Showing papers on "Episodic ataxia published in 2006"

Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia.

Abstract: Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (KCa) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that KCa channels may constitute a potential therapeutic target in EA2.

Pathomechanisms in channelopathies of skeletal muscle and brain

Abstract: Ion channelopathies are a diverse array of human disorders caused by mutations in ion channel genes. This review focuses on the pathogenic mechanisms of channelopathies affecting skeletal muscle and brain arising from mutations of voltage-gated ion channels and fast ligand-gated ion channels expressed at the surface membrane. Derangements in channel function alter the electrical excitability of the cell and thereby increase susceptibility to transient symptomatic attacks including myasthenia, periodic paralysis, myotonic stiffness, seizures, headache, dyskinesia, or episodic ataxia. Although these disorders are rare, they stand out as exemplary cases for which disease pathogenesis can be traced from a point mutation to altered protein function, to altered cellular activity, and to clinical phenotype. The study of these disorders has provided insights on channel structure-function relations, the physiological roles of ion channels, and rational approaches toward therapeutic intervention for many disorders of cellular excitability.

Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4‐1.1/Kvβ1.1 and Kv1.4‐1.1/Kvβ1.2

Abstract: 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.

Acetazolamide acts directly on the human skeletal muscle chloride channel

Abstract: Acetazolamide, a carbonic anhydrase inhibitor, is used empirically in neuromuscular diseases with episodic ataxia, weakness, and myotonia, although not all of the mechanisms responsible for its therapeutic effects are understood. To elucidate whether acetazolamide acts directly on the human skeletal muscle voltage-gated chloride channel (ClC-1), which is associated with myotonia, we evaluated the effects of acetazolamide on ClC-1 expressed in cultured mammalian cells, using whole-cell recording. Acetazolamide significantly shifted the voltage dependency of the open probability (P(o)) toward negative potentials in a dose-dependent manner, resulting in an increase of chloride conductance at voltages near the resting membrane potential. This effect was attenuated when using a pipette solution containing 30 mmol/L Hepes. These results suggest that acetazolamide can influence the voltage-dependent opening gate of ClC-1 through a mechanism related to intracellular acidification by inhibiting carbonic anhydrase, and that the therapeutic effects of acetazolamide in neuromuscular diseases may be mediated by activation of ClC-1.

Chronic neuromyotonia as a phenotypic variation associated with a new mutation in the KCNA1 gene.

Abstract: Sirs: Episodic ataxia type 1 (EA1) is an autosomal dominant disorder ascribed to mutations in KCNA1 encoding voltage-gated delayedrectifier type potassium channels (Kv1.1). Patients typically develop in early childhood brief episodes of cerebellar ataxia and dysarthria with persistent interictal myokymia [9]. We describe a family exhibiting intrafamilial phenotypic variability (Fig. 1). The proband (IV-1), a 28 year old woman developed episodic ataxia at the age of four. Attacks were triggered by physical training, sudden movement and emotional upset. Their frequency varied from 0–10 times a day to once a week and lasted from a few seconds to minutes. During episodes, ataxia, dysarthria, nodding movements of the head and rhythmic jerks of the arms were present. As she grew up, attacks were progressively replaced by a permanent and continuous rippling of muscles in the lower limbs and neck. Physical exertion, cold weather and hyperventilation increased muscular undulations and induced severe cramps and muscle stiffness. Physical examination showed myokymia and hypertrophy of both calves and the left sternocleidomastoid muscle with a pseudo-dystonic attitude of the neck. Cerebellar signs were absent. Electroencephalography and cerebellar MRI were normal. Electromyography (EMG) showed continuous motor unit activity at rest in all the tested muscles. Myokymic discharges had a frequency of 3 to 5 Hz. Motor nerve conduction velocities were normal. Clonazepam, carbamazepine and amitriptyline were ineffective. Eleven members of the proband’s family were reported to suffer from typical attacks of ataxia since childhood with resolution in adulthood. Three of them were examined (III-2, III-3, III7). They had fine muscle rippling in facial muscles, hands and forearms or thighs and calves without hypertrophy, and myokymia on EMG. After informed consent, genetic analysis was performed on five affected members. Direct DNA sequence analysis of the entire KCNA1 gene revealed a heterozygous change consisting in a C to T transition at position 913. This mutation, confirmed by double restriction digestion, resulted in a Leucine to Phenylalanine substitution at codon 305 in the fourth transmembrane segment of the protein and was not detected in 174 control chromosomes (Fig. 2). Several mutations in KCNA1 gene have been identified with various familial phenotypes. The most frequent is EA1 [1, 8] but clinical variations consisting in isolated neuromyotonia or ataxia, association of epilepsy and myokymia, epilepsy and ataxia, EA1 and muscle weakness have been reported [2, 4, 5, 11]. Usually all the affected members have the same clinical pattern in a given family. Here we report a family with intrafamilial phenotypic variability. Some patients had typical EA1 with disappearance of attacks in adulthood. Others experienced occasional attacks persisting in late adulthood, associated with mild myokymia. The most unusual presentation LETTER TO THE EDITORS

Alternating hemiplegia of childhood: no mutations in the glutamate transporter EAAT1.

