This is also termed 'periodic vestibulocerebellar ataxia' and 'North Carolina autosomal dominant ataxia'. It is reported in 2 families from North Carolina, suggesting a common single founder. It is characterized by ataxia, vertigo, episodic impaired smooth pursuit, gaze-evoked nystagmus, and diplopia. The onset is between 30-60 years, and symptoms worsen over time. It resembles EA2 but without interictal nystagmus, and it does not respond to acetazolamide. Gabapentin may relieve vertigo symptoms in EA4. Linkage studies in 1996 excluded autosomal dominant ataxias with known chromosomal localization at that time, including KCNA1, CACNA1A, SCAs 1-5 and DRPLA. Autopsy findings in a 91-year old EA4 patient showed polyglutamine repeats in Purkinje and granule cells, without intranuclear inclusions, similar to SCA6 brains. This was of interest as SCA6 can present as a fluctuating ataxia.
This was reported in a single French-Canadian family 20 years ago, with a mutation in CACNB4 gene, coding for the beta4 auxiliary subunit of voltage-gated calcium channels (Cav2.1). It is late onset and responds to acetazolamide. There were attacks of vertigo and ataxia lasting for several hours, although 1 family member had a single attack lasting for weeks. Interictal examination revealed spontaneous downbeat and gaze-evoked nystagmus, mild dysarthria and truncal ataxia. However no additional cases have subsequently been identified, despite frequent screening of CACNB4 mutation in EA patients. Meanwhile, the same mutation was reported in a family with epilepsy. Other CACNB4 mutations have been associated with epilepsies. Some researchers have questioned whether there is sufficient data to support EA5.
EA6 has been reported in several Caucasian and Korean families to date, and associated with SLC1A3 mutations in all cases. The phenotype resembles EA2 with long duration attacks, interictal nystagmus, similar triggers, and acetazolamide response. Migraine, alternating hemiplegia, progressive ataxia and epilepsy may co-occur. Childhood and adult onset is reported, and it appears to have reduced penetrance. The SLC1A3 gene codes for EAAT1 (excitatory amino acid transporter), a glial Na+-dependent glutamate transporter and ion channel. Functional studies suggest SLC1A3 mutations impair EAAT1 by altering transport function in various ways via reduced or enhanced glutamate uptake and/or anion currents. There are differing clinical phenotypes, according to the glutamate reuptake capability. A SLC1A3 mutation underlying EA6 has also been reported in a family with adult-onset progressive ataxia. SCL1A3 mutations have also been found in migraine, ADHD, autism and Tourette syndrome. In a patient with familial migraine, the mutation impaired K+ binding to the EAAT1 channel and completely disrupted glutamate transport.
This was reported in 7 members of a 4-generation family in 2007. It is similar to EA2 but without interictal nystagmus. This was mapped to 19q13 with a LOD score slightly above significance cutoff. Sequencing of 2 candidate genes in this region (KCNC3, SLC17A7) did not identify a mutation.
This was first reported in 2016 in an Irish 3-generation family. This presented by age 2, much earlier than EAs 1-7. There are episodic attacks with impaired balance, dysarthria, and generalized weakness. Attacks can be triggered by physical fatigue or stress. Interictal examination can show intention tremor, eyelid myokymia, and impaired tandem gait. Attacks vary in duration from minutes to hours, and frequency ranges from daily to every few months. Migraine with aura may co-occur. Attacks respond to clonazepam and are not improved with acetazolamide. The gene has been mapped to a large region on 1p36.13-p34.3 with a LOD score near to cutoff. Exome sequencing revealed variants in 2 genes, SPG2 and UBR4. UBR4 had a greater likelihood of pathogenicity than SPG2, as UBR4 is ubiquitin ligase protein that interacts with calmodulin and may potentially disrupt calcium sensor in neurons as hypothesis for ataxia. A Korean study reported 2 patients with mutations in both UBR4 and CACNA1A, and suggested UBR4 may act as a genetic modifier with synergic effects on abnormal CACNA1A activity. No functional analysis studies have been performed as yet for UBR4.
There are a growing number of genetic disorders that can present with EA either alone or embedded in a complex syndrome. These include chronic ataxia disorders (SCA-14, SCA-27, SCA-35, SCA-42, AOA2, CAPOS,), genetic epilepsy syndromes (KCNA2, SCN2A, PRRT2, TBC1D24), GLUT-1, mitochondrial disorders (PDHA1, PDHX, TPK1, DARS2, ACO2), metabolic disorders [aminoacidopathies (Maple syrup urine disease: BCKDHA, BCKDHB, DBT; Hartnup disease: SLC6A19), urea cycle defects (type I citrullinemia: ASS1), thiamine metabolism defects (thiamine pyrophosphate deficiency: TPK1) biotin metabolism (biotinidase deficiency: BTD),] and others (KCND3, NALCN, FHM2/ATP1A2, PACS1, CEP290). Some of these might explain prior classical familial EA cases that were negative for EA1 and EA2 and genetic loci of other EAs. Three of them (SCA-27/FGF14, SCA-42/CACNA1G, and SCN2A) have been proposed to be categorized as EA9 or EA10.
SCA-14 is a dominantly inherited slowly progressive ataxia, sometimes accompanied by parkinsonism, dystonia, myoclonus and cognitive impairment. It is caused by mutations in PRKCG gene encoding protein kinase C gamma (PRKgamma). PRKCG mutations may also present with adult-onset episodic ataxia, with a frequency of 1/14 PRKCG-positive patients.
SCA-27 is a late-onset progressive ataxia with parkinsonism, postural tremor and titubation; 20% have coexistent episodic ataxia. It is caused by mutations in FGF14 gene which encodes Fibroblast Growth Factor 14. This protein is highly expressed in the brain, especially Purkinje cells, where it interacts with voltage-gated Na+ channels to regulate neuronal excitability. Isolated EA is also reported to be caused by heterozygous FGF14 gene mutations. Onset age ranges widely from early childhood to adulthood. Attacks may be accompanied by vertigo, dizziness, unsteadiness, with interictal nystagmus and tremor. Attacks are highly variable, lasting seconds up to several days. There are a variety of triggers; a fever trigger with a prolonged attack in a young child can mimic febrile cerebellitis. Attacks may respond to acetazolamide, and may improve with age. Developmental delay and paroxysmal dyskinesia have also been observed. Some authors suggested designating this EA9.
CACNA1G encodes the pore-forming alpha1G subunit of T-type voltage gated calcium channel (VGCC). Mutations in CACNA1G cause generalized absence epilepsy and SCA42. A single family is reported with episodic vestibulocerebellar ataxia associated with a mutation in the CACNA1G gene. There were attacks of dizziness, unsteadiness, headache and facial numbness, and head-movement induced vertigo. Attacks lasted up to several months in duration. Interictal examination showed cerebellar findings and bilateral vestibulopathy. The attack duration and absence of myokymia or tinnitus distinguishes this from EA3. Attacks were worsened by acetazolamide, and suppressed by carbamazepine. The authors proposed this be designated EA10.