Paroxysmal Exercise-induced Dystonia Research Articles

Fasting Dependent Paroxysmal Exercise Induced Dystonia as Presenting Symptom in PRKN Type of Parkinson's Disease.

Paroxysmal exercise-induced dystonia (PED) can occur as a symptom of early-onset Parkinson's disease (EOPD), Dopa-responsive dystonia (DRD), or Glut1 deficiency syndrome (Glut1DS). Red flags of PED in Glut1DS include influence of diet, while diurnal fluctuations are characteristic for DRD.1 A 22-year-old White-European man presented with a 5-year history of paroxysmal involuntary movements of his left foot. Past medical history and family history were unremarkable without known consanguinity. At the age of 17 (BMI 38 kg/m2), he started a diet and regular physical exercise and lost 35 kg weight. After approximately 30 min of physical exercise, he occasionally noticed mild and involuntary abnormal posturing of his left foot. Symptoms only occurred in the evening or after fasting. Since then, symptoms have worsened, and abnormal movements started after 15 min of exercise in the morning and after 5 min in the evening or when fasting. Recently, he also noticed a mild tremor and clumsiness of his right hand. Physical examination revealed mild rigidity of neck and extremities, mild resting tremor of the right hand and mild bradykinesia of upper and lower limbs (right dominant). He had reduced arm swing, but otherwise walking was unremarkable (see Video 1). After 10 min of running, he developed dystonia of his left foot (see Video 2), which ceased shortly after resting. A 3-Tesla-MRI of the brain, CSF/serum fasting glucose ratio and a metabolic panel including blood/CSF amino acids and neurotransmitters were unremarkable. A (123)I-Ioflupane single-photon emission computed tomography was abnormal. A genetic panel including known genes causing EOPD, DRD and Glut1DS was ordered. Both next generation sequencing and exon-specific PCR detected a homozygous deletion of exons 2–4 of the PRKN gene. Levodopa/benserazide 50/12.5 mg QID led to marked improvement of parkinsonian symptoms and PED. To the best of our knowledge, this is the first reported case of the PRKN type of EOPD featuring PED with marked diurnal fluctuation and worsening with fasting as presenting symptom. In 16% of PRKN mutation carriers symptoms start in adolescence.2 Initial foot dystonia, in some cases induced by exercise,1, 3 and diurnal fluctuation are recognized features.4 However, symptom provocation by fasting is a novel finding. The products of several PD-associated genes including PRKN have important roles in mitochondrial biology and fasting induces an upregulation of protein markers of mitophagy. Our patient noticed remission of PED with regular carbohydrate intake. A low protein-to-carbohydrate ratio has been shown to increase lifespan, motor ability and mitochondrial function in a PRKN mutant Drosophila model of PD,5 providing a potential pathophysiological link to our finding. A deletion of exons represents the most common mutation of the PRKN gene; deletions of exons 2–4 are classified as definitely pathogenic.2 Another reported case presenting with juvenile-onset PED had a deletion of exon 4.3 Worsening with fasting was neither described in a published case series4 nor in patients with deletions of exons 2–4 of the PRKN gene within the MDS gene database. In conclusion, diurnally fluctuating PED that worsens with carbohydrate restriction may be the presenting symptom in the PRKN type of EOPD. We would like to thank our patient for giving us the opportunity to publish this case report. We also thank Johann Semmler-Bruckner for his assistance in genetic analyses and database research. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Data Collection: A. Clinical Assessment, B. Genetic Analysis, C. Literature Review; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. L.G.: 1B, 1C, 2A, 2C, 3A C.W.: 1B, 1C, 2B, 3B P.K.W.: 1B, 1C, 2A, 3B P.S.: 1A, 1B, 1C, 2A, 2C, 3B Ethical Compliance Statement: No formal approval by an ethics committee was required; the Journal's Ethical Publication guidelines and the Declaration of Helsinki were followed. Informed written consent on video acquisition and case publication was obtained from the patient using our standardized patient's video consent form. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for Previous 12 Months: L. Gattermeyer, C. Windpassinger and P. Katschnig-Winter declare that there are no additional disclosures to report. P. Schwingenschuh reports personal fees from Bial.

A Rare Cause of Paroxysmal Movement Disorder Associated with TBC1D24 Gene Mutation in Two Siblings.

A Rare Cause of Paroxysmal Movement Disorder Associated with TBC1D24 Gene Mutation in Two Siblings.

