Genetic Ataxias Research Articles

Movement Disorders in Genetic Pediatric Ataxias.

Genetic pediatric ataxias are heterogeneous rare disorders, mainly inherited as autosomal-recessive traits. Most forms are progressive and lack effective treatment, with relevant socioeconomical impact. Albeit ataxia represents the main clinical feature, the phenotype can be more complex, with additional neurological and nonneurological signs being described in several forms. In this review, we provide an overview of the occurrence and spectrum of movement disorders in the most relevant forms of childhood-onset genetic ataxias. All types of hypokinetic and hyperkinetic movement disorders of variable severity have been reported. Movement disorders occasionally represent the symptom of onset, predating ataxia even of a few years and therefore challenging an early diagnosis. Their pathogenesis still remains poorly defined, as it is not yet clear whether movement disorders may directly relate to the cerebellar pathology or result from an extracerebellar dysfunction, including the basal ganglia. Recognition of the complete movement disorder phenotype in genetic pediatric ataxias has important implications for diagnosis, management, and genetic counseling.

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

Diagnostic algorithm for autosomal recessive ataxia

To develop a complex algorithm for autosomal recessive ataxia (ARA) diagnosis applicable for Russian patients with degenerative ataxias. 48 patients with of presumably degenerative ataxias were examined. Clinical evaluation was performed with the use of the SARA and ICARS scales (for ataxia) and MoCA (cognitive functions), and a set of laboratory tests was carried out, including electromyography, brain MRI, and DNA analysis of mutations responsible for Friedreich's disease and spinocerebellar ataxias (SCAs) types 1, 2, 3, 6 and 17. 28 patients underwent mutation screening using a multigenic MPS panel. 8 patients (16.7%) with non-hereditary causes of ataxia were identified: cerebellar alcoholic degeneration (n = 6) and multiple system atrophy of cerebellar type (n = 2); 3 patients (6.3%) with genetic ataxias were identified using routine DNA tests, such as with SCA type 1, 2 and 17, and 9 (18.8%) patients with Friedreich's disease. The MPS panel enabled molecular diagnosis of ARA in 8 patients (28.6%): ataxia-telangiectasia (n = 2), SANDO syndrome (n = 2), ataxia with oculomotor apraxia type 2 (n = 1), SCAR10 (n = 1), SCAR16 (n = 1), and atypical form of neuroaxonal dystrophy (n = 1). The diagnosis was not established in 20 patients. We have proposed an appropriate algorithm for degenerative ataxia diagnosis which is recommended to be used when examining patients with sporadic and autosomal recessive cases of the disorders with dyscoordination of movements.

Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers

BackgroundSpinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers.MethodsIn order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms.ResultsPreclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset.ConclusionsEBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.

SnapShot: Biology of Genetic Ataxias

Genetic ataxias are a clinically important group of disabling, mostly neurodegenerative, diseases of the cerebellum. This SnapShot shows that the vast majority of established monogenic causes of dominant and recessive ataxias can be captured by a limited number of affected cellular components and biological processes in the cerebellum. To view this SnapShot, open or download the PDF.

Effects of a wearable proprioceptive stabilizer on kinematics and spatio-temporal gait parameters in young with genetic ataxias

Effects of a wearable proprioceptive stabilizer on kinematics and spatio-temporal gait parameters in young with genetic ataxias

Central Lesions With Selective Semicircular Canal Involvement Mimicking Bilateral Vestibulopathy.

