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Yiguo Shen - One of the best experts on this subject based on the ideXlab platform.
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Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Yiguo Shen, Hsien-yang Lee, Arisa Hirano, Astrid Rohlmann, Markus Missler, Richard W. Tsien, Lily Yeh JanAbstract:Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.
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Mutations in PNKD Causing Paroxysmal Dyskinesia Alters Protein Cleavage and Stability (IN10-1.005)
Neurology, 2012Co-Authors: Louis J. Ptáček, Yiguo ShenAbstract:Objective: To characterize biochemical properties of wild type and mutant PNKD protein. Background Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare autosomal dominant movement disorder triggered by stress, fatigue or consumption of either alcohol or caffeine. Attacks last 1–4 h and consist of dramatic dystonia and choreoathetosis in the limbs, trunk and face. The disease is associated with single amino acid changes (A7V or A9V) in PNKD, a protein of unknown function. PNKD is homologous to a superfamily of enzymes with conserved b-lactamase domains. It shares highest homology with glyoxalase II but does not catalyze the same reaction. Design/Methods: Here we studied the stability, cellular localization and enzymatic activity of the PNKD protein in cultured cells and transgenic animals. Results: The N-terminus of the wild-type (WT) long PNKD isoform (PNKD-L) undergoes a cleavage event in vitro, resistance to which is conferred by disease-associated mutations. Mutant PNKD-L protein is degraded faster than the WT protein. Lower glutathione levels were found in cortex lysates from PNKD knockout mice versus WT littermates. Conclusions: These results suggest that the disease mutations underlying PNKD may disrupt protein processing in vivo, a hypothesis supported by our observation of decreased cortical PNKD-L levels in mutant transgenic mice. Our results suggest an important role for the PNKD protein in maintaining cellular redox status. Supported by: A Fellowship from the Dystonia Medical Research Foundation (Y.S.), a Bachmann Strauss Dystonia and Parkinson Foundation grant (L.J.P.), the Sandler Neurogenetics fund (L.J.P.) and National Institutes of Health grant NS043533 (L.J.P.). L.J.P. is an Investigator of the Howard Hughes Medical Institute. Disclosure: Dr. Ptacek has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Fu has nothing to disclose.
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PNKD Functions in RIM-Dependent Pathway To Regulate Exocytosis (IN10-2.004)
Neurology, 2012Co-Authors: Louis J. Ptáček, Yiguo ShenAbstract:Objective: We set out to determine the wild type function of the PNKD protein by identifying interactions with other proteins. Identification of pathway(s) in which PNKD functions could yield insights into the function of this protein. Background Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene and generated a PNKD mouse model demonstrating dysregulated dopamine signaling. However, the normal function of the encoded protein remains unknown. Design/Methods: We utilized co-immunoprcipitation and mass spectrometry, sucrose gradiant centrifugation, immuno-gold electron microscopy, in vitro exocytosis assays, and standard slice electrophysiolgy. Results: Here, we show that PNKD localizes to the synaptic membrane and inhibits neurotransmitter release through its interaction with synaptic active zone proteins RIM1 and RIM2. Mutant PNKD protein is less effective than wild-type at inhibiting RIM2-dependent exocytosis in vitro . In PNKD -/- mouse brain, RIM1/2 protein levels are reduced and there is impairment of synaptic transmission and synaptic facilitation. Conclusions: Thus, the PNKD is a novel synaptic membrane protein with a role in synaptic regulation. Supported by: A Postdoctoral Fellowship from the Dystonia Medical Research Foundation to Y.S. and a Bachmann-Strauss Dystonia & Parkinson Foundation Grant to L.J.P. Disclosure: Dr. Ptacek has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Fu has nothing to disclose.
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Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia
The Journal of clinical investigation, 2012Co-Authors: Hsien-yang Lee, Yiguo Shen, Junko Nakayama, Xueliang Fan, Maha Karouani, Emmanuel N. Pothos, Ellen J. Hess, Robert H. EdwardsAbstract:Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse PNKD locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neuro-transmitter release in response to stress and other precipitating factors.
