Episodic movement disorders as channelopathies

University of Rochester, Rochester, New York, United States
Movement Disorders (Impact Factor: 5.68). 06/2000; 15(3):429-33. DOI: 10.1002/1531-8257(200005)15:3<429::AID-MDS1001>3.0.CO;2-R
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    • "PDK is a paroxysmal neurological disorder disease with a favorable response to the ion-channel blocker carbamazepine at a low dose. PKD is believed to be an ion channelopathy [13]. As a transmembrane protein, PRRT2 might be involved in ion channels or regulation of ion channels related to PKD [14]. "
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    ABSTRACT: Background Mutations in proline-rich transmembrane protein 2 (PRRT2) are a cause of paroxysmal kinesigenic dyskinesia (PKD). In this study, we investigated the PRRT2 gene mutation in a Chinese Han family with PKD and study the pathogenesis of the mutation with PRRT2 gene. Methods Peripheral venous blood was taken from the family members. Sanger sequencing was used for novel mutation sequencing. For the pathogenesis with the novel mutation was analyzed by bioinformatics, real-time PCR, subcellular localization and Western blot. Results The Sanger sequencing showed a novel mutation, c.186-187delGC, a deletion mutation, in exon 2 of the PRRT2 gene, the frameshift mutation generated a truncated protein that was stably expressed in transfected Human embryonic kidney (HEK) 293 cells. A subcellular localization assay in COS-7 cells with GFP-tagged protein showed nuclear localization for the mutant protein while the wild-type protein was localized in membranes. Co-transfection of HEK293 cells with wild-type and mutant expression plasmids cells did not influence mRNA or protein expression from the wild-type plasmid. Conclusions Our findings demonstrated that the c.186-187delGC mutation resulted in a truncated protein from the PRRT2 gene to involve in PKD pathogenesis with haploinsufficiency. The results extend the mutation spectrum of the PRRT2 gene and provide a new example for studying the pathogenesis of the mutated PRRT2 gene.
    Full-text · Article · Jul 2014 · BMC Neurology
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    • "The attacks in EA type1 (EA1), as in PKD, may be triggered by sudden movements, physical and emotional stress, and also by startle. Patients with EA1 have varying degrees of neuromyotonia and brief attacks (seconds to minutes) of ataxia up to 30 times a day (Bhatia et al., 2000), with an onset in early childhood. Aura-like symptoms may precede attacks (Jen et al., 2007). "
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    ABSTRACT: Startle syndromes are paroxysmal and show stimulus sensitivity, placing them in the differential diagnosis of epileptic seizures. Startle syndromes form a heterogeneous group of disorders with three categories: hyperekplexia (HPX), stimulus-induced disorders, and neuropsychiatric syndromes. HPX is characterized by an exaggerated motor startle reflex combined with stiffness and is caused by mutations in different parts of the inhibitory glycine receptor, leading to brainstem pathology. The preserved consciousness distinguishes it from epileptic seizures. Clonazepam is the first-choice therapy. The stimulus-induced disorders cover a broad range of epileptic and nonepileptic disorders, and distinguishing the two can be difficult. Additional information from electroencephalography (EEG) and video registration can help. Many stimulus-induced disorders now have an identified gene defect. Antiepileptic drugs, including benzodiazepines, are frequently mentioned as the best treatment option. Neuropsychiatric syndromes are on the borderland of neurology and psychiatry, and their etiology is poorly understood. These syndromes include startle-induced tics, culture-specific disorders such as Latah, and functional startle syndromes. The electromyography (EMG) startle reflex in these syndromes is characterized by variable recruitment patterns and the presence of a second "orienting" response. Treatment options are limited, but urgently required. In the clinical setting, the patient's history and a (home) video recording together with genetic and electrophysiologic testing help to classify these challenging disorders.
    Full-text · Article · Dec 2012 · Epilepsia
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    • "Although the clinical features of these disorders are diverse, the underlying causes of the conditions and the triggers that bring on attacks are strikingly similar. Many of these disorders are associated with ion channel gene mutations, and are therefore known as channelopathies (Bhatia et al., 2000; Cannon, 2006; Ptacek, 1999). Further, regardless of etiology, attacks are induced in many episodic disorders by psychological or physical stress, and the consumption of caffeine or alcohol (Bhatia, 2001; Frucht et al., 2000; Ptacek, 1999). "
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    ABSTRACT: Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the Ca(V)2.1 calcium channel mouse mutant tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the tottering mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in Ca(V)2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked.
    Full-text · Article · Sep 2012 · Neurobiology of Disease
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