Showing papers on "Episodic ataxia published in 2008"

Benign paroxysmal tonic upgaze, benign paroxysmal torticollis, episodic ataxia and CACNA1A mutation in a family.

Abstract: JO N 2 98 2 sodes of abnormal rotation and inclination of the head usually alternating from side to side associated with nausea, pallor, ataxia and sometimes abnormal truncal posture [1]. Attacks last a few hours to several days. Between the episodes of PTU or BPTI, neurological examination is normal; PTU and BPTI are both characterized by onset during the first year of life and time-limited occurrence. EA type 2 has onset during childhood (usually first or second decade) and persists into adulthood; episodes consist of attacks of ataxia lasting between 10 minutes to a few hours; half of the patients display vertigo, nausea, headache or weakness along with the ataxia; interictal nystagmus is common [7]. EA 2 is linked to the CACNA1A gene [9]. This gene, expressed throughout the nervous system, and particularly in the cerebellum and at the neuromuscular junction, encodes the pore forming subunit of the main transmembrane neuronal (P/Q type) voltage-gated calcium channel [8]. The pathophysiology of PTU and PBTI is still debated. We report a two-generation family (Fig. 1) with several individuals affected, respectively, by periAgathe Roubertie Bernard Echenne Julie Leydet Sophie Soete Benjamin Krams François Rivier Florence Riant Elisabeth Tournier-Lasserve

Hereditary episodic ataxias.

Abstract: Hereditary episodic ataxia (EA) syndromes are rare monogenic disorders that are phenotypically and genetically heterogeneous. The number of identified EA phenotypes is expanding. So far, mutations have been identified in four genes, all coding for membrane proteins including ion channels and transporters. The study of EA has illuminated previously unrecognized but important roles of ion channels and transporters in cerebellar function. This review summarizes recent advances and focuses on practical approaches in the diagnosis and treatment of episodic ataxia.

Aminopyridines for the treatment of cerebellar and ocular motor disorders

Abstract: Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus. It is hypothesized to occur when physiological inhibitory cerebellar input, namely of the flocculus, to the vestibular nuclei is inhibited. The second most frequent form of acquired nystagmus is upbeat nystagmus (UBN). UBN is probably caused by an imbalance of vertical vestibulo-ocular reflex tone. GABA-ergic substances like baclofen have been used to treat DBN and UBN, but they have had only moderate success. Animal experiments have shown that aminopyridines [3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP)], nonselective blockers of the Kv family of voltage-gated potassium channels, increase Purkinje-cell (PC) excitability. It was assumed that such enhancement of PC activity could restore to normal levels the inhibitory influence of the cerebellar cortex on vertical eye movements. On the basis of these assumptions, we evaluated the efficacy and underlying mechanisms of aminopyridines in DBN and UBN as well as in another cerebellar disorder with an impaired PC function: episodic ataxia type 2 (EA2), which is caused by mutations of the PQ-calcium channel. In a placebo-controlled trial on 17 patients we demonstrated that 3,4-DAP significantly reduces the intensity of DBN. This was confirmed in a recent study with 4-AP, which also showed that 4-AP restores gaze-holding ability independently of fixation in DBN. The efficacy of 4-AP in UBN was demonstrated in single patients. Finally, in an open trial on three patients with EA2 we showed that 4-AP prevents attacks of ataxia. This was also found in an animal model (the tottering mouse) of EA2. The clinical efficacy of 4-AP in EA2 is being further evaluated in an ongoing randomized controlled crossover trial. In conclusion, the use of aminopyridines in DBN, UBN, and EA2 is a new treatment principle for vestibular, cerebellar, and ocular motor disorders.

Novel mutation in KCNA1 causes episodic ataxia with paroxysmal dyspnea.

Abstract: Episodic ataxia type 1 (EA1) is an autosomal-dominant neurological disease caused by point mutations in the potassium channel-encoding gene KCNA1. It is characterized by attacks of ataxia and continuous myokymia. Respiratory muscle involvement has not been previously reported in EA1. We clinically evaluated a family with features of EA1 and paroxysmal shortness of breath. Coding and flanking intronic regions of KCNA1 were sequenced. We identified a novel 3-nucleotide deletion mutation in KCNA1 in the affected individuals. Our findings of a deletion mutation with unusual respiratory muscle involvement expand the genetic and clinical spectrum of EA1.

Large CACNA1A Deletion in a Family With Episodic Ataxia Type 2

Abstract: Background Episodic ataxia (EA) is an ion channel disorder that manifests as paroxysmal attacks of imbalance and incoordination. Episodic ataxia type 2 (EA2) is characterized by prolonged episodes of ataxia with interictal nystagmus and is caused by mutations inCACNA1A. All mutations identified thus far (to our knowledge) are nonsense or missense point mutations. Objective To describe a family with EA2 having a novel mutation deleting several exons ofCACNA1A. Design Clinical and molecular study of a family manifesting EA2 attacks. Setting Academic research. Patients DNA was extracted from blood samples of 3 family members. Main Outcome Measures Microsatellite genotyping ofCACNA1A, quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF), and sequencing were performed. Results Genotyping ofCACNA1Ashowed nonmendelian inheritance of a CAG repeat located at the 3′ end of the gene in a mother and daughter, suggesting a deletion event, which was subsequently confirmed by QMPSF analysis and sequencing. This 39.5-kilobase deletion removes the last 16 coding exons of the gene. Conclusion Deletion of several exons ofCACNA1Amay cause EA2 and should be assessed in patients having EA2 without aCACNA1Apoint mutation.