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Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability
Human molecular genetics, 2011Co-Authors: Yiguo Shen, Hsien-yang Lee, Joel Rawson, Sunil Ojha, Patricia C. Babbitt, Louis J. PtáčekAbstract:Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare autosomal dominant movement disorder triggered by stress, fatigue or consumption of either alcohol or caffeine. Attacks last 1-4 h and consist of dramatic dystonia and choreoathetosis in the limbs, trunk and face. The disease is associated with single amino acid changes (A7V or A9V) in PNKD, a protein of unknown function. Here we studied the stability, cellular localization and enzymatic activity of the PNKD protein in cultured cells and transgenic animals. The N-terminus of the wild-type (WT) long PNKD isoform (PNKD-L) undergoes a cleavage event in vitro, resistance to which is conferred by disease-associated mutations. Mutant PNKD-L protein is degraded faster than the WT protein. These results suggest that the disease mutations underlying PNKD may disrupt protein processing in vivo, a hypothesis supported by our observation of decreased cortical PNKD-L levels in mutant transgenic mice. PNKD is homologous to a superfamily of enzymes with conserved β-lactamase domains. It shares highest homology with glyoxalase II but does not catalyze the same reaction. Lower glutathione levels were found in cortex lysates from PNKD knockout mice versus WT littermates. Taken together, our results suggest an important role for the PNKD protein in maintaining cellular redox status.
Hsien-yang Lee - One of the best experts on this subject based on the ideXlab platform.
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Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Yiguo Shen, Hsien-yang Lee, Arisa Hirano, Astrid Rohlmann, Markus Missler, Richard W. Tsien, Lily Yeh JanAbstract:Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.
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Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia
The Journal of clinical investigation, 2012Co-Authors: Hsien-yang Lee, Yiguo Shen, Junko Nakayama, Xueliang Fan, Maha Karouani, Emmanuel N. Pothos, Ellen J. Hess, Robert H. EdwardsAbstract:Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse PNKD locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neuro-transmitter release in response to stress and other precipitating factors.
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Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability
Human molecular genetics, 2011Co-Authors: Yiguo Shen, Hsien-yang Lee, Joel Rawson, Sunil Ojha, Patricia C. Babbitt, Louis J. PtáčekAbstract:Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare autosomal dominant movement disorder triggered by stress, fatigue or consumption of either alcohol or caffeine. Attacks last 1-4 h and consist of dramatic dystonia and choreoathetosis in the limbs, trunk and face. The disease is associated with single amino acid changes (A7V or A9V) in PNKD, a protein of unknown function. Here we studied the stability, cellular localization and enzymatic activity of the PNKD protein in cultured cells and transgenic animals. The N-terminus of the wild-type (WT) long PNKD isoform (PNKD-L) undergoes a cleavage event in vitro, resistance to which is conferred by disease-associated mutations. Mutant PNKD-L protein is degraded faster than the WT protein. These results suggest that the disease mutations underlying PNKD may disrupt protein processing in vivo, a hypothesis supported by our observation of decreased cortical PNKD-L levels in mutant transgenic mice. PNKD is homologous to a superfamily of enzymes with conserved β-lactamase domains. It shares highest homology with glyoxalase II but does not catalyze the same reaction. Lower glutathione levels were found in cortex lysates from PNKD knockout mice versus WT littermates. Taken together, our results suggest an important role for the PNKD protein in maintaining cellular redox status.
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Paroxysmal Non-Kinesigenic Dyskinesia Caused by the Mutation of MR-1 in a Large Polish Kindred
European neurology, 2008Co-Authors: Andrzej Friedman, Hsien-yang Lee, Louis J. Ptáček, Beata Zakrzewska-pniewska, Izabela Domitrz, Hubert KwiecińskiAbstract:Paroxysmal non-kinesigenic dyskinesia (PNKD) is a clinical syndrome of sudden involuntary movements, mostly of dystonic type, which may be triggered by alcohol or coffee intake, stress and fatigue. Th
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Genotype–phenotype correlation of paroxysmal nonkinesigenic dyskinesia
Neurology, 2007Co-Authors: Michiko K. Bruno, Hsien-yang Lee, Georg Auburger, Andrzej Friedman, Jørgen E. Nielsen, Anthony E. Lang, Enrico Bertini, P. Van Bogaert, Y. Averyanov, Mark HallettAbstract:Background: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. Methods: We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had MR-1 mutations and 6 did not. Results: Patients with PNKD with MR-1 mutations had their attack onset in youth (infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. Conclusions: Paroxysmal nonkinesigenic dyskinesia (PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation (which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 ( MR-1 ) gene mutations. Other “PNKD-like” families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia.
