Proline‐rich transmembrane protein 2 regulates the magnitude and frequency of dopamine release by repetitive neuronal stimuli in the striatum of L‐dopa‐treated mice
Daisuke HattaShiho MakiyaKaito KanamotoKaori WatanabeYuki FuchigamiShigeru KawakamiAkira KinoshitaKoh-ichiro YoshiuraNaohiro KurotakiKeiro ShirotaniNobuhisa Iwata
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Abstract Mutations in proline‐rich transmembrane protein 2 ( PRRT2 ) cause paroxysmal kinesigenic dyskinesia (PKD). Recently, we reported that a Prrt2 mutation exacerbated L‐dopa‐induced motor deficits in mice, suggesting that the basal ganglia might contribute to PKD pathology. Here, we demonstrated that the Prrt2 mutation enhanced depolarization stimuli‐induced extracellular dopamine levels in the mouse striatum, which were attenuated by repeated stimulation. L‐dopa administration maintained high dopamine levels in Prrt2 ‐KI mice even during repetitive stimuli but did not affect dopamine levels in wild‐type mice. Thus, the enhanced and prolonged responsiveness of dopamine release in nigrostriatal dopaminergic neurons to sequential excitation may be partially implicated in Prrt2‐related dyskinesia.Keywords:
Paroxysmal dyskinesia
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Background and PurposeParoxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder.Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity.We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children.Methods Fifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled.We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED).We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records.Results Forty patients were categorized as PKD, 14 as PNKD, and 1 as PED.Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53years (mean±SD).Dystonia was the most common symptom (38 patients, 69.1%).Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1.All of the patients with PRRT2 mutations presented with PKD alone.The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet.Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%).There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups.Conclusions This study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children.We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.
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Paroxysmal dyskinesia is a clinically and etiologically polymorphic group of diseases, the main clinical manifestation of which is transient attacks of extrapyramidal movements, with different conditions of occurrence. Paroxysmal kinesigenic dyskinesia belongs to the group of primary dyskinesias, which also includes paroxysmal non-kinesigenic dyskinesia and exercise-induced paroxysmal dyskinesia. The most common cause of paroxysmal kinesiogenic dyskinesia is mutations in the PRRT2 gene; in cases of non-kinesiogenic dyskinesia, a mutation in the MR1 gene is detected. The diagnosis of primary dyskinesias causes significant difficulty for clinicians due to the rarity of occurrence, as well as the large spectrum of conditions occurring with paroxysmal motor disorders in childhood. The article describes the clinical observation of 16-year-old twin brothers with transient attacks of dystonic, choreic and ballistic hyperkinesis that suddenly arose during movement. Patients were treated for tics and epilepsy for 12 years. Taking into account the clinical picture - transient attacks of hyperkinesis, their connection with movement, as well as data from video-electroencephalographic monitoring, a diagnosis of paroxysmal kinesiogenic dyskinesia was established, which in a further diagnostic search was confirmed by targeted sequencing of the pathological variant of the PRRT2 gene previously described in patients with kinesiogenic dyskinesia. The administration of carbamazepine, which is the drug of choice in the treatment of this category of patients, has achieved significant control over hyperkinesis in twins. Thus, molecular genetic diagnosis helps confirm the diagnosis of paroxysmal dyskinesias, but careful analysis of the clinical picture, considering the provoking factor, remains the basis of diagnosis.Пароксизмальные дискинезии — полиморфная группа заболеваний, основным клиническим проявлением которой являются транзиторные атаки экстрапирамидных гиперкинезов, с разными условиями возникновения. Первичные дискинезии являются генетически детерминированными и включают пароксизмальную кинезиогенную дискинезию, пароксизмальную некинезиогенную дискинезию, пароксизмальную дискинезию, индуцированную физическими нагрузками. Наиболее частой причиной пароксизмальной кинезиогенной дискинезии являются мутации в гене PRRT2, в случаях некинезиогенной дискинезии выявляют мутацию в гене MR1. Постановка диагноза первичных дискинезий вызывает значительные затруднения у клиницистов из-за редкой встречаемости, а также из-за большого спектра состояний, протекающих с пароксизмальными двигательными расстройствами в детском возрасте. В статье приводится описание клинического наблюдения братьев-близнецов 16 лет с транзиторными атаками дистонических, хореических и баллических гиперкинезов, внезапно возникавшими при движении. Пациенты в течение 12 лет проходили лечение по поводу тиков и эпилепсии. С учетом клинической картины — транзиторных атак гиперкинезов, их связи с движением, а также данных видео-электроэнцефалографического мониторинга был установлен диагноз пароксизмальной кинезиогенной дискинезии, который при дальнейшем диагностическом поиске был подтвержден методом таргетного секвенирования патологического варианта гена PRRT2, ранее описанного у пациентов с кинезиогенной дискинезией. Назначение карбамазепина, который является препаратом выбора в лечении данной категории пациентов, позволило достичь значительного контроля над гиперкинезами у близнецов. Таким образом, молекулярно-генетическая диагностика помогает подтвердить диагноз пароксизмальных дискинезий, однако тщательный анализ клинической картины с учетом провоцирующего фактора остается основой диагностики.
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Abstract Differentiating characteristics of paroxysmal dyskinesia and epileptic seizures Implementing appropriate diagnostic work-up in a cat or a dog with paroxysmal dyskinesia Understanding principles and current knowledge of treatment of paroxysmal dyskinesia
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We have grouped attacks showing choreic, athetotic, and dystonic movements together in this section. Sometimes it is difficult to determine whether the movement disturbance in a particular type of paroxysm is choreic or dystonic. This can be due to the brief duration of the bout, the presence of both elements, or inadequate descriptions in the literature. Thus, it has been believed that the movements in paroxysmal kinesigenic dyskinesia tend to be choreic, while those in paroxysmal dystonic dyskinesia and paroxysmal exercise-induced dyskinesia are dystonic. However, this may not necessarily be the case and a range of dyskinesias can occur in these disorders (Demirkirin and Jankovic 1995, Bhatia 1997, Houser et al. 1999). Similarly, there are a variety of choreic, myoclonic, and dystonic actions in the disorder we have chosen to call 'paroxysmal hypnic dystonia' but sustained posturing seems to be the most prominent.
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The striatum is the input component of the basal ganglia circuits. It provides a hub for the interaction among multiple afferents and local intrastriatal networks that regulate basal ganglia function. Via their distinct cortical connections, different components of the striatum are key elements for control of different aspects of behavior: the nucleus accumbens is primarily involved in reward-based action learning, the caudate nucleus in goal-based action selection, and the putamen in habit formation and action sequencing.
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Abstract We describe the first case of paroxysmal nonkinesogenic dyskinesia secondary to pallidal ischaemia, which is uniquely and specifically triggered by alcohol. © 2002 Movement Disorder Society
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