Episodic Ataxia Type Ii

CLINICAL CHARACTERISTICS: Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting minutes to days in duration. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache.

1. Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/ myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 1994;8: 136–140.CrossRefPubMedGoogle Scholar
2. Maylie B, Bissonnette E, Virk M, Adelman JP, Maylie JG. Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvβ1-induced N-type inactivation. J Neurosci 2002;22: 4786–4793.PubMedGoogle Scholar
3. Vaamonde J, Artieda J, Obeso JA. Hereditary paroxysmal ataxia with neuromyotonia. Mov Disord 1991;6: 180–182.CrossRefPubMedGoogle Scholar
4. Steckley JL, Ebers GC, Cader MZ, McLachlan RS. An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus. Neurology 2001;57: 1499–1502.PubMedGoogle Scholar
5. Farmer TW, Mustian VM. Vestibulocerebellar ataxia: a newly defined hereditary syndrome with periodic manifestations. Arch Neurol 1963;8: 471–480.PubMedGoogle Scholar
6. Escayg A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calcium-channel β4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 2000;66: 1531–1539.CrossRefPubMedGoogle Scholar
7. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 2005;65: 529–534.CrossRefPubMedGoogle Scholar
8. Auburger G, Ratzlaff T, Lunkes A, et al. A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197. Genomics 1996;31: 90–94.CrossRefPubMedGoogle Scholar
9. Griggs RC, Nutt JG. Episodic ataxias as channelopathies. Ann Neural 1995;37: 285–287.CrossRefGoogle Scholar
10. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87: 543–552.CrossRefPubMedGoogle Scholar
11. Brandt T, Strupp M. Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo). Audiol Neurootol 1997;2: 373–383.CrossRefPubMedGoogle Scholar
12. Imbrici P, Eunson LH, Graves TD, et al. Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A. Neurology 2005;65: 944–946.CrossRefPubMedGoogle Scholar
13. Gancher ST, Nutt JG. Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov Disord 1986;1: 239–253.CrossRefPubMedGoogle Scholar
14. Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology 2004;62: 17–22.PubMedGoogle Scholar
15. Brandt T, Strupp M. Migraine and vertigo: Classification, clinical features and special treatment considerations. Headache Currents 2006;3: 12–19.CrossRefGoogle Scholar
16. Oh AK, Lee H, Jen JC, Corona S, Jacobson KM, Baloh RW. Familial benign recurrent vertigo. Am J Med Genet 2001;100: 287–291.CrossRefPubMedGoogle Scholar
17. Lempert T, Neuhauser H. Migrainous vertigo. Neurol Clin 2005; 23: 715–30, vi.CrossRefPubMedGoogle Scholar
18. Sasaki O, Jen JC, Baloh RW, Kim GW, Isawa M, Usami S. Neurotological findings in a family with episodic ataxia. J Neurol 2003;250: 373–375.CrossRefPubMedGoogle Scholar
19. Rucker JC, Jen J, Stahl JS, Natesan N, Baloh RW, Leigh RJ. Intemuclear ophthalmoparesis in episodic ataxia type 2. Ann N Y Acad Sci 2005;1039: 571–574.CrossRefPubMedGoogle Scholar
20. Mochizuki Y, Kawata A, Mizutani T, et al. Hereditary paroxysmal ataxia with mental retardation: a clinicopathological study in relation to episodic ataxia type 2. Acta Neuropathol (Berl) 2004;108: 345–349.CrossRefGoogle Scholar
21. Spacey SD, Materek LA, Szczygielski BI, Bird TD. Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. Arch Neurol 2005;62: 314–316.CrossRefPubMedGoogle Scholar
22. Van Bogaert P, Szliwowski HB. EEG findings in acetazolamide-responsive hereditary paroxysmal ataxia. Neurophysiol Clin 1996; 26: 335–340.CrossRefPubMedGoogle Scholar
23. Imbrici P, Jaffe SL, Eunson LH, et al. Dysfunction of the brain calcium channel Cav2.1 in absence epilepsy and episodic ataxia. Brain 2004;127: 2682–2692.CrossRefPubMedGoogle Scholar
24. Vighetto A, Froment JC, Trillet M, Aimard G. Magnetic resonance imaging in familial paroxysmal ataxia. Arch Neurol 1988;45: 547–549.PubMedGoogle Scholar
