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Laura P.w. Ranum - One of the best experts on this subject based on the ideXlab platform.
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Spinocerebellar Ataxia type 5.
Handbook of Clinical Neurology, 2011Co-Authors: Katherine A. Dick, Yoshio Ikeda, Laura P.w. RanumAbstract:In 1994, Ranum and colleagues identified a ten-generation American kindred with a relatively mild autosomal dominant form of Spinocerebellar Ataxia (Ranum et al., 1994). The mutation was mapped to the centromeric region of chromosome 11, and the disorder designated SCA5 (Ranum et al., 1994). Using a multifaceted mapping approach, Ikeda et al. (2006) discovered that β-III spectrin (SPTBN2) mutations cause Spinocerebellar Ataxia type 5 (SCA5) in the American kindred and two additional independently reported SCA5 families. The American and French families have separate in-frame deletions of 39 and 15 bp, respectively, in the third of 17 spectrin repeat motifs. A third mutation, found in a German family, is located in the second calponin homology domain, a region known to bind actin and Arp1. Consistent with Purkinje cell degeneration in SCA5, β-III spectrin is highly expressed in cerebellar Purkinje cells. TIRF microscopy performed on cell lines transiently transfected with mutant or wild-type spectrin shows that mutant β-III spectrin fails to stabilize the glutamate transporter EAAT4 at the plasma membrane. Additionally, marked differences in EAAT4 and GluRδ2 were found by protein blot and cell fractionation in SCA5 autopsy tissue. This review summarizes data showing that β-III spectrin mutations are a novel cause of neurodegenerative disease, which may affect the stabilization or trafficking of membrane proteins.
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frequency of kcnc3 dna variants as causes of Spinocerebellar Ataxia 13 sca13
PLOS ONE, 2011Co-Authors: Karla P Figueroa, Laura P.w. Ranum, Christopher M. Gomez, Natali A Minassian, Diane M Papazian, Michael F Waters, Vartan Garibyan, Thomas D Bird, Stefan M PulstAbstract:Background Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant Spinocerebellar Ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial Ataxia presenting to three US Ataxia clinics at academic medical centers. Methodology DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with Ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes. Principal Findings Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel. Conclusions Mutations in KCNC3 are a rare cause of Spinocerebellar Ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.
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the clinical and genetic spectrum of Spinocerebellar Ataxia 14
Neurology, 2005Co-Authors: Dong Hui Chen, Laura P.w. Ranum, Huda Y. Zoghbi, Patrick J Cimino, Ichiro Yabe, Lawrence J Schut, Russell L Margolis, Hillary Lipe, A Feleke, Mark MatsushitaAbstract:Spinocerebellar Ataxia 14 (SCA14) is associated with missense mutations in the protein kinase C γ gene (PRKCG), rather than a nucleotide repeat expansion. In this large-scale study of PRKCG in patients with Ataxia, two new missense mutations, an in-frame deletion, and a possible splice site mutation were found and can now be added to the four previously described missense mutations. The genotype/phenotype correlations in these families are described.
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Molecular genetics of Spinocerebellar Ataxia type 8 (SCA8)
Cytogenetic and Genome Research, 2003Co-Authors: A.k. Mosemiller, Joline C. Dalton, Laura P.w. RanumAbstract:We previously reported that a transcribed but untranslated CTG expansion causes a novel form of Ataxia, Spinocerebellar Ataxia type 8 (SCA8) (Koob et al., 1999). SCA8 was the first example of a dominant Spinocerebellar Ataxia that is not caused by the expansion of a CAG repeat translated into a polyglutamine tract. This slowly progressive form of Ataxia is characterized by dramatic repeat instability and a high degree of reduced penetrance. The clinical and genetic features of the disease are discussed below.
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an untranslated ctg expansion causes a novel form of Spinocerebellar Ataxia sca8
Nature Genetics, 1999Co-Authors: Michael D. Koob, Lawrence J Schut, Thomas D Bird, Melinda L Moseley, Kellie A Benzow, Laura P.w. RanumAbstract:Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of Spinocerebellar Ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an Ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.
Karla P Figueroa - One of the best experts on this subject based on the ideXlab platform.