Paroxysmal and non-paroxysmal dystonia in 3 patients with biallelic ECHS1 variants: Expanding the neurological spectrum and therapeutic approaches

BackgroundECHS1 encodes the mitochondrial short chain enoyl CoA hydratase 1 (SCEH). Biallelic ECHS1 variants have been associated with Leigh-like presentations and milder phenotypes with paroxysmal exercise-induced dystonia. Patients/methodsWe used exome sequencing to investigate molecular bases of paroxysmal and non-paroxysmal dystonia in three patients and performed functional studies in fibroblasts. Disease presentation and response upon dietary interventions were documented. ResultsWe identified compound heterozygous ECHS1 missense variants in all individuals; all of them harbouring an c.518C > T (p.Ala173Val) variant. SCEH activity was impaired in patients’ fibroblasts, respiratory chain-, and pyruvate-dehydrogenase-complex activities were normal in one individual.Patient 1 presented from the age of 2.5 years on with paroxysmal opisthotonic posturing. Patient 2 had a first metabolic crisis at the age 20 months developing recurrent exercise-induced dystonic episodes. Disease history of patient 3 was unremarkable for neurological findings until he first presented at the age of 20 years with persistent dystonia. Ketogenic diet had beneficial effects in patient 1. Neither ketogenic nor low protein diets led to milder symptoms in patient 2. Patient 3 benefits from low protein diet with improvement of his torticollis. ConclusionsIn line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p.Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes.

053 GLUT-1 deficiency presenting as dopa-responsive dystonia: an atypical phenotype of a rare disease

IntroductionThe SLC2A1 gene encodes the glucose transporter GLUT1, responsible for normal glucose transport across the blood-brain barrier. Mutations in this gene have classically been associated with an epileptic encephalopathy referred to as GLUT-1 Deficiency Syndrome, which typically presents with early-onset refractory epilepsy, developmental delay and complex movement disorders.1 2 More recently, SLC2A1 variants have been identified in patients with paroxysmal exercise-induced dyskinesia (PED), with or without a history of epilepsy.3 4 Response to medication is typically poor; however, both seizures and dyskinesia may improve following implementation of a ketogenic diet.5 A single case of levodopa responsiveness has previously been described in a subject with SLC2A1 mutation and PED.5Methods and resultsWe describe a 47-year-old female with mild intellectual disability since childhood but no history of epilepsy, who developed episodic dystonia affecting the lower limbs in her early 20’s. A clinical diagnosis of dopa-responsive dystonia was made following a marked, sustained response to levodopa. There was no significant family history. In her 40’s she developed breakthrough dystonia with exertion and choreiform movements affecting the fingers and face. A subsequent dystonia panel identified a heterozygous variant c.[1199G>T];[=] (p.Arg400Leu) in the SLC2A1 gene. Cerebrospinal fluid glucose concentration was low (2.0 mmol/L). She declined a trial of a ketogenic diet.SLC2A1 variants are associated with PED; however, response to levodopa has not been widely reported.ConclusionIt is becoming increasingly evident that the phenotypic presentations of GLUT1 deficiency are diverse, and SLC2A1 testing should be considered in a broader range of patients.ReferencesWang, D, Kranz-Eble P, De Vivo DK. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 Deficiency Syndrome. Human Mutation 2001;16:224–231.Klepper J, Leiendecker B. GLUT1 deficiency syndrome – 2007 update. Developmental Medicine & Child Neurology 2007;49:707–716.Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I, Quinn NP, Weber YG, et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord 2009;24(11):1684–1696.Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, endoding the glucose transporter GLUT1. Brain 2008;131:1831–1844.Baschieri F, Batla A, Erro R, Ganos C, Cordivari C, Bhatia KP. Paroxysmal exercise-induced dystonia due to GLUT-1 mutation can be responsive to levodopa: a case report. J Neurol 2014;261:615–616.

The Clinical Syndrome of Paroxysmal Exercise-Induced Dystonia: Diagnostic Outcomes and an Algorithm.

Paroxysmal exercise-induced dyskinesia (PED) is characterized by recurrent episodes of involuntary movement disorders usually precipitated by sustained walking or running. Recently, mutations in the gene encoding for glucose transporter type 1 (GLUT-1) were described in a number of families with autosomal dominant PED. However, the underlying etiology of PED is quite heterogeneous. We describe a large series of patients presenting with PED. Of 16 patients, we reached a conclusive diagnosis for 11 (4 patients with GLUT-1 mutations, 4 patients with early Parkinson's disease, 2 with dopa-responsive dystonia, and one with a psychogenic/functional movement disorder). For the remaining 5 patients, the final diagnosis remained descriptive. Although certain clinical features might allow etiological distinction between cases, clinical examination alone is not always conclusive. Based on our series, we propose a diagnostic algorithm to aid the differential diagnosis of PED.

Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report

Dear Sirs,Paroxysmal exercise-induced dyskinesia (PED) is a disor-der characterized by brief episodes of dystonia or choreausually lasting a few minutes [1]. Invariably, the movementdisorder affects the part of the body which is exercised.Less than 30 % of PED cases are due to a mutation in theSLC2A1 gene encoding for the glucose transporter type 1(GLUT1) [2–4]. This disorder is difficult to treat, and anumber of drugs have been proven unhelpful [5]. Recently,ketogenic diet has been suggested to be useful [6]. How-ever, such diet is difficult to follow and long-term com-pliance is poor [6]; also, it has been reported to worsen theattacks in some patients [7]. Hence, there is a need for othersymptomatic treatments. Here we report a case of PEDassociated with a GLUT1 mutation where the patientresponded dramatically to levodopa.This 47-year-old gentleman, with no family history forany neurological disorder, developed his first symptomsduring childhood, with dystonic attacks affecting mainlyhis legs after physical exercise. The attacks lasted20–165 min and occurred daily on average. He had nofurther symptoms in between attacks. The neurologicalexamination was normal interictally. A number of inves-tigations, including routine blood tests, brain CT scan andMRI, and dopamine transporter SPECT were normal.Cerebrospinal fluid to blood glucose ratio was consistentwith GLUT1 deficiency (ratio = 0.45; normal values[0.60 [2, 3]). He was therefore tested and found positivefor a previously reported mutation (p.R333Q) in theSLC2A1 gene.Our patient refused treatment with ketogenic diet (whichshould be considered the first-line option [5]) and preferredto try pharmacological approaches. Trials with oxazepam,diazepam, carbamazepine, clonazepam, sodium valproate,and acetazolamide were completely unhelpful. Finally, weempirically treated him with levodopa to reach a dose of800 mg daily. Since being on this dose of levodopa, hemarkedly improved, with a reduction of both frequency andintensity of the attacks. At some stage, he spontaneouslyreduced the levodopa to 200 mg daily, making his condi-tion much worse with frequent and severe episodes.Therefore, he went back to 800 mg daily; since then, he hashad only one minor episode over 6 months.Pathophysiological underpinnings of PED are not yetestablished. However, there are some suggestions thatdopamine can be involved in the pathogenesis of PED.Firstly, from a phenomenological perspective, dyskinesiasassociated with GLUT1 affect the legs and somehowresemble diphasic dyskinesias of Parkinson’s disease(which are usually seen during low dopaminergic states)and respond to high dose of levodopa, unlike what happenswith peak dose dyskinesias. Secondly, CSF analysis ofpterins and monoamine metabolites before and after anattack in a patient with PED has given evidence that theremight be an altered dopaminergic transmission whichcontributes to the clinical appearance of the abnormal

Clinical analysis of nine cases of paroxysmal exercise-induced dystonia

This study was aimed to analyze the clinical features of paroxysmal kinesigenic dyskinesia (PKD) and extend the understanding of this disease. From August, 2008 to October, 2010, 9 patients were diagnosed with PKD in the Department of Neurology of the First Affiliated Hospital of Zhejiang University, China. The data involving clinical demographic characteristics, somatosensory evoked potentials, results of electromyography, video electroencephalography (EEG), brain magnetic resonance imaging (MRI) and computerized tomography (CT) were collected. All PKD patients exhibited unilateral or bilateral recurrent episodic dyskinetic attacks triggered by sudden voluntary movements. The duration of the attacks ranged from several seconds to one minute. The attack frequency ranged from approximately once in several months to more than 10 times in a day. Patients suffered from no conscious disorders during the attack, and no neurological signs were found during the period between attacks. No abnormal somatosensory evoked potentials were found. Routine EEG, video EEG monitoring or brain imaging showed normal findings. Classical treatment for anti-epilepsy, including carbamazepine and topiramate, was administered to the patients and proved to be effective. It was concluded that PKD is characteristically triggered by sudden voluntary movement; no abnormal electroneurophysiological findings are observed in PKD, and antiepileptic drugs are effective in treating the disorder.