Bilateral vestibulopathy (BVP), which is due to peripheral lesions, may selectively involve certain semicircular canal (SCC). Recent eye movement recordings with search coil and video head impulse test (HIT) have provided insight in central lesions that can cause bilateral and selective SCC deficit mimicking BVP. Since neurological signs or ocular motor deficits maybe subtle or absent, it is critical to recognize central lesions correctly since there is prognostic and treatment implication. Acute floccular lesions cause bilateral horizontal SCC (HC) impairment while leaving vertical SCC function unaffected. Vestibular nuclear lesions affect bilateral HC and posterior SCC (PC) function, but anterior SCC (AC) function is spared. When both eyes are recorded, medial longitudinal fasciculus lesions cause horizontal dysconjugacy in HC function and catch-up saccades, as well as selective deficiency of PC over AC function. Combined peripheral and central lesions may be difficult to distinguish from BVP. Anterior inferior cerebellar artery stroke causes two types of deficits: 1. ipsilateral pan-SCC deficits and contralateral HC deficit and 2. bilateral HC deficit with vertical SCC sparing. Metabolic disorders such as Wernicke encephalopathy characteristically involve HC but not AC or PC function. Gaucher disease causes uniform loss of all SCC function but with minimal horizontal catch-up saccades. Genetic cerebellar ataxias and cerebellar-ataxia neuropathy vestibular areflexia syndrome typically do not spare AC function. While video HIT does not replace the gold-standard, search coil HIT, clinicians are now able to rapidly and accurately identify specific pattern of SCC deficits, which can aid differentiation of central lesions from BVP.

Identification of a Splicing Mutation in ITPR1 via WES in a Chinese Early-Onset Spinocerebellar Ataxia Family

Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) lead to SCA15, SCA16, and SCA29. To date, only a few families with SCA29 have been reported. A three-generation Chinese family including four affected persons and two unaffected persons were enrolled in this study. We conducted whole-exome sequencing (WES) of the proband DNA initially to find the causal gene. We ascertained the family with autosomal dominant type of congenital nonprogressive cerebellar ataxia (CNPCA) associated with delayed motor and cognitive impairment. WES study was performed with two patients and identified c.1207-2A–T transition, in exon 14 of ITPR1, which was a splicing mutation. Sanger sequencing showed that four patients within this family carried the mutation and two unaffected members did not carry it. The results showed that the novel splicing mutation of ITPR1 was the causative gene for SCA29. In conclusion, we identified a novel SCA29 causative splicing mutation of ITPR1 in a Chinese family. We suggest ITPR1 gene analysis shall be a priority for diagnosis of patients with early-onset CNPCA. Our study demonstrated that whole-exome sequencing might rapidly improve the diagnosis of genetic ataxias.

Diagnosis of multiple system atrophy.

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs.

Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients

BackgroundCerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe...

Chapter 23 - Cerebellar disorders: clinical/radiologic findings and modern imaging tools

Cerebellar disorders, also called cerebellar ataxias, comprise a large group of sporadic and genetic diseases. Their core clinical features include impaired control of coordination and gait, as well as cognitive/behavioral deficits usually not detectable by a standard neurologic examination and therefore often overlooked. Two forms of cognitive/behavioral syndromes are now well identified: (1) the cerebellar cognitive affective syndrome, which combines an impairment of executive functions, including planning and working memory, deficits in visuospatial skills, linguistic deficiencies such as agrammatism, and inappropriate behavior; and (2) the posterior fossa syndrome, a very acute form of cerebellar cognitive affective syndrome occurring essentially in children. Sporadic ataxias include stroke, toxic causes, immune ataxias, infectious/parainfectious ataxias, traumatic causes, neoplasias and paraneoplastic syndromes, endocrine disorders affecting the cerebellum, and the so-called "degenerative ataxias" (multiple system atrophy, and sporadic adult-onset ataxias). Genetic ataxias include mainly four groups of disorders: autosomal-recessive cerebellar ataxias, autosomal-dominant ataxias (spinocerebellar ataxias and episodic ataxias), mitochondrial disorders, and X-linked ataxias. In addition to biochemical studies and genetic tests, brain imaging techniques are a cornerstone for the diagnosis, clinicoanatomic correlations, and follow-up of cerebellar ataxias. Modern radiologic tools to assess cerebellar ataxias include: functional imaging studies, magnetic resonance spectroscopy, volumetric studies, and tractography. These complementary methods provide a multimodal appreciation of the whole long-range cerebellar network functioning, and allow the extraction of potential biomarkers for prognosis and rating level of recovery after treatment.