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antisense oligonucleotide therapy for Spinocerebellar Ataxia type 2
Nature, 2017Co-Authors: Daniel R Scoles, Karla P Figueroa, Pratap Meera, Matthew Schneider, Sharan Paul, Warunee Dansithong, Gene Hung, Frank Rigo, Frank C Bennett, Thomas S OtisAbstract:Antisense oligonucleotides against ATXN2 improved motor neuron function and restored firing frequency in cerebellar Purkinje cells in mouse models of Spinocerebellar Ataxia type 2. Ataxin-2 polyglutamine expansions increase the risk for amyotrophic lateral sclerosis (ALS) and cause Spinocerebellar Ataxia type 2 (SCA2), two neurodegenerative diseases without a cure. A pair of papers this week report therapeutic approaches towards reducing ataxin 2. Daniel Scoles et al. test antisense oligonucleotides (ASOs) against ataxin-2 in mice models of SCA2 that recreate progressive adult-onset dysfunction and degeneration of the neuronal network. The most promising therapeutic lead is ASO7, which downregulates ATXN2 mRNA and protein and delays the onset of SCA2 phenotypes. Moreover, treatment of symptomatic mice normalizes firing of cerebellar Purkinje cells and improves motor functioning. Nearly all ALS patients have toxic aggregates of the protein TDP-43 in the brain and spinal cord. Lowering ataxin-2 has been shown to suppress TDP-43 toxicity in yeast and flies, and, elsewhere in this issue, Lindsay Becker et al. show that lowering ataxin-2 in mice, genetically or with antisense oligonucleotides, reduces TDP-43 aggregation and toxicity, improves motor function and increases lifespan. Both papers suggest that antisense oligonucleotide-based therapeutic approaches could be used to tackle neurodegeneration. There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies1 in two mouse models of Spinocerebellar Ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease2. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function3,4. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.
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modulation of the age at onset in Spinocerebellar Ataxia by cag tracts in various genes
Brain, 2014Co-Authors: Alexandra Durr, Yaeko Ichikawa, Alessandro Brussino, Sophie Tezenas Du Montcel, Peter Bauer, Karla P Figueroa, Sylvie Forlani, Maria Rakowicz, Ludger ScholsAbstract:Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause Spinocerebellar Ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (Spinocerebellar Ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in Spinocerebellar Ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with Spinocerebellar Ataxia types 1, 6 and 7. Except for individuals with Spinocerebellar Ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in Spinocerebellar Ataxia type 2; ATXN2, ATN1 and HTT in Spinocerebellar Ataxia type 3; ATXN1 and ATXN3 in Spinocerebellar Ataxia type 6; and ATXN3 and TBP in Spinocerebellar Ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.
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amyotrophic lateral sclerosis and Spinocerebellar Ataxia type 2 in a family with full cag repeat expansions of atxn2
JAMA Neurology, 2013Co-Authors: Sirinan Tazen, Karla P Figueroa, Justin Y Kwan, Jill Goldman, Ann L Hunt, Jacinda Sampson, Laurie Gutmann, Stefan M Pulst, Hiroshi MitsumotoAbstract:Importance A family with coexistence of Spinocerebellar Ataxia type 2 and amyotrophic lateral sclerosis (ALS) is described. Observations Intermediate or full CAG repeat expansions of ATXN2 are associated with ALS. However, no coexistence of Spinocerebellar Ataxia type 2 and ALS in a family has been reported in the literature. We describe a 47-year-old woman with an 11-year history of Ataxia and her paternal uncle with ALS who were evaluated at Columbia University Medical Center since July 2006. Both our patient with Ataxia and her uncle with ALS have full pathological CAG repeat expansions of ATXN2. Conclusions and Relevance The diverse clinical phenotypes of ATXN2 CAG expansions and their coexistence in a single family are highlighted. A clinician should consider the diagnosis of Spinocerebellar Ataxia type 2 when encountering a patient with Ataxia and a family history of ALS.
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frequency of kcnc3 dna variants as causes of Spinocerebellar Ataxia 13 sca13
PLOS ONE, 2011Co-Authors: Karla P Figueroa, Laura P.w. Ranum, Christopher M. Gomez, Natali A Minassian, Diane M Papazian, Michael F Waters, Vartan Garibyan, Thomas D Bird, Stefan M PulstAbstract:Background Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant Spinocerebellar Ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial Ataxia presenting to three US Ataxia clinics at academic medical centers. Methodology DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with Ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes. Principal Findings Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel. Conclusions Mutations in KCNC3 are a rare cause of Spinocerebellar Ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.
