Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease/SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion-chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementation with vitamin E. Familial episodic ataxias with (EA1-chromosome 12p) and without (chromosome 19p-EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 11q) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better understanding of the pathogenesis and eventual treatment of the several forms of hereditary ataxias.
 ...
PMID:[Hereditary cerebellar ataxias: from hammer to genetics]. 962 25

Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized by brief episodes of ataxia associated with continuous interattack myokymia. Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on chromosome 12p13 have recently been shown to associate with EA1. A Scottish family with EA1 harbouring a novel mutation in this gene is reported. Of the five affected individuals over three generations, two had partial epilepsy in addition to EA1. The detailed clinical, electrophysiological and molecular genetic findings are presented. The heterozygous point mutation is located at nucleotide position 677 and results in a radical amino acid substitution at a highly conserved position in the second transmembrane domain of the potassium channel. Functional studies indicated that mutant subunits exhibited a dominant negative effect on potassium channel function and would be predicted to impair neuronal repolarization. Potassium channels determine the excitability of neurons and blocking drugs are proconvulsant. A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members. These observations indicate that this mutation is pathogenic and suggest that the epilepsy in EA1 may be caused by the dysfunctional potassium channel. It is possible that such dysfunction may be relevant to other epilepsies in man.
 ...
PMID:A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. 1035 68

Episodic ataxia type 1 is a rare, autosomal dominant neurological disorder caused by missense mutations of the Kv1.1 gene from the Shaker K+ channel subfamily. To study the functional effects of the disease-causing mutations in a robust K+ channel background, we introduced seven different episodic ataxia type 1 substitutions into the corresponding, conserved residues of the Shaker K+ channel. K+ channel currents expressed in Xenopus oocytes were studied by electrophysiology. All episodic ataxia type 1 mutations produced functional K+ channels. In a Shaker N-terminal deletion mutant with fast inactivation removed, current amplitudes were significantly reduced in channels harboring an episodic ataxia type 1 mutation. Six of the seven mutations also showed depolarizing shifts (+9 to +36 mV) in the conductance voltage dependence. One mutation (F307I) shifted the midpoint of the conductance-voltage relationship by 23 mV in the hyperpolarizing direction. Episodic ataxia type 1 mutations were also expressed in ShakerH4 with intact N-terminal inactivation. In this construct, current amplitudes for episodic ataxia type 1 mutants were not significantly different from wild-type channels. All mutations altered the voltage range of steady-state inactivation; most changes were coupled to the changes in activation gating. Some episodic ataxia type 1 mutants also caused significant changes in the kinetics of N-type (F307I, E395D) or C-type (F307I, E395D, V478A) inactivation. These results suggest that episodic ataxia type 1 mutations may change K+ channel function by two mechanisms: (i) reduced channel expression and (ii) altered channel gating.
 ...
PMID:Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium channel. 1039 59

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.
 ...
PMID:The inherited episodic ataxias: how well do we understand the disease mechanisms? 1148 47

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.
 ...
PMID:An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus. 1167

The familial episodic ataxias are prototypical inherited channelopathies that result in episodes of vertigo and ataxia triggered by stress and exercise. Episodic ataxia type 1 (EA-1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA-2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A. These ion channels are crucial for both central and peripheral neurotransmission. Within the last few years, the genetic mechanisms underlying these relatively rare familial episodic ataxia syndromes have been worked out. They provide a model for understanding the mechanisms of more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine. Migraine affects as many as 15-20% of the general population, and it has been estimated that about 25% of patients with migraine experience spontaneous attacks of vertigo and ataxia. We identified 24 families with migraine and benign recurrent vertigo inherited in an autosomal dominant fashion. These families have numerous features in common with EA-1 and EA-2 (particularly EA-2), suggesting that benign recurrent vertigo may be an inherited channelopathy. An ion channel mutation shared by brain and inner ear could explain the combined central and peripheral features of the syndrome.
 ...
PMID:Genetics of familial episodic vertigo and ataxia. 1196 Aug 17

