Paroxysmal Movement Disorders Research Articles

Aicardi-Goutières syndrome: clinical, laborchemical and neuroradiological findings in the first two years of life of an early diagnosed patient

Introduction: Aicardi-Goutières syndrome (AGS) is a rare progressive encephalopathy. AGS is caused by homozygous mutations of at least 4 genes. The clinical syndrome is characterised by acquired microcephaly, bilateral basal ganglia calcifications, early loss of myelin, chronic cerebrospinal fluid (CSF) lymphocytosis and high interferon-alpha levels in plasma and in CSF. Case report: We report of a 5-month–old male patient who presented with irritability, feeding difficulties, psychomotor delay and trunk hypotonia. The patient showed a paroxysmal movement disorder characterized by crying spells with hypertonia and limb dystonia, occasionally triggered by acustic/tactile stimuli and lasting for several hours. Imaging revealed diffuse leucodystrophy without calcifications. Abnormal CSF findings included lactic acidosis, high protein content, lymphocytosis and extremely high neopterin and tetrahydrobiopterin combined with normal 5-methyltetrahydrofolate levels. The high titer of interferon-alpha in serum and CSF in the absence of any signs of infection pointed towards the diagnosis, which was established by the identification of pathogenic mutations in the AGS3/AYP1-gene (D39Y/D115fs).

Mouvements anormaux paroxystiques non épileptiques de l'enfant

Paroxysmal movement disorders are not uncommon in childhood, but are probably under-recognised. Paroxysmal movement disorders are a distinctive group of disorders that represents various clinical situations, characterised by intermittent and episodic disturbances of movement. Diagnosis relies on semiological analysis, mainly based on parental description of the manifestations; video recording (during an EEG-video monitoring or home made video) are often helpful to establish the correct diagnosis. In the large majority of the cases, paroxysmal movement disorders are benign situations. Some of them are transient, as they spontaneously stop over time (benign torticolis of infancy, paroxysmal tonic upgaze). Being familiar with these disorders will lead to accurate diagnosis, so avoiding useless investigations. Most of the time, no treatment will be required, and the families will be informed of the good prognosis.

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.

Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca(2+) sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.

Classification conundrums in paroxysmal dyskinesias: A new subtype or variations on classic themes?

Paroxysmal movement disorders are a group of heterogeneous entities that have been categorized based on their most salient features. The four classic categories of paroxysmal dyskinesias are kinesigenic, nonkinesigenic, hypnogenic, and exercise-induced. The phenotypic variability of these disorders, coupled with new insights into their possible etiologies, has made the task of classification increasingly problematic. We describe 4 cases that do not fit easily into the current classification scheme, compare them with four others recently described in the literature, and raise the question as to whether they constitute a new subtype.

Ictal movement disorders and hypothalamic hamartoma

We report the case of a woman presenting with unusual, symptomatic epilepsy related to a hypothalamic hamartoma, in the absence of mental retardation or precocious puberty. The seizures manifested themselves clinically as characteristic, paroxysmal movement disorders, such as choreic/ballistic movement. This type of phenomenon is rarely of epileptic origin: we thus suggest that the movement disorder observed here could be due to functional disorganization of the basal ganglia network by the epileptic discharge, causing loss of the inhibition of thalamic activity and thus allowing the occurrence of abnormal movements. [Published with videosequences]

Channels and Disease

Episodic neurological phenotypes make up an interesting and important group of diseases affecting humans. These include disorders of the skeletal and cardiac muscles, peripheral nerves, and brain. They range from episodic weakness syndromes to rare paroxysmal movement disorders. More common episodic phenomena include cardiac arrhythmias, epilepsy syndromes, and headache. Molecular characterization of these disorders is shedding light on their pathophysiologic features and will ultimately lead to better diagnosis and treatment of patients.

Dystonia: recent advances.

Dystonia may be primary or symptomatic. Most, if not all, primary torsion dystonias are genetic diseases and manifest as 'pure dystonia', without consistent biochemical or neuropathological changes. Symptomatic dystonias may be (a) secondary to drugs or other environmental factors, (b) part of a 'dystonia plus' syndrome or (c) part of several heredodegenerative diseases. In the last few years, there have been rapid advances in the genetic classification of primary torsion dystonia. The gene for one form (DYT1dystonia), particularly common in Ashkenazi Jews, has been isolated. In this review, I present a basic clinical overview of dystonia and focus on the recent advances in molecular genetics of primary torsion dystonia (PTD). Treatment of dystonia is a large subject, worthy of a review in itself, and is not covered here. Several of the paroxysmal movement disorders may manifest with dystonia, but these are usually considered separately, as I have done in this review. Copyright 1999 Harcourt Publishers Ltd.

