Paroxysmal Dyskinesia Research Articles

Phenotypic characterisation of canine epileptoid cramping syndrome in the Border terrier

OBJECTIVESTo characterise the phenotype of Border terriers suspected to be affected by canine epileptoid cramping syndrome and to identify possible contributing factors.METHODSOwners of Border terriers with suspected canine epileptoid cramping syndrome were invited to complete an online questionnaire. The results of these responses were collated and analysed.RESULTSTwenty-nine Border terriers were included. Most affected dogs had their first episode before 3 years of age (range: 0·2 to 7·0 years). The majority of episodes lasted between 2 and 30 minutes (range: 0·5 to 150 minutes). The most frequent observations during the episodes were difficulty in walking (27 of 29), mild tremor (21 of 29) and dystonia (22 of 29). Episodes most frequently affected all four limbs (25 of 29) and the head and neck (21 of 29). Borborygmi were reported during episodes in 11 of 29 dogs. Episodes of vomiting and diarrhoea occurred in 14 of 29, with 50% of these being immediately before or after episodes of canine epileptoid cramping syndrome (7 of 14). Most owners (26 of 29) had changed their dog's diet, with approximately 50% (14 of 26) reporting a subsequent reduction in the frequency of episodes.CLINICAL SIGNIFICANCEThis study demonstrates similarities in the phenotype of canine epileptoid cramping syndrome to paroxysmal dystonic choreoathetosis, a paroxysmal dyskinesia reported in humans. This disorder appears to be associated with gastrointestinal signs in some dogs and appears at least partially responsive to dietary adjustments.

PRRT2 mutations: exploring the phenotypical boundaries

BackgroundMutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However...

Late onset of atypical paroxysmal non-kinesigenic dyskinesia with remote history of Graves’ disease

Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare hyperkinetic movement disorder and falls under the category of paroxysmal movement disorders. In this condition, episodes are spontaneous, involuntary, and involve dystonic posturing with choreic and ballistic movements. Attacks last for minutes to hours and rarely occur more than once per day. Attacks are not typically triggered by sudden movement, but may be brought on by alcohol, caffeine, stress, fatigue, or chocolate. We report a patient with multiple atypical features of PNKD. She had a 7-year history of this condition with onset at the age of 59, and a remote history of Graves’ disease requiring total thyroidectomy. The frequency of attacks in our case ranged from five to six times a day to a minimum of twice per week, and the duration of episode was short, lasting not more than 2 min. Typically, PNKDs occur at a much younger age and have longer attack durations with low frequency. Administering clonazepam worked to reduce her symptoms, although majority of previous research suggests that pharmacological interventions have poor outcomes.

Recent advances of paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is the most frequently described subtype of paroxysmal dyskinesias.The precipitating factor is usually sudden movement or startle.Clinically, PKD cases suffer involuntary movements including unilateral or bilateral chorea, athetosis, dystonia or ballismus, with preserved consciousness.Family history is commonly noted in idiopathic PKD, but sporadic cases are also reported.Familial PKD is inherited in an autosomal dominant fashion with incomplete penetrance.To date, 2 loci 16p11-q12 and 16q13-q22 have been mapped to PKD, although a 3rd locus is also suspected.PRRT2, which was located in 16p12.1, was recently identified as causative gene of PKD.However, culprit genes in the other 2 loci remain to be investigated.The potential mechanism of PKD remains largely unclear and the role of mutant PRRT2 in the pathogenesis of PKD is still unknown.In this review, the recent advances of PKD were summarized and hypothesis regarding the mechanisms of PKD was put up, which may make significant contributions to the diagnosis and treatment of PKD. Key words: Paroxysmal kinesigenic dyskinesia; Causative gene; PRRT2

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.

Episodic Movement Disorders: From Phenotype to Genotype and Back

Episodic dyskinetic movement disorders are a heterogeneous group of rare conditions. Paroxysmal dyskinesias constitute the core of this group and usually exhibit normal interepisodic neurologic findings. Contrariwise, episodic dyskinesias occur as a particular feature of complex chronic neurologic disorders. Conjunction of accurate phenotyping with up-to-date methods of molecular genetics recently provided remarkable new insights concerning the genetic causes of episodic dyskinesia. The identification of heterozygous mutations in the PRRT2 gene in paroxysmal kinesigenic dyskinesia as well as in benign familial infantile seizures linked episodic movement disorders with epilepsy. Alternating hemiplegia of childhood, the prototype of a chronic multisystem disease with episodic dyskinesia as a clinical hallmark, was recently found to be caused by heterozygous de novo mutations in the ATP1A3 gene. The clinical spectra of PRRT2 as well as of ATP1A3 mutations are still expanding. This review summarizes new genetic findings and clinical aspects in episodic dyskinesias.