In the past decade, the genetic etiologies accounting for most cases of adult-onset dominant cerebellar ataxia have been discovered. This group of disorders, generally referred to as the spinocerebellar ataxias (SCAs), can now be classified by a simple genetic nosology, essentially a sequential list in which each new SCA is given a number. However, recent advances in the elucidation of SCA pathogenesis provide the opportunity to subclassify the disorders into three discrete groups based on pathogenesis: 1) the polyglutamine disorders, SCAs 1, 2, 3, 7, and 17, which result from proteins with toxic stretches of polyglutamine; 2) the channelopathies, SCA6 and episodic ataxia types 1 and 2 (EA1 and EA2), which result from disruption of calcium or potassium channel function; and 3) the gene expression disorders, SCAs 8, 10, and 12, which result from repeat expansions outside of coding regions that may quantitatively alter gene expression. SCAs 4, 5, 9, 11, 13-16, 19, 21, and 22 are of unknown etiology, and may or may not fit into one of these three groups. At present, most diagnostic and therapeutic strategies apply equally to all of the SCAs. Therapy specific for individual diseases or types of diseases is a realistic goal in the foreseeable future.
 ...
PMID:The spinocerebellar ataxias: order emerges from chaos. 1216 26

We describe a unique family in which several individual are affected with episodes of ataxia that best fit the phenotype of episodic ataxia type 2 (EA2). All of the affected family members had episodes typically lasting for several hours, and none of them had muscle abnormalities including myokymia. Episodic ataxia type 1 (EA1) was not considered initially as a clinical diagnosis for the affected individuals in this family. However, by linkage mapping, sequencing and polymorphism analysis, all affecteds were found to have a novel mutation in KCNA1. Numerous missense mutations have been described previously in KCNA1 that cause EA1. The mutation c.1025G>T replaces a highly conserved serine with isoleucine at position 342 (p.Ser342Ile) in the highly conserved fifth transmembrane domain of the KCNA1. This mutation leads to a distinct clinical phenotype without myokymia broadening the scope of clinical characteristics of EA1 and highlighting the heterogeneity of phenotypic effects from distinct missense mutations.
 ...
PMID:A novel mutation in KCNA1 causes episodic ataxia without myokymia. 1553 32

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by constant muscle rippling movements (myokymia) and episodic attacks of ataxia. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene KCNA1 (hKv1.1), which alter the delayed-rectifier function of the channel. Shaker-like channels of different cell types may be formed by unique hetero-oligomeric complexes comprising Kv1.1, Kv1.4 and Kvbeta1.x subunits. Here we show that the human Kvbeta1.1 and Kvbeta1.2 subunits modulated the functional properties of tandemly linked Kv1.4-1.1 wild-type channels expressed in Xenopus laevis oocytes by (i) increasing the rate and amount of N-type inactivation, (ii) slowing the recovery rate from inactivation, (iii) accelerating the cumulative inactivation of the channel and (iv) negatively shifting the voltage dependence of inactivation. To date, the role of the human Kv1.4-1.1, Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2 channels in the aetiopathogenesis of EA1 has not been investigated. Here we also show that the EA1 mutations E325D, V404I and V408A, which line the ion-conducting pore, and I177N, which resides within the S1 segment, alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N-type inactivation and by accelerating the recovery from fast inactivation. Furthermore, the E325D, V404I and I177N mutations shifted the voltage dependence of the steady-state inactivation to more positive potentials. The results demonstrate that the human Kvbeta1.1 and Kvbeta1.2 subunits regulate the proportion of wild-type Kv1.4-1.1 channels that are available to open. Furthermore, EA1 mutations alter heteromeric channel availability which probably modifies the integration properties and firing patterns of neurones controlling cognitive processes and body movements.
 ...
PMID:Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2. 1715 68

Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.
 ...
PMID:Episodic ataxia type 1: a neuronal potassium channelopathy. 1739 36


1 2 3 4 Next >>