Louis J. Ptáček - One of the best experts on this subject based on the ideXlab platform.
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PNKD Functions in RIM-Dependent Pathway To Regulate Exocytosis (IN10-2.004)
Neurology, 2012Co-Authors: Louis J. Ptáček, Yiguo ShenAbstract:Objective: We set out to determine the wild type function of the PNKD protein by identifying interactions with other proteins. Identification of pathway(s) in which PNKD functions could yield insights into the function of this protein. Background Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene and generated a PNKD mouse model demonstrating dysregulated dopamine signaling. However, the normal function of the encoded protein remains unknown. Design/Methods: We utilized co-immunoprcipitation and mass spectrometry, sucrose gradiant centrifugation, immuno-gold electron microscopy, in vitro exocytosis assays, and standard slice electrophysiolgy. Results: Here, we show that PNKD localizes to the synaptic membrane and inhibits neurotransmitter release through its interaction with synaptic active zone proteins RIM1 and RIM2. Mutant PNKD protein is less effective than wild-type at inhibiting RIM2-dependent exocytosis in vitro . In PNKD -/- mouse brain, RIM1/2 protein levels are reduced and there is impairment of synaptic transmission and synaptic facilitation. Conclusions: Thus, the PNKD is a novel synaptic membrane protein with a role in synaptic regulation. Supported by: A Postdoctoral Fellowship from the Dystonia Medical Research Foundation to Y.S. and a Bachmann-Strauss Dystonia & Parkinson Foundation Grant to L.J.P. Disclosure: Dr. Ptacek has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Fu has nothing to disclose.
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Mutations in PNKD Causing Paroxysmal Dyskinesia Alters Protein Cleavage and Stability (IN10-1.005)
Neurology, 2012Co-Authors: Louis J. Ptáček, Yiguo ShenAbstract:Objective: To characterize biochemical properties of wild type and mutant PNKD protein. Background Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare autosomal dominant movement disorder triggered by stress, fatigue or consumption of either alcohol or caffeine. Attacks last 1–4 h and consist of dramatic dystonia and choreoathetosis in the limbs, trunk and face. The disease is associated with single amino acid changes (A7V or A9V) in PNKD, a protein of unknown function. PNKD is homologous to a superfamily of enzymes with conserved b-lactamase domains. It shares highest homology with glyoxalase II but does not catalyze the same reaction. Design/Methods: Here we studied the stability, cellular localization and enzymatic activity of the PNKD protein in cultured cells and transgenic animals. Results: The N-terminus of the wild-type (WT) long PNKD isoform (PNKD-L) undergoes a cleavage event in vitro, resistance to which is conferred by disease-associated mutations. Mutant PNKD-L protein is degraded faster than the WT protein. Lower glutathione levels were found in cortex lysates from PNKD knockout mice versus WT littermates. Conclusions: These results suggest that the disease mutations underlying PNKD may disrupt protein processing in vivo, a hypothesis supported by our observation of decreased cortical PNKD-L levels in mutant transgenic mice. Our results suggest an important role for the PNKD protein in maintaining cellular redox status. Supported by: A Fellowship from the Dystonia Medical Research Foundation (Y.S.), a Bachmann Strauss Dystonia and Parkinson Foundation grant (L.J.P.), the Sandler Neurogenetics fund (L.J.P.) and National Institutes of Health grant NS043533 (L.J.P.). L.J.P. is an Investigator of the Howard Hughes Medical Institute. Disclosure: Dr. Ptacek has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Fu has nothing to disclose.