25. Hawkes CH. Familial paroxysmal ataxia: report of a family. J Neurol Neurosurg Psychiatry 1992;55: 212–213.CrossRefPubMedGoogle Scholar
26. Bain PG, O'Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol 1992;31: 147–154.CrossRefPubMedGoogle Scholar
27. Harno H, Heikkinen S, Kaunisto MA, et al. Decreased cerebellar total creatine in episodic ataxia type 2: a 1H MRS study. Neurology 2005;64: 542–544.PubMedGoogle Scholar
28. Vahedi K, Joutel A, Van Bogaert P, et al. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 1995;37: 289–293.CrossRefPubMedGoogle Scholar
29. von Brederlow B, Hahn AF, Koopman WJ, Ebers GC, Bulman DE. Mapping the gene for acetazolamide responsive hereditary paryoxysmal cerebellar ataxia to chromosome 19p. Hum Mol Genet 1995; 4: 279–284.CrossRefGoogle Scholar
30. Shapiro MS, Gomeza J, Hamilton SE, et al. Identification of subtypes of muscarinic receptors that regulate Ca²⁺ and K⁺ channel activity in sympathetic neurons. Life Sci 2001;68: 2481–2487.CrossRefPubMedGoogle Scholar
31. Eunson LH, Graves TD, Hanna MG. New calcium channel mutations predict aberrant RNA splicing in episodic ataxia. Neurology 2005;65: 308–310.CrossRefPubMedGoogle Scholar
32. Wan J, Khanna R, Sandusky M, Papazian DM, Jen JC, Baloh RW. CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology 2005;64: 2090–2097.CrossRefPubMedGoogle Scholar
33. Guida S, Trettel F, Pagnutti S, et al. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 2001; 68: 759–764.CrossRefPubMedGoogle Scholar
34. Wappl E, Koschak A, Poteser M, et al. Functional consequences of P/Q-type Ca²⁺ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 2002; 277: 6960–6966.CrossRefPubMedGoogle Scholar
35. Jodice C, Mantuano E, Veneziano L, et al. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet 1997;6: 1973–1978.CrossRefPubMedGoogle Scholar
36. Tottene A, Fellin T, Pagnutti S, et al. Familial hemiplegic migraine mutations increase Ca²⁺ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci USA 2002;99: 13284–13289.CrossRefPubMedGoogle Scholar
37. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nat Genet 1997;15: 62–69.CrossRefPubMedGoogle Scholar
38. Maselli RA, Wan J, Dunne V, et al. Presynaptic failure of neuromuscular transmission and synaptic remodeling in EA2. Neurology 2003;61: 1743–1748.PubMedGoogle Scholar
39. Walter JT, Alvina K, Womack MD, Chevez C, Khodakhah K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci 2006;9: 389–397.CrossRefPubMedGoogle Scholar
40. Strupp M, Kalla R, Dichgans M, Freilinger T, Glasauer S, Brandt T. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004;62: 1623–1625.PubMedGoogle Scholar
41. Hirose H, Arayama T, Takita J, Igarashi T, Hayashi Y, Nagao Y. A family of episodic ataxia type 2: no evidence of genetic linkage to the CACNA1A gene. Int J Mol Med 2003;11: 187–189.PubMedGoogle Scholar
42. Cader MZ, Steckley JL, Dyment DA, McLachlan RS, Ebers GC. A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia. Neurology 2005;65: 156–158.CrossRefPubMedGoogle Scholar
43. D'Adamo MC, Imbrici P, Sponcichetti F, Pessia M. Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K⁺ channel function. FASEB J 1999;13: 1335–1345.PubMedGoogle Scholar
44. Sappey-Marinier D, Vighetto A, Peyron R, Broussolle E, Bonmartin A. Phosphorus and proton magnetic resonance spectroscopy in episodic ataxia type 2. Ann Neurol 1999;46: 256–259.3.0.CO%3B2-6'>CrossRefPubMedGoogle Scholar
45. Fletcher CF, Lutz CM, O'Sullivan TN, et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 1996;87: 607–617.CrossRefPubMedGoogle Scholar
46. Fureman BE, Hess EJ. Noradrenergic blockade prevents attacks in a model of episodic dysfunction caused by a channelopathy. Neurobiol Dis 2005;20: 227–232.CrossRefPubMedGoogle Scholar
