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Christopher M. Gomez - One of the best experts on this subject based on the ideXlab platform.

  • second cistron in cacna1a gene encodes a transcription factor mediating cerebellar development and sca6
    Cell, 2013
    Co-Authors: Xiaofei Du, Jun Wang, Lorenzo Rinaldo, Kaymarie Lamar, Ann C Palmenberg, Christian Hansel, Christopher M. Gomez
    Abstract:

    Summary The CACNA1A gene, encoding the voltage-gated calcium channel subunit α1A, is involved in pre- and postsynaptic Ca 2+ signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A coordinates gene expression using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized α1A subunit. The second expresses a transcription factor, α1ACT, which coordinates expression of a program of genes involved in neural and Purkinje cell development. α1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes Spinocerebellar Ataxia type 6 (SCA6). When expressed as an independent polypeptide, α1ACT—bearing an expanded polyQ tract—lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to Ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy.

  • Spinocerebellar Ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age dependent accumulation of mutant cav2 1 channels
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Kei Watase, Kinya Ishikawa, Toshinori Unno, Curtis F Barrett, Taisuke Miyazaki, Taro Ishiguro, Yuanxin Hu, Sayumi Kasai, Masahiko Watanabe, Christopher M. Gomez
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG repeat expansions within the voltage-gated calcium (CaV) 2.1 channel gene. It remains controversial whether the mutation exerts neurotoxicity by changing the function of CaV2.1 channel or through a gain-of-function mechanism associated with accumulation of the expanded polyglutamine protein. We generated three strains of knockin (KI) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice expressing hyperexpanded polyglutamine (Sca684Q) developed progressive motor impairment and aggregation of mutant CaV2.1 channels. Electrophysiological analysis of cerebellar Purkinje cells revealed similar Ca2+ channel current density among the three KI models. Neither voltage sensitivity of activation nor inactivation was altered in the Sca684Q neurons, suggesting that expanded CAG repeat per se does not affect the intrinsic electrophysiological properties of the channels. The pathogenesis of SCA6 is apparently linked to an age-dependent process accompanied by accumulation of mutant CaV2.1 channels.

  • evaluation of sleep and daytime somnolence in Spinocerebellar Ataxia type 6 sca6
    Neurology, 2006
    Co-Authors: Michael J Howell, Mark W Mahowald, Christopher M. Gomez
    Abstract:

    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).

  • Spinocerebellar Ataxia type 6 gaze evoked and vertical nystagmus purkinje cell degeneration and variable age of onset
    Annals of Neurology, 1997
    Co-Authors: Christopher M. Gomez, David S. Zee, Randall Thompson, Jason T Gammack, Susan Perlman, William B Dobyns, Charles L Truwit, Brent H Clark, John H Anderson
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar Ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the α1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large Ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of Ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.

Kinya Ishikawa - One of the best experts on this subject based on the ideXlab platform.

  • Decreased metabotropic glutamate receptor type 1 availability in a patient with Spinocerebellar Ataxia type 6: A 11C-ITMM PET study
    Journal of the Neurological Sciences, 2015
    Co-Authors: Kenji Ishibashi, Kinya Ishikawa, Yoshiharu Miura, Kenji Ishii, Kiichi Ishiwata
    Abstract:

    Abstract Objective Imaging of metabotropic glutamate receptor type 1 (mGluR1), localized exclusively in the cerebellar Purkinje cells and related to cerebellar function, has recently become possible using positron emission tomography (PET). We report the initial mGluR1 imaging in a 74-year-old woman with Spinocerebellar Ataxia type 6 (SCA6). Methods The patient and 9 age-matched healthy controls underwent PET scanning with a mGluR1 radiotracer, N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl] -4-11C-methoxy-N-methylbenzamide. Volumes-of-interest were placed on the anterior and posterior lobes, vermis, and flocculus. Binding potential (BPND) was calculated to estimate mGluR1 availability using the simplified reference tissue model. A partial volume correction was applied to the BPND values. Additionally, the volume of the whole cerebellum was measured using MRI. Results The corrected BPND values of the cerebellar subregions and the volume of the whole cerebellum in the patient were 51.0% to 68.3% and 72.6%, respectively, of the controls. Thus, the magnitude of reduced BPND values was relatively larger than the magnitude of cerebellar atrophy in the patient. Conclusion These findings suggest that the measurement of mGluR1 availability is more sensitive than morphological measurements by MRI to detect reduced cerebellar function. Thus, imaging of mGluR1, probably reflecting the number and distribution of Purkinje cells, can be a specific and sensitive marker for estimation of cerebellar function.

