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 in Purkinje cells of the cerebellum 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. The tottering mouse is a widely used model to study EA2, as it developed a spontaneous homologous mutation in Cacna1a in the early 1960s. Alternatively, some CACNA1A mutations, such as those seen in familial 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 of spinocerebellar 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 and diplopia. 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. As EA3 is extremely rare, there is currently no known causative gene. The locus for this disorder has been mapped to the long arm of chromosome 1 (1q42).
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 they have nystagmus and dysarthria. These patients are responsive to acetazolamide. 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 to phenylalanine 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 hyperexcitability
Coding 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, identified initially in a 10-year-old boy who first presented with 30 minute bouts of decreased muscle tone during infancy.