Pyruvate Dehydrogenase Deficiency Presenting as Intermittent Isolated Acute Ataxia

Abstract: Objective: The aim of this study is to report and emphasize unusual presentations of pyruvate dehydrogenase (PDH) deficiency (OMIM 312170). Methods: PDH activity and PDHA1 gene were studied in two siblings presenting with intermittent ataxia in childhood. Similar presentations in reported PDH-deficient patients were searched for using the Medline database. Results: Both patients had PDH deficiency caused by a new mutation (G585C) in the PDHA1 gene, which is predicted to replace a highly conserved glycine at codon 195 by alanine. Although this mutation lies within the thiamine pyrophosphate binding domain, there was no thiamine responsiveness in vivo. The patients presented recurrent episodes of acute isolated ataxia in infancy. Both had normal blood and CSF lactate levels. Although symptoms initially resolved between episodes during the first decade, both patients subsequently worsened and developed progressive and severe encephalopathy, leading to death in their twenties. The spectrum of intermittent presentations in PDH deficiency includes episodic ataxia, intermittent peripheral weakness, recurrent dystonia and extrapyramidal movement disorders. Conclusions: PDH deficiency should be considered in patients with unexplained intermittent and recurrent acute neurological symptoms. Long-term prognosis and outcome remain uncertain. PDH deficiency can occur even with normal CSF lactate concentration.

Progressive cerebellar ataxia with variable episodic symptoms--phenotypic diversity of R1668W CACNA1A mutation.

Abstract: We describe a family with an R1668W mutation in the CACNA1A gene who presented with a broader clinical spectrum and more variable features than previously reported. The mother had a pure progressive cerebellar ataxia of late onset with downbeat nystagmus, whereas her daughter suffered from episodic ataxia, hemiplegic migraine, and progressive cerebellar ataxia with horizontal gaze-evoked and rebound nystagmus. In both patients, treatment with acetazolamide was ineffective and worsened baseline ataxia, whereas flunarizine ameliorated episodic symptoms. Our report highlights profound phenotypic variability that can be associated with CACNA1A mutations and adds important therapeutic considerations.

Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family

Abstract: Clinical examinations and mutational analyses were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.

Axonal function in a family with episodic ataxia type 2 due to a novel mutation.

Abstract: Episodic ataxia type 2(EA-2) is a rare, autosomal dominantdisorder characterised by recurrentepisodes of ataxia and dysarthria,due to mutations in the CACNA1A gene on chromosome 19encoding voltage-dependent Ca2+channels. The aim of the presentstudy was to explore whether axonalmembrane properties, assessedusing nerve excitability techniques, were abnormal in patients with EA-2 . Nerve excitability techniqueswere applied to the median nerveof three individuals from threegenerations of a single family, all ofwhom had typical features of EA-2. This family was found to have anovel mutation at codon 1451 ofthe Ca2+ channel alpha 1A subunit.Nerve excitability testing demonstratedsignificant abnormalities,with all patients outside the normal95 % confidence limits in having ahigh rheobase and reduced earlyhyperpolarizing threshold electrotonus. On average there were alsosignificant reductions in refractoriness,late subexcitability and earlydepolarizing threshold electrotonus.Mathematical modelling indicatedthat a similar pattern of abnormalitiesmay result from areduced voltage dependence ofslow K+ channels (KCNQ channels). There are significant and distinctivechanges in peripheralnerve excitability in EA-2 patients,which are presumably induced indirectly. These findings raise thepossibility that excitability testingmay prove a convenient screeningtest for patients with this suspectedchannelopathy.

Episodic ataxia: SLC1A3 and CACNB4 do not explain the apparent genetic heterogeneity.

Abstract: JO N 2844 pedigree with an EA2-like phenotype (now denoted EA5) and another with juvenile myoclonic epilepsy. However, there were another 69 families where no mutation was identified. The importance of CACNB4 mutations in EA2 remains unclear [5]. Mutant β4-subunits showed a modest functional effect when co-assembled with the α1-subunit [5]. Recently, a mutation was identified in SLC1A3 in a patient with episodic ataxia, hemiplegic migraine and epilepsy, now denoted EA6. SLC1A3 encodes the astrocyte-specific excitatory amino acid transporter, EAAT1. The mutant protein showed dramatically reduced function in vitro [6]. Mutations in CACNB4 and SLC1A3 have not been reported in pure EA2 cases. We analysed these in a cohort of EA2 patients with complex phenotypes including epilepsy. Samples were referred from around the UK and were selected by having a classical clinical history of EA2 (e.g. age of onset, attack duration, triggers, response to acetazolamide) [1]. Three patients with a typical history of familial hemiplegic migraine (FHM), as defined by the International Headache Society, were also included. Of these 16 patients, 14 had epilepsy or an epileptiform EEG in addition to EA2. A further 5 patients were selected as SLC1A3 candidates due to a complicated phenotype including EA2 +/– FHM, in addition to epilepsy, cognitive impairment or coma. No patients had mutations in the coding regions of CACNA1A. FHM patients were not screened for mutations in ATP1A3 or SCN1A. A total of 21 patients were screened for SLC1A3 and 16 for CACNB4, see Table 1. CACNB4 was amplified as previously described [5], except exons 1A, 5 and 13, for which new primers were designed. SLC1A3 was amplified with 9 pairs of oligonucleotide primers (sequences Tracey D. Graves Michael G. Hanna