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Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability
Human molecular genetics, 2011Co-Authors: Yiguo Shen, Hsien-yang Lee, Joel Rawson, Sunil Ojha, Patricia C. Babbitt, Louis J. PtáčekAbstract:Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare autosomal dominant movement disorder triggered by stress, fatigue or consumption of either alcohol or caffeine. Attacks last 1-4 h and consist of dramatic dystonia and choreoathetosis in the limbs, trunk and face. The disease is associated with single amino acid changes (A7V or A9V) in PNKD, a protein of unknown function. Here we studied the stability, cellular localization and enzymatic activity of the PNKD protein in cultured cells and transgenic animals. The N-terminus of the wild-type (WT) long PNKD isoform (PNKD-L) undergoes a cleavage event in vitro, resistance to which is conferred by disease-associated mutations. Mutant PNKD-L protein is degraded faster than the WT protein. These results suggest that the disease mutations underlying PNKD may disrupt protein processing in vivo, a hypothesis supported by our observation of decreased cortical PNKD-L levels in mutant transgenic mice. PNKD is homologous to a superfamily of enzymes with conserved β-lactamase domains. It shares highest homology with glyoxalase II but does not catalyze the same reaction. Lower glutathione levels were found in cortex lysates from PNKD knockout mice versus WT littermates. Taken together, our results suggest an important role for the PNKD protein in maintaining cellular redox status.
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Paroxysmal Non-Kinesigenic Dyskinesia Caused by the Mutation of MR-1 in a Large Polish Kindred
European neurology, 2008Co-Authors: Andrzej Friedman, Hsien-yang Lee, Louis J. Ptáček, Beata Zakrzewska-pniewska, Izabela Domitrz, Hubert KwiecińskiAbstract:Paroxysmal non-kinesigenic dyskinesia (PNKD) is a clinical syndrome of sudden involuntary movements, mostly of dystonic type, which may be triggered by alcohol or coffee intake, stress and fatigue. Th
Kailash P. Bhatia - One of the best experts on this subject based on the ideXlab platform.
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Treatment of Paroxysmal Dyskinesia.
Neurologic Clinics, 2020Co-Authors: Anna Latorre, Kailash P. BhatiaAbstract:Paroxysmal dyskinesia (PxD) is a heterogeneous group of syndromes characterized by recurrent attacks of abnormal movements, triggered by detectable factors, without loss of consciousness. According to the precipitating factors, they are classified as paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dystonia (PED). PxD treatment is based on the combination of nonpharmacologic and pharmacologic approaches. Pharmacologic and nonpharmacologic treatments effective for PNKD and PED also are available. In PxD refractory to conventional treatment, surgery might be an alternative therapeutic option. The course of PRRT2-PKD and MR-1-PNKD is benign, and treatment might not be needed with advancing age.
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The clinical and genetic heterogeneity
2016Co-Authors: Kailash P. Bhatia, Henry HouldenAbstract:These authors contributed equally to this work. Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35 % of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotype
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Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification.
Movement disorders : official journal of the Movement Disorder Society, 2014Co-Authors: Roberto Erro, Una-marie Sheerin, Kailash P. BhatiaAbstract:Paroxysmal movement disorders are a heterogeneous group of conditions manifesting as episodic dyskinesia with sudden onset and lasting a variable duration. Based on the difference of precipitating factors, three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise induced (PED). The elucidation of the genetic cause of various forms of paroxysmal dyskinesia has led to better clinical definitions based on genotype-phenotype correlations in the familial forms. However, it has been increasingly recognized that (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; and (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. We aimed to review the clinical features of 500 genetically proven cases published to date. Based on our results, it is clear that there is not a complete phenotypic-genotypic correlation, and therefore we suggest an algorithm to lead the genetic analyses. Given the fact that the reliability of current clinical categorization is not entirely valid, we further propose a novel classification for paroxysmal dyskinesias, which takes into account the recent genetic discoveries in this field.
