Paroxysmal Nonkinesigenic Dyskinesia Research Articles

Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dtsz mutant

Striatal dysfunctions seem to play a key role in the pathophysiology of dystonia in the dt sz mutant hamster, a model of paroxysmal non-kinesigenic dyskinesia, in which stress precipitates dystonic episodes. Previous examinations have shown changes in kynurenic acid levels and antidystonic effects of the kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy- N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfon-amide (Ro 61-8048) after systemic treatment in dt sz hamsters. In the present study, intrastriatal injections of Ro 61-8048 (60–80 μg/hemisphere) significantly reduced the severity of dystonia in dt sz hamsters, suggesting that kynurenine 3-hydroxylase inhibitors may be interesting candidates for managing dyskinesias which are related to striatal dysfunction.

Paroxysmal dyskinesias

Substantial progress has been made recently in understanding characteristic features of the paroxysmal dyskinesias and underlying genetic causes. This review summarizes the most important findings and discusses their implications. The classification of paroxysmal dyskinesias has been confusing until recently when descriptive schemes were advocated over historical terminology. The descriptive classification scheme has aided phenotypic characterization in genetic studies. Recent genetic studies have revealed causes for some of the more important forms of paroxysmal dyskinesias. In particular, the major form of paroxysmal nonkinesigenic dyskinesia has been shown not to be a channelopathy. Furthermore, substantial phenotypic homogeneity has been demonstrated with each type of paroxysmal dyskinesia. The recent phenotype characterization and genetic studies have provided important information that simplified the diagnosis and treatment of the paroxysmal dyskinesias. These advances enhance our understanding of mechanisms underlying paroxysmal nonepileptic as well as some epileptic disorders.

Levetiracetam-Responding Paroxysmal Nonkinesigenic Dyskinesia

We report on a patient with 7-year history of short-lasting paroxysmal nonkinesigenic dyskinesia. The episodes occurred 100 to 125 times per day, lasted from 5 seconds to 3 minutes, and were not suppressed with sleeping, underlining the heterogeneity of phenomenology in paroxysmal dyskinesias. Neuroimaging studies showed calcifications in the basal ganglia, thalamus, brain stem, and subcortical and cerebellar regions. He was diagnosed with idiopathic hypoparathyroidism. After failure of valproate, he responded well to levetiracetam (1000 mg/d). This report revealed that intracerebral calcifications secondary to hypoparathyroidism could present as paroxysmal nonkinesigenic dyskinesia, and levetiracetam could be effective in this particular entity.

Genotype–phenotype correlation of paroxysmal nonkinesigenic dyskinesia

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. 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. 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. 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.

Paroxysmal nonkinesigenic dystonia and celiac disease

Celiac disease has been associated with ataxia and other neurological signs but has not been associated with paroxysmal nonkinesigenic dyskinesias (PNKD) to date. We present a child with biopsy-proven celiac disease and a movement disorder resembling PNKD since the age of 6 months. She had complete resolution of her neurological symptoms with introduction of a gluten-free diet. Because a susceptibility locus for celiac disease has been reported on 2q33 and studies in PNKD show linkage to 2q, this report suggests further genetic investigations around this locus may be useful. We also review the literature regarding the genetic susceptibility to PNKD and celiac disease.

New family with paroxysmal exercise-induced dystonia and epilepsy

To date, there are few reports of paroxysmal exercise-induced dystonia associated with familial epilepsy. We describe a family with 4 affected members spanning 3 generations, suggestive of autosomal-dominant inheritance, who exhibited typical exercise-induced dystonia, different types of epilepsy (absence and primary generalized seizures), developmental delay, and migraine in variable combinations. Linkage of the disease to loci on chromosome 2 (paroxysmal nonkinesigenic dyskinesia) and chromosome 16 (paroxysmal kinesigenic choreoathetosis, infantile convulsions with choreoathetosis) was excluded, suggesting an as yet unidentified underlying genetic basis.

Fahr's disease presenting with paroxysmal non-kinesigenic dyskinesia: A case report

Fahr's disease is characterized by presence of abnormal calcifications in certain areas of the brain. We report on 23-year-old man admitted to us with the episodes of paroxysmal non-kinesigenic dyskinesia. He was detected to have symmetrical intracerebral calcifications in basal ganglia, thalamus and cerebellar hemispheres, and diagnosed as sporadic Fahr's disease. Paroxysmal dyskinesia was well responded to oxcarbazepine (600 mg/day) treatment.

Paroxysmal eating-induced dystonic choreoathetosis – a second case

Background: Most of the paroxysmal dyskinesias in childhood are abnormal involuntary movements precipitated either by voluntary movements or exercise or they occur spontaneously. After the first case of a paroxysmal movement disorder triggered by oral stimulation in a boy with a Neuhauser syndrome we describe a second case of eating-induced choreoathetosis.

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 ( approximately 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.

Paroxysmal Nonkinesigenic Dyskinesia

A Canadian family of European descent with paroxysmal nonkinesigenic dyskinesia (PNKD), and a gene locus that links to a distinct region on chromosome 2q31, is reported by researchers at University of British Columbia, Canada.