Application of VEEG+SEMG in diagnosing different motor seizure types

To explore the value of video-electroencephalography plus surface electromyography (VEEG+SEMG) in providing theoretic rationales for clinical diagnosis of different motor seizure types and differentiating the application value of paroxysmal diseases. A total of 116 suspected and repetitive motion epileptics underwent VEEG+SEMG from 2009 to 2012. According to their clinical features, different muscles were selected to record electromyography (EMG) under different activations and stimulations (bodily movement and posture activation, touching, sound stimulus, tapping tendons and arms straight test, etc) and monitor their seizure states. Among 68 patients, 567 attacks were recorded, including 443 epileptic seizures in 41 patients (229 epileptic mycological seizures in 22 patients, 95 tonic seizures in 8, 118 epileptic spasms in 10 and 1 atonic seizure in 1). The average durations of different epileptic motor seizures were (0.16 ± 0.04), (2.9 ± 2.4), (1.4 ± 0.8) and 2 s respectively. Their features of ictal EEG and SEMG varied.Non-epileptic seizures were recorded, including 43 non-epileptic myoclonus (NEMS) in 2 patients 81 PKD in 25. The primary differential diagnoses of epileptic motor seizures were NEMS and paroxysmal kinesigenic dyskinesia (PKD). VEEG+SEMG is a reliable tool for diagnosing different types of epileptic seizures and differentiating among paroxysmal diseases.

Research progress and diagnostic strategy of genetic pathogenesis of dystonia

Dystonia is a syndrome of abnormal involuntary movements that are repetitive, twisting or patterned, and can result in abnormal postures. Genetic factors play an important role in the pathogenesis of dystonia. To date, at least 20 dystonic syndromes have been distinguished on a genetic basis ( DYT1-21 , except DYT14 ), 10 of which have had clear causing genes. Recently, major discoveries have appeared in the genetic field: mutations in the transcription factor THAP1 and DNA replication factor CIP1-interacting zinc finger protein 1 ( CIZ1 ) have been linked to adult-onset primary dystonia; proline-rich transmembrane protein 2 ( PRRT2 ) has been tied to paroxysmal kinesigenic dyskinesia; DYT14 has been redefined as DYT5 due to a deletion mutation in guanosine triphosphate cyclohydrolase 1 ( GCH1 ). In addition, the existing diagnostic algorithms for dystonic syndromes rely on the clinicians' experience, without a streamlined diagnostic pathway. Non-specialist clinicians and neurologists may, therefore, find diagnosis of dystonic syndromes difficult. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances. Also an eight-question approach is proposed in this review to inform specialists and general neurologists on the appropriate diagnostic test for each patient with a possible dystonic syndrome.

Advances in molecular genetic studies of primary dystonia

Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting, repetitive movements and abnormal postures. In recent years, there was a great advance in molecular genetic studies of primary dystonia. This paper will review the clinical characteristics and molecular genetic studies of primary dystonia, including early-onset generalized torsion dystonia ( DYT1 ), whispering dysphonia ( DYT4 ), dopa⁃responsive dystonia ( DYT5 ), mixed-type dystonia ( DYT6 ), paroxysmal kinesigenic dyskinesia ( DYT10 ), myoclonus⁃dystonia syndrome ( DYT11 ), rapid-onset dystonia parkinsonism ( DYT12 ), adult-onset cervical dystonia ( DYT23 ), craniocervical dystonia ( DYT24 ) and primary torsion dystonia ( DYT25 ).

Progress in the research of genetics and clinical manifestation of paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is a disorder characterized by recurrent and brief attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity. Familial PKD are mostly autosomal dominant inherited and proline-rich transmembrare protein 2 ( PRRT2 ) gene has been identified as the causative gene for PKD. So far 56 mutations have been documented and most of them are nonsense ones. No obvious genotype-phenotype correlation has been observed and the function of PRRT2 is still unclear, but the interaction between PRRT2 and synaptosomal-associated protein 25 (SNAP25) will shed the light on the research of PKD mechanism.

Caffeine improved paroxysmal dyskinesia caused by the PRRT2 mutation

Caffeine improved paroxysmal dyskinesia caused by the <i>PRRT2</i> mutation

Paroxysmal dyskinesia due to PRRT2 mutation in 15-year-old female patient with benign familial infantile convulsions

Paroxysmal dyskinesia due to PRRT2 mutation in 15-year-old female patient with benign familial infantile convulsions

Good outcome in patients with early dietary treatment of GLUT‐1 deficiency syndrome: results from a retrospective Norwegian study

The aim of this study was to characterize patients diagnosed with glucose transporter protein-1 deficiency syndrome (GLUT-1 DS) clinically and genetically, and to evaluate the effect of treatment with the classic ketogenic or modified Atkins diet. We retrospectively studied medical records of 10 patients diagnosed with GLUT-1 DS. Four females and six males with a median age of 15 years were included. The study illustrates the genetic and clinical heterogeneity of GLUT-1 DS. Analysis of the SLC2A1 gene disclosed a variety of mutation types. The time between onset of symptoms and diagnosis was more than 11 years on average. The outcome in those with early diagnosis and intervention was surprisingly good. All but one patient with the classic phenotype became seizure free after treatment with the classic ketogenic or modified Atkins diet. Acetazolamide was effective in one patient with paroxysmal exercise-induced dyskinesia. A point prevalence of GLUT-1 DS in Norway was estimated as 2.6 per 1,000,000 inhabitants. Although the long-term prognosis in patients with GLUT-1 DS partly depends on the underlying genetics, our study supports the assumption that early initiation of treatment with a ketogenic diet may positively affect the outcome.