Abstract: Alternating hemiplegia of childhood (AHC) is a severe brain disorder, mainly characterised by episodes of hemiplegia, progressive mental retardation, and other severe paroxysmal and permanent neurological symptoms. Clinically and genetically, there is some overlap with sporadic (SHM) and familial (FHM) hemiplegic migraine, a severe monogenic subtype of migraine. Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2 ATP1A2 gene in a family with AHC. Recently, a missense mutation was found in the SLC1A3 gene that encodes the glutamate transporter EAAT1, in a patient with alternating hemiplegia, episodic ataxia, seizures, and headache. Because of the remarkable clinical similarities and the potential role of glutamate in AHC, we analysed six sporadic patients with AHC for mutations in the SLC1A3 gene. No mutations were found. The SLC1A3 EAAT1 glutamate transporter gene does not seem to be involved in the pathogenesis of AHC.

Aggravation of Ataxia Due to Acetazolamide Induced Hyperammonaemia in Episodic Ataxia

Abstract: Acetazolamide has been used to reduce the number of attacks in patients with episodic ataxia type 2 (EA 2), presumably by inhibiting carbonic anhydrase, which results in brain acidosis and reduction of brain lactate and pyruvate levels.1 However, metabolic acidosis itself may give rise to several clinical manifestations, and there have been case reports describing drowsy mentality with metabolic acidosis by acetazolamide intoxication.2,3 We report on a patient with EA 2, who initially had a good response to acetazolamide for 2 years but later developed aggravation of ataxia with drowsy mentality caused by acetazolamide induced hyperammonaemia. A 49-year-old man reported dizziness and ataxia which had started 4 days before admission. He had experienced several episodes of similar symptoms for the past 4 years. He had recurrent episodes of headaches, dizziness, nausea/vomiting, dysarthria and ataxia which had lasted for hours to days. Between the episodes, he showed gaze evoked nystagmus without spontaneous nystagmus. Horizontal head thrust tests were normal. Vibratory stimuli on both mastoids, horizontal head oscillation or hyperventilation did not induce nystagmus. Other findings of the neurological examination were normal. During the episodes, examination disclosed downbeat and aggravated gaze evoked nystagmus, rebound nystagmus, positional downbeat nystagmus, impaired smooth pursuit, hypometric saccades, slurred speech, and gait and limb ataxia. Vibratory stimuli on both mastoids, and horizontal head oscillation augmented …

Ацетазоламид в детской неврологической практике: история и перспективы практического применения

Abstract: Resume the up tob date pharmacological and clinical findings have revealed new opportunities for the use of known for a long time pharmaceutical agents in various fields of practical medicine For more than 50 years acetozolamide, systemic carbonic anhydrase inhibitor, has been used in neurology to correct liquorodynamic disorders High clinical efficacy and good tolerb ability in longbterm use has made acetazolamide an essential agent in pediatric neurology, along with this the true therapeutic application of acetazolamide is much wider than it was traditionally thought This review analyzes the experience of administration of the drug in different branches of pediatric neurology, including those where acetazolamide has been traditionally used along with novel applications to administration of the drug in children Key words: acetozolamide, carboanhydrase, children, sleep apnea syndrome, glaucoma, hydrocephaly, episodic ataxia type II, migraine, intracranial idiopathic benign hemiplegic hypertension

Headache characteristics in episodic ataxia.

Abstract: We report a 33-year-old English female, presented elsewhere with frequent headaches for few months. The headaches were incapacitating, involved either temporoparietal region, throbbing, lasting 4–5 h and associated with photophobia, phonophobia, and nausea and vomiting. There was no preceding aura or associated neurological deficits. She denied any past or family history of migraine. Headaches continued despite propranolol and ergot preparations. Few weeks later during an episode of headache, she complained of blurred vision and pain around left eye. Additionally, she had few falls that occurred without warning or loss of consciousness. Magnetic resonance imaging (MRI) of brain was normal. With a clinical diagnosis of retrobulbar neuritis, oral steroids were started. As there was no relief, she decided to come to our tertiary care center for further evaluation. At our center, she mostly preferred to stay in bed due to incapacitating headache, severe photophobia and a sense of unsteadiness. Initial neurological and ophthalmological examinations were unremarkable with no clinical evidence of retrobulbar neuritis. A mild weakness with Babinski’s response was noted in her left leg, which she related to horse riding injuries in childhood. The blood investigations, cerebrospinal fluid analysis and MRI studies of brain, cervical and thoraco-lumbar spine were unremarkable. No oligoclonal bands were seen in the cerebrospinal fluid. Various agents like amitryptiline, carbamazepine, propranolol and flunarazine in different combinations resulted in only partial and temporary relief. During one of the hospitalizations, some transient episodes of intermittent intention tremors of left hand, nystagmus, slurred speech and ataxia were observed. The episodic nature of ataxic attacks and unremarkable investigations led to a possible diagnosis of episodic ataxia and detailed family history was sought. She was found to be an adopted child with no details about her original parentage. She confessed of being clumsy child with frequent falls . Further genetic studies showed mutation in alpha-1 subunit of CACNA1Aconsistent with a diagnosis of Episodic Ataxia-2 (EA-2). Acetazolamide, 250 mg twice daily, resulted in a dramatic response in headache as well as ataxic attacks sustained over the subsequent 2 years of follow-up.