Inter-rater reliability and validity of two ataxia rating scales in children with brain tumours.

This study aimed to investigate the inter-rater reliability and construct validity of the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) in children with posterior fossa tumours. These scales have been developed for adults with genetic ataxias, and the performance of these scales in children with brain tumours has not previously been described. The participants, who had undergone surgical resection for a posterior fossa tumour (inclusion criteria age 4-18years), were recruited from the neuro-oncology service at a tertiary children's hospital. Children were assessed using the SARA, BARS and Paediatric Evaluation of Disability Index (PEDI) mobility domain, a measure of function. Children were independently rated by two therapists to determine the inter-rater reliability of the SARA and BARS. The construct validity was determined by assessing the correlation between the two scales with the PEDI. Forty-four children were recruited. Inter-rater reliability was good for both scales, demonstrating the strong correlations (SARA, r = 0.94; BARS, r = 0.91) and the good consistency (93% of SARA and 90% of BARS paired scores differing by less than 2 points) between two raters. Both ataxia scales demonstrated a strong negative correlation with the mobility domain of the PEDI (SARA, r = -0.77; BARS, r = -0.76), indicating that more severe ataxia was associated with worse mobility. The mean time for completion of the SARA was 4.5 and 2.7min for the BARS. The SARA and BARS are reliable and valid measures and appear to be of equal value in determining the severity of ataxia in children with posterior fossa tumours.

Genetic cerebellar ataxias.

This review broadly covers the commoner genetic ataxias, concentrating on their clinical features. Over the last two decades there has been a potentially bewildering profusion of newly described genetic ataxias. However, at least half of dominant ataxias (SCAs) are caused by (CAG)n repeat expansions resulting in expanded polyglutamine tracts (SCAs 1, 2, 3, 6, 7, 17, and DRPLA), although of the remainder only SCAs 8, 10, 12, 14, 15/16, and 31 are frequent enough that the described phenotype is probably representative. Though the SCAs can be difficult to separate clinically, variations in prevalence in different populations, together with various clinical and radiological features, at least help to order the pretest probabilities. The X-linked disorder, fragile-X tremor ataxia syndrome occurs in fragile-X permutation carriers, and typically causes a late-onset ataxia-plus syndrome. The recessive ataxias are not named systematically: The most frequent are Friedreich, ataxia telangiectasia, ARSACS, AOA1 and 2, and the various POLG syndromes. Although rare, several other recessive disorders such as AVED are potentially treatable and should not be missed. Another group of genetic ataxias are the dominant episodic ataxias, of which EA1 and EA2 are the most important. Lastly, the neurologist's role in ongoing management, rather than just diagnosis, is addressed.

Genes and genetic testing in hereditary ataxias.

Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial fashion. A common mechanism of dominant ataxias is repeat expansions, where increasing lengths of repeated DNA sequences result in non-functional proteins that accumulate in the body causing disease. Greater understanding of all ataxia genes has helped identify several different pathways, such as DNA repair, ubiquitination, and ion transport, which can be used to help further identify new genes and potential treatments. Testing for the most common mutations in these genes is now clinically routine to help with prognosis and treatment decisions, but next generation sequencing will revolutionize how genetic testing will be done. Despite the large number of known ataxia causing genes, however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies, expression studies, and increased knowledge of ataxia pathways will aid in the identification of new ataxia genes.

Prevalence of ataxia in children: a systematic review.

