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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Familial (idiopathic) paroxysmal dyskinesias: an update. 1134 27

Paroxysmal movement disorders are a relatively rare and heterogenous group of conditions manifesting as episodic dyskinesia lasting a brief duration. Three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), nonkinisegenic (PNKD), and exercise induced (PED). There have been major advances in the understanding of the pathophysiological mechanisms and the genetics of these disorders, leading to better clinical definitions based on genotype-phenotype correlations in the familial idiopathic forms. PKD is genetically heterogenous, but there is linkage to chromosome 16 in a number of families. PNKD is due to mutations of the MR-1 gene. PED is genetically heterogenous, but a number of familial and sporadic cases may be due to GLUT-1 gene mutations. The GLUT1 gene-related form of PED may respond to a ketogenic diet. Potassium and calcium channel mutations underlie the 2 main forms of episodic ataxia (EA1 and EA2), whereas benign torticollis of infancy may also be a calcium channel disorder.
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PMID:Paroxysmal dyskinesias. 2162 59

Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia and we identified a novel PNKD gene deletion in familial hemiplegic migraine. We found that some PRRT2 loss-of-function mutations cause nonsense mediated decay, except when in the last exon, whereas missense mutations do not affect mRNA. In the PNKD family with a novel deletion, mRNA was truncated losing the C-terminus of PNKD-L and still likely loss-of-function, leading to a reduction of the inhibition of exocytosis, and similar to PRRT2, an increase in vesicle release. This study highlights the frequency, novel mutations and clinical and molecular spectrum of PRRT2, SLC2A1 and PNKD mutations as well as the phenotype-genotype overlap among these paroxysmal movement disorders. The investigation of paroxysmal movement disorders should always include the analysis of all three genes, but around half of our paroxysmal series remain genetically undefined implying that additional genes are yet to be identified.
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PMID:The clinical and genetic heterogeneity of paroxysmal dyskinesias. 2659 94

Paroxysmal movement disorders comprise both paroxysmal dyskinesia, characterized by attacks of dystonic and/or choreic movements, and episodic ataxia, defined by attacks of cerebellar ataxia. They may be primary (familial or sporadic) or secondary to an underlying cause. They can be classified according to their phenomenology (kinesigenic, non-kinesigenic or exercise-induced) or their genetic cause. The main genes involved in primary paroxysmal movement disorders include PRRT2, PNKD, SLC2A1, ATP1A3, GCH1, PARK2, ADCY5, CACNA1A and KCNA1. Many cases remain genetically undiagnosed, thereby suggesting that additional culprit genes remain to be discovered. The present report is a general overview that aims to help clinicians diagnose and treat patients with paroxysmal movement disorders.
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PMID:Paroxysmal movement disorders: An update. 2756 59

Introduction: Paroxysmal dyskinesias and episodic ataxias are often caused by mutations in genes related to cell membrane and synaptic function. Despite the exponential increase in publications of genetically confirmed cases, management remains largely clinical based on non-systematic evidence. Areas covered: The authors provide a historical and clinical review of the main types of paroxysmal dyskinesias and episodic ataxias, with recommendations for diagnosis and management of patients suffering from these conditions. Expert opinion: After secondary paroxysmal dyskinesias, the most common paroxysmal movement disorders are likely to be PRRT2-associated paroxysmal kinesigenic dyskinesias, which respond well to small doses of carbamazepine, and episodic ataxia type 2, which often responds to acetazolamide. Familial paroxysmal non-kinesigenic dyskinesias are largely caused by mutations in PNKD and have poor response to therapy but improve with age. Exercise-induced dyskinesias are genetically heterogeneous, caused by disorders of glucose transport, mitochondrial function, dopaminergic pathways or neurodegenerative conditions amongst others. GNAO1 and ADCY5 mutations can also cause paroxysmal movement disorders, often in the context of ongoing motor symptoms. Although a therapeutic trial is justified for classic cases and in limited resource settings, genetic testing may help direct initial or rescue therapy. Deep brain stimulation may be an option for severe cases.
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PMID:Paroxysmal movement disorders - practical update on diagnosis and management. 3135 80