Showing papers on "Episodic ataxia published in 2001"

Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity.

Abstract: SPECIFIC AIMSP/Q-type voltage-dependent calcium channel CACNA1A mutations cause dominantly inherited migraine, episodic ataxia, and cerebellar atrophy in humans and recessively inherited ataxia, ep...

Ion channels and epilepsy.

Abstract: Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, mutations in ion channel encoding genes are found in a variety of inherited diseases associated with hyper- or hypoexcitability of the affected tissue, the so-called 'channelopathies.' An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1). These rare disorders provide interesting models to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies can be developed, as has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels.

An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus

Abstract: The authors report an autosomal dominant episodic ataxia that is clinically distinct from the other episodic ataxias. Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide. Linkage analyses of markers flanking the EA1 and EA2 loci demonstrate genetic exclusion from the other autosomal dominant episodic ataxias. The authors suggest EA3 for periodic vestibulocerebellar ataxia and EA4 for the disorder described here.

Familial (idiopathic) paroxysmal dyskinesias: an update.

Abstract: 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 FED 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.

Missense CACNA1A mutation causing episodic ataxia type 2.

Abstract: Objectives To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. Background Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A , is located on chromosome 19 and encodes the α1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. Methods All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. Results A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. Conclusions The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder.

Abstract: We describe here familial dyskinesia and facial myokymia (FDFM), a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia. We report a 5-generation family with 18 affected members (10 males and 8 females) with FDFM. The disorder has an early childhood or adolescent onset. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. A candidate gene and haplotype analysis was performed in 9 affected and 3 unaffected members from 3 generations of this family using primers for polymorphic loci closely flanking or within genes of interest. We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine. Our results provide further evidence of genetic heterogeneity in autosomal dominant movement disorders and suggest that a novel gene underlies this new condition.

The Inherited Episodic Ataxias: How Well Do We Understand the Disease Mechanisms?

Abstract: The past few years have seen the elucidation of several neurological diseases caused by inherited mutations of ion channels In contrast to many other types of genetic disorders, the "channelopathies" can be studied with high precision by applying electrophysiological methods This review evaluates the success of this approach in explaining the mechanisms of two forms of episodic ataxia that are known to be caused by mutations of ion channels: episodic ataxia type 1 (EA1, caused by K+ channel mutations) and episodic ataxia type 2 (EA2, caused by Ca2+ channel mutations) Although both of these disorders are rare, they raise many important questions about the roles of identified channels in brain function Indeed, a resolution of the mechanisms by which both diseases occur will represent a major milestone in understanding diseases of the CNS, in addition to opening the way to novel possible treatments

Hemiplegic migraine--downstream of a single-base change.

Abstract: Hemiplegic migraine (with or without cerebellar signs), spinocerebellar ataxia, and episodic ataxia can all result from changes in the gene that encodes the P/Q-type neuronal calcium channel, just one of the 35,000 or so genes that make up the human blueprint. The varied consequences of calcium-channel mutations have been a source of consternation for neuroscientists and geneticists. How can different mutations in the same gene result in both paroxysmal and progressive disorders? Why does the clinical expression of disease vary in patients within the same family with the same genetic change, and why is there so much clinical overlap among . . .

Clinical features of a large Australian pedigree with episodic ataxia type 1.

Abstract: Episodic ataxia type 1 (EA1, MIM 160120) is a rare autosomal dominant disorder characterised by brief episodes of ataxia and tremor of childhood onset. 1 Sudden movement or startle are common precipitants. Continuous myokymia of hand and facial muscles is a common interictal feature, but may only be detectable on electromyography (EMG). 2 The disorder is caused by various missense mutations in the KCNA1 voltage-gated potassium channel gene. 1,3

Canalopatías en neurología

Abstract: Introduction The main function of ionic channels are the conduction, recognition and selection of specific ions. They open and close in respond answer to electrical, mechanical and chemical stimulus, acting in the excitation or transmission of diverse tissues. Development The clinical and molecular manifestations of channelophathies are varied and use to shown up in continuous or paroxystic ways. Alteration of Ca channels cause muscle dysfunction periodic paralysis with or without potassium changes, myasthenia or myasthenic disorders, like Lambert Eaton syndrome, amyotrophic lateral sclerosis, Central Core disease, malignant hyperthermia. Cl and Na channels alterations produce myotonic diseases: Thomsen, Becker and paramyothonies, potassium sensible paralysis, fluctuant congenital myotonic, Andersen s syndrome. Channelopathies also produce various episodic ataxia type 1, type 2, spinocerebellar 6 and familial hemiplegic migraine. Abnormal paroxystic movements are present as channelophaties: episodic nocturnal dystonia, paroxystic dyskinesia. In some families are associates abnormal episodic movements and epilepsy. Several epileptic syndromes are also related with channels dysfunction: frontal lobe nocturnal epilepsy, choreoatetosis epilepsy, benign neonatal convulsions, generalized epilepsy with febrile convulsions plus. Conclusions Voltage gated channels dysfunction are related to diseases with episodic phenomena or permanent conditions on muscle or neuronal tissues, with clinical and genetic heterogenous manifestations.