To estimate the prevalence of childhood ataxia resulting from both genetic and acquired causes. A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Five databases were searched for articles reporting a frequency measure (e.g., prevalence, incidence) of ataxia in children. Included articles were first grouped according to the World Health Organization (WHO) regions and subsequently classified according to etiology (genetic, acquired, or mixed). Each article was assessed for its risk of bias on the domains of sampling, measurement, and analysis. Incidence values were converted to prevalence estimates whenever possible. European prevalence estimates for different etiologies of ataxia were summed to gauge the overall prevalence of childhood ataxia. One hundred fifteen articles were included in the review. More than 50% of the data originated from the Europe WHO region. Data from this region also showed the least susceptibility to bias. Little data were available for Africa and Southeast Asia. The prevalence of acquired ataxias was found to vary more greatly across regions than the genetic ataxias. Ataxic cerebral palsy was found to be a significant contributor to the overall prevalence of childhood ataxia across WHO regions. The prevalence of childhood ataxias in Europe was estimated to be ∼26/100,000 children and likely reflects a minimum prevalence worldwide. The findings show that ataxia is a common childhood motor disorder with a higher prevalence than previously assumed. More research concerning the epidemiology, assessment, and treatment of childhood ataxia is warranted.

Iberiotoxin-sensitive and -insensitive BK currents in Purkinje neuron somata

Purkinje cells have specialized intrinsic ionic conductances that generate high-frequency action potentials. Disruptions of their Ca or Ca-activated K (KCa) currents correlate with altered firing patterns in vitro and impaired motor behavior in vivo. To examine the properties of somatic KCa currents, we recorded voltage-clamped KCa currents in Purkinje cell bodies isolated from postnatal day 17-21 mouse cerebellum. Currents were evoked by endogenous Ca influx with approximately physiological Ca buffering. Purkinje somata expressed voltage-activated, Cd-sensitive KCa currents with iberiotoxin (IBTX)-sensitive (>100 nS) and IBTX-insensitive (>75 nS) components. IBTX-sensitive currents activated and partially inactivated within milliseconds. Rapid, incomplete macroscopic inactivation was also evident during 50- or 100-Hz trains of 1-ms depolarizations. In contrast, IBTX-insensitive currents activated more slowly and did not inactivate. These currents were insensitive to the small- and intermediate-conductance KCa channel blockers apamin, scyllatoxin, UCL1684, bicuculline methiodide, and TRAM-34, but were largely blocked by 1 mM tetraethylammonium. The underlying channels had single-channel conductances of ∼150 pS, suggesting that the currents are carried by IBTX-resistant (β4-containing) large-conductance KCa (BK) channels. IBTX-insensitive currents were nevertheless increased by small-conductance KCa channel agonists EBIO, chlorzoxazone, and CyPPA. During trains of brief depolarizations, IBTX-insensitive currents flowed during interstep intervals, and the accumulation of interstep outward current was enhanced by EBIO. In current clamp, EBIO slowed spiking, especially during depolarizing current injections. The two components of BK current in Purkinje somata likely contribute differently to spike repolarization and firing rate. Moreover, augmentation of BK current may partially underlie the action of EBIO and chlorzoxazone to alleviate disrupted Purkinje cell firing associated with genetic ataxias.

