Showing papers on "Episodic ataxia published in 1999"
TL;DR: Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology, nephrology, and cardiology, with interesting parallels in mechanisms of disease emphasized.
Abstract: By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes
550 citations
TL;DR: It is reported that alternative splicing of the α1A subunit gene results in channels with distinct kinetic, pharmacological and modulatory properties, as well as multiple phenotypic variants.
Abstract: P-type and Q-type calcium channels mediate neurotransmitter release at many synapses in the mammalian nervous system. The α1A calcium channel has been implicated in the etiologies of conditions such as episodic ataxia, epilepsy and familial migraine, and shares several properties with native P- and Q-type channels. However, the exact relationship between α1A and P- and Q-type channels is unknown. Here we report that alternative splicing of the α1A subunit gene results in channels with distinct kinetic, pharmacological and modulatory properties. Overall, the results indicate that alternative splicing of the α1A gene generates P-type and Q-type channels as well as multiple phenotypic variants.
407 citations
TL;DR: A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members, suggesting that the epilepsy in EA1 may be caused by the dysfunctional potassium channel.
Abstract: 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.
320 citations
TL;DR: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine, and to delineate better the clinical spectrum.
Abstract: Objective: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. Background: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the α1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified—in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype–phenotype correlations relied on the analysis of very few families. Methods: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. Results: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. Conclusion: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).
191 citations
TL;DR: Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.
Abstract: What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are “paroxysmal disorders” whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.
186 citations
TL;DR: Haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events and could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.
Abstract: Summary Familial hemiplegic migraine (HM) is an autosomal dominant migraine with aura. In 20% of HM families, HM is associated with a mild permanent cerebellar ataxia (PCA). The CACNA1A gene encoding the α1A subunit of P/Q-type voltage-gated calcium channels is involved in 50% of unselected HM families and in all families with HM/PCA. Four CACNA1A missense mutations have been identified in HM: two in pure HM and two in HM/PCA. Different CACNA1A mutations have been identified in other autosomal dominant conditions: mutations leading to a truncated protein in episodic ataxia type 2 (EA2), small expansions of a CAG trinucleotide in spinocerebellar ataxia type 6 and also in three families with EA2 features, and, finally, a missense mutation in a single family suffering from episodic ataxia and severe progressive PCA. We screened 16 families and 3 nonfamilial case patients affected by HM/PCA for specific CACNA1A mutations and found nine families and one nonfamilial case with the same T666M mutation, one new mutation (D715E) in one family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HM families whose disease appears to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.
182 citations
TL;DR: A nonsense mutation in CACNA1A causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.
Abstract: Objective: To identify the disease-causing mutation and to characterize penetrance and phenotypic variability in a large pedigree with episodic ataxia type 2 (EA-2) previously linked to chromosome 19. Background: Mutations in the CACNA1A gene on chromosome 19 encoding a calcium channel subunit cause EA-2, which is characterized by recurrent attacks of imbalance with interictal eye movement abnormalities. Methods: The authors used single-strand conformation polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing to identify mutations in CACNA1A. Allele-specific oligonucleotides were designed to detect the presence of the diseased allele in members of their pedigree as well as in normal control subjects. Results: Reassessment of members of the pedigree revealed two notable clinical features. Diffuse weakness during attacks of ataxia was a prominent complaint. Two affected individuals had had episodic hemiplegia, one with typical migraine headaches. SSCP analysis revealed aberrant bands in exon 29 in affected members but not in normal control subjects. Direct sequencing of exon 29 identified a C-to-T change at position 4914 of the coding sequence of CACNA1A, predicting an early stop code at codon 1547. Two asymptomatic mutation carriers demonstrated the incomplete penetrance of this mutation. Conclusions: A nonsense mutation in CACNA1A causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.
123 citations
TL;DR: Using behavioral and immediate-early gene indicators of regional brain excitability, it is found that a seizure-sensitive predisposition exists in Kv1.1 –/– animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated.
Abstract: Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 alpha-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (-/-, +/-, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 -/- animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/- mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1. 1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.
104 citations
TL;DR: The results demonstrate that human Kv1.2 and KV1.1 subunits coassemble to form a novel channel with distinct gating properties that are altered profoundly by EA‐1 mutations, thus uncovering novel physiopathogenetic mechanisms of episodic ataxia type‐1 myokymia syndrome.
Abstract: Episodic ataxia type-1 syndrome (EA-1) is an autosomal dominant neurological disorder that manifests itself during infancy and results from point mutations in the voltage-gated potassium channel gene hKv1.1. The hallmark of the disease is continuous myokymia and episodic attacks of spastic contractions of the skeletal muscles, which cause permanent disability. Coexpression of hKv1.1 and hKv1.2 subunits produces heteromeric potassium channels with biophysical and pharmacological properties intermediate between the respective homomers. By using tandemly linked subunits, we demonstrate that hKv1.1 subunits bearing the EA-1 mutations V408A and E325D combine with hKv1.2 to produce channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence. Moreover, hKv1.1V408A single-channel analysis reveals a ∼threefold reduction of the mean open duration of the channel compared with the wild-type, and this mutation alters the open-state stability of both homomeric and heteromeric...
