizawa 2012].In individuals with sporadic cerebellar ataxia, SCA10 molecular testing gives a low yield. However, the testing may be considered if cerebellar ataxia is accompanied by epilepsy, especially when other extracerebellar manifestations are absent or mild. Clinical diagnosis must be confirmed by the presence of an ATTCT repeat expansion.Targeted mutation analysis and Southern blot analysis may be performed sequentially or concurrently. Analysis by PCR detects normal alleles. The presence of heterozygous ATXN10 alleles excludes the diagnosis of SCA10.If PCR analysis shows only one allele, an alternate PCR test — the ATTCT-repeat-primed PCR [Matsuura & Ashizawa 2002] — can detect presence or absence of large numbers of repeats of reduced-penetrant or fully-penetrant ATXN10 alleles, but it cannot determine the size of the repeat tract. The clear absence of large numbers of repeats excludes the diagnosis of SCA10. Southern blot analysis of genomic DNA is necessary to determine the size of expanded alleles and to differentiate reduced-penetrance from full-penetrance alleles [Matsuura & Ashizawa 2002, Cagnoli et al 2004]. Long-range PCR may be a potentially useful clinical test in the future to distinguish between these two categories of alleles [Matsuura et al 2006, Kurosaki et al 2008].Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.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 with the pentanucleotide expansion of ATXN10 have been reported.
The clinical findings of SCA10 are relatively homogeneous. Ataxia causes progressive disability, and seizures may become life threatening if status epilepticus emerges. Reported age of onset ranges from 12 to 48 years [Matsuura et al 1999, Zu et al 1999, Rasmussen et al 2001, Teive et al 2004]. ...
Natural HistoryThe clinical findings of SCA10 are relatively homogeneous. Ataxia causes progressive disability, and seizures may become life threatening if status epilepticus emerges. Reported age of onset ranges from 12 to 48 years [Matsuura et al 1999, Zu et al 1999, Rasmussen et al 2001, Teive et al 2004]. Ataxia. The central feature of the phenotype is slowly progressive cerebellar ataxia that usually starts as poor balance and unsteady gait. The gait ataxia gradually worsens, leading to an increasing number of falls and necessitating use of a cane, walker, and eventually wheelchair. In the advanced stage, the affected individual is unable to stand or sit without support.Scanning dysarthria, a type of slurred speech typically seen in cerebellar ataxia, appears within a few years after the onset of gait ataxia. Scanning speech is the result of impaired coordination of the movements of the vocal cords, tongue, palate, cheeks, and lips. Impaired coordination of the diaphragm and other respiratory muscles contributes to the speech impairment.Poor coordination of tongue, throat, and mouth muscles causes dysphagia in later stages of the disease, often leading to life-threatening aspiration pneumonia. Upper-limb coordination begins deteriorating within a few years after the onset of gait ataxia. Handwriting and other fine motor tasks, such as buttoning, are the first to be impaired, followed by increasing difficulties in daily activities such as feeding, dressing, and personal hygiene.Most individuals develop abnormal tracking eye movements: fragmented ocular pursuit, ocular dysmetria, and occasionally ocular flutter. Impaired ocular movements are attributable to cerebellar dysfunction. Some individuals with relatively severe ataxia show coarse gaze-induced nystagmus. Saccade velocity is normal.Ataxia may be induced by small amounts of alcohol [Teive et al 2011a] or during pregnancy and puerperium [Teive et al 2011b].Seizures. In most individuals, seizures are noted after the onset of gait ataxia. Recurrent seizures have been reported in 20%-100% of affected individuals [Matsuura et al 1999, Zu et al 1999, Rasmussen et al 2001]. Generalized motor seizures are most common, but complex partial seizures occur. An attack of complex partial seizures may occasionally be followed by a generalized motor seizure, suggesting secondary generalization of focal seizure activity. Seizure characteristics do not appear to change with age. Family-dependent factors may alter the seizure phenotype and frequency [Grewal et al 2002]. Without treatment, generalized motor seizures may occur daily and complex partial seizures may occur up to several times a day. Poorly treated seizures may result in life-threatening status epilepticus and/or death [Grewal et al 2002].Seizures were found to occur in three of 80 Brazilians (3.75%) with SCA10; this in contrast to 40 Mexicans studied, in whom 24 (60%) were reported to have seizures [Teive et al 2004, Alonso et al 2006, Teive et al 2010].Other. While overt progressive dementia is not observed, some individuals with SCA10 exhibit mild cognitive dysfunctions (IQ ~70) as well as mood disorders. Mild pyramidal signs (either hyperreflexia, Babinski sign, or both), behavioral disturbances (including psychosis), dystonia, and peripheral neuropathy have been seen [Rasmussen et al 2001, Gatto et al 2007, Wexler & Fogel 2011]. Extraneural abnormalities including hepatic failure, anemia, and/or thrombocytopenia have been recorded in one family [Rasmussen et al 2001].Low IQ, behavioral disturbances, and extraneural abnormalities have not been found in Brazilians with SCA10, although mild or equivocal pyramidal tract signs and rare sensory polyneuropathy were noted [Teive et al 2004, Alonso et al 2006].
