Inherited neuronal ion channelopathies:
new windows on complex neurological diseases

Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D.
Department of Pharmacology,
University of Washington,
Seattle, Washington 98195-7280, USA.
J Neurosci. 2008 Nov 12;28(46):11768-77.


Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium channel Na(V)1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. Mutations in the peripheral sodium channel Na(V)1.7 cause familial pain syndromes. Gain-of-function mutations cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain because of attenuation of action potential firing. These experiments have defined correlations between genotype and phenotype in chronic pain diseases and focused attention on Na(V)1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca(V)2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. These mutations increase activation at negative membrane potentials and increase evoked neurotransmitter release at cortical glutamatergic synapses. Studies of a mouse genetic model show that these gain-of-function effects lead to cortical spreading depression, aura, and potentially migraine. Overall, these experiments indicate that imbalance in the activity of excitatory and inhibitory neurons is an important underlying cause of these diseases.
Eugenics talk
Liberal Eugenics
'Designer babies'
Private eugenics
Analgesic therapies
Psychiatric genetics
Human self-domestication
Selecting potential children
Mood genes and human nature
Preimplantation genetic diagnosis
'A