Showing papers on "Episodic ataxia published in 2011"

A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias

Abstract: Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 ( p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP ( p = 0.08). The VDADL score decreased from 6.00 to 1.50 ( p = 0.02). 4AP was well-tolerated. Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

Management of vestibular migraine

Abstract: Vestibular migraine is considered to be the second most common cause of vertigo and the most common cause of spontaneous episodic vertigo. The duration of attacks varies from seconds to days, usually lasting minutes to hours, and they mostly occur independently of headaches. Long-lasting individual attacks are treated with generic antivertiginous and antiemetic drugs. Specific antimigraine drugs are unlikely to be very effective for rescue. The mainstay of the management of vestibular migraine is prophylactic medication. To date, there are no controlled trials available; the body of knowledge builds on case series and retrospective or observational studies. Most drugs are also used for the prevention of migraine headaches. The choice of medication should be guided by its side effect profile and the comorbidities of patients. Betablockers such as propanolol or metoprolol are preferred in patients with hypertension but in the absence of asthma. Anticonvulsants include topiramate when patients are obese, valproic acid and lamotrigine. Lamotrigine is preferred if vertigo is more frequent than headaches. Calcium antagonists include verapamil and flunarizine. If patients have anxiety, tricyclic antidepressants such as amitryptiline or nortryptiline or SSRIs and benzodiazepines such as clonazepam are recommended. Acetazolamide is effective in rare genetic disorders related to migraine-like episodic ataxia; however, its place in vestibular migraine is still to be established. Nonpharmacological measures such as diet, sleep, hygiene and avoidance of triggers are recommended as they are for migraine. Vestibular rehabilitation might be useful when there are complications such as loss of confidence in balance or visual dependence.

Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation

Abstract: Background Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2 , and drug treatments have remained elusive. Methods Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions. Results The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL. Conclusions This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2 -associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2 -mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

Genetics of recurrent vertigo and vestibular disorders

Abstract: We present recent advances in the genetics of recurrent vertigo, including familial episodic ataxias, migraneous vertigo, bilateral vestibular hypofunction and Meniere's disease.Although several vestibular disorders are more common within families, the genetics of vestibulopathies is largely not known. Genetic loci and clinical features of familial episodic ataxias have been defined in linkage disequilibrium studies with mutations in neuronal genes KCNA1 and CACNA1A. Migrainous vertigo is a clinical disorder with a high comorbidity within families much more common in females with overlapping features with episodic ataxia and migraine. Bilateral vestibular hypofunction is a heterogeneous clinical group defined by episodes of vertigo leading to progressive loss of vestibular function which also can include migraine. Meniere's disease is a clinical syndrome characterized by spontaneous episodes of recurrent vertigo, sensorineural hearing loss, tinnitus and aural fullness and familial Meniere's disease in around 10-20% of cases. An international collaborative effort to define the clinical phenotype and recruiting patients with migrainous vertigo and Meniere's disease is ongoing for genome-wide association studies.

Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2.

Abstract: Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.

Episodic ataxia type 1 mutations affect fast inactivation of K+ channels by a reduction in either subunit surface expression or affinity for inactivation domain.

Abstract: Episodic ataxia type 1 (EA1) is an autosomal dominant disorder characterized by continuous myokymia and episodic attacks of ataxia Mutations in the gene KCNA1 that encodes the voltage-gated potassium channel Kv11 are responsible for EA1 In several brain areas, Kv11 coassembles with Kv14, which confers N-type inactivating properties to heteromeric channels It is therefore likely that the rate of inactivation will be determined by the number of Kv14 inactivation particles, as set by the precise subunit stoichiometry We propose that EA1 mutations affect the rate of N-type inactivation either by reduced subunit surface expression, giving rise to a reduced number of Kv11 subunits in heterotetramer Kv11-Kv14 channels, or by reduced affinity for the Kv14 inactivation domain To test this hypothesis, quantified amounts of mRNA for Kv14 or Kv11 containing selected EA1 mutations either in the inner vestibule of Kv11 on S6 or in the transmembrane regions were injected into Xenopus laevis oocytes and the relative rates of inactivation and stoichiometry were determined The S6 mutations, V404I and V408A, which had normal surface expression, reduced the rate of inactivation by a decreased affinity for the inactivation domain while the mutations I177N in S1 and E325D in S5, which had reduced subunit surface expression, increased the rate of N-type inactivation due to a stoichiometric increase in the number of Kv14 subunits

Candidate screening of the TRPC3 gene in cerebellar ataxia.