A comparison of clinical data and genotypes in individuals with SCA10 revealed an inverse correlation between expansion size and age of onset (p = 0.018) [Matsuura et al 2000]. The number of repeats ranged from 800 to 4500 and age of onset from 11 to 48 years. The correlation coefficient (r2) was 0.34, suggesting that the ATTCT expansion size can explain only about one third of the variation in age of onset and implying the existence of other determinants of age of onset. A more recent study of Brazilians with SCA10 showed a similar inverse correlation with r2=0.532 and p<0.01 [Teive et al 2004]....
Genotype-Phenotype CorrelationsA comparison of clinical data and genotypes in individuals with SCA10 revealed an inverse correlation between expansion size and age of onset (p = 0.018) [Matsuura et al 2000]. The number of repeats ranged from 800 to 4500 and age of onset from 11 to 48 years. The correlation coefficient (r2) was 0.34, suggesting that the ATTCT expansion size can explain only about one third of the variation in age of onset and implying the existence of other determinants of age of onset. A more recent study of Brazilians with SCA10 showed a similar inverse correlation with r2=0.532 and p<0.01 [Teive et al 2004].Though not as yet assessed quantitatively, the severity of the disease in individuals with SCA10 does not appear to correlate with expansion size, suggesting the influence of family-dependent factors on disease severity. No correlation between expanded allele size and seizure phenotype has appeared [Teive et al 2004].Longitudinal clinical data are needed to examine whether repeat size correlates with disease progression.
Significant overlap exists in the clinical presentation of the SCAs (see Hereditary Ataxia Overview). All are characterized by ataxia, and some by other neurologic signs. Clinical presentation may vary even among affected members of the same family. SCA type cannot generally be determined by clinical or neuroimaging studies of single individuals....
Differential DiagnosisSignificant overlap exists in the clinical presentation of the SCAs (see Hereditary Ataxia Overview). All are characterized by ataxia, and some by other neurologic signs. Clinical presentation may vary even among affected members of the same family. SCA type cannot generally be determined by clinical or neuroimaging studies of single individuals.Although the combination of "pure" cerebellar ataxia (lacking other motor or cranial nerve involvement) and seizures is typical for SCA10 and has seldom been seen in other autosomal dominant cerebellar ataxias, it is possible that in some families, SCA10 could be a pure cerebellar ataxia without seizures.Seizures occur in some individuals with DRPLA and SCA17 [Nakamura et al 2001], but individuals affected with these diseases also exhibit other conspicuous neurologic signs (such as extrapyramidal signs) not seen in SCA10. Seizures may accompany relatively "pure" cerebellar ataxia in some individuals with SCA14, which is caused by point mutations in the protein kinase C gamma gene, PRKCG [Alonso et al 2005]. SCA13, caused by mutations in KCNC3, may also present with “pure” cerebellar ataxia with seizures, mimicking SCA10. However, the ethnic and geographic populations affected by SCA13 (Filipino and French) and SCA14 (Europeans and Japanese) have been distinct from those of SCA10 (American continents/Amerindians).In individuals with SCA10, pyramidal signs are subtle and not as robust as those observed in SCA1.Individuals with SCA10 do not show the slow saccadic eye movements often found in people with SCA2. Unlike individuals with SCA3, those with SCA10 exhibit few extrapyramidal signs and little involvement of lower motor neurons.Individuals with SCA10 have never shown retinopathy with macular degeneration, which is a hallmark of SCA7. It should also be noted that axial myoclonus, characteristic of SCA14 [Yamashita et al 2000], and head tremor, frequently found in SCA12 [Holmes et al 1999, O'Hearn et al 2001] and SCA16 [Miyoshi et al 2001], are not observed in SCA10.Nerve conduction velocity studies indicate the presence of polyneuropathy in some individuals with SCA10; however, unlike those with SCA4, they have few signs or symptoms [Flanigan et al 1996].Friedreich ataxia, characterized by autosomal recessive inheritance and sensorispinal ataxia, is easily distinguishable from SCA10 on the basis of clinical findings. Unlike SCA10, in which all reported cases showed onset before age 50 years, fragile X-associated tremor/ataxia syndrome develops after age 50 years [Hagerman & Hagerman 2002]. However, some individuals with ATXN10 expanded alleles with reduced penetrance may develop ataxia at later ages [Alonso et al 2006, Matsuura et al 2006].Because neurocysticercosis is one of the most common causes of seizures in Mexican Americans, it needs to be considered in individuals who do not have a strong family history of seizures. The MRI and CT findings of neurocysticercosis consist of either solid or cystic lesions associated with calcification and surrounding edema. 