Paroxysmal dyskinesias: Clinical features and classification

We studied 46 patients with paroxysmal dyskinesia and classified them according to phenomenology, duration of attacks, and etiology. There were 13 patients, 7 females, who had paroxysmal kinesigenic dyskinesia (PKD), 10 with attacks lasting 5 minutes or less (short lasting) and 3 with attacks lasting longer than 5 minutes (long lasting). Twentysix patients, 18 females, had paroxysmal nonkinesigenic dyskinesia (PNKD), 9 with short-lasting and 17 with longlasting PNKD. Five patients, 3 females, had paroxysmal exertion-induced dyskinesia (PED), 3 with short-lasting PED and the other 2 with long-lasting PED. In addition, there was 1 patient with paroxysmal hypnogenic dyskinesia (PhD) and 1 with paroxysmal superior oblique myokymia. Only 2 patients, 1 with PKD and 1 with PhD, had family history of paroxysmal dyskinesias. No specific cause could be identified in 21 patients; in the other 23 patients the etiologies included the following: psychogenic (9 patients), cerebrovascular diseases (4), multiple sclerosis (2), encephalitis (2), cerebral trauma (2), peripheral trauma (2), migraine (1), and kernicterus (1). Nine of 10 (90%) patients with PKD improved with medications, mostly anticonvulsants, compared with only 7 of 19 (37%) with PNKD. This new classification, based chiefly on precipitating events, allowed appropriate categorization of the attacks in all our patients with paroxysmal dyskinesias.     

Paroxysmal kinesigenic dyskinesias

The paroxysmal dyskinesias (PxDs) are involuntary, intermittent movement disorders manifested by dystonia, chorea, athetosis, ballismus or any combination of these hyperkinetic disorders. Paroxysmal kinesigenic dyskinesia (PKD), one of the four main types of PxD, involves sudden attacks of dyskinesias induced by voluntary movements. PKD most commonly occurs sporadically or as an autosomal-dominant familial trait with variable penetrance. Many causes of secondary PKD are being recognized. The exact pathophysiology of the PxDs awaits further elucidation, although basal ganglia dysfunction appears to play a major role. Although the precise gene remains unknown, genetic linkage studies have isolated loci on chromosome 16, which colocalizes with the locus for familial infantile convulsions and paroxysmal choreoathetosis in some studies. The episodic nature of PKD and its relationship with other episodic diseases, such as epilepsy, migraine, and episodic ataxia, suggests channelopathy as a possible underlying etiology. PKD may remit spontaneously, but it also responds well to anticonvulsants as well as some other agents.     

发作性运动障碍(附33例临床分析和文献复习)

目的　了解发作性运动障碍的临床特点以及治疗方法。方法　分析 33例发作性运动障碍病例的临床表现和实验室检查。结果　 (1)发作性运动诱发性运动障碍 (PKD) 32例 (96 .97% ) ;(2 )发作性非运动诱发性运动障碍 (PNKD) 3例 (9.0 9% ) ;(3)发作性过度运动导致的运动障碍 (PED) 6例 (18.18% ) ;(4)发作性睡眠诱发性运动障碍 (PHD) 3例 (9.0 9% )。除 2 4例为单纯 PKD外 ,其余病例均与其它类型互相重叠。 EEG大多正常 (32 /33) ,32例 CT/MRI正常。部分可合并癫痫 (5 /33) ,抗癫痫治疗多数 (2 9/33)有效。结论　发作性运动障碍是一种少见的运动障碍疾病 ,和癫痫有一定关系 ,各型可互相重叠 ,EEG大多正常 ,大部分抗癫痫药物治疗有效。     

Moyamoya-induced paroxysmal dyskinesia.

Moyamoya disease (MMD) is an uncommon intracranial vasculopathy that typically presents with ischemic or hemorrhagic stroke. Persistent choreoathetosis has been identified as a rare early manifestation of MMD. We present 2 patients with paroxysmal dyskinesia as the initial symptom of MMD, one resembling paroxysmal kinesigenic dyskinesia (PKD) and the other paroxysmal non-kinesigenic dyskinesia (PNKD). We also review the cases of moyamoya-induced chorea reported previously, none of which resembled PKD or PNKD. We hypothesize that both hormonal and ischemic factors may be implicated in the pathogenesis of these abnormal involuntary movements. These cases suggest that MMD should be included in the differential diagnosis of PKD and PNKD.     

Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia

Paroxysmal dyskinesia (PxD) is a group of movement disorders characterized by recurrent episodes of involuntary movements. Familial paroxysmal kinesigenic dyskinesia (PKD) is caused by PRRT2 mutations, but a distinct etiology has been suggested for sporadic PKD. Here we describe a cohort of patients collected from our movement disorders outpatient clinic in the period 1996–2011. Fifteen patients with sporadic PxD and 23 subjects from three pedigrees with familial PKD were screened for mutations in candidate genes. PRRT2 mutations co-segregated with PKD in two families and occurred in two sporadic cases of PKD. No mutations were detected in patients with non-kinesigenic or exertion-induced dyskinesia, and none in other candidate genes including PNKD1 (MR-1) and SLC2A1 (GLUT1). Thus, PRRT2 mutations also cause sporadic PKD as might be expected given the variable expressivity and reduced penetrance observed in familial PKD. Further genetic heterogeneity is suggested by the absence of candidate gene mutations in both sporadic and familial PKD suggesting a contribution of other genes or non-coding regions.     

发作性运动障碍10例临床分析

目的:探讨发作性运动障碍的临床特点、诊断、治疗及误诊原因。方法:回顾性分析发作性运动障碍患者的临床表现、影像学与EEG/video-EEG(视频脑电图)检查及治疗。结果:本组10例,男8例,女2例,起病年龄6~14岁,病程半年~9年;9例由突然的运动诱发,1例为自发发生;临床表现为姿势性肌张力障碍6例,舞蹈样动作2例,投掷样运动1例,手足徐动样动作1例,均为单侧受累;发作时间多为10余秒;6例患者每日有发作,最多1d可发作30余次;CT/MRI均正常,EEG/video-EEG大多正常(9/10);9例卡马西平治疗有效,1例氯硝西泮部分有效。结论:9例为发作性运动障碍中的阵发性运动诱发性运动异常,1例为阵发性非运动诱发性运动异常,前者抗癫药治疗能全部控制发作,后者仅部分有效。     

Psychogenic paroxysmal movement disorders – Clinical features and diagnostic clues

BackgroundThe diagnosis of psychogenic paroxysmal movement disorders (PPMD) can be challenging, in particular their distinction from the primary paroxysmal dyskinesias (PxD) remains difficult.MethodsHere we present a large series of 26 PPMD cases, describe their characteristics, contrast them with primary PxD and focus on their distinguishing diagnostic features.ResultsMean age at onset was 38.6 years, i.e. much later than primary PxD. Women were predominantly affected (73%). Most subjects (88.4%) had long attacks, and unlike primary PxD there was a very high within-subject variability for attack phenomenology, duration and frequency. Dystonia was the most common single movement disorder presentation, but 69.2% of the patients had mixed or complex PxD. In 50% of PPMD cases attack triggers could be identified but these were unusual for primary PxD. 42.3% of patients employed unusual strategies to alleviate or stop the attacks. Response to typical medication used for primary PxD was poor. Precipitation of the disorder due to physical or emotional life events and stressors were documented in 57.6% and 65.3% of the cases respectively. Additional interictal psychogenic signs were documented in 34.6% and further medically unexplained somatic symptoms were present in 50% of the cases. 19.2% of patients had a comorbid organic movement disorder and 26.9% had pre-existing psychiatric comorbidities.ConclusionAlthough the phenotypic presentation of PPMD can be highly diverse, certain clinical characteristics help in distinguishing this condition from the primary forms of PxD. Recognition is important as multidisciplinary treatment approaches led to significant improvement in most cases.     

A homozygous <Emphasis Type="Italic">PIGN</Emphasis> missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia

Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers of the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records and videos of episodes from 25 affected dogs were reviewed. The episodes of hyperkinesia and dystonia lasted from several minutes to several hours and could occur as often as >10/day. They were not associated with strenuous exercise or fasting but were sometimes triggered by excitement. The canine PxD phenotype most closely resembled paroxysmal non-kinesigenic dyskinesia (PNKD) of humans. Whole genome sequences were generated with DNA from 2 affected dogs and analyzed in comparison to 100 control canid whole genome sequences. The two whole genome sequences from dogs with PxD had a rare homozygous PIGN:c.398C > T transition, which predicted the substitution of an isoleucine for a highly conserved threonine in the encoded enzyme. All 25 PxD-affected dogs were PIGN:c.398T allele homozygotes, whereas there were no c.398T homozygotes among 1185 genotyped dogs without known histories of PxD. PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors a variety of proteins including CD59 to the cell surface. Flow cytometry of PIGN-knockout HEK239 cells expressing recombinant human PIGN with the c.398T variant showed reduced CD59 expression. Mutations in human PIGN have been associated with multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1). Movement disorders can be a part of MCAHS1, but this is the first PxD associated with altered GPI anchor function.     