Dystonic tremor caused by mutation of the glucose transporter gene GLUT1

Glucose transporter 1 deficiency syndrome (GLUT1-DS) is due to heterozygous mutation of the glucose transporter type 1 gene (GLUT1/SLC2A1). GLUT1-DS is characterized by movement disorders, including paroxysmal exercise-induced dystonia (PED), as well as seizures, mental retardation and hypoglycorrhachia. Tremor was recently shown to be part of the phenotype, but its clinical and electrophysiological features have not yet been described in detail, and GLUT1 tremor reports are rare. We describe two patients, a young woman and her mother, who were referred to us for tremor. We also systematically review published cases of GLUT1-DS with tremor (14 cases, including ours), focusing on clinical features. In most cases (10/14), the tremor, which involved the limbs and voice, fulfilled clinical criteria for dystonic tremor (DT), occurring in body areas affected by dystonia. Tremor was the only permanent symptom in 2 cases. Recordings, reported here for the first time, showed an irregular 6- to 8.5-Hz tremor compatible with DT in our two patients. These findings show that tremor, and particularly DT, may be a presenting symptom of GLUT1-DS. Patients who present with dystonic tremor, with or without mental retardation, seizures, movement disorders and/or a family history, should therefore be screened for GLUT1-DS.

Familial paroxysmal exercise‐induced dystonia: atypical presentation of autosomal dominant GTP‐cyclohydrolase 1 deficiency

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of L-Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals.

Paroxysmal exercise-induced dystonia with optic atrophy: A-30-year follow-up

Paroxysmal exercise-induced dystonia with optic atrophy: A-30-year follow-up

Targeting therapy for movement disorders

It remains a common misconception that neurologists are physicians who are skilled only in making a diagnosis but who are disinterested in therapy of patients. However, there have been major advances on several neurological fronts in the past 50 years. Therapeutics of Parkinson's Disease and Other Movement Disorders, edited by Mark Hallett and Werner Poewe, is a well organised summary of the state-of–the-art treatments in movement disorders. The book is divided into nine sections covering the major areas in movement disorders: Parkinson's disease (PD) and atypical parkinsonism, tremor, dystonia, and muscle spasms, other hyperkinetic movement disorders, cerebellar, gait, and balance disorders, and psychogenic movement disorders. The editors have assembled a panel of leading international experts as chapter authors within each section, who ably provide the balance between scientific rigour and “personal clinical acumen and therapeutic wisdom”. Each chapter and section is led by a concise summary of disease pathophysiology, followed by a detailed review of treatment. This approach enables understanding of the therapies within a broader mechanistic framework. Rather than simply putting together a list of randomised controlled trials or declaring therapy an evidence-free zone, most of the contributors synthesise the body of current knowledge and present a practical approach to help deal with the immediate needs of the individual patient. Their work is both cause for optimism and sober reflection. James Parkinson recommended “at whatever period of the disease it might be proposed to attempt the cure, blood should be first taken from the upper part of the neck…” as therapy for shaking palsy. The Nobel-prize winning discovery by Arvid Carlsson that dopamine is a neurotransmitter led to dopamine-replacement therapy for PD more than 40 years ago—one of the greatest success stories in neurological therapeutics. Yet this effective symptomatic therapy remains an exception rather than the rule for neurodegenerative diseases, and, almost 200 years on from Parkinson's recommendations, we are still searching for a cure. Most of the chapters cite up-to-date references, but, as inevitably happens with the prolonged process of publishing a book, some findings have been omitted. For example, some of the more recent gene discoveries in familial PD and the link between glucose transporter gene defects and paroxysmal exercise-induced dystonia are not included. Recent randomised, double-blind, controlled studies supporting the use of domperidone as treatment for orthostatic hypotension and macrogol as treatment for constipation in PD, two common non-motor symptoms, escape mention. The chapter on Wilson's disease is written by a recognised authority who strongly advocates avoiding D-penicillamine; however, this treatment remains favoured by other experts and is the only affordable option in many countries. Some practical guidance for those who have need of its use would have been beneficial. The chapter on myoclonus could have been enhanced by more detailed discussion of the importance of neurophysiological characterisation of myoclonus for therapy, and the section on neuroleptic-induced movement disorders could have been improved by a broader discussion of the nosological, diagnostic, and management challenges of neuroleptic malignant syndrome. Overall, this book can be strongly recommended and is an asset to libraries of both movement disorder specialists and general neurologists. Its logical structure, linking therapy with underlying pathophysiology, means that it will remain a useful reference even as new therapies inevitably emerge.