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 in an individual diagnosed with spinocerebellar ataxia type 10 (SCA10), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 10 (SCA10), the following evaluations are recommended:MRI. The extent of cerebellar atrophy on serial MRI studies may be useful for documenting the progression of the disease. EEG. EEG is of particular importance, as many individuals with SCA10 develop epilepsy and epilepsy-related deaths have been recognized [Grewal et al 2002]. Nerve conduction tests. Nerve conduction studies are needed only when affected individuals have clinical evidence of polyneuropathy. Neuropsychological tests. Formal neuropsychological tests are appropriate for individuals with problems in learning and social adaptation. Speech pathology evaluation may be needed 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.Medical genetics consultationTreatment of ManifestationsControl of seizures is the most important management issue, as uncontrolled seizures may lead to potentially fatal status epilepticus. Conventional anticonvulsants such as phenytoin, carbamazepine, and valproic acid achieve reasonable control, although occasional breakthrough seizures may occur. When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration. Severe dysphagia may require percutaneous placement of a gastric tube for prevention of aspiration and maintenance of nutritional intake.Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.Although not specifically studied in SCA10, intensive coordinative training has shown sustainable improvements in motor performance in individuals with degenerative ataxias [Ilg et al 2009, Ilg et al 2010]. Canes and walkers help prevent falling. Modification of the home with grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.Weighted eating utensils and dressing hooks help maintain a sense of independence. Prevention of Primary ManifestationsNo therapy is known to delay or halt the progression of the disease.No drugs have been proven to provide symptomatic relief of ataxia; however, minor tranquilizers may show some benefits in motor coordination in those persons who experience anxiety. Prevention of Secondary ComplicationsNo dietary factor that curtails symptoms has been documented; however, vitamin supplements are recommended, particularly for those with poor nutritional status.Falls and aspiration are two major threats to individuals with ataxia, including those with SCA10. Walking aids and proactive plans for feeding strategies are useful.SurveillanceFollow-up outpatient clinical evaluation every four to six months is indicated to identify early signs of potential complications and to adjust anticonvulsant treatments.Agents/Circumstances to AvoidAlcohol and drugs known to adversely affect cerebellar functions should be avoided. Falls should be avoided because resulting injuries may greatly compromise motor function and the ability to perform activities of daily living.Any activities that are potentially dangerous to individuals with ataxia or epilepsy should be avoided, depending on the severity of the manifestations.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management At-risk individuals should be aware of the possibility of inducing ataxia during pregnancy or puerperium [Teive et al 2011b]. Epilepsy should be managed during pregnancy according to the American Academy of Neurology Practice Parameter Update: Management issues for women with epilepsy (an evidence-based review).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.OtherAlthough taltirelin hydrate is widely used for symptomatic treatment of ataxia in Japan, it has never been used for individuals with SCA10.Tremor-controlling drugs, such as beta blockers and primidone, are ineffective for cerebellar tremors.
