- Episodic ataxia
Episodic ataxia (EA) is an
autosomal dominant disorder characterized by sporadic bouts ofataxia (severe discoordination) with or without myokymia (continuous muscle movement). Ataxia can be provoked by stress, startle, or heavy exertion such as exercise. Symptoms can first appear in infancy. There are at least 6 loci for EA, of which 4 are known genes. Some patients with EA also have migraine or progressive cerebellar degenerative disorders, symptomatic of eitherfamilial hemiplegic migraine orspinocerebellar ataxia . Some patients respond toacetazolamide though others do not.Infobox_Disease
Name = PAGENAME
Caption =
DiseasesDB = 32380
ICDO =
OMIM = 160120
OMIM_mult = OMIM2|108500 OMIM2|606554 OMIM2|606552
MedlinePlus =
eMedicineSubj = neuro
eMedicineTopic = 556
MeshID =igns/Symptoms
Typically, episodic ataxia presents as bouts of
ataxia induced by startle, stress, or exertion. Some patients also have continuous tremors of various motor groups, known as myokymia. Other patients havenystagmus , vertigo,tinnitus ,diplopia orseizure s.Cause
The various symptoms of EA are caused by dysfunction of differing areas. Ataxia, the most common symptom, is due to misfiring of
Purkinje cell s in thecerebellum . This is either due to direct malfunction of these cells, such as in EA2, or improper regulation of these cells, such as in EA1. Seizures are likely due to altered firing of hippocampalneurons (KCNA1 null mice have seizures for this reason).Pathophysiology
EA1: KCNA1
Type 1 episodic ataxia (EA1) is characterized by attacks of generalized
ataxia induced by emotion or stress, with myokymia both during and between attacks. This disorder is also known as episodic ataxia with myokymia (EAM), hereditary paroxysmal ataxia with neuromyotonia and Isaacs-Mertens syndrome. Onset of EA1 occurs during early childhood to adolescence and persists throughout the patient's life. Attacks last from seconds to minutes. Mutations of the gene KCNA1, which encodes thevoltage-gated potassium channel KV1.1, are responsible for this subtype of episodic ataxia. KV1.1 is expressed heavily in basket cells and interneurons that form GABAergic synapses onPurkinje cell s. The channels aid in the repolarization phase of action potentials, thus affecting inhibitory input into Purkinje cells and, thereby, all motor output from thecerebellum . There are currently 17 KV1.1 mutations associated with EA1, Table 1 and Figure 1. 15 of these mutations have been at least partly characterized incell culture based electrophysiological assays wherein 14 of these 15 mutations have demonstrated drastic alterations in channel function. As described in Table 1, most of the known EA1 associated mutations result in a drastic decrease in the amount of current through KV1.1 channels. Furthermore, these channels tend to activate at more positive potentials and slower rates, demonstrated by positive shifts in their V½ values and slower τ activation time constants, respectively. Some of these mutations, moreover, produce channels that deactivate at faster rates (deactivation τ), which would also result in decreased current through these channels. While these biophysical changes in channel properties likely underlie some of the decrease in current observed in experiments, many mutations also seem to result in misfolded or otherwise mistrafficked channels, which is likely to be the major cause of dysfunction and disease pathogenesis. It is assumed, though not yet proven, that decrease in KV1.1 mediated current leads to prolonged action potentials in interneurons and basket cells. As these cells are important in the regulation of Purkinje cell activity, it is likely that this results increased and aberrant inhibitory input into Purkinje cells and, thus, disrupted Purkinje cell firing and cerebellum output.EA2: CACNA1A
Type 2 episodic ataxia (EA2) is characterized by acetazolamide-responsive attacks of ataxia with or without migraine. Patients with EA2 may also present with progressive cerebellar atrophy,
nystagmus , vertigo, visual disturbances and dysarthria. These symptoms last from hours to days, in contrast with EA1, which lasts from seconds to minutes. Like EA1, attacks can be precipitated by emotional or physical stress, but also bycoffee andalcohol . EA2 is caused by mutations in CACNA1A, which encodes the P/Q-type voltage-gated calcium channel CaV2.1, and is also the gene responsible for causingspinocerebellar ataxia type-6 andfamilial hemiplegic migraine type-1. EA2 is also referred to as episodic ataxia with nystagmus, hereditary paroxysmal cerebellopathy, familial paroxysmal ataxia and acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (AHPCA). There are currently 19 mutations associated with EA2, though only 3 have been characterized electrophysiologically, table 2 and figure 2. Of these, all result in decreased current through these channels. It is assumed that the other mutations, especially the splicing and frameshift mutations, also result in a drastic decrease in CaV2.1 currents, though this may not be the case for all mutations. CACNA1A is heavily expressed inPurkinje cell s of thecerebellum where it is involved in coupling action potentials with neurotransmitter release. Thus, decrease in Ca2+ entry through CaV2.1 channels is expected to result in decreased output from Purkinje cells, even though they will fire at an appropriate rate. Alternatively, some CACNA1A mutations, such as those seen infamilial hemiplegic migraine type-1, result in increased Ca2+ entry and, thereby, aberrant transmitter release. This can also result in excitotoxicity, as may occur in some cases ofspinocerebellar ataxia type-6 .EA3: 1q42