  • development of purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of sca6
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Toshinori Unno, Kinya Ishikawa, Minoru Wakamori, Masato Koike, Yasuo Uchiyama, Hisahiko Kubota, Takashi Yoshida, Hiroko Sasakawa, Christoph Peters, Hidehiro Mizusawa
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Cav2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Cav2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.

  • the effect of 3 4 diaminopyridine on the patients with hereditary pure cerebellar Ataxia
    Journal of the Neurological Sciences, 2010
    Co-Authors: Kinya Ishikawa, Taiji Tsunemi, Kei Tsukui, Takuro Sumi, Ken Kitamura, Hidehiro Mizusawa
    Abstract:

    Abstract Background Downbeat nystagmus (DBN) is often seen in patients with pure cerebellar type of Spinocerebellar Ataxia (SCA) like Spinocerebellar Ataxia type 6 (SCA6). DBN frequently presents with other cerebellar symptoms such as postural imbalance or Ataxia. A potassium channel blocker 3,4-diaminopyridine (3,4-DAP) has been reported to reduce DBN by increasing the excitability of Purkinje cells. Objective The objective of this study is to determine whether 3,4-DAP has a beneficial effect on DBN along with postural imbalance and ataxic symptoms in 10 patients with SCA6 and five patients with chromosome 16q22.1-linked autosomal dominant cerebellar Ataxia (16q-ADCA). Results The patients took 20 mg of 3,4-DAP twice a day for a week. DBN was observed in seven patients with SCA6 and two with 16q-ADCA. Although 3,4-DAP significantly reduced DBN ( P Conclusion 3,4-DAP may be effective on DBN and oscillopsia, although it was not proved to be effective on other symptoms of Ataxia in SCA patients.

  • Spinocerebellar Ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age dependent accumulation of mutant cav2 1 channels
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Kei Watase, Kinya Ishikawa, Toshinori Unno, Curtis F Barrett, Taisuke Miyazaki, Taro Ishiguro, Yuanxin Hu, Sayumi Kasai, Masahiko Watanabe, Christopher M. Gomez
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG repeat expansions within the voltage-gated calcium (CaV) 2.1 channel gene. It remains controversial whether the mutation exerts neurotoxicity by changing the function of CaV2.1 channel or through a gain-of-function mechanism associated with accumulation of the expanded polyglutamine protein. We generated three strains of knockin (KI) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice expressing hyperexpanded polyglutamine (Sca684Q) developed progressive motor impairment and aggregation of mutant CaV2.1 channels. Electrophysiological analysis of cerebellar Purkinje cells revealed similar Ca2+ channel current density among the three KI models. Neither voltage sensitivity of activation nor inactivation was altered in the Sca684Q neurons, suggesting that expanded CAG repeat per se does not affect the intrinsic electrophysiological properties of the channels. The pathogenesis of SCA6 is apparently linked to an age-dependent process accompanied by accumulation of mutant CaV2.1 channels.