Paroxysmal movement disorders in severe myoclonic epilepsy in infancy

We report on the electroclinical findings and the results of a molecular genetic study of a patient with typical severe myoclonic epilepsy in infancy (TSME) and three with borderline SME (BSME) who showed paroxysmal movement disorders, such as choreoathetosis, dystonia and ballismus, during their clinical course. BSME was defined as a clinical entity that shares common characteristics with TSME but lacks myoclonic seizures associated with ictal EEG changes. When the paroxysmal movement disorders were first observed, all the patients in this study were being treated with polytherapy including phenytoin (PHT), and these abnormal movements disappeared when PHT was discontinued or reduced. However, on other occasions, two of our cases also showed the same abnormal movements even when not being treated with PHT. One patient with TSME and two of the three patients with BSME had SCN1A gene mutations that lead to truncation of the associated protein. We conclude that paroxysmal movement disorders seen in SME patients were closely related to their AED therapy, especially the use of PHT. It is thought that patients with both TSME and BSME have some predisposition toward paroxysmal movement disorders, and that this predisposition is partly related to sodium channel dysfunction, although some other factors might influence the occurrence of this phenomenon.

Ataxia and Paroxysmal Dyskinesia in Mice Lacking Axonally Transported FGF14

Fibroblast growth factor 14 (FGF14) belongs to a distinct subclass of FGFs that is expressed in the developing and adult CNS. We disrupted the Fgf14 gene and introduced an Fgf14 N-β-Gal allele that abolished Fgf14 expression and generated a fusion protein (FGF14N-β-gal) containing the first exon of FGF14 and β-galactosidase. Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder. Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists. The paroxysmal hyperkinetic movement disorder phenocopies a form of dystonia, a disease often associated with dysfunction of the putamen. Strikingly, the FGF14N-β-gal chimeric protein was efficiently transported into neuronal processes in the basal ganglia and cerebellum. Together, these studies identify a novel function for FGF14 in neuronal signaling and implicate FGF14 in axonal trafficking and synaptosomal function.

Secondary paroxysmal dyskinesias.

Paroxysmal dyskinesias (PxDs) are involuntary, episodic movements that include paroxysmal kinesigenic (PKD), paroxysmal nonkinesigenic (PNKD), and paroxysmal hypnogenic (PHD) varieties. Although most PxDs are primary (idiopathic or genetic), we found 17 of our 76 patients with PxD (22%) to have an identifiable cause for their PxD (10 men; mean age, 41.4 years). Causes included peripheral trauma (in three patients), vascular lesions (in four), central trauma (in four), kernicterus (in two), multiple sclerosis (in one), cytomegalovirus encephalitis (in one), meningovascular syphilis (in one), and migraine (in one). The latency from insult to symptom onset ranged from days (trauma) to 18 years (kernicterus), with a mean of 3 years. Nine patients had PNKD, two had PKD, five had mixed PKD/PNKD, and one had PHD. Hemidystonia was the most common expression of the paroxysmal movement disorder, present in 11 patients. Both of the patients with PKD had symptom durations of <5 minutes. Symptom duration ranged from 10 seconds to 15 days for PNKD and from 5 minutes to 45 minutes for mixed PKD/PNKD. There were no uniformly effective therapies, but anticonvulsant drugs, clonazepam, and botulinum toxin injections were the most beneficial. Awareness of the variable phenomenology and the spectrum of causes associated with secondary PxD will allow for more timely diagnosis and early intervention.

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 second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16.

Paroxysmal kinesigenic choreoathetosis (PKC) is a rare paroxysmal movement disorder characterized by recurrent and brief attacks of choreiform or dystonic movements triggered or exacerbated by sudden voluntary movements. Some patients with PKC also have a history of infantile afebrile convulsions. PKC can be sporadic, or familial with autosomal dominant inheritance. PKC has been mapped to the pericentromeric region of human chromosome 16 in several Japanese families and in an African-American family, to regions which overlap by 9.8 cM (centiMorgan). Both regions overlap by 3.4 cM with a region containing a gene responsible for 'infantile convulsions and paroxysmal choreoathetosis' (ICCA). We have identified a second PKC locus (EKD2) on the long arm of chromosome 16 in a large Indian family with PKC. A maximum two-point LOD score of 3.66 (recombination fraction = 0.00, penetrance = 0.80) was obtained between PKC and D16S419. Haplotype and recombinant analysis localized EKD2 to a 15.8 cM region between D16S685 and D16S503. This region does not overlap with that identified in Japanese families, or with the ICCA locus. These results exclude one locus on chromosome 16 which causes both the ICCA and PKC syndromes; this suggests that there may be a cluster of genes on human chromosome 16 which lead to paroxysmal disorders.

