|M.Sc Student||Furman-Dargif Chaya|
|Subject||Genetic Mapping and Mutation Detection in Three Distinct|
|Department||Department of Medicine||Supervisors||Clinical Professor Zvi Borochowitz|
|Dr. Adel Shlata|
|Full Thesis text - in Hebrew|
Muscle membrane excitability which is critical for muscle function is regulated by voltage-gated ion channels. Therefore it is rational that ion channels are involved in the pathogenesis of disease of skeletal muscle, a group of disorders termed "Skeletal Muscle Channelopathies".
Clinically, skeletal muscle ion channelopathies appears as recurring episodes of muscle stiffness or weakness triggered by typical circumstances such as cold, exercise, oral K+ load, or drug.
Muscle stiffness termed "Myotonia" ameliorates by exercise (a "warm up" effect) and can be associated with transient weakness during quick movements lasting only for seconds. On the contrary, "Paradoxical Myotonia" or "Paramyotonia" worsens with exercise and cold and is followed by long spells of limb weakness lasting from hours to days.
Myotonia is the clinical phenotype brought about by uncontrolled repetitive firing of action potentials leading to involuntary muscle contraction that can be detected as myotonic burst in the electromyogram (EMG).
Mutations in two different genes coding respectively for the voltage-dependent skeletal muscle specific Chloride and Sodium channels underline hereditary pure myotonia.
The function of these two genes in membrane excitability is opposite: while the Sodium channel renders the membrane excitable, allowing it to fire action potentials, the Chloride channel dampens excitability and stabilizes the resting potential.
Basic Pathology of the myotonic reaction in Myotonia Congenita, both the dominant form (Thomsen's disease), and the recessive form (Becker myotonia), is reduced chloride conductance that fails to sufficiently buffer the after de-potential and triggers new premature action potentials caused by mutations in the CLCN1 gene.
In paramyotonia the increased sarcolemal excitability is due to mutations in the SCN4A gene. Inactivation defects of this Sodium channels that mediate the upstroke of the action potential results in channel re-opening and intracellular sodium accumulation which depolarizes the muscle cells and thus elicits additional action potentials
We describe herein, the clinical characterization of three families from an Arabic origin: a) a large family with multiple affected Myotonia Congenita individuals, in whom a novel dominant mutation, the G190S, located in a conserved CLC-chloride channel motif, was identified. b) a small family with several affected Myotonia congenita individuals, in which a recessive mutation V851M was recently identified.
c) a small family affected with Paramyotonia congenita in which no mutation was found yet.