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.

Vigabatrin improves paroxysmal dystonia in succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase (SSADH; E.C. 1.2.1.24) deficiency (MIM#271980) is a rare defect of the gamma-aminobutyric acid (GABA) catabolic pathway, resulting in 4-hydroxybutyric acid (GHB) accumulation.1 We report the occurrence of an unusual paroxysmal movement disorder in two affected siblings born of healthy nonconsanguineous Italian parents. This 18-year-old boy presented during childhood with autism, motor stereotypies (trunk swinging), hyperactivity, clumsiness, and hypotonia. Generalized epilepsy manifested at age 7 years, and sleep disorder (compulsive limb movements) manifested at age 10 years. Starting from age 15 years, he had a transient discomfort in the lower limbs while walking. On examination at age 16 years, he presented severe mental retardation, dysarthria, motor stereotypies (chaotic gesticulation, trunk swinging), mild dystonic postures of upper limbs, and paroxysmal exercise-induced dystonia (PED). PED emerged after approximately 100 steps as large amplitude abductor movements of the legs, gait freezing, frightful expression, and occasionally, falling (video E-1 on the Neurology Web site at www.neurology.org); he was able to walk again after resting 5 to …

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.

Post-traumatic paroxysmal exercise-induced dystonia: case report and review of the literature

A young Chinese man sustained a back injury in a motorcycle accident in 2000 and had left lower limb weakness due to a lumbosacral plexopathy, diagnosed clinically and electromyographically. With rehabilitation, he recovered full function, but developed paroxysmal dystonia of the left leg only with prolonged exertion. He responded well to oral baclofen, relapsed when he stopped taking it, and remains well on low dose maintenance therapy. Dystonia occurring after trauma is well documented, but paroxysmal exercise-induced dystonia occurring after trauma has yet to be described. Paroxysmal exercise-induced dystonia responds variably to anticonvulsant therapy, but the literature does not report response to baclofen, especially in low doses.

Idiopathic epilepsy and paroxysmal dyskinesia.

Although some motor manifestations of epilepsy and of paroxysmal dyskinesia may be difficult to differentiate clinically, the current understanding is that the two disorders are clinically distinct. However, there are several recent reports of families in which different individuals had either disorder or both manifestations, with age-related expression. Co-occurrence makes it likely that a common, genetically determined, pathophysiologic abnormality is variably expressed in the cerebral cortex and in basal ganglia. A rather homogeneous syndrome of autosomal dominant infantile convulsions and paroxysmal (dystonic) choreoathetosis (ICCA) was described in six families from France, China and Japan. Linkage analysis in the French and Chinese families allowed the mapping of the disease gene in a 10-cM interval within the pericentromeric region of chromosome 16. An Italian pedigree in which three members in the same generation were affected by rolandic epilepsy, paroxysmal exercise-induced dystonia (PED), and writer's cramp was subsequently reported. Linkage analysis showed a common homozygous haplotype in a critical region spanning 6 cM and entirely included within the ICCA critical region. Clinical analogies and linkage findings suggest that the same gene could be responsible for rolandic epilepsy, PED, writer's cramp (WC), and ICCA, with specific mutations accounting for each of these mendelian disorders. Evidence for a major gene or a cluster of genes for epilepsy and paroxysmal dyskinesia to the pericentromeric region of chromosome 16 is reinforced by the recent linkage of a family with autosomal dominant paroxysmal dyskinesia to a critical region partially overlapping with ICCA and contiguous to the RE-PED-WC regions. Additional autosomal dominant pedigrees are on record, from Australia and Italy, in which epilepsy was variably associated with paroxysmal kinesigenic or exercise-induced dystonia. Ion channel genes are potentially interesting candidates for syndromes featuring both these paroxysmal neurologic disorders. Increased awareness of their possible co-occurrence will certainly increase the number of observations in the next few years.

Familial (idiopathic) paroxysmal dyskinesias: an update.