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DYT8, Paroxysmal Non-kinesiogenic Dyskinesia-PNKD
Encyclopedia of Movement Disorders, 2010Co-Authors: Susanne A. Schneider, Kailash P. BhatiaAbstract:Paroxysmal movement disorders are defined as abnormal involuntary movements that are intermittent or episodic in nature, with sudden onset and with no change in consciousness. Subgroups can be distinguished according to triggering factors and include the nonkinesigenic variant (PNKD). Here, attacks are typically triggered by alcohol or coffee intake and last minutes to hours. Gene mutations in the MR1 gene have been detected in some cases, however, there is suggestion of genetic heterogeneity. Clonazepam was beneficial in 97% in one study of 49 gene-proven cases. Clinical features, genetic findings, pathophysiology, diagnostic principles, and treatment responses are further discussed in this article.
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A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study
Journal of neurology neurosurgery and psychiatry, 2000Co-Authors: A. Münchau, Enza Maria Valente, Gholam Ali Shahidi, Lh Eunson, Michael G. Hanna, Np Quinn, Anthony H.v. Schapira, Nicholas W. Wood, Kailash P. BhatiaAbstract:OBJECTIVE To characterise the phenotype of a family with paroxysmal exercise induced dystonia (PED) and migraine and establish whether it is linked to the paroxysmal non-kinesigenic dyskinesia (PNKD) locus on chromosome 2q33–35, the familial hemiplegic migraine (FHM) locus on chromosome 19p, or the familial infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome) locus on chromosome 16. METHODS A family, comprising 30 members, was investigated. Fourteen family members in two generations including three spouses were examined. Haplotypes were reconstructed for all the available family members by typing several microsatellite markers spanning the PNKD, FHM, and ICCA loci. Additionally, the four exons containing the known FHM mutations were sequenced. RESULTS Of 14 members examined four were definitely affected and one member was affected by history. The transmission pattern in this family was autosomal dominant with reduced penetrance. Mean age of onset in affected members was 12 (range 9–15 years). Male to female ratio was 3:1. Attacks of PED in affected members were predominantly dystonic and lasted between 15 and 30 minutes. They were consistently precipitated by walking but could also occur after other exercise. Generalisation did not occur. Three of the affected members in the family also had migraine without aura. Linkage of the disease to the PNKD, FHM, or ICCA loci was excluded as no common haplotype was shared by all the affected members for each locus. In addition, direct DNA sequential analysis of the FHM gene (CACNL1A4) ruled out all known FHM point mutations. CONCLUSIONS This family presented with the classic phenotype of PED and is not linked to the PNKD, FHM, or ICCA loci. A new gene, possibly coding for an ion channel, is likely to be the underlying cause of the disease.
Jørgen E. Nielsen - One of the best experts on this subject based on the ideXlab platform.
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Genotype–phenotype correlation of paroxysmal nonkinesigenic dyskinesia
Neurology, 2007Co-Authors: Michiko K. Bruno, Hsien-yang Lee, Georg Auburger, Andrzej Friedman, Jørgen E. Nielsen, Anthony E. Lang, Enrico Bertini, P. Van Bogaert, Y. Averyanov, Mark HallettAbstract:Background: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. Methods: We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had MR-1 mutations and 6 did not. Results: Patients with PNKD with MR-1 mutations had their attack onset in youth (infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. Conclusions: Paroxysmal nonkinesigenic dyskinesia (PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation (which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 ( MR-1 ) gene mutations. Other “PNKD-like” families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia.
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The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway
Human molecular genetics, 2004Co-Authors: Hsien-yang Lee, Georg Auburger, Anthony E. Lang, Yong Huang, Andrew H. Ahn, Massimo Pandolfo, Hubert Kwieciński, David A. Grimes, Jørgen E. NielsenAbstract:Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue. We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD in 50 individuals from eight families. The mutations cause changes (Ala to Val) in the N-terminal region of two MR-1 isoforms. The MR-1L isoform is specifically expressed in brain and is localized to the cell membrane while the MR-1S isoform is ubiquitously expressed and shows diffuse cytoplasmic and nuclear localization. Bioinformatic analysis reveals that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress. Our results suggest a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD. Stress response pathways will be important areas for elucidation of episodic disease genetics where stress is a common precipitant of many common disorders like epilepsy, migraine and cardiac arrhythmias.