Christopher M. Gomez - One of the best experts on this subject based on the ideXlab platform.
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A family with Spinocerebellar Ataxia and retinitis pigmentosa attributed to an ELOVL4 mutation.
Neurology Genetics, 2019Co-Authors: Changrui Xiao, Brent L. Fogel, Elaine Binkley, Jessica E. Rexach, Amy Knight-johnson, Pravin Khemani, Edwin M. Stone, Christopher M. GomezAbstract:Objective To identify the genetic cause of autosomal dominant Spinocerebellar Ataxia and retinitis pigmentosa in a large extended pedigree. Methods Clinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study. Records were obtained from an 11th, deceased, individual. Neurologic and dermatological examinations were performed. Ophthalmologic evaluation including funduscopic examination and in some cases ocular coherence tomography were used to identify the presence of retinal disease. Whole exome sequencing (WES), in conjunction with Sanger sequencing and segregation analysis, was used to identify potential genetic mutation. Results Affected individuals reported slowly progressive cerebellar Ataxia with age at onset between 38 and 57. Imaging demonstrated cerebellar atrophy (3/3). WES identified a novel heterozygous mutation in the elongation of very long chain fatty acids 4 (ELOVL4) gene (c.512T>C, p.Ile171Thr) that segregated with Ataxia in 7 members tested. Four of 8 members who underwent ophthalmologic evaluation were found to have retinitis pigmentosa. No skin findings were identified or reported. Ocular movement abnormalities and pyramidal tract signs were also present with incomplete penetrance. Conclusions We report a family with both Spinocerebellar Ataxia and retinal dystrophy associated with an ELOVL4 mutation. In addition, to supporting prior reports that ELOVL4 mutations can cause Spinocerebellar Ataxia, our findings further broaden the spectrum of clinical presentations associated with Spinocerebellar Ataxia 34.
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The Neural Substrate of Predictive Motor Timing in Spinocerebellar Ataxia
The Cerebellum, 2011Co-Authors: Martin Bares, Christopher M. Gomez, Ovidiu V. Lungu, Tobias Waechter, James AsheAbstract:The neural mechanisms involved in motor timing are subcortical, involving mainly cerebellum and basal ganglia. However, the role played by these structures in predictive motor timing is not well understood. Unlike motor timing, which is often tested using rhythm production tasks, predictive motor timing requires visuo-motor coordination in anticipation of a future event, and it is evident in behaviors such as catching a ball or shooting a moving target. We examined the role of the cerebellum and striatum in predictive motor timing in a target interception task in healthy ( n = 12) individuals and in subjects ( n = 9) with Spinocerebellar Ataxia types 6 and 8. The performance of the healthy subjects was better than that of the Spinocerebellar Ataxia. Successful performance in both groups was associated with increased activity in the cerebellum (right dentate nucleus, left uvula (lobule V), and lobule VI), thalamus, and in several cortical areas. The superior performance in the controls was related to activation in thalamus, putamen (lentiform nucleus) and cerebellum (right dentate nucleus and culmen—lobule IV), which were not activated either in the Spinocerebellar subjects or within a subgroup of controls who performed poorly. Both the cerebellum and the basal ganglia are necessary for the predictive motor timing. The degeneration of the cerebellum associated with Spinocerebellar types 6 and 8 appears to lead to quantitative rather than qualitative deficits in temporal processing. The lack of any areas with greater activity in the Spinocerebellar group than in controls suggests that limited functional reorganization occurs in this condition.
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frequency of kcnc3 dna variants as causes of Spinocerebellar Ataxia 13 sca13
PLOS ONE, 2011Co-Authors: Karla P Figueroa, Laura P.w. Ranum, Christopher M. Gomez, Natali A Minassian, Diane M Papazian, Michael F Waters, Vartan Garibyan, Thomas D Bird, Stefan M PulstAbstract:Background Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant Spinocerebellar Ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial Ataxia presenting to three US Ataxia clinics at academic medical centers. Methodology DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with Ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes. Principal Findings Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel. Conclusions Mutations in KCNC3 are a rare cause of Spinocerebellar Ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.
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evaluation of sleep and daytime somnolence in Spinocerebellar Ataxia type 6 sca6
Neurology, 2006Co-Authors: Michael J Howell, Mark W Mahowald, Christopher M. GomezAbstract:To determine the frequency of subjective sleep problems in Spinocerebellar Ataxia type 6 (SCA6), the authors surveyed 25 patients and 25 age-matched controls with the Epworth Sleepiness Scale (ESS) and Pittsburgh Seep Quality Index (PSQI). The ESS was higher in patients with SCA6 (9.12 ± 5.80; CI: 2.28) than in controls (4.96 ± 3.01; CI: 1.18) ( p = 0.003, t test). The PSQI was higher in patients with SCA6 (7.96 ± 4.65; CI: 1.86) than in controls (5.08 ± 3.39; CI: 1.36) ( p = 0.018, t test).
Jon Infante - One of the best experts on this subject based on the ideXlab platform.
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sca functional index a useful compound performance measure for Spinocerebellar Ataxia
Neurology, 2008Co-Authors: Tanja Schmitzhubsch, Paola Giunti, C. Globas, Maria Rakowicz, D A Stephenson, L Baliko, Francesco Sacca, C Mariotti, Sandra Szymanski, Jon InfanteAbstract:OBJECTIVE: To evaluate the usefulness of functional measures in patients with Spinocerebellar Ataxia (SCA). METHODS: We assessed three functional measures-8 m walking time (8MW), 9-hole peg test (9HPT), and PATA repetition rate-in 412 patients with autosomal dominant SCA (genotypes 1, 2, 3, and 6) in a multicenter trial. RESULTS: While PATA rate was normally distributed (mean/median 21.7/20.5 per 10 s), the performance times for 8MW (mean/median 10.8/7.5 s) or 9HPT (mean/median 47.2/35.0 s in dominant, 52.2/37.9 s in nondominant hand) were markedly skewed. Possible learning effects were small and likely clinically irrelevant. A composite functional index (SCAFI) was formed after appropriate transformation of subtest results. The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntington's disease Rating Scale functional assessment, and disease duration. Correlations for SCAFI with each of these parameters were stronger (Pearson r = -0.441 to -0.869) than for each subtest alone. Furthermore, SCAFI showed a linear decline over the whole range of disease severity, while 9HPT and 8MW had floor effects with respect to SARA. Analysis of possible confounders showed no effect of genotype or study site and only minor effects of age for 8MW. CONCLUSION: The proposed functional measures and their composite SCAFI have favorable properties to assess patients with Spinocerebellar Ataxia.
Stefan M Pulst - One of the best experts on this subject based on the ideXlab platform.
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amyotrophic lateral sclerosis and Spinocerebellar Ataxia type 2 in a family with full cag repeat expansions of atxn2
JAMA Neurology, 2013Co-Authors: Sirinan Tazen, Karla P Figueroa, Justin Y Kwan, Jill Goldman, Ann L Hunt, Jacinda Sampson, Laurie Gutmann, Stefan M Pulst, Hiroshi MitsumotoAbstract:Importance A family with coexistence of Spinocerebellar Ataxia type 2 and amyotrophic lateral sclerosis (ALS) is described. Observations Intermediate or full CAG repeat expansions of ATXN2 are associated with ALS. However, no coexistence of Spinocerebellar Ataxia type 2 and ALS in a family has been reported in the literature. We describe a 47-year-old woman with an 11-year history of Ataxia and her paternal uncle with ALS who were evaluated at Columbia University Medical Center since July 2006. Both our patient with Ataxia and her uncle with ALS have full pathological CAG repeat expansions of ATXN2. Conclusions and Relevance The diverse clinical phenotypes of ATXN2 CAG expansions and their coexistence in a single family are highlighted. A clinician should consider the diagnosis of Spinocerebellar Ataxia type 2 when encountering a patient with Ataxia and a family history of ALS.
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frequency of kcnc3 dna variants as causes of Spinocerebellar Ataxia 13 sca13
PLOS ONE, 2011Co-Authors: Karla P Figueroa, Laura P.w. Ranum, Christopher M. Gomez, Natali A Minassian, Diane M Papazian, Michael F Waters, Vartan Garibyan, Thomas D Bird, Stefan M PulstAbstract:Background Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant Spinocerebellar Ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial Ataxia presenting to three US Ataxia clinics at academic medical centers. Methodology DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with Ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes. Principal Findings Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel. Conclusions Mutations in KCNC3 are a rare cause of Spinocerebellar Ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.