  • japanese families with autosomal dominant pure cerebellar Ataxia map to chromosome 19p13 1 p13 2 and are strongly associated with mild cag expansions in the Spinocerebellar Ataxia type 6 gene in chromosome 19p13 1
    American Journal of Human Genetics, 1997
    Co-Authors: Kinya Ishikawa, Mitsunori Watanabe, Hirosato Tanaka, Masaaki Saito, Norio Ohkoshi, Toshiro Fujita, Kazuo Yoshizawa, Takeshi Ikeuchi, A Hayashi, Yoshihisa Takiyama
    Abstract:

    Summary Autosomal dominant cerebellar Ataxia is a group of clinically and genetically heterogeneous disorders. We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar Ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of CAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (Spinocerebellar Ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21–25), compared with alleles observed in neurologically normal Japanese (range 5–20 repeats). Inverse correlation between the CAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied. We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.

Liana Veneziano - One of the best experts on this subject based on the ideXlab platform.

  • molecular mechanism of Spinocerebellar Ataxia type 6 glutamine repeat disorder channelopathy and transcriptional dysregulation the multifaceted aspects of a single mutation
    Frontiers in Cellular Neuroscience, 2015
    Co-Authors: Paola Giunti, Elide Mantuano, Marina Frontali, Liana Veneziano
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar Ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism.

  • clusters of non truncating mutations of p q type ca2 channel subunit ca v 2 1 causing episodic Ataxia 2
    Journal of Medical Genetics, 2004
    Co-Authors: Elide Mantuano, Liana Veneziano, Carla Jodice, Paola Giunti, M Spadaro, S Guida, M G Leggio, L Verriello, Nicholas W Wood, Marina Frontali
    Abstract:

    Episodic Ataxia type 2 (EA2, MIM 108500) is one of three allelic disorders due to mutations of the CACNA1A gene coding for the Cav2.1 subunit of P/Q type voltage gated Ca2+ channels. The other two allelic diseases are familial hemiplegic migraine (FHM, MIM 141500) and Spinocerebellar Ataxia type 6 (SCA6, MIM 183086). EA2 is characterised by a complex and highly variable phenotype, widely overlapping that of SCA6.1,2 Its main features are episodes of vertigo or Ataxia of variable duration and frequency, a permanent cerebellar deficit of variable severity, sometimes progressive, and a cerebellar atrophy typically starting from the anterior portion of vermis. Recently dyskynesia,3 muscular weakness,4 and epilepsy5 have been described in association with EA2. FHM, on the other hand, is characterised by migraine attacks preceded by symptoms such as unilateral limb paresis or paralysis, paraesthesias, and dysphasia. Interictal cerebellar signs are reported in about 50% of patients.6 The CACNA1A gene product is the pore forming subunit of P/Q type Ca2+ channels, expressed in the brain and particularly in cerebellar Purkinje and granule cells, as well as in neuromuscular junctions.7,8 The protein is predicted to have four domains or repeats, each formed by six transmembrane hydrophobic segments (fig 1). Segments S5 and S6 of each domain line the pore region. The S5–S6 linkers are highly conserved sequences folded to leave their extremes in the extracellular space, and place within the pore a P sequence which exerts a critical role for ion selectivity and permeation of the Ca2+ channel.9 Figure 1 Predicted structure of the Cav 2.1 subunit of Ca2+ channels type P/Q and sites of non-truncating/disrupting (NTR) mutations causing EA2. Point mutations in the CACNA1A gene are responsible for EA2 and FHM, whereas small expansions of …

  • complete loss of p q calcium channel activity caused by a cacna1a missense mutation carried by patients with episodic Ataxia type 2
    American Journal of Human Genetics, 2001
    Co-Authors: Serena Guida, Elide Mantuano, Liana Veneziano, Flavia Trettel, Stefano Pagnutti, Angelita Tottene, Tommaso Fellin, M Spadaro, Kenneth A Stauderman, Mark E Williams
    Abstract:

    Familial hemiplegic migraine, episodic Ataxia type 2 (EA2), and Spinocerebellar Ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the α1A subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype—that is, T→C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human α1A-2 subunit, together with human β4 and α2δ subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.

