FUNCTIONAL DETERMINANTS OF EPISODIC ATAXIA/MYOKYMIA SYNDROME

Episodic ataxia type-1 (EA1) is an autosomal dominant neurological disorder affecting both the central and peripheral nervous systems. The first symptoms manifest during infancy or early childhood and persist through the whole life severely compromising the quality of life of affected individuals. EA1 affected patients show constant muscle rippling movements (myokymia), and by episodic attacks of ataxia that are characterised by imbalance with jerking movements of the head, arms and legs, and can be triggered by emotional stress or fatigue. Some patients undergo several attacks a day of severe ataxia, lasting from minutes to hours. Genetic studies led to the discovery of a number of point mutations in the potassium channel gene KCNA1 that encodes for the potassium channel hKv1.1 (Browne et al., 1994). By using advanced molecular biology and electrophysiological techniques we have described several important mechanisms causing episodic ataxia type-1 (D’Adamo et al., 2002). Zinc ions are relatively abundant in the brain. We observed that a mutant channel (F184C) showed a higher affinity to zinc block than the normal channel. This may be a possible novel mechanism causing EA1. We also observed that Kv1.1 channels play a significant role in determining the excitability of the vestibular neurons. These neurons are located within the vestibular system, a brain area important for our sense of balance and position in space. These observations strongly suggest that these mechanisms may contribute significantly to causing EA1 symptoms. Therefore, our proposed studies on EA1 may provide important and valuable information able to clarify some of the mechanism(s) and factor(s) that precipitate attacks of ataxia. In addition, the proposed neurophysiological experiments may uncover some neurological dysfunctions responsible for the symptoms of the disease and may provide insight for the search of new and more effective medications.