Genetic heterogeneity in paroxysmal nonkinesigenic dyskinesia

Paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by attacks of dystonia or chorea lasting minutes to hours. Recently, mutations in the myofibrillogenesis regulator 1 gene (MR-1) have been identified in 10 unrelated PNKD kindreds. The authors describe a Canadian PNKD family who does not have mutations in the MR-1 gene and links to a separate locus at 2q31. This indicates that there are at least two different genes responsible for PNKD.

Long-term improvement of paroxysmal dystonic choreathetosis with acetazolamide

Sirs: Paroxysmal dyskinesias are a heterogeneous group of movement disorders characterized by recurrent brief episodes of abnormal involuntary movements [1–3] Among them, paroxysmal dystonic choreoathetosis (PDC) is associated with dystonic or choreic attacks unrelated to movement. It may occur spontaneously at rest without any triggering factors but attacks are frequently precipitated by caffeine or alcohol consumption, stress and fatigue. In contrast to paroxysmal kinesigenic choreathetosis (PKC), PDC attacks are more dystonic, usually last longer, and are less frequent with long attack-free intervals [3, 4]. Although most cases are familial, sporadic and secondary forms of PDC have been reported [4, 5]. We report a patient with a sporadic severe PDC which has been dramatically improved by acetazolamide over a period of three years. This 17-year-old boy who had a normal birth and no familial history developed his first symptoms at the age of 12. He presented recurrent episodes of left arm mild dystonia, along with attacks of paroxysmal non-kinesigenic dyskinesia involving the whole body. Short attacks (20 to 120 s) occurred 3 times a week to several times per day. They manifested as dystonia frequently beginning in the lower limbs, either on the left or right side of the body, spreading to the trunk and upper limbs and finally leading to falls. No aura or changes in consciousness were noted and no precipitating factors were reported. Clinical examination was normal. Occasionally, a mild left hand dystonic posture was observed when walking. Blood chemistry was normal. Wilson’s disease was excluded. Antibasal ganglia antibodies were negative on two examinations. Brain MRI, interictal electroencephalograms and iodobenzamide SPECT were normal. A videoencephalogram was performed for three consecutive days during which the patient exhibited several attacks without any epileptic activity on the EEG during attacks. Psychiatric evaluation was unremarkable. Owing to the analogy with paroxysmal ataxia (EA2) [6], screening was performed for CACNA1A gene. Screening by direct DNA sequence analysis of the 47 exons of the CACNA1A gene did not reveal any mutation. Analysis of triplets (involved in SCA6) was also normal. We also sought a mutation in the MR-1 gene encoding for the Myofrillogenesis Receptor 1 [7, 8]. Sequencing of the 10 exons of the transcript specifically expressed in the brain did not detect any mutation in the MR-1 gene. Tiapride chlorydrate, valproate sodium, carbamazepine and clonazepam at usual dosage were ineffective. Owing to similarities between attacks of PDC and periodic ataxia, acetazolamide (10 mg/ kg/day) was used off-label and the attacks resolved within two weeks. During the subsequent three years of follow up, the patient reported only two episodes of attacks during holidays. They clearly occurred when the patient neglected to take his treatment in the morning and they disappeared with acetazolamide, showing the strict correlation between relapse of attacks and drug intake. Treatment with acetazolamide was clinically well tolerated and regular examinationof blood samples was unremarkable. The clinical presentation of our patient points to a diagnosis of PDC because the paroxysmal dystonic attacks were not triggered by any particular movement, unlike in paroxysmal kinesigenic dyskinesia (PKD). Attacks were of short duration but a wide variability of symptoms is frequently noted in PDC, particularly concerning attack duration [2–4]. For example, one patient (P7) in the series of Bressman et al. [4] had attacks lasting only 10 sec to 5min, close to those observed in our patient. The dystonic nature of the attacks, the normal consciousness, and above all the absence of EEG V. Michel, MD AE D. Guehl, MD, PhD B. Bioulac, MD, PhD P. Burbaud, MD, PhD (&) Service de Neurophysiologie clinique Hopital Pellegrin Avenue Amelie-Rabat Leon 33076 Bordeaux, France Tel.: + 33/5 57 57 15 86 Fax: + 33/5 56 89 20 61 E-Mail: Pierre.Burbaud@umr5543. u-bordeaux2.fr

Myofibrillogenesis regulator 1 gene ( MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia

Two recurrent missense mutations (c.20C>T: A7V; c.26C>T: A9V) in the gene encoding the myofibrillogenesis regulator 1 ( MR-1) have been shown to cause autosomal dominant paroxysmal nonkinesigenic dyskinesia (PNKD) in 13 families of primarily European ancestry. Here we report an Omani PNKD family with seven affected family members and autosomal dominant inheritance. Our linkage analysis provided consistent positional evidence that the MR-1 gene could be the responsible disease gene. Sequence analysis identified a MR-1 missense mutation (c.20C>T; A7V) in the affected family members, whereas it was not present in five unaffected family members and 129 population controls. Taking into account that previous haplotype analyses did not reveal evidence for common founders among several PNKD families, our present findings strengthen three implications: (1) autosomal dominant PNKD seems to be a homogenous disorder, for which the MR-1 gene is the major disease gene; (2) mainly two recurrent MR-1 missense mutations (57% V7, 43% V9) account for the genetic variance of familial PNKD; (3) it supports current evidence that some of the recurrent MR-1 mutations may have arisen independently by de novo mutation at functionally convergent key sites of the brain-specific MR-1L isoform.

