Episodic Ataxia Syndrome: Genotype-Phenotype Correlation and Longitudinal Study

Individuals with episodic ataxia experience recurrent attacks of dizziness and incoordination; between attacks patients are typically normal. The majority of cases are likely caused by an inherited genetic mutation. However, in some patients we are unable to identify the mutation. So far, 2 genes have been identified which cause different types of episodic ataxia. Ultimately, when the actual mutation is identified the protein product of the gene can be studied and specific medications can be designed. During this study, we will clinically evaluate patients with EA and follow them over time to help us better characterize the disease. We will also obtain blood samples to test for the known genetic mutations. In the future, we plan to coordinate trials of medications for the treatment of these disorders.

• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Longitudinal
• Total number of consented subjects: 131
• Subject Sample Telemetry Report (SSTR)

Inclusion criteria

The target population for this study will be individuals ≥ 5 years of age with a clinically confirmed diagnosis of EA as described in below and will include EA1, EA2, and EA other. Each subject must be able and willing to sign informed consent or assent (in the case of a minor).

Diagnostic Categories:
• EA1:
º Symptomatic: Clinical diagnostic criteria met and KCNA1 mutation confirmed.
º Asymptomatic: Does not meet clinical criteria but KCNA1 mutation present.

• EA2:
º Symptomatic: Clinical diagnostic criteria met and CACNA1A mutation confirmed.
º Asymptomatic: Does not meet clinical criteria but CACNA1A mutation present.

• EA other: overlapping clinical features with EA1 and/or EA2 but no mutation present in either KCNA1 or CACNA1A.

Exclusion Criteria

Other disorders known to cause episodic ataxia. No subject will be excluded from having his or her clinical information entered into the database.

In 1963, Farmer and Mustian first described a large family with episodic attacks of vertigo, diplopia, and ataxia 7. However it was not until years later that clinically distinct syndromes became apparent 5, 8, 20. After linkage studies in families with EA and myokymia localized the disease to a region near voltage gated potassium channel genes 13, Browne et al. 4 reported four different missense mutations in the potassium channel KCNA1 in four unrelated EA-1 pedigrees. This was the first report of a mutation in a human gene coding for a potassium channel and the first known ion channel mutation involving the brain. In 1995, the disease locus for EA-2 was localized to a region on chromosome 19p that was previously shown to be the disease locus for familial hemiplegic migraine 2, 12, 19. A calcium channel gene mapped to this locus on chromosome 19p, and Ophoff et al 14 defined the complex structure of the CACNA1A gene, which spans 300,000 base pairs and consists of 47 exons that encode the α1A subunit of the P/Q calcium channel. Analysis of the exons and flanking introns of CACNA1A identified point mutations that resulted in a premature stop codon or interfered with splicing in two families with EA-2 and missense mutations in four families with FHM, thus proving that EA-2 and FHM are allelic disorders. Although descriptions of EA3 and EA4 have appeared in the literature 6, 17 , no specific gene or linkage has been identified in these families. Therefore, we feel it is best to designate such patients and families as "EA other."

• Primary Phenotype: Ataxia

• Clinical Trials
  • NCT00266760

• Principal Investigator
  • Robert Baloh, MD. University of California Los Angeles, Los Angeles, CA, USA.
• Funding Source
  • U54 #NS059065. National Institutes of Health, Bethesda, MD, USA.