47. Weisz CJ, Raike RS, Soria-Jasso LE, Hess EJ. Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering. J Neurosci 2005;25: 4141–4145.CrossRefPubMedGoogle Scholar
48. Lorenzon NM, Lutz CM, Frankel WN, Beam KG. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. J Neurosci 1998;18: 4482–4489.PubMedGoogle Scholar
49. Mori Y, Wakamori M, Oda S, et al. Reduced voltage sensitivity of activation of P/Q-type Ca²⁺ channels is associated with the ataxic mouse mutation rolling Nagoya (tg^roI). J Neurosci 2000;20: 5654–5662.PubMedGoogle Scholar
50. Calandriello L, Veneziano L, Francia A, et al. Acetazolamide-responsive episodic ataxia in an Italian family refines gene mapping on chromosome 19p13. Brain 1997;120: 805–812.CrossRefPubMedGoogle Scholar
51. Griggs RC, Moxley RT 3rd, Lafrance RA, McQuillen J. Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 1978; 28: 1259–1264.PubMedGoogle Scholar
52. Harno H, Hirvonen T, Kaunisto MA, et al. Acetazolamide improves neurotological abnormalities in a family with episodic ataxia type 2 (EA-2). J Neurol 2004;251: 232–234.CrossRefPubMedGoogle Scholar
53. Griggs RC, Engel WK, Resnick JS. Acetazolamide treatment of hypokalemic periodic paralysis: prevention of attacks and improvement of persistent weakness. Ann Intern Med 1970;73: 39–48.PubMedGoogle Scholar
54. Vroom FW, Jarrell MA, Maren TH. Acetazolamide treatment of hypokalemic periodic paralysis: probable mechanism of action. Arch Neurol 1975;32: 385–392.PubMedGoogle Scholar
55. Johnsen T. Effect upon serum insulin, glucose and potassium concentrations of acetazolamide during attacks of familial periodic hypokalemic paralysis. Acta Neurol Scand 1977;56: 533–541.CrossRefPubMedGoogle Scholar
56. Goulon M, Raphael JC, Simon N. Periodic familial paralysis with hypokalemia: hemodynamic and metabolic studies: favorable effect of acetazolamide [In French]. Rev Neurol (Paris) 1978;134: 655–672.Google Scholar
57. Donat JR, Auger R. Familial periodic ataxia. Arch Neurol 1979; 36: 568–569.PubMedGoogle Scholar
58. Zasorin NL, Baloh RW, Myers LB. Acetazolamide-responsive episodic ataxia syndrome. Neurology 1983;33: 1212–1214.PubMedGoogle Scholar
59. Kuzmenkin A, Muncan V, Jurkat-Rott K, et al. Enhanced inactivation and pH sensitivity of Na⁺ channel mutations causing hypokalaemic periodic paralysis type II. Brain 2002; 125: 835–843.CrossRefPubMedGoogle Scholar
60. Woodhull AM. Ionic blockage of sodium channels in nerve. J Gen Physiol 1973;61: 687–708.CrossRefPubMedGoogle Scholar
61. Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP. Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol 2004;56: 213–220.CrossRefPubMedGoogle Scholar
62. Brunt ER, van Weerden TW. Familial paroxysmal kinesigenic ataxia and continuous myokymia. Brain 1990;113: 1361–1382.CrossRefPubMedGoogle Scholar
63. Scoggan KA, Friedman JH, Bulman DE. CACNAIA mutation in a EA-2 patient responsive to acetazolamide and valproic acid. Can J Neurol Sci 2006;33: 68–72.PubMedGoogle Scholar
64. Strupp M, Schuler O, Krafczyk S, et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology 2003;61: 165–170.PubMedGoogle Scholar
65. Etzion Y, Grossman Y. Highly 4-aminopyridine sensitive delayed rectifier current modulates the excitability of guinea pig cerebellar Purkinje cells. Exp Brain Res 2001;139: 419–425.CrossRefPubMedGoogle Scholar
66. Kullmann DM, Hanna MG. Neurological disorders caused by inherited ion-channel mutations. Lancet Neurol 2002;1: 157–166.CrossRefPubMedGoogle Scholar
67. Kordasiewicz HB, Gomez CM. Molecular pathogenesis of spinocerbellar ataxia type 6. Neurotherapeutics 2007;4: 285–294.CrossRefPubMedGoogle Scholar
68. Rajakulendran S, Schorge S, Kullmann DM, Hanna MG. Episodic ataxia type 1: A neuronal potassium channelopathy. Neurotherapeutics 2007;4: 258–266.CrossRefPubMedGoogle Scholar