发作性运动诱发性运动障碍八个家系临床特点分析

目的分析及探讨家族性发作性运动诱发性运动障碍（PKD）的临床特征、诊断和治疗特点。方法观察8个PKD家系的临床表现，进行家系调查分析，对患者进行脑电图或视频脑电图、头颅磁共振成像（MRI）或CT检查。结果8个家系共有患者28例，男性20例，女性8例，发病年龄8～18岁，平均10．8岁。全部患者均表现为突然运动诱发的一侧或双侧异常运动，发作时间短于1min，发作时意识清楚；发作间期均无神经系统阳性体征。同一家系中患者症状轻重不一，随年龄增大发作逐渐减少，以至消失。脑电图、视频脑电图及头颅影像学均未发现明显异常。患者使用抗癫痫药物治疗有效。结论PKD是发作性异常运动中常见的一种，突然运动诱发是其主要特点，家族性患者不少见，主要遗传方式是常染色体显性遗传，有外显不全现象，不排除有其他的遗传方式。临床发作形式与癫痫不同，但抗癫痫药物治疗有效。     

Paroxysmal dyskinesias revisited: A review of 500 genetically proven cases and a new classification

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. © 2014 International Parkinson and Movement Disorder Society     

Phenotypic overlap among paroxysmal dyskinesia subtypes: Lesson from a family with PRRT2 gene mutation

Paroxysmal dyskinesia (PD) is a group of rare neurological conditions which was divided into paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exercise-induced dyskinesia (PED) according to their clinical features. PRRT2 gene was initially identified as the major gene responsible for PKD followed by presence of various PRRT2 mutations discovered in families with benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathetosis (ICCA). We describe a family with characteristic PD showing overlaps in clinical pictures among the three PD subgroups, and a nonsense PRRT2 mutation c.649C > T (p.Arg217X) was also detected. This broadens the phenotypic spectrum in PRRT2-related disorders. In addition, an unusual exercise trigger observed in the proband, likely representing an underestimated occurrence, together with the current clinical PD classification is also elucidated.     

Paroxysmal kinesigenic dyskinesia and generalized seizures: clinical and genetic analysis in a Spanish pedigree

Familial paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder featuring brief, dystonic or choreoathetotic attacks, typically triggered by sudden movements. Symptoms usually start in mid-childhood, although in several pedigrees infantile convulsions have been reported as the presenting sign. Previous linkage studies have identified two PKD loci on 16 p12.1-q21. We report here the clinical features of a Spanish kindred with autosomal dominant PKD, in which haplotype data are compatible with linkage to the pericentromeric region of chromosome 16 and exclude linkage to the locus for Paroxysmal Non Kinesigenic Dyskinesia (PNKD) on chromosome 2 q35. In this family, the conservative candidate region for the disease lies between markers D16S3145 and GATA140E03 on 16 p12.1-q21 and partially overlaps with both the Paroxysmal Kinesigenic Dyskinesia - Infantile Convulsions (PKD-IC) critical interval and the Episodic Kinesigenic Dyskinesia 2 (EKD2) locus. Unusual findings in our pedigree were early infantile onset of the dyskinesias in one patient and generalized seizures as adults in two, adding to previous observations of phenotypic overlap between epileptic and non-epileptic paroxysmal disorders. Further clinical and genetic studies are needed to elucidate whether PKD and PKD-IC are allelic disorders with age-dependent phenotypic expression.     