Episodic ataxia type-3 (EA3) is similar to EA1 but often also presents with
tinnitus and vertigo. Patients typically present with bouts of ataxia lasting less than 30 minutes and occurring once or twice daily. During attacks, they also have vertigo, nausea, vomiting, tinnitus anddiplopia . These attacks are sometimes accompanied by headaches and precipitated by stress, fatigue, movement and arousal after sleep. Attacks generally begin in early childhood and last throughout the patients' lifetime. Acetazolamide administration has proved successful in some patients.cite journal | author = Steckley J, Ebers G, Cader M, McLachlan R | title = An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus. | journal = Neurology | volume = 57 | issue = 8 | pages = 1499–502 | year = 2001 | pmid = 11673600] As EA3 is extremely rare, there is currently no known causative gene. The locus for this disorder has been mapped to the q arm of chromosome 1 (1q42).cite journal | author = Cader M, Steckley J, Dyment D, McLachlan R, Ebers G | title = A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia. | journal = Neurology | volume = 65 | issue = 1 | pages = 156–8 | year = 2005 | pmid = 16009908 | doi = 10.1212/01.wnl.0000167186.05465.7c]EA4
Also known as periodic vestibulocerebellar ataxia, type-4 episodic ataxia (EA4) is an extremely rare form of episodic ataxia differentiated from other forms by onset in the third to sixth generation of life, defective smooth pursuit and gaze-evoked nystagmus. Patients also present with vertigo and ataxia. There are only two known families with EA4, both located in
North Carolina . The locus for EA4 is unknown.EA5: CACNB4
There are two known families with type-5 episodic ataxia (EA5).
These patients can present with an overlapping phenotype of ataxia and seizures similar to
juvenile myoclonic epilepsy . In fact, juvenile myoclonic epilepsy and EA5 are allelic and produce proteins with similar dysfunction.Patients with pure EA5 present with recurrent episodes of ataxia with vertigo.Between attacks the have
nystagmus anddysarthria . These patients are responsive toacetazolamide .Both juvenile myoclonic epilepsy and EA5 are a result of mutations in CACNB4, a gene that encodes the
calcium channel β4 subunit. This subunit coassembles with α-subunits and produces channels that slowly inactivate after opening.EA5 patients have a
cysteine tophenylalanine mutation at position 104.Thus results in channels with 30% greater current than wild-type.
As this subunit is expressed in the
cerebellum , it is assumed that such increased current results in neuronal hyperexcitabilityCoding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.
EA6: SLC1A3
Type-6 episodic ataxia (EA6) is a rare form of episodic ataxia, occurring in only one known patient. This patient, a 10 year-old boy at the time of clinical study, first presented with 30 minute bouts of decreased muscle tone during infancy. He required "balance therapy" as a young child to aid in walking and has a number of ataxic attacks, each separated by months to years. These attacks were precipitated by fever. He has cerebellar atrophy and subclinical seizures. During later attacks, he also presented with distortions of the left hemifield, ataxia, slurred speech, followed by headache. After enrolling in school, he developed bouts of rhythmic arm jerking with concomitant confusion, also lasting approximately 30 minutes. He also has presented, at various times, with migraines. This patient carries a
proline toarginine substitution in the fifth transmembrane-spanning segment of the geneSLC1A3 . This gene encodes the excitatory amino acid transporter 1 (EAAT1) protein, which is responsible forglutamate uptake. In cell culture assays, this mutation results in drastically decreased glutamate uptake in a dominant-negative manner. This is likely due to decreased synthesis or protein stability. As this protein is expressed heavily in thebrainstem andcerebellum , it is likely that this mutation results in excitotoxicity and/or hyperexcitability leading to ataxia and seizures.cite journal | author = Jen J, Wan J, Palos T, Howard B, Baloh R | title = Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. | journal = Neurology | volume = 65 | issue = 4 | pages = 529–34 | year = 2005 | pmid = 16116111 | doi = 10.1212/01.WNL.0000172638.58172.5a]Treatment
Depending on subtype, many patients find that
acetazolamide therapy is useful in preventing attacks. In some cases, persistent attacks result in tendon shortening, for which surgery is required.External links
* [http://www.ataxia.org National Ataxia Society]
* [http://members.aol.com/mark24609/ataxia/ Webpage of a patient with EA, including information on the disorder in both English and Spanish]Footnotes
Wikimedia Foundation. 2010.