75 citations
TL;DR: It is concluded that the lower expression level in the F184C mutant channels is due to a reduced number of functional channels on the cell surface, and this study confirms and extends earlier studies on the functional consequences of Kv1.1 wild‐type or mutant channels.
Abstract: Episodic ataxia type 1 (EA-1) is a rare neurological disorder and was the first ionic channel disease to be associated with defects in a potassium channel. Until now 10 different point mutations in the KCNA1-gene have been reported to cause this disorder. We have investigated the functional consequences of two mutations leading to amino acid substitutions in the first and sixth transmembrane segments of a Kv1.1 channel subunit, by means of the patch-clamp technique; we injected cRNA coding for, respectively, F184C and V408A mutant Kv1.1 channels into mammalian cells and compared the resulting currents with those in the wild-type. The expression levels of F184C and V408A mutant channels relative to that of the wild-type was 38 and 68%, respectively. Since the single-channel conductance of the F184C mutant was similar to that of the wild-type (12 pS) without an apparent change in the maximum open probability, we conclude that the lower expression level in the F184C mutant channels is due to a reduced number of functional channels on the cell surface. F184C activated slower, and at more depolarized potentials, and deactivated faster compared with the wild-type. V408A channels deactivated and inactivated faster compared with the wild-type. Studies with different extracellular cations and tetraethylammonium gave no indication that the pore structure was changed in the mutant channels. Acetazolamide, that is helpful in some patients suffering from EA-1, was without effect on Kv1.1 wild-type or mutant channels. This study confirms and extends earlier studies on the functional consequences of Kv1.1 mutations associated with EA-1, in an attempt to understand the pathophysiology of the disease.
37 citations
Journal Article•
TL;DR: The observations in these two families suggest that the co-occurrence of epilepsy (particularly benign infantile convulsions), paroxysmal movement disorders and migraine is not due to chance and these distinct clinical phenomena could have a shared biological basis and ion channel defects are an attractive possibility.
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 co-occurrence 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.
TL;DR: In a large kindred with EA1 where two out of five affected family members have epilepsy, a previously undescribed point mutation in the second membrane-spanning domain of KCNA1 results in a change of threonine at amino acid position 226 to arginine (T226R), and patients were heterozygous for T226R, while none of the unaffected family members nor 100 control individuals carried the mutation.
Abstract: pisodic ataxia type 1 (EA1) is a rare autosomal dominant neurological disorder in which patients develop sudden episodes of ataxia precipitated by physical or emotional stress. These can last seconds to minutes, and between attacks patients often have spontaneous, repetitive muscle activity (myokymia), which is not always clinically apparent. Missense point mutations in KCNA1, the gene encoding the human orthologue of Kv1.1 on chromosome 12p13, have been linked to EA1, and the physiological properties of some mutations have been studied. In a large kindred with EA1 where two out of five affected family members have epilepsy we recently detected a previously undescribed point mutation in the second membrane-spanning domain of KCNA1. This mutation results in a change of threonine at amino acid position 226 to arginine (T226R). Further linkage study using mismatch primer PCR revealed that patients were heterozygous for T226R, while none of the unaffected family members nor 100 control individuals carried the mutation. T226 is highly conserved in the Kv1 subfamily through different species, and the replacement by an arginine side chain is a radical exchange. We therefore expressed wild-type and mutant hKv1.1 subunits in Xenopus laevis oocytes to investigate the functional implications of T226R.
TL;DR: The 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.
TL;DR: The pedigree of a 39-year-old woman with a history of simultaneous Familial hemiplegic migraine and hemicrania continua gives further evidence that cyclic syndromes in childhood belong to the spectrum of migraine.
Abstract: A case is presented of a 39-year-old woman with a history of simultaneous Familial hemiplegic migraine (FHM) and hemicrania continua (HC). The family history of the patient revealed different types of migraine and cyclic syndromes in childhood in four generations. The possible links between FHM and HC are discussed. The pedigree gives further evidence that cyclic syndromes in childhood belong to the spectrum of migraine.
TL;DR: It is concluded that the SCA6 CAG repeat is not associated with schizophrenia susceptibility, however, it remains possible that other variants in the region could be involved.
Abstract: The P/Q type Ca2+ channel alpha 1-subunit (CACN1A4) gene on chromosome 19p13 is a promising candidate susceptibility locus for schizophrenia. Point mutations in CACN1A4 cause familial hemiplegic migraine and episodic ataxia. Expansion in a coding 3' CAG repeat causes spino-cerebellar ataxia type 6 (SCA6). The mouse mutant phenotype totterer has a form of petit-mal epilepsy. These are neurological conditions, all of which exhibit features in common with schizophrenia. The 19p13 area is also paralogous to other genomic regions of interest in schizophrenia genetics. For these reasons, we performed an association study with the CAG repeat and schizophrenia using 225 Scottish schizophrenia and 198 unrelated Scottish controls. The repeat was not associated with the disorder (P = 0.72) and neither did the schizophrenics have significantly longer alleles than the controls (P = 0.45). We conclude that the SCA6 CAG repeat is not associated with schizophrenia susceptibility. However, it remains possible that other variants in the region could be involved.