Phenotypic Spectrum of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)

Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.

PRRT2 mutations and paroxysmal disorders

In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.

PRRT2-related disorders: further PKD and ICCA cases and review of the literature

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307, c.388delG/p.Ala130Profs 46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80-100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.

Secondary paroxysmal dyskinesia associated with 2009 H1N1 infection

Neurological complications associated with 2009 H1N1 infection in children have been reported and recognized worldwide. The most commonly reported neurological complications are seizures and encephalopathy. Secondary movement disorders are also associated with the infection, but such cases are rarely reported. Here, we describe the case of a 14-year-old boy with paroxysmal kinesigenic dyskinesia secondary to 2009 H1N1 infection, who presented with dystonia and choreic movement triggered by sudden voluntary movement.

Paroxysmal Nonkinesigenic Dyskinesia with Tremor

Introduction. Paroxysmal nonkinesigenic dyskinesia (PNKD) consists of episodes of chorea, athetosis, or dystonia which are not triggered by movement, with complete remission between episodes. A case of genetically confirmed PNKD with simultaneous tremor has not been previously reported. Case Report. The patient is an 86-year-old right-handed female who presented with episodic stiffness, with onset at age 9. Attacks have a prodrome of difficulty in speaking, followed by abnormal sensation in extremities. Episodes consist of dystonia of trunk associated with upper and lower extremity chorea. There is complete resolution between attacks except for persistent mild head tremor and action tremor of both extremities. Attack frequency and duration as well as tremor amplitude escalated two and a half years ago, in correlation with development of breast carcinoma. Episodes improved after successful cancer treatment, but higher amplitude tremor persisted. There is an autosomal dominant family history of similar episodes but not tremor. Genetic diagnosis was confirmed via A7V mutation of the myofibrillogenesis regulator (MR-1) gene. Conclusion. Exacerbation due to another medical or psychiatric condition should be considered if there is unexpected deterioration in episode frequency or length. PNKD due to MR-1 mutation may exist even in the presence of action tremor.

Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes

Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, 10 familial and 21 sporadic cases with PDs and PDs-related phenotypes were collected. Genomic DNA was screened for PRRT2 mutations by direct sequencing. Seven PRRT2 mutations were identified in nine (90.0%) familial cases and in six (28.6%) sporadic cases. Five mutations are novel: two missense mutations (c.647C>G/p.Pro216Arg and c.872C>T/p.Ala291Val) and three truncating mutations (c.117delA/p.Val41TyrfsX49, c.510dupT/p.Leu171SerfsX3 and c.579dupA/p.Glu194ArgfsX6). Autosomal dominant inheritance with incomplete penetrance was observed in most of the familial cases. In the sporadic cases, inheritance was heterogeneous including recessive inheritance with compound heterozygous mutations, inherited mutations with incomplete parental penetrance and de novo mutation. Variant phenotypes associated with PRRT2 mutations, found in 36.0% of the affected cases, included febrile convulsions, epilepsy, infantile non-convulsive seizures (INCS) and nocturnal convulsions (NC). All patients with INCS or NC, not reported previously, displayed abnormalities on electroencephalogram (EEG). No EEG abnormalities were recorded in patients with classical infantile convulsions and paroxysmal choreoathetosis (ICCA)/paroxysmal kinesigenic dyskinesia (PKD). Our study further confirms that PRRT2 mutations are the most common cause of familial PDs, displaying both dominant and recessive inheritance. Epilepsy may occasionally occur in ICCA/PKD patients with PRRT2 mutations. Variant phenotypes INCS or NC differ from classical ICCA/PKD clinically and electroencephalographically. They have some similarities with, but not identical to epilepsy, possibly represent an overlap between ICCA/PKD and epilepsy.

Polysomnographic recording of a child with paroxysmal hypnogenic dyskinesia and NREM parasomnia

Paroxysmal dyskinesias are rare movement disorders characterized by involuntary episodicmovements including any combination of dystonia, ballism, chorea, or athetosis. Paroxysmal kinesigenic dyskinesias (PKD) and nonkinesigenic dyskinesias (PNKD) are the most common types. Though, paroxysmal hypnogenic dyskinesia (PHD) characterized by events occurring during non-rapid eye movement (NREM) sleep is rarely encountered [1].