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 10: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATXN1022q13.31Ataxin-10ATXN10 homepage - Mendelian genesATXN10Data 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 10 (View All in OMIM) View in own window 603516SPINOCEREBELLAR ATAXIA 10; SCA10 611150ATAXIN 10; ATXN10Normal allelic variants. ATXN10 consists of 12 exons spanning 172.8 kb. The open reading frame is 1428 bp. An ATTCT repeat is located within the 66.4-kb intron 9. Normal alleles are ten to 32 ATTCT repeats in length [Matsuura et al 2000, Matsuura et al 2006]. ATTCT repeats ranging from 400 to 760 have been found in Brazilian individuals with SCA10; whether they are full-penetrance alleles is at present unclear [Alonso et al 2006]. Alleles of 280, 360, and 370 ATTCTs may be intermediate alleles with reduced or no penetrance [Alonso et al 2006, Matsuura et al 2006]. A category of mutable normal alleles has not been identified. Note: See Molecular Genetic Testing, Allele sizes for issues related to the differentiation of reduced- and full-penetrance alleles.Pathologic allelic variants. Expanded alleles range from about 800 to 4,500 ATTCT repeats [Matsuura et al 2000] Structure of ATTCT repeatsNormal alleles. Sequence analysis of ATXN10 alleles ranging from 11 to 16 repeats showed tandem ATTCT repeats without interruptions [Matsuura et al 2000]. About 70% of large normal alleles (≥17 repeats), which comprise about 7% of normal alleles, have ATTGT-TTTCT or TTTCT interruptions at the second to the last repeat [Matsuura et al 2006].Reduced-penetrance alleles. The sequence of one allele of 280 ATTCT repeats with apparent reduced penetrance showed a complex pattern of interruptions, including multiple repetitive ATGCT repeats at the 5' end of the expansion and ATTCTAT septanucleotide repeats at the 3' end. Full-penetrance alleles. Limited sequencing of fully expanded ATTCT repeat alleles showed interruptions by multiple ATTTTCTs and ATATTCTs or uninterrupted ATTCTs, depending on the family from which the mutant allele was obtained [Matsuura et al 2006].Mechanism. In vitro studies with plasmid constructs showed that uninterrupted alleles of 11 to 46 ATTCT repeats formed unpaired structures [Potaman et al 2003]. These short ATTCT repeats undergo repeat-length mutations involving complex events including inversion and transition at the 3' end within the AGAAT, presumably derived from inversion repeat [Potaman et al 2006]. Studies in yeast suggested that the instability of ATTCT repeats is dependent on Rad5 and Tof1, genes involved in replication irregularities [Cherng et al 2011]. Whether the behavior of these plasmid constructs of relatively short ATTCT repeats is relevant to the expanded ATTCT repeat in humans is unclear. However, inter- and intramolecular strand switches may play a role in derivation of the complex interruptions of the expanded ATTCT repeat observed in individuals with SCA10.Evolution. Comparative genome analysis showed that the ATXN10 pentanucleotide repeat originated from the poly (A) tail of AluSx inserted into an early primate genome and evolved into unstable ATTCT repeats during primate evolution, similar to the trinucleotide repeats that cause Friedreich ataxia and myotonic dystrophy type 2 [Kurosaki et al 2009, Kurosaki et al 2012]. Instability of expanded ATTCT repeatsGender effects. The expanded ATTCT repeat shows repeat-size instability when it is transmitted from generation to generation [Matsuura et al 2004]. The pattern of the instability depends on the gender of the transmitting parent. During paternal transmission, the expanded ATTCT repeats are highly unstable, whereas maternal transmission is mostly accompanied by no changes or changes of a smaller magnitude. Somatic instability. The expansion size is unstable in somatic tissues as evidenced by the "smeared" appearance of expanded alleles and multiple distinct expansion alleles on PCR and Southern blot analyses; however, the instability in some individuals with SCA10 is relatively limited compared with that seen in other repeat-expansion disorders. For example, blood samples obtained over a five-year interval showed no changes of expanded alleles. Expanded ATXN10 alleles show a greater degree of instability in a small number of sperm samples, consistent with the instability observed with paternal transmissions. Judging from the stable maternal transmission of expanded alleles, the expansion size is expected to be relatively stable in female germline cells. No data regarding the instability of expanded alleles during fetal development are available.Table 2. Selected ATXN10 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid Change Reference SequencesNormalc.1430+54822_54826ATTCT(10_32) (10 to 32 ATTCT repeats)NoneNM_013236.2 NP_037368.1Pathologic 2,3c.1430+54822_54826ATTCT[280] 2Nonec.1430+54822_54826ATTCT(360_370) 2(360 to 370 ATTCT repeats)Nonec.1430+54822_54826ATTCT(400_760) 2 (400 to 760 ATTCT repeats)Nonec.1430+54822_54826ATTCT(850) 2 (850 ATTCT repeats)Nonec.1430+54822_54826ATTCT(800_4500) 3(800 to 4500 ATTCT repeats)NoneSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. May be alleles with reduced or no penetrance [Alonso et al 2006, Matsuura et al 2006]. See Molecular Genetic Testing, Allele Sizes. 