Episodic Ataxia Type 2 Prognosis

Episodic ataxia (EA) is an autosomal dominant disorder characterized by sporadic bouts of ataxia (severe discoordination) with or without myokymia (continuous muscle movement). There are seven types recognised but the majority are due to two recognized entities.^[1] 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 either familial hemiplegic migraine or spinocerebellar ataxia. Some patients respond to acetazolamide though others do not.

• 3Pathophysiology

Signs and symptoms[edit]

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 have nystagmus, vertigo, tinnitus, diplopia or seizures.

Cause[edit]

The various symptoms of EA are caused by dysfunction of differing areas. Ataxia, the most common symptom, is due to misfiring of Purkinje cells in the cerebellum. 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[edit]

EA1: KCNA1[edit]

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 the voltage-gated potassium channel K_V1.1, are responsible for this subtype of episodic ataxia. K_V1.1 is expressed heavily in basket cells and interneurons that form GABAergic synapses on Purkinje cells. The channels aid in the repolarization phase of action potentials, thus affecting inhibitory input into Purkinje cells and, thereby, all motor output from the cerebellum. EA1 is an example of a synaptopathy. There are currently 17 K_V1.1 mutations associated with EA1, Table 1 and Figure 1. 15 of these mutations have been at least partly characterized in cell 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 K_V1.1 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 K_V1.1 mediated current leads to prolonged action potentials in interneurons and basket cells. As these channels 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[edit]

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. Attacks can be accompanied by increased heart rate and blood pressure, moderate to severe shaking, and stuttering. Like EA1, attacks can be precipitated by exercise, emotional stress/agitation, physical stress,or heat (overheated body temperature) but also by coffee and alcohol. EA2 is caused by mutations in CACNA1A, which encodes the P/Q-type voltage-gated calcium channel Ca_V2.1, and is also the gene responsible for causing spinocerebellar ataxia type-6 and familial 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 Ca_V2.1 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 Ca_V2.1 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.^[20] 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[edit]

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.^[31] 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).^[32]

Episodic Ataxia Type Ii Syndrome

EA4[edit]

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.

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. Attacks can be accompanied by increased heart rate and blood pressure, moderate to severe shaking, and stuttering. Like EA1, attacks can be precipitated by exercise, emotional stress/agitation, physical stress,or heat (overheated body temperature) but also by coffee and alcohol. EA2 is caused by mutations in CACNA1A, which encodes the P/Q-type voltage-gated calcium channel Ca_V2.1, and is also the gene responsible for causing spinocerebellar ataxia type-6 and familial 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 Ca_V2.1 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 Ca_V2.1 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.^[20] 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[edit]

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.^[31] 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).^[32]

Episodic Ataxia Type Ii Syndrome

EA4[edit]

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[edit]

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.

Type I Diabetes

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

Ataxia Type 2

Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.

Treatment For Episodic Ataxia

EA6: SLC1A3[edit]

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. 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 to arginine substitution in the fifth transmembrane-spanning segment of the gene SLC1A3. This gene encodes the excitatory amino acid transporter 1 (EAAT1) protein, which is responsible for glutamate 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 the brainstem and cerebellum, it is likely that this mutation results in excitotoxicity and/or hyperexcitability leading to ataxia and seizures.^[33] Mutations in EAAT1 (GLAST) have subsequently been identified in a family with episodic ataxia.^[34]

Episodic Ataxia Type Ii 2

Diagnosis[edit]

Treatment[edit]

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.

References[edit]