The clinical, pathophysiological and genetic features of some of the familial (idiopathic) paroxysmal movement disorders are reviewed. The paroxysmal dyskinesias share features and therefore may have the same pathophysiological mechanisms as other episodic neurological disorders which are known to be channelopathies. Paroxysmal kinesigenic choreoathetosis/dyskinesias (PKC/PKD) is a condition in which brief and frequent dyskinetic attacks are provoked by sudden movement. Antiepileptics particularly carbamazepine are very helpful for this condition. PKC has similarities to episodic ataxia type 1 which is caused by mutations of the KCNA1 gene. PKC and a related disorder in which infantile convulsions are associated (ICCA syndrome) have recently been linked to the pericentromic region of chromososme 16 in the vicinity of some ion channel genes. Paroxysmal exercise-induced dystonia (PED) is a rare disorder manifesting as episodes of dystonia mostly affecting the feet induced by continuous exercise like walking or running. The pathophysiology of PED is unknown and antiepileptic drugs are generally unhelpful. In paroxysmal dystonic choreoathetosis/nonkinesigenic dyskinesias (PDC/PNKD) the attacks are of long duration and induced by a variety of factors including coffee, tea, alcohol and fatigue but not by sudden movement. The gene for familial PDC has been linked to chromosome 2q close to a cluster of ion channel genes. Paroxysmal nocturnal dyskinesia is now known to be a form of frontal lobe epilepsy in some cases which may be familial with an autosomal dominant inheritance and has been given the eponym ADNFLE. ADNFLE is a genetically heterogenous condition. Mutations of the neuronal nicotinic acetylcholine receptor gene that have chromosome 20q have been reported in some families with ADNFLE. However, another family with ADNFLE has been linked to chromosome 15 in the area of another nicotinic acetylcholine receptor gene. Thus the familial paroxysmal dyskinesias appear to be clinically and genetically heterogeneous.

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

OBJECTIVETo 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...

The paroxysmal dyskinesias.

The clinical, pathophysiological and genetic features of some of the paroxysmal movement disorders are reviewed. Paroxysmal kinesigenic choreoathetosis/dyskinesias (PKC/PKD) is a condition in which brief and frequent dyskinetic attacks are provoked by sudden movement. PKC is more common in men and can be idiopathic (commonly familial) or due to a variety of causes. The pathophysiology of PKC is uncertain but it could be an ion-channel disorder. Antiepileptic drugs particularly carbamazepine are very helpful in a large proportion of cases. Paroxysmal exercise induced dystonia (PED) is a rare disorder manifesting as episodes of dystonia mostly affecting the feet induced by continuous exercise like walking or running. Although the initial cases were familial, there is a higher proportion of sporadic cases. The pathophysiology of PED is unknown and antiepileptic drugs are generally unhelpful. In paroxysmal dystonic choreoathetosis/non-kinesigenic dyskinesias (PDC/PNKD) the attacks are of long duration and induced by variety of factors including coffee, tea, alcohol and fatigue but not by sudden movement. PDC can be idiopathic (familial or sporadic) or symptomatic due to a variety of causes. The gene for familial PDC has been linked in 2 families to chromosome 2 q close to a cluster of ion channel genes again suggesting that this disorder may also be a channelopathy. Other paroxysmal disorders include paroxysmal nocturnal dyskinesia, a form of frontal lobe epilepsy in some cases which may be familial with autosomal dominant inheritance (ADNFLE). The gene for ADNFLE in one family has been found to be a mutation in the neuronal acetylcholine receptor gene (CHRNA4) on chromosome 20q. Tonic spasms in multiple sclerosis and Sandiffers syndrome producing intermittent torticollis in infants and children are other paroxysmal movement disorders.

Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2.

We describe a pedigree in which 3 members in the same generation are affected by Rolandic epilepsy (RE), paroxysmal exercise-induced dystonia (PED), and writer's cramp (WC). Both the seizures and paroxysmal dystonia had a strong age-related expression that peaked during childhood, whereas the WC, also appearing in childhood, has been stable since diagnosis. Genome-wide linkage analysis performed under the assumption of recessive inheritance identified a common homozygous haplotype in a critical region spanning 6 cM between markers D16S3133 and D16S3131 on chromosome 16, cosegregating with the affected phenotype and producing a multipoint LOD score value of 3.68. Although its features are unique, this syndrome presents striking analogies with the autosomal dominant infantile convulsions and paroxysmal coreoathetosis (ICCA) syndrome, linked to a 10 cM region between D16S401 and D16S517, which entirely includes the 6 cM of the RE-PED-WC critical region. The same gene may be responsible for both RE-PED-WC and ICCA, with specific mutations explaining each of these Mendelian disorders. This report shows that idiopathic focal disorders such as epilepsy and dystonia, can be caused by the same genetic abnormality, may have a transient expression, and may be inherited as an autosomal recessive trait.