3. Alleles with full penetrance. The lower end of the fully penetrance allele range of 800 is not well defined; overlap with reduced-penetrance alleles exists. Normal gene product. The 475-amino acid ataxin-10 protein is a globular protein that tends to form a tip-to-tip homotrimeric complex with the concave sides of the molecule facing each other in solution [Marz et al 2004]. The protein is without transmembrane domains, nuclear localization signal, or other type of signal peptide (Golgi, peroxisomal, vacuolar, or endoplasmic reticulum retention). It does not appear to contain any known functional motifs, clusters, or unusual patterns of charged amino acids or internal repeats of specific amino acid runs. The predicted tertiary structure is unremarkable [Matsuura et al 2000]. However, the C-terminal domain (287-433) contains two armadillo repeat domains [Marz et al 2004]. ATXN10 is ubiquitously expressed. Strong expression is observed in brain, heart, muscle, kidney, and liver [Wakamiya et al 2006]. The physiologic function of ataxin-10 is poorly understood. However, ataxin-10 deficiency by small interfering RNA (siRNA) caused apoptosis of cerebellar neurons in primary cell culture [Marz et al 2004]. Ataxin-10 has been shown to interact with O-linked GlcNAc transferase, which catalyzes modifications of several nuclear and cytoplasmic proteins in metazoans [Andrali et al 2005], and with heteromeric G-protein beta 2 subunit (Gβ2) [Waragai et al 2006]. PC12 cells overexpressing ataxin-10 show evidence of enhanced differentiation with long neurite outgrowth. Coexpression of ataxin-10 and Gβ2 further potentiates the ataxin-10-induced differentiation by activating the Ras-MAP kinase-Elk-1 cascade in PC12 cells [Waragai et al 2006]. Thus, ataxin-10 may play a role in survival and differentiation of neurons or neuron-like cells.Abnormal gene product. Data from in vitro and animal model systems support a RNA-gain-of-function hypothesis as the cause of SCA10. .Because the ATTCT repeat is located within intron 9, it does not code for a protein. The pathogenic effect of the ATTCT expansion in intron 9 of ATXN10 is not fully understood. However, studies of lymphoblastoid cells, fibroblasts, and somatic cell hybrids derived from individuals with SCA10 suggest that expansion of the ATTCT repeat does not interfere with the transcription and post-transcriptional processing of mutant ATXN10 [Wakamiya et al 2006]. Therefore, the expanded ATTCT repeat is transcribed into expanded AUUCU repeats in the unprocessed mutant RNA transcript, and intron 9 containing the expanded AUUCU repeat is correctly spliced out. Consequently, the level of processed mRNA from mutant ATXN10 is unaltered. Furthermore, genetically altered mice heterozygous for ataxin-10 deficiency exhibit no disease phenotype, while homozygous deficiency of ataxin-10 is embryonically lethal [Wakamiya et al 2006]. In addition, a case of balanced translocation that disrupts ATXN10 showed no phenotype, suggesting that haploinsufficiency is an unlikely mechanism for SCA10 [Keren et al 2010]. These data suggest that aberrant ataxin-10 proteins are unlikely to play a role in SCA10 pathogenesis, and raises the hypothesis that gain of function by the mutant RNA leads to abnormal cellular functions in target tissues. In fibroblasts derived from individuals affected with SCA10 and in cells ectopically expressing expanded AUUCU repeats, RNA foci containing AUUCU repeats were observed. AUUCU repeats bind in vitro to the heterogeneous nuclear ribonucleoprotein K (hnRNP K), a ribonuclear protein which regulates RNA homeostasis. The RNA foci colocalize with hnRNP K, suggesting that expanded AUUCU repeats sequester hnRNP K. Overexpression of expanded AUUCU induces caspase 3-mediated apoptosis, as does down-regulation of hnRNP K by siRNA. Overexpression of hnRNP K rescued the cells expressing expanded AUUCU from apoptosis. The sequestration of hnRNP K leads to translocation of protein kinase C delta (PKCδ) to mitochondria, a process known to induce apoptosis. Sequestration of hnRNP K also induces changes in splicing of its target transcripts [White et al 2010]. The hnRNP K sequestration and mitochondrial translocation of PKCδ were recapitulated in two transgenic mouse models that express untranslated expanded AUUCU repeats. These mice show neuronal loss, a motor phenotype, and susceptibility to seizures [White et al 2010, White et al 2012].