Abstract: The hereditary cerebellar ataxias are a diverse group of neurodegenerative disorders primarily characterised by loss of balance and coordination due to dysfunction of the cerebellum and its associated pathways. Although many genetic mutations causing inherited cerebellar ataxia have been identified, a significant percentage of patients remain whose cause is unknown. The transient receptor potential (TRP) family member TRPC3 is a non-selective cation channel linked to key signalling pathways that are affected in cerebellar ataxia. Furthermore, genetic mouse models of TRPC3 dysfunction display cerebellar ataxia, making the TRPC3 gene an excellent candidate for screening ataxic patients with unknown genetic aetiology. Here, we report a genetic screen for TRPC3 mutations in a cohort of 98 patients with genetically undefined late-onset cerebellar ataxia and further ten patients with undefined episodic ataxia. We identified a number of variants but no causative mutations in TRPC3. Our findings suggest that mutations in TRPC3 do not significantly contribute to the cause of late-onset and episodic human cerebellar ataxias.

Familial episodic ataxia type II.

Abstract: The familial episodic ataxia type II is a rare, dominantly inherited disease characterized by episodes of ataxia of early onset, often with completely normal cerebellar function between attacks. We report a family with affected members who had features of episodic ataxia type II and cerebellar atrophy on MRI imaging. All the affected members were successfully treated with acetazolamide, a carbonic anhydrase inhibitor. They are asymptomatic at 2 year follow-up.

Neurological potassium channelopathies

Abstract: Potassium channel dysfunction has been implicated in a variety of genetic and acquired neurological disorders that are collectively referred to as the potassium channelopathies. These include acquired neuromyotonia, episodic ataxia type‐1, hereditary deafness syndromes, benign familial neonatal convulsions and hypokalaemic periodic paralysis. Insight into potassium channel structure and function is crucial to understanding the pathophysiology of these conditions. This article describes potassium channel structure and function and then outlines what is known about the immunology and genetics of the neurological potassium

News on ion channels: erythromelalgia, treatment of episodic ataxia and faciobrachial dystonic seizures

Abstract: A large variety of neurological disorders, including myopathies, peripheral nerve disorders, different forms of epilepsy, hemiplegic migraine and limbic encephalitis, can now be classified as ion-channel disorders. Due to our detailed knowledge of the function and dysfunction of the different types of ion channels, the pathophysiology of many of these disorders has been thoroughly evaluated and this has also led to the development of new therapeutics and therapeutic principles. This month’s Journal Club will focus on three recent articles in this field. The first deals with a specific mutation of the sodium channel in inherited erythromelalgia, which leads to shifts in activation and in slow inactivation which modulates the neuron hyperexcitability. These findings could be correlated with the clinical presentation and the effectiveness of certain pharmacological agents. In the second article, a new therapeutic principle for the prophylactic treatment of episodic ataxia type 2 is described: the use of the potassium channel blocker 4-aminopyridine, which is evidently a reasonable alternative to acetazolamide. In the third article, it is clearly shown that faciobrachial dystonic seizures precede voltagegated potassium channel antibody limbic encephalitis. This type of epilepsy does not respond to antiepileptic drugs, but to immunotherapies, which is of clinical relevance in this specific form of epileptic seizures. Deletion mutation of a sodium channel in inherited erythromelalgia

Cerebellar ataxias: news on genetics and the excitability of affected neurons

Abstract: This month’s Journal Club will focus on three articles that deal with cerebellar ataxias. In the first article, a novel causative gene of spinal cerebellar ataxias was identified using exome sequencing. This study not only identifies a new gene, but also demonstrates that exome sequencing is a promising method to significantly reduce the time required for the identification of novel mutations. The second article deals with cortical excitability in episodic ataxia type 2, the most frequent cause of episodic ataxia. It shows an increased excitability in the motor cortex of patients with episodic ataxia. On the other hand, subjects with familial hemiplegic migraine who have mutations in the same calcium channel gene did not have changes compared to control subjects. In the third article, threshold tracking techniques were applied to study nerve excitability in vivo in patients with episodic ataxia type 1, which is caused by mutations of a fast potassium channel. This technique showed significant differences between affected patients and controls. Thus, this simple 15 min test may also be a useful clinical diagnostic tool to support the diagnosis of episodic ataxia type 1 with high sensitivity and specificity.