1. ^Riant F, Vahedi K, Tournier-Lasserve E (2011) Hereditary episodic ataxia. Rev Neurol (Paris)
2. ^ ^abcdBrowne D, Gancher S, Nutt J, Brunt E, Smith E, Kramer P, Litt M (1994). 'Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1'. Nat Genet. 8 (2): 136–40. doi:10.1038/ng1094-136. PMID7842011.
3. ^ ^abcBrowne D, Brunt E, Griggs R, Nutt J, Gancher S, Smith E, Litt M (1995). 'Identification of two new KCNA1 mutations in episodic ataxia/myokymia families'. Hum Mol Genet. 4 (9): 1671–2. doi:10.1093/hmg/4.9.1671. PMID8541859.
4. ^ ^abcdefAdelman J, Bond C, Pessia M, Maylie J (1995). 'Episodic ataxia results from voltage-dependent potassium channels with altered functions'. Neuron. 15 (6): 1449–54. doi:10.1016/0896-6273(95)90022-5. PMID8845167.
5. ^ ^abcdefZerr P, Adelman J, Maylie J (1998). 'Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency'. J Neurosci. 18 (8): 2842–8. doi:10.1523/JNEUROSCI.18-08-02842.1998. PMID9526001.
6. ^ ^abcScheffer H, Brunt E, Mol G, van der Vlies P, Stulp R, Verlind E, Mantel G, Averyanov Y, Hofstra R, Buys C (1998). 'Three novel KCNA1 mutations in episodic ataxia type I families'. Hum Genet. 102 (4): 464–6. doi:10.1007/s004390050722. PMID9600245.
7. ^Imbrici P, Cusimano A, D'Adamo M, De Curtis A, Pessia M (2003). 'Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels'. Pflügers Arch. 446 (3): 373–9. doi:10.1007/s00424-002-0962-2. PMID12799903.
8. ^ ^abBretschneider F, Wrisch A, Lehmann-Horn F, Grissmer S (1999). 'Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA-1)'. Eur J Neurosci. 11 (7): 2403–12. doi:10.1046/j.1460-9568.1999.00659.x. PMID10383630.
9. ^ ^abcZerr P, Adelman J, Maylie J (1998). 'Characterization of three episodic ataxia mutations in the human Kv1.1 potassium channel'. FEBS Lett. 431 (3): 461–4. doi:10.1016/S0014-5793(98)00814-X. PMID9714564.
10. ^Comu S, Giuliani M, Narayanan V (1996). 'Episodic ataxia and myokymia syndrome: a new mutation of potassium channel gene Kv1.1'. Ann Neurol. 40 (4): 684–7. doi:10.1002/ana.410400422. PMID8871592.
11. ^Zuberi S, Eunson L, Spauschus A, De Silva R, Tolmie J, Wood N, McWilliam R, Stephenson J, Kullmann D, Hanna M (1999). 'A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy'. Brain. 122 (5): 817–25. doi:10.1093/brain/122.5.817. PMID10355668.
12. ^ ^abcdEunson L, Rea R, Zuberi S, Youroukos S, Panayiotopoulos C, Liguori R, Avoni P, McWilliam R, Stephenson J, Hanna M, Kullmann D, Spauschus A (2000). 'Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability'. Ann Neurol. 48 (4): 647–56. doi:10.1002/1531-8249(200010)48:4<647::AID-ANA12>3.0.CO;2-Q. PMID11026449.
13. ^ ^abD'Adamo M, Liu Z, Adelman J, Maylie J, Pessia M (1998). 'Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel'. EMBO J. 17 (5): 1200–7. doi:10.1093/emboj/17.5.1200. PMC1170468. PMID9482717.
14. ^ ^abD'Adamo M, Imbrici P, Sponcichetti F, Pessia M (1999). 'Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function'. FASEB J. 13 (11): 1335–45. doi:10.1096/fasebj.13.11.1335. PMID10428758.
15. ^ ^abMaylie B, Bissonnette E, Virk M, Adelman J, Maylie J (2002). 'Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvbeta 1-induced N-type inactivation'. J Neurosci. 22 (12): 4786–93. doi:10.1523/JNEUROSCI.22-12-04786.2002. PMID12077175.
16. ^Knight M, Storey E, McKinlay Gardner R, Hand P, Forrest S (2000). 'Identification of a novel missense mutation L329I in the episodic ataxia type 1 gene KCNA1--a challenging problem'. Hum Mutat. 16 (4): 374. doi:10.1002/1098-1004(200010)16:4<374::AID-HUMU15>3.0.CO;2-4. PMID11013453.
17. ^Lee H, Wang H, Jen J, Sabatti C, Baloh R, Nelson S (2004). 'A novel mutation in KCNA1 causes episodic ataxia without myokymia'. Hum Mutat. 24 (6): 536. doi:10.1002/humu.9295. PMID15532032.
18. ^Herson P, Virk M, Rustay N, Bond C, Crabbe J, Adelman J, Maylie J (2003). 'A mouse model of episodic ataxia type-1'. Nat Neurosci. 6 (4): 378–83. doi:10.1038/nn1025. PMID12612586.
