Consider DravetGenetic Mechanisms

GENETIC MECHANISMS

Approximately 70%-80% of patients with Dravet syndrome carry rare mutations in the sodium channel gene SCN1A, which encodes an important component of neuronal firing. We each carry two copies of the SCN1A gene, one each of our two copies of chromosome 2. Many Dravet mutations inactivate one copy of the gene, leaving only one functioning copy. This results in a condition called haplo-insufficiency, since one copy and only 50% of normal channel levels is insufficient to prevent seizures. Approximately 90% of Dravet mutations are ‘de novo’, meaning that they are not inherited from a parent, but rather are new mutations in the child.

 

Interpreting the results of SCN1A testing depends on the type of mutation that is observed. Approximately half of Dravet mutations introduce a “stop” codon into the protein, resulting in synthesis of a partial protein that lacks function. The interpretation of these “protein truncation” mutations is straightforward. The other 50% of mutations result in a change in one amino acid of the protein – similar to a change in a single letter of a sentence. Interpretation of the effects of these substitution mutations is based on previous observations in other patients or knowledge of the structure of the channel and the predicted effect of the substitution. Additional functional testing of the mutated channel can be carried out to understand more about the impact of the mutation, but mutation-specific therapy is not yet available.

 

Questions on genetic mechanisms may be directed to DSF Scientific Advisory Board member,

Dr. Miriam Meisler