Paroxysmal dyskinesias as a paradigm of paroxysmal movement disorders.

Paroxysmal dyskinesias are genetically and clinically heterogeneous. Paroxysmal kinesigenic choreoathetosis is frequently familial, with autosomal-dominant transmission. Benign infantile convulsions can be observed in these families and both diseases as linked to the pericentromeric region of chromosome 16. Two different forms of paroxysmal dystonic choreoathetosis are distinguished on clinical grounds, by the presence or absence of spasticity, and genetically, as they are linked with loci on different chromosomes. Among the paroxysmal disorders, these diseases may belong to the group of channelopathies.

Trastornos del movimiento paroxísticos

Paroxysmal movement disorders are of sudden onset, paroxystic or intermittent, with normality or at least absence of abnormal movements between episodes. They are uncommon conditions with high familial incidence. The commonest form is paroxystic dystony. Paroxystic ataxia and paroxystic tremor are much rarer. Paroxystic dystony is seen clinically as paroxystic episodes of variable duration, consisting of dystonic movements and postures which present spontaneously or are triggered by certain stimuli or situations. There are different types: kinesgenic paroxystic choreoathetosis, dystonic paroxystic choreoathetosis, intermediate paroxystic choreoathetosis and nocturnal paroxystic choreoathetosis. The paroxystic ataxias are characterized by recurrent episodes of ataxia in the absence of any known metabolic defect. In type 1 episodic ataxia there are also episodes of ataxia and myochemical changes. The gene responsible for this condition has been found on the short arm of chromosome 12. Type 2 episodic ataxia is characterized by its excellent response to acetazolamide. The gene responsible is found on the short arm of chromosome 19. Very few cases of paroxystic tremor have been described.

Epilepsy and paroxysmal movement disorders in families: evidence for shared mechanisms

ABSTRACT The epilepsies have been regarded as clinically distinct from the paroxysmal movement disorders. Recently, a variety of ion channel defects have been identified as the biological basis of certain familial epilepsies and paroxysmal movement disorders. We studied two families with the cooccurrence of epilepsy, movement disorders and migraine. Information was obtained on 147 individuals in the two families. In family WF, there was a co‐occurrence of epilepsy (benign infantile convulsions, idiopathic generalized epilepsy), episodic ataxia (with cerebellar atrophy and without myokymia) and common migraine. In family CL, epilepsy (febrile seizures, febrile seizures plus), kinesigenic paroxysmal dyskinesia and migraine (including hemiplegic migraine) were observed in various combinations over 3 generations. The observations in these two families, together with review of the literature, suggest that the co‐occurrence of epilepsy (particularly benign infantile convulsions), paroxysmal movement disorders and migraine is not due to chance. Thus, these distinct clinical phenomena could have a shared biological basis and ion channel defects are an attractive possibility.

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.

A case report of paroxysmal dystonic choreoathetosis due to hypoglycaemia induced by an insulinoma.

Hypoglycaemia due to an insulinoma can mimic acute disorders of cognition, consciousness, epilepsy, transient ischaemia, or psychosis, and chronic disorders of dementia and neuropathy. Misdiagnosis and delay in treatment are common and prolonged hypoglycaemia can lead to permanent neurological deficit or fatal coma. A 27 year old woman with hypoglycaemia induced by an insulinoma presented with features typical of paroxysmal non-kinesiogenic dystonic choreoathetosis. Striatal dysfunction as a consequence of hypoglycaemia has rarely been described. Insulinoma is a readily treatable condition that should be considered in the differential diagnosis of a paroxysmal movement disorder.

Acquired paroxysmal movement disorders

Acquired paroxysmal movement disorders are reported less frequently than the familial forms of paroxysmal dyskinesias. Three children, with the acquired form of the disorder which followed an early childhood encephalopathic event, are described. Three similarly affected children have been reported previously. Movement disorders developing after perinatal encephalopathy appear to be a distinct entity. Patients with this condition demonstrated clinical improvement following the initiation of antiepileptic medications.