19. ^Manganas L, Akhtar S, Antonucci D, Campomanes C, Dolly J, Trimmer J (2001). 'Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties'. J Biol Chem. 276 (52): 49427–34. doi:10.1074/jbc.M109325200. PMID11679591.
20. ^Green, M. C.; Sidman, R. L. (September 1962). 'Tottering--a neuromusclar mutation in the mouse. And its linkage with oligosyndacylism'. The Journal of Heredity. 53 (5): 233–237. doi:10.1093/oxfordjournals.jhered.a107180. ISSN0022-1503. PMID13950100.
21. ^ ^abcdvan den Maagdenberg A, Kors E, Brunt E, van Paesschen W, Pascual J, Ravine D, Keeling S, Vanmolkot K, Vermeulen F, Terwindt G, Haan J, Frants R, Ferrari M (2002). 'Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene'. J Neurol. 249 (11): 1515–9. doi:10.1007/s00415-002-0860-8. PMID12420090.
22. ^ ^abWan J, Khanna R, Sandusky M, Papazian D, Jen J, Baloh R (2005). 'CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics'. Neurology. 64 (12): 2090–7. doi:10.1212/01.WNL.0000167409.59089.C0. PMID15985579.
23. ^Yue Q, Jen J, Nelson S, Baloh R (1997). 'Progressive ataxia due to a missense mutation in a calcium-channel gene'. Am J Hum Genet. 61 (5): 1078–87. doi:10.1086/301613. PMC1716037. PMID9345107.
24. ^ ^abcdefgDenier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, Castelnovo G, Deonna T, Gérard P, Devoize J, Gayou A, Perrouty B, Soisson T, Autret A, Warter J, Vighetto A, Van Bogaert P, Alamowitch S, Roullet E, Tournier-Lasserve E (1999). 'High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2'. Neurology. 52 (9): 1816–21. doi:10.1212/WNL.52.9.1816. PMID10371528.
25. ^ ^abOphoff R, Terwindt G, Vergouwe M, van Eijk R, Oefner P, Hoffman S, Lamerdin J, Mohrenweiser H, Bulman D, Ferrari M, Haan J, Lindhout D, van Ommen G, Hofker M, Ferrari M, Frants R (1996). 'Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4'. Cell. 87 (3): 543–52. doi:10.1016/S0092-8674(00)81373-2. PMID8898206.
26. ^Yue Q, Jen J, Thwe M, Nelson S, Baloh R (1998). 'De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia'. Am J Med Genet. 77 (4): 298–301. doi:10.1002/(SICI)1096-8628(19980526)77:4<298::AID-AJMG9>3.0.CO;2-J. PMID9600739.
27. ^Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, Fellin T, Spadaro M, Stauderman K, Williams M, Volsen S, Ophoff R, Frants R, Jodice C, Frontali M, Pietrobon D (2001). 'Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2'. Am J Hum Genet. 68 (3): 759–64. doi:10.1086/318804. PMC1274487. PMID11179022.
28. ^Friend K, Crimmins D, Phan T, Sue C, Colley A, Fung V, Morris J, Sutherland G, Richards R (1999). 'Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM'. Hum Genet. 105 (3): 261–5. doi:10.1007/s004390051099. PMID10987655.
29. ^Tonelli A, D'Angelo M, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi A, Bresolin N, Bassi M (2006). 'Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene'. J Neurol Sci. 241 (1–2): 13–7. doi:10.1016/j.jns.2005.10.007. PMID16325861.
30. ^Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E (2001). 'Missense CACNA1A mutation causing episodic ataxia type 2'. Arch Neurol. 58 (2): 292–5. doi:10.1001/archneur.58.2.292. PMID11176968.
31. ^Steckley J, Ebers G, Cader M, McLachlan R (2001). 'An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus'. Neurology. 57 (8): 1499–502. doi:10.1212/wnl.57.8.1499. PMID11673600.
32. ^Cader M, Steckley J, Dyment D, McLachlan R, Ebers G (2005). 'A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia'. Neurology. 65 (1): 156–8. doi:10.1212/01.wnl.0000167186.05465.7c. PMID16009908.
33. ^Jen J, Wan J, Palos T, Howard B, Baloh R (2005). 'Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures'. Neurology. 65 (4): 529–34. doi:10.1212/01.WNL.0000172638.58172.5a. PMID16116111.
34. ^de Vries B, Mamsa H, Stam AH, et al. (2009). 'Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake'. Arch. Neurol. 66 (1): 97–101. doi:10.1001/archneurol.2008.535. PMID19139306.

External links[edit]

Episodic Ataxia Type Ii Symptoms