C9ORF72 expansion is not a significant cause of sporadic spinocerebellar ataxia

Hexanucleotide expansions within the first intron of the C9ORF72 gene are a significant cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), alone or in combination, as well as sporadic ALS worldwide.1–3 Several recent reports have described cases which broaden the clinical phenotype to include behavioral variant FTD with or without early psychiatric presentations and parkinsonian features,4,5 and primary progressive aphasia.6 There is also a report of a patient with a family history of ALS and cerebellar ataxia,5 an intriguing finding as neuroimaging of C9ORF72 patients shows cerebellar atrophy, which is not typically observed with other FTD-related mutations such as MAPT or GRN.7 Cerebellar neuronal cytoplasmic inclusions have also been observed in multiple studies,6,7 yet clinical cerebellar ataxia has not been detected in any large cohorts of C9ORF72 patients with FTD and/or ALS.1–3,7 Since a majority of adult-onset ataxia cases are of unknown etiology, these observations raise the possibility that C9ORF72 may contribute to the development of sporadic spinocerebellar ataxia. To address this question, we examined 209 adult-onset sporadic ataxia patients for C9ORF7 hexanucleotide expansion (Table I). All patients were screened for common genetic spinocerebellar ataxias including SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia. Most patients (40%) had pure cerebellar ataxia but, given the known C9ORF72 phenotypes, cases associated with upper motor neuron signs, dementia, and parkinsonism were also included. Approximately one-third of these patients met possible or probable criteria for multiple system atrophy. Testing was performed as previously described3 and only one positive case was identified (1/209, 0.5%). Table Patient Demographics (N=209). This patient, currently age 53, developed slowly progressive cerebellar dysfunction in her early 20’s with falls by age 25. Upper motor neuron features of increased lower extremity tone and hyper-reflexia were present but annual assessments have shown no lower motor neuron involvement or cognitive decline. MRI has shown cerebellar atrophy with no frontal or temporal involvement. Evaluation for other genetic causes involving the APTX, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, ATXN8, ATXN10, CACNA1A, FMR1, FXN, KCNC3, PRKCG, PP2R2B, SACS, SETX, SPTBN2, and TBP genes was unremarkable. She is Caucasian with French-Canadian ancestry. As with the prior reported C9ORF72 ataxia case,5 family history was notable for her father and paternal uncle being diagnosed with ALS and dying within 2 years of symptom onset. There were no other affected family members. We speculate that the clinical findings seen in our patient represent a rare (<1%) C9ORF72 phenotype,5 however, given the lack of other affected family members or unrelated cases, we cannot confirm this. C9ORF72 penetrance varies by age, with full penetrance occurring by the 9th decade,1 and it is possible that our patient will still develop a more classic phenotype. Regardless, this study does not support genetic testing for C9ORF72 expansion in sporadic spinocerebellar ataxia, although, as our study only examined sporadic-onset cases, it remains possible that C9ORF72 may contribute more significantly to dominant familial forms. For now, C9ORF72 testing would only be indicated for ataxia patients with a family history of ALS and/or FTD.

Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia

Sporadic-onset ataxia is common in a tertiary care setting but a significant percentage remains unidentified despite extensive evaluation. Rare genetic ataxias, reported only in specific populations or families, may contribute to a percentage of sporadic ataxia. Patients with adult-onset sporadic ataxia, who tested negative for common genetic ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia), were evaluated using a stratified screening approach for variants in 7 rare ataxia genes. We screened patients for published mutations in SYNE1 (n = 80) and TGM6 (n = 118), copy number variations in LMNB1 (n = 40) and SETX (n = 11), sequence variants in SACS (n = 39) and PDYN (n = 119), and the pentanucleotide insertion of spinocerebellar ataxia type 31 (n = 101). Overall, we identified 1 patient with a LMNB1 duplication, 1 patient with a PDYN variant, and 1 compound SACS heterozygote, including a novel variant. The rare genetic ataxias examined here do not significantly contribute to sporadic cerebellar ataxia in our tertiary care population.

Clinical neurophysiology of the episodic ataxias: Insights into ion channel dysfunction in vivo

Clinical neurophysiology has become an invaluable tool in the diagnosis of muscle channelopathies, but the situation is less clear cut with neuronal channelopathies. The genetic episodic ataxias are a group of disorders with heterogeneous phenotype and genotype, but share in common the feature of intermittent cerebellar dysfunction. Episodic ataxia (EA) types 1 and 2 are the most widely recognised of the autosomal dominant episodic ataxias and are caused by dysfunction of neuronal voltage-gated ion channels. There are central and peripheral nervous system manifestations in both conditions, and they are therefore good models of neuronal channelopathies to study neurophysiologically. To date most work has focussed upon characterising the electrophysiological properties of mutant channels in vitro. This review summarises the role of voltage-gated potassium and calcium channels, mutations of which underlie the main types of episodic ataxia types 1 and 2. The clinical, genetic and electrophysiological features of EA1 and EA2 are outlined, and a protocol for the assessment of these patients is proposed.