Clinical, genetic and expression studies of human CNS channelopathies.

Abstract: This thesis describes clinical, molecular genetic and electrophysiological studies in two dominantly inherited CNS disorders; episodic ataxia type 1 (EA1) and episodic ataxia type 2 (EA2). Shortly before this work was initiated, evidence had been published that EA1 associated with mutations in the voltage gated potassium channel gene (KCNA1) and EA2 associated with mutations in the P/Q-type voltage gated calcium channel gene (CACNA1A). However, the frequency of mutations in these genes in patients with EA1 and EA2 was unknown. Furthermore, the range of phenotypes associated with mutations in these channels and their molecular mechanisms had not been defined. Through National and International collaboration, 42 individuals were identified from 20 families with a phenotype compatible with Kvl.l dysfunction. In addition, 29 individuals were identified from 20 families with a phenotype compatible with P/Q-type calcium channel dysfunction. Five previously unreported pathogenic heterozygous mutations were identified (A242P, P244FI, T226R, V404I and R417X) in the KCNAl gene. Although two of these mutations associated with typical EA1, three mutations associated with phenotypes which had not been reported previously. These included EA1 with epilepsy, epilepsy with myokymia and isolated myokymia. In addition to observing this new phenotypic variation between families, marked phenotypic variation within one family was observed. In family F, with the T226R mutation, the index case exhibited unusually severe disabling neuromyotonia without episodic ataxia, while his mother exhibited typical EA1 with mild neuromyotonia. This study shows the mechanism for this variability was not due to polymorphisms in a related potassium channel Kv1.2, which is known to co-assemble with Kvl.l. Using site directed mutagenesis, cDNA constructs harbouring each of the novel mutations were produced and the electrophysiological consequences of these mutations on the function of the potassium channel in a Xenopus laevis Oocyte system was studied. This revealed that all mutations reduced the delayed rectifying function of this channel to different degrees. This is predicted to result in increased neuronal excitability, which is likely to be the basis of the clinical phenotypes. There was some correlation between the electrophysiological data and the severity of the clinical phenotype. Five previously unreported heterozygous mutations were identified in CACNAlA (R1820X, Y1854X, 3404 ins ATCCAATCC, 6056 + 4 del AGTG and 3698 + 1 G>A) which are likely to be pathogenic. Although three of these new mutations (Y1854X, 6056 + 4 del AGTG and 3698 + 1 G>A) associated with typical EA2 phenotypes, one of them represented a previously undescribed mutational mechanism of intronic deletion (6056 + 4 del AGTG). RT-PCR analysis of this mutation provided evidence that the RNA was unstable. Two of the new mutations associated with previously unrecognised phenotypes. The first patient (R1820X) exhibited absence epilepsy and mental retardation in addition to EA2. This is the first evidence that dysfunction of this calcium channel may associate with epilepsy in humans and provides a link with a large body of data in mouse models of absence epilepsy. The second patient (3404 ins ATCCAATCC) exhibited a late onset, pure, non-episodic ataxia, similar to the phenotype associated with an abnormal CAG repeat expansion in the C-terminal region of CACNAlA (resulting in spinocerebellar ataxia type 6). One of the EA2 families without a mutation in CACNAlA was large enough to confirm linkage to CACNAlA. This suggests that mutations in non-coding regions of CACNAlA may also cause EA2. A cDNA construct harbouring the R1820X mutation was produced, allowing detailed molecular expression studies in the Xenopus laevis Oocyte system. This showed that the R1820X mutation resulted in a loss of function of the calcium channel. This is likely to be the basis of the disease, including the epilepsy, in this patient. These studies have identified novel pathogenic mutations in KCNAl and CACNAlA and have extended our knowledge about the clinical phenotypes associated with dysfunction of these ion channels. In addition, it has provided insights into the molecular mechanisms that underlie these CNS channelopathies.

Molecular genetic findings in migraine

Abstract: This review focuses on the different molecular genetic findings in migraine. Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura, which is inherited as an autosomal dominant. Half the cases of FHM are caused by point mutations in the CACNA1A gene on the short arm of chromosome 19 (19p). The gene encodes a calcium ion channel. Other mutation types cause episodic ataxia 2 (EA-2). Expansions of the CAG repeat in the 3' end bring about spinocerebellar ataxia 6 (SCA 6). Some families with FHM link to loci on the long arm of chromosome 1 (1q). The genes have not yet been identified. Some families neither link to 1q nor to 19p. Population-based family and twin studies have shown that migraine both with and without aura have a multifactorial inheritance. The CACNA1A gene may be of importance for ordinary forms of migraine in a few families. Mutations in genes on the X chromosome, dopamine receptor genes, and the ACE gene appear to be involved in migraine in a few families, whereas genes for nitric oxide synthase, serotonin receptors, and mitochondrial DNA do not seem to be involved. The positive associations have not been reproduced in other studies and therefore they should be interpreted with care. It is to be hoped that in the next few years much more will be known about the molecular genetic mechanisms of migraine with and without aura. FHM is an ion channel disorder, and many factors suggest that migraine is also an ion channel disorder, which is consistent with the paroxysmal nature of the illness.