  • episodic Ataxia type 2 ea2 and Spinocerebellar Ataxia type 6 sca6 due to cag repeat expansion in the cacna1a gene on chromosome 19p
    Human Molecular Genetics, 1997
    Co-Authors: Carla Jodice, Elide Mantuano, Liana Veneziano, Flavia Trettel, G Sabbadini, L Calandriello, Ada Francia, Marcel Spadaro, Francesco Pierelli, Fabrizio Salvi
    Abstract:

    Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic Ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive Spinocerebellar Ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar Ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar Ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar Ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.

Elide Mantuano - One of the best experts on this subject based on the ideXlab platform.

  • molecular mechanism of Spinocerebellar Ataxia type 6 glutamine repeat disorder channelopathy and transcriptional dysregulation the multifaceted aspects of a single mutation
    Frontiers in Cellular Neuroscience, 2015
    Co-Authors: Paola Giunti, Elide Mantuano, Marina Frontali, Liana Veneziano
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar Ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism.

  • clusters of non truncating mutations of p q type ca2 channel subunit ca v 2 1 causing episodic Ataxia 2
    Journal of Medical Genetics, 2004
    Co-Authors: Elide Mantuano, Liana Veneziano, Carla Jodice, Paola Giunti, M Spadaro, S Guida, M G Leggio, L Verriello, Nicholas W Wood, Marina Frontali
    Abstract:

    Episodic Ataxia type 2 (EA2, MIM 108500) is one of three allelic disorders due to mutations of the CACNA1A gene coding for the Cav2.1 subunit of P/Q type voltage gated Ca2+ channels. The other two allelic diseases are familial hemiplegic migraine (FHM, MIM 141500) and Spinocerebellar Ataxia type 6 (SCA6, MIM 183086). EA2 is characterised by a complex and highly variable phenotype, widely overlapping that of SCA6.1,2 Its main features are episodes of vertigo or Ataxia of variable duration and frequency, a permanent cerebellar deficit of variable severity, sometimes progressive, and a cerebellar atrophy typically starting from the anterior portion of vermis. Recently dyskynesia,3 muscular weakness,4 and epilepsy5 have been described in association with EA2. FHM, on the other hand, is characterised by migraine attacks preceded by symptoms such as unilateral limb paresis or paralysis, paraesthesias, and dysphasia. Interictal cerebellar signs are reported in about 50% of patients.6 The CACNA1A gene product is the pore forming subunit of P/Q type Ca2+ channels, expressed in the brain and particularly in cerebellar Purkinje and granule cells, as well as in neuromuscular junctions.7,8 The protein is predicted to have four domains or repeats, each formed by six transmembrane hydrophobic segments (fig 1). Segments S5 and S6 of each domain line the pore region. The S5–S6 linkers are highly conserved sequences folded to leave their extremes in the extracellular space, and place within the pore a P sequence which exerts a critical role for ion selectivity and permeation of the Ca2+ channel.9 Figure 1 Predicted structure of the Cav 2.1 subunit of Ca2+ channels type P/Q and sites of non-truncating/disrupting (NTR) mutations causing EA2. Point mutations in the CACNA1A gene are responsible for EA2 and FHM, whereas small expansions of …

  • complete loss of p q calcium channel activity caused by a cacna1a missense mutation carried by patients with episodic Ataxia type 2
    American Journal of Human Genetics, 2001
    Co-Authors: Serena Guida, Elide Mantuano, Liana Veneziano, Flavia Trettel, Stefano Pagnutti, Angelita Tottene, Tommaso Fellin, M Spadaro, Kenneth A Stauderman, Mark E Williams
    Abstract:

    Familial hemiplegic migraine, episodic Ataxia type 2 (EA2), and Spinocerebellar Ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the α1A subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype—that is, T→C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human α1A-2 subunit, together with human β4 and α2δ subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.

  • episodic Ataxia type 2 ea2 and Spinocerebellar Ataxia type 6 sca6 due to cag repeat expansion in the cacna1a gene on chromosome 19p
    Human Molecular Genetics, 1997
    Co-Authors: Carla Jodice, Elide Mantuano, Liana Veneziano, Flavia Trettel, G Sabbadini, L Calandriello, Ada Francia, Marcel Spadaro, Francesco Pierelli, Fabrizio Salvi
    Abstract:

    Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic Ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive Spinocerebellar Ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar Ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar Ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar Ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.