Clinical characteristics of paroxysmal nonkinesigenic dyskinesia in serbian family with Myofibrillogenesis regulator 1 gene mutation

The aim of this study was to describe the clinical features of a large Serbian family with paroxysmal nonkinesigenic dyskinesia (PNKD) and one of the two previously described mutations in the Myofibrillogenesis regulator 1 gene (MR‐1), which causes an alanine‐to‐valine substitution at position 9. In 5 examined out of 12 affected family members, attacks of dyskinesias appeared in the first 6 months of life. Both frequency and severity of attacks showed an age‐dependent incremental–decremental pattern with a peak between 13 to 15 years of age. They were frequently precipitated by stress, caffeine, fever, hunger, tiredness, as well as abrupt changes in temperature. Three of our patients differentiated two types of attacks: mild (120–180 minutes), with a predominance of functionally insignificant choreoathetoid movements, and severe (～ 15–30 minutes), characterized by disabling dystonic and choreic movements of the extremities, trunk, and face. Sleep was the most reliable factor to discontinue an attack. This Serbian family further demonstrates that recurrent MR‐1 mutations are associated with PNKD worldwide, which will affect genetic testing. © 2006 Movement Disorder Society     

Paroxysmal dyskinesias

Paroxysmal movement disorders are a relatively rare and heterogenous group of conditions manifesting as episodic dyskinesia lasting a brief duration. Three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), nonkinisegenic (PNKD), and exercise induced (PED). There have been major advances in the understanding of the pathophysiological mechanisms and the genetics of these disorders, leading to better clinical definitions based on genotype–phenotype correlations in the familial idiopathic forms. PKD is genetically heterogenous, but there is linkage to chromosome 16 in a number of families. PNKD is due to mutations of the MR‐1 gene. PED is genetically heterogenous, but a number of familial and sporadic cases may be due to GLUT‐1 gene mutations. The GLUT1 gene–related form of PED may respond to a ketogenic diet. Potassium and calcium channel mutations underlie the 2 main forms of episodic ataxia (EA1 and EA2), whereas benign torticollis of infancy may also be a calcium channel disorder. © 2011 Movement Disorder Society     

A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study

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.     

Paroxysmal dyskinesia with interictal myoclonus and dystonia: a report of two cases

Idiopathic paroxysmal dyskinesias (PxD) are characterized by attacks of hyperkinetic movement, with no inter-ictal symptoms. We report two cases, one with paroxysmal kinesigenic dyskinesia and another with paroxysmal exercise-induced dystonia, both of whom had myoclonus and dystonia between attacks. This previously unreported association highlights the heterogeneity of paroxysmal movement disorders.     

Chronic thalamic stimulation for treatment of dystonic paroxysmal nonkinesigenic dyskinesia

The authors report the effect of chronic stimulation of the ventrointermediate (Vim) thalamus for treatment of dystonic paroxysmal nonkinesigenic dyskinesias (PNKD). A 37-year-old patient had a 4-year history of severe and painful PNKD of the right arm. Chronic stimulation through a stereotactically implanted monopolar electrode in the left Vim resulted in a decrease of the frequency, duration, and intensity of the dystonic paroxysmal movement disorder. The benefit of stimulation has been maintained over 4 years of follow-up.     

Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia

Many types of spinocerebellar ataxias (SCAs) manifest as progressive disorders with cerebellar involvement. SCA type 27 (SCA27) is a rare type of SCA caused by mutations in the fibroblast growth factor 14 gene (FGF14). FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD). This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1). We hypothesized that the remaining 40% of patients with PNKD may have FGF14 mutations; therefore, the nucleotide sequences of MR-1 and FGF14 were analyzed in another six patients with PNKD, but no nucleotide alterations were observed in these genes for these patients. Further studies should be conducted on the phenotypic heterogeneity of FGF14 mutations and/or haploinsufficiency in SCA27 and PNKD.     

Complete suppression of paroxysmal nonkinesigenic dyskinesia by globus pallidus internus pallidal stimulation.

Stereotactic functional surgery is being explored as potential therapies for medically intractable paroxysmal dyskinesias (PxD). We report on a 59-year-old man in whom stimulation of globus pallidus internus produced immediate and sustained relief of paroxysmal non-kinesigenic dyskinesia secondary to a rotator cuff tears on the left shoulder. Our finding strongly suggests that altered function of neuronal circuits of the basal ganglia underlies the manifestation of PxD.     

Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation

Background and Purpose

Given the diverse phenotypes including combined non-dyskinetic symptoms in patients harboring mutations of the gene encoding proline-rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations.

Methods

Familial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation.

Results

Among the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups.

Conclusions

This is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients.