Showing papers on "Episodic ataxia published in 2016"

Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia

Abstract: Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy

Abstract: Objective: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations. Methods: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes. Results: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor. Conclusions: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders.

Episodic Ataxias: Clinical and Genetic Features.

Abstract: Episodic ataxia (EA) is a clinically heterogeneous group of disorders that are characterized by recurrent spells of truncal ataxia and incoordination lasting minutes to hours. Most have an autosomal dominant inheritance pattern. To date, 8 subtypes have been defined according to clinical and genetic characteristics, and five genes are known to be linked to EAs. Both EA1 and EA2, which are caused by mutations in KCNA1 and CACNA1A, account for the majority of EA, but many patients with no identified mutations still exhibit EA-like clinical features. Furthermore, genetically confirmed EAs have mostly been identified in Caucasian families. In this article, we review the current knowledge on the clinical and genetic characteristics of EAs. Additionally, we summarize the phenotypic features of the genetically confirmed EA2 families in Korea.

Eye movement disorders are an early manifestation of CACNA1A mutations in children

Abstract: Free to read at publisher Aim The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital. Method We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005–2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed. Results Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes. Interpretation Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes.

Disruption of an EAAT-Mediated Chloride Channel in a Drosophila Model of Ataxia.

Abstract: Patients with Type 6 episodic ataxia (EA6) have mutations of the excitatory amino acid transporter EAAT1 (also known as GLAST), but the underlying pathophysiological mechanism for EA6 is not known. EAAT1 is a glutamate transporter expressed by astrocytes and other glia, and it serves dual function as an anion channel. One EA6-associated mutation is a P>R substitution (EAAT1P>R) that in transfected cells has a reduced rate of glutamate transport and an abnormal anion conductance. We expressed this EAAT1P>R mutation in glial cells of Drosophila larvae and found that these larvae exhibit episodic paralysis, and their astrocytes poorly infiltrate the CNS neuropil. These defects are not seen in Eaat1 -null mutants, and so they cannot be explained by loss of glutamate transport. We instead explored the role of the abnormal anion conductance of the EAAT1P>R mutation, and to do this we expressed chloride cotransporters in astrocytes. Like the EAAT1P>R mutation, the chloride-extruding K+-Cl− cotransporter KccB also caused astroglial malformation and paralysis, supporting the idea that the EAAT1P>R mutation causes abnormal chloride flow from CNS glia. In contrast, the Na+-K+-Cl− cotransporter Ncc69, which normally allows chloride into cells, rescued the effects of the EAAT1P>R mutation. Together, our results indicate that the cytopathology and episodic paralysis in our Drosophila EA6 model stem from a gain-of-function chloride channelopathy of glial cells. SIGNIFICANCE STATEMENT We studied a mutation found in episodic ataxia of the dual-function glutamate transporter/anion channel EAAT1, and discovered it caused malformation of astrocytes and episodes of paralysis in a Drosophila model. These effects were mimicked by a chloride-extruding cotransporter and were rescued by restoring chloride homeostasis to glial cells with a Na+-K+-2Cl− cotransporter. Our findings reveal a new pathophysiological mechanism in which astrocyte cytopathology and neural circuit dysfunction arise via disruption of the ancillary function of EAAT1 as a chloride channel. In some cases, this mechanism might also be important for neurological diseases related to episodic ataxia, such as hemiplegia, migraine, and epilepsy.

Acute Ataxia in Childhood 11-Year Experience at a Major Pediatric Neurology Referral Center

Abstract: We categorized the causes of acute ataxia in the pediatric population-referred to the Division of Neurology-at a large, urban pediatric medical center. Of the 120 cases identified over the past 11 years, post-infectious cerebellar ataxia was the most commonly diagnosed (59%), followed by drug intoxication, opsoclonus-myoclonus ataxia syndrome, episodic ataxia, acute cerebellitis, cerebellar stroke, ADEM, meningitis, cerebral vein thrombosis, Leigh's disease, Miller-Fisher syndrome, and concussion. Among the patients with post-infectious cerebellar ataxia, 85% were 1-6 years old and all had a history of antecedent viral illness. CSF pleocytosis was present in 40% of patients; all had normal brain MRIs. The majority (91%) recovered within 30 days. We conclude that post-infectious cerebellar ataxia remains the most common cause of acute ataxia in childhood and that it carries a good prognosis. We also differentiate acute post-infectious cerebellar ataxia from other causes with similar presentations.

The Genetics of Benign Paroxysmal Torticollis of Infancy: Is There an Association With Mutations in the CACNA1A Gene?

Abstract: Benign paroxysmal torticollis of infancy is an unusual movement disorder, often accompanied by a family history of migraine. Some benign paroxysmal torticollis cases are associated with CACNA1A mutations. The authors sought to determine the frequency of CACNA1A mutations in benign paroxysmal torticollis by testing 8 children and their parents and by searching the literature for benign paroxysmal torticollis cases with accompanying CACNA1A mutations or other disorders linked to the same gene. In our 8 benign paroxysmal torticollis cases, the authors found 3 different polymorphisms, but no pathogenic mutations. By contrast, in the literature, the authors found 4 benign paroxysmal torticollis cases with CACNA1A mutations, 3 with accompanying family histories of 1 or more of familial hemiplegic migraine, episodic ataxia, and paroxysmal tonic upgaze. Thus, CACNA1A mutations are more likely to be found in children with benign paroxysmal torticollis if accompanied by family histories of familial hemiplegic migraine, episodic ataxia, or paroxysmal tonic upgaze.

Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations

Abstract: Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.

A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia.

Abstract: Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.

The Revolution in Migraine Genetics: From Aching Channels Disorders to a Next-Generation Medicine.

Abstract: Channelopathies are a heterogeneous group of neurological disorders resulting from dysfunction of ion channels located in cell membranes and organelles. The clinical scenario is broad and symptoms such as generalized epilepsy (with or without fever), migraine (with or without aura), episodic ataxia and periodic muscle paralysis are some of the best known consequences of gain- or loss-of-function mutations in ion channels. We review the main clinical effects of ion channel mutations associated with a significant impact on migraine headache. Given the increasing and evolving use of genetic analysis in migraine research – greater emphasis is now placed on genetic markers of dysfunctional biological systems –, we also show how novel information in rare monogenic forms of migraine might help to clarify the disease mechanisms in the general population of migraineurs. Next-generation sequencing and more accurate and precise phenotyping strategies are expected to further increase understanding of migraine pathophysiology and genetics.

Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia.

Abstract: Background Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the α subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients. Methods A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function. Results Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation. Conclusions Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. © 2016 International Parkinson and Movement Disorder Society

The episodic ataxia type 1 mutation I262T alters voltage-dependent gating and disrupts protein biosynthesis of human Kv1.1 potassium channels.

Abstract: Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient.

Early Infantile Epileptic Encephalopathy in an STXBP1 Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function.

Abstract: A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders. STXBP1 mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified a de novo c.1651C>T (p.R551C) mutation in STXBP1. Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature of STXBP1 disease.

Neuropathology in a case of episodic ataxia type 4.

Abstract: Episodic ataxia type 4 (EA4), also called periodic vestibulocerebellar ataxia and North Carolina autosomal dominant ataxia, is a movement disorder that occurs in several families in Johnston County, North Carolina. EA4 (MIM #606552) is one of eight EA syndromes which, along with the more common spinocerebellar ataxias (SCAs), belong to the family of autosomal dominant cerebellar ataxias (ADCA), all of which result in cerebellar and brain stem dysfunction [1–3]. Features of EA4 include gaze-evoked nystagmus, defective smooth pursuit, diplopia, paroxysmal dizziness, vertigo and lack of coordination [4,5]. Symptoms begin at ages 30–60 and gradually worsen with time. The mutation causing EA4 has not been identified, nor has the disease-causing gene been localized to a specific chromosome [6]. To our knowledge, no histopathology has been described for any EA syndrome. The clinical and genetic features of the eight EAs have been described previously [1,3]. This patient was a 91-year-old Caucasian female from a large family in North Carolina where EA4 is prevalent. Available information from three generations of this family indicates an autosomal dominant pattern of inheritance with a high degree of penetrance. Her family reports that her symptoms started in her mid-30s with episodes of nausea, unsteadiness and diplopia. Over a period of some years, the symptoms became more constant. She developed prominent nystagmus, had frequent falls and persistent incoordination of head and eye movements. Myokimia was not observed. She suffered from these symptoms for 55 years and died of pneumonia. Consent for acquisition of the brain for research purposes was obtained from the family at the time of autopsy. NIH guidelines for the study of autopsy tissue were followed. The brain weight was 1120 g. Grossly, the cerebellum was found to be mildly to moderately atrophic with all lobules being similarly involved (Figure 1A). Pallor of the substantia nigra was observed (Figure 1B). The cerebral hemisphere also displayed mild cortical atrophy consistent with the age of the patient (Figure 1C). Multiple sections were obtained from different regions including the cerebellum (vermis, dentate nucleus and flocculus) and brainstem (midbrain and pons). Formalinfixed sections were processed overnight and embedded in paraffin blocks. Five-micron thick sections were obtained and stained by the hematoxylin and eosin (H&E) method. Microscopic examination revealed occasional foci of dystrophic calcification likely related to age in the cerebral and cerebellar cortices. Routine H&E and immunostains were performed to assess the brainstem nuclei. The reticular nuclei, red nuclei and inferior olivary complex were found to be within normal limits with no clear neuronal loss. The midbrain was remarkable for mild diffuse reactive astrocytosis. This is a non-specific finding and may be due to hypoxia brought about by end-stage pulmonary insufficiency. Moderate to severe loss of Purkinje cells was observed in the cerebellar cortices and was particularly prominent in the vermis (Figure 2A). Calbindin immunohistochemistry also displayed thickened dendrites and dendritic spines within the Purkinje cell population, particularly in the flocculus (Figure 2B). Bielschowsky stain and parvalbumin immunohistochemistry further highlighted the Purkinje cell abnormalities, demonstrating loss of Purkinje cells and loss of dendritic arborization (data not shown). Scattered empty baskets and occasional axonal torpedoes were also observed (Figure 2C). Some loss of neurones in the dentate nucleus was noted. This is of interest because, in another ADCA, the presence of torpedoes has been linked to a loss of proper synaptic connections between the Purkinje cells and their target neurones in the dentate nucleus [7]. In the substantia nigra, mild loss in the pigmented neurones was observed. Scattered classic Lewy bodies and pale bodies were observed in brainstem structures (substantia nigra and locus coeruleus; Figure 2D) that were confirmed by α-synuclein immunohistochemistry (Figure 2E). Such a finding is common at this age and may represent preclinical Parkinson’s disease rather than a manifestation of EA4. Neuronal intranuclear inclusions (NIIs) were not observed in this brain with α-synuclein staining.

[Missense mutation R1345Q in CACNA1A gene causes a new type of ataxia with episodic tremor: clinical features, genetic analysis and treatment in a familial case].

Abstract: OBJECTIVE Mutations in CACNA1A, which encodes the P/Q-type calcium channel subunit, are responsible for at least 3 allelic diseases, namely type 2 episodic ataxia (EA-2), familial hemiplegic migraine?type-1 (FHM1), and spinocerebellar ataxia type-6?(SCA 6). Herein we present a case of ataxia with episodic tremors in a 19-year-old man with a missense mutation of CACNA1A gene and summarize the clinical features, genetic analysis and treatment in this case and in his affected family members. METHODS Physical examinations were conducted for the patient and his affected family members. DNA sample from the proband was analyzed with next-generation sequencing technology to identify the causative mutation. Sanger sequencing was used to confirm the gene mutation in the family members. RESULTS Physical examinations of the patient revealed signs of ataxia, drunken gait, and tremor of his head and body. Four other members in his family had similar but much milder symptoms. A heterozygous missense mutation in CACNA1A (NM_001127221.1 c.4034G->A, p.R1345Q, exon 25) was identified in the proband, which was confirmed in the affected family members. The proband did not respond to methazolamide treatment, but his tremor symptom was well controlled with flunarizine, a calcium channel blocker. CONCLUSION Based on the clinical features, mutation analysis and treatment response, we suggest that this patient with a missense CACNA1A mutation, R1345Q, has a new type of ataxia with episodic tremor other than any of EA2, FHM1, or SCA 6.

Clinical Characteristics of Spontaneous Downbeat Nystagmus in Koreans: Analysis of 218 Cases

Abstract: Background: Downbeat nystagmus is the most-common type of central nystagmus. However, no published study has attempted to analyze the etiology and clinical features of downbeat nystagmus in a large sample of Korean patients. Methods: We analyzed the demographic and clinical features of spontaneou s downbeat nystagmus in 218 Korean patients who had been evaluated at the Dizziness Clinic of Seoul National University Bundang Hospital from 2003 to 2014. Results: All patients were aged from 15 to 92 years (mean±SD: 58.7±18.0 years), and they included 117 (53.7%) men. Underlying causes were found in 162 patients (74.3%, secondary group), while no etiology was identified in the remaining patients (idiopathic group). The age and sex distributions did not differ between the idiopathic and secondary groups. The underlying etiology included hereditary disorders (n＝48, 22.0%), vascular diseases (n＝46, 21.1%), and inflammatory diseases (n＝19, 8.7%). Infarctions (n＝34, 15.6%) and episodic ataxia (n＝32, 14.7%) were the most-frequent underlying disorders. The most-common site of lesions identified by MRI was the cerebellum (68.9%), followed by the brainstem (28.6%). Among the 74 patients with lesions confirmed by MRI, 25 (33.7%) showed an isolated cerebellar involvement, while 35 (47.6%) had lesions in multiple areas. Conclusions: This study extends the clinical features of spontaneous downbeat nystagmus to Korean patients. Cerebellum is the most-common lesion site, which is consistent with the results of previous studies. The prevalence of Arnold-Chiari malformation is relatively low, which may be a di stinct finding relative to those of previous studies involving other ethnic populations. J Korean Neurol Assoc 34(1):27-32, 2016

Spinocerebellar Ataxia Type 6

Abstract: Spinocerebellar ataxia type 6 (SCA6) is a hereditary neurodegenerative disease causing late-onset progressive cerebellar ataxia. SCA6 is associated with a trinucleotide expansion within the bicistronic CACNA1A gene encoding Ca v 2.1, the α 1 A subunit of the neuronal P/Q-type voltage-gated calcium channel, as well as α 1 ACT, a transcription factor important in cerebellar development. This article discusses the pathogenesis, diagnosis, and management of SCA6.