Robert W Baloh - One of the best experts on this subject based on the ideXlab platform.

  • otolith function in cerebellar Ataxia due to mutations in the calcium channel gene cacna1a
    Brain, 2001
    Co-Authors: Gerald Wiest, Robert W Baloh, Junru Tian, Benjamin T Crane, Joseph L Demer
    Abstract:

    The vestibulo-ocular reflexes stabilize retinal images during head movements. While there is a wealth of information about the interaction between the cerebellum and vestibulo-ocular reflexes mediated by the semicircular canals, little is known about the role of the cerebellum in the generation of the otolith-mediated linear vestibulo-ocular reflex (LVOR). By means of transient linear acceleration of the whole body along the interaural axis, we examined the LVOR in six patients with hereditary cerebellar Ataxia due to mutations of the calcium channel gene CACNA1A, five with Spinocerebellar Ataxia type 6 (SCA6) and one with episodic Ataxia type 2 (EA-2). Six age-matched normal subjects served as controls. Using a peak acceleration of 0.5 g in combination with recording by the binocular scleral magnetic search coil method, it was possible to study the latency and sensitivity of the LVOR in the first 150 ms after motion onset. The normal LVOR showed a significant dependence on viewing distance and covaried with vergence angle, and could be enhanced by the presence of a visible target. In contrast, the LVOR of ataxic patients had normal latency but significantly decreased sensitivity that was not enhanced with visible or nearer targets despite normal vergence. Substituting for the normal smooth LVOR slow phase, ataxic patients employed catch-up saccades 150-250 ms after motion onset. These findings suggest a critical role of the cerebellum in the modulation of otolith-ocular signals that is independent of motor vergence.

  • Spinocerebellar Ataxia type 6 with positional vertigo and acetazolamide responsive episodic Ataxia
    Journal of neurology neurosurgery and psychiatry, 1998
    Co-Authors: Joanna C. Jen, Stanley F Nelson, Qing Yue, Juliana Karrim, Robert W Baloh
    Abstract:

    The SCA6 mutation, a small expansion of a CAG repeat in a calcium channel gene CACNA1A, was identified in three pedigrees. Point mutations in other parts of the gene CACNA1A were excluded and new clinical features of SCA6 reported—namely, central positional nystagmus and episodic Ataxia responsive to acetazolamide. The three allelic disorders, episodic Ataxia type 2, familial hemiplegic migraine, and SCA6, have overlapping clinical features.

  • Spinocerebellar Ataxia type 6 frequency of the mutation and genotype phenotype correlations
    Neurology, 1997
    Co-Authors: Daniel H Geschwind, Karla P Figueroa, Robert W Baloh, Susan Perlman, Juliana Karrim, Stefan M Pulst
    Abstract:

    Spinocerebellar Ataxia type 6 (SCA6) is the most recently identified mutation causing autosomal-dominant cerebellar Ataxia without retinal degeneration (ADCA). The SCA6 mutation is allelic with episodic Ataxia type 2(EA-2), but the two differ clinically because of the presence of progressive, rather than episodic, Ataxia in SCA6. SCA6 accounts for 12% of families with ADCA in an ethnically heterogeneous population of patients. Clinical examination, quantitative eye movement testing, and imaging data show that the brainstem is normal in most patients with SCA6, especially within the first 10 years of symptoms. Most patients show progressive Ataxia from the onset, but several patients show an episodic course resembling EA-2. Thus, SCA6 mutations not only account for patients with ADCA I and ADCA III phenotypes but also for some patients presenting with episodic features that are typical for EA-2. Interestingly, a compound heterozygote for the SCA6 expansion manifested an earlier onset and more rapid course than family members with the same larger expanded allele.