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.

Presence of Alanine-to-Valine Substitutions in Myofibrillogenesis Regulator 1 in Paroxysmal Nonkinesigenic Dyskinesia

Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by attacks of involuntary movements brought on by stress, alcohol, or caffeine, but not by movement. An autosomal dominant form of this disorder was mapped to chromosome 2q33-36, and different missense mutations in exon 1 of the myofibrillogenesis regulator 1 (MR1) gene were identified recently in 2 kindreds. To describe studies on a new pedigree with PNKD, to explore the possibility of locus heterogeneity, and to further delineate the spectrum of mutations in MR1 in 2 families with PNKD. All 10 exons of MR1 were sequenced in DNA from members of 2 pedigrees with autosomal dominant PNKD. Different missense mutations in exon 1 of MR1 that cosegregate with disease were identified in each multiplex family. These single-nucleotide mutations predicted substitution of valine for alanine in residue 7 in one family and residue 9 in the other. The same mutations were found in the only 2 families previously published. Family history and haplotype analysis make it unlikely that the families with the same mutations are related. The function of MR1 is unknown, but the 2 mutations identified in the 4 families with PNKD studied to date are predicted to disrupt the amino terminal alpha-helix suggesting that this region of the gene is critical for proper gene function under stressful conditions. Study of additional families will be important to determine whether analysis of a single exon (MR1 exon 1) is sufficient for genetic testing purposes.

Decreased adenosine receptor binding in dystonic brains of the dtsz mutant

In patients with paroxysmal non-kinesigenic dyskinesias, episodes of dystonia can be provoked by stress and also by methylxanthines (e.g. caffeine), which inhibit adenosine A 1/A 2A receptors. In the dt sz mutant hamster, a model of this movement disorder, adenosine A 1 receptor antagonists were previously found to worsen dystonia, while adenosine A 1 and A 2A receptor agonists exerted pronounced beneficial effects. Therefore, in the present study, adenosine receptor A 1 and A 2A binding was determined by autoradiographic analyses in dt sz hamsters under basal conditions, i.e. in the absence of a dystonic attack, and in a group of mutant hamsters which exhibited severe stress-induced dystonic attacks prior to kill. In comparison with non-dystonic control hamsters, [ 3H]DPCPX (8-cyclopentyl-1,3-dipropylxanthine) binding to adenosine A 1 receptors and [ 3H]CGS 21680 (2 p-(2carboxyethylphen-ethylamino-5′- N-ethlycarboxamindoadenosine) binding to adenosine A 2A receptors were significantly lower throughout the brain of dystonic animals. Under normal resting conditions, mutant hamsters showed significant decreases in adenosine A 1 (−12 to−42%) and in A 2A (−19 to−34%) receptor binding compared with controls. Stressful stimulation increased adenosine A 1 and A 2A receptor binding in almost all brain regions in both control and dystonic hamsters. The stress-induced increase was more marked in mutant hamsters, leading to a disappearance of differences in most regions compared with stimulated controls, except the striatum. In view of previous findings of striking beneficial effects of adenosine A 1 and A 2A receptor agonists and of striatal dysfunctions in the dt sz mutant, the reduced adenosine receptor binding may be an important factor in the pathogenesis of paroxysmal dystonia.

The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway

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.

Paroxysmal non-kinesigenic dyskinesia in antiphospholipid syndrome.

We report on a patient with a mixed movement disorder classifiable as a paroxysmal nonkinesigenic dyskinesia, occurring as the first manifestation of primary antiphospholipid syndrome (PAPS). Possible pathophysiology is discussed based on recent literature, and we stress that PAPS must be considered in movement disorders of a paroxysmal nature.

Sublingual lorazepam in the treatment of familial paroxysmal nonkinesigenic dyskinesia

Familial paroxysmal nonkinesigenic dyskinesia (Mount and Reback syndrome) is characterized by episodes of dystonia and chorea, which are precipitated by fatigue, emotional stress, alcohol, or foods. We report two children from a large kindred with this condition who responded to sublingual lorazepam.

Sublingual lorazepam in the treatment of familial paroxysmal nonkinesigenic dyskinesia

Familial paroxysmal nonkinesigenic dyskinesia (Mount and Reback syndrome) is characterized by episodes of dystonia and chorea, which are precipitated by fatigue, emotional stress, alcohol, or foods. We report two children from a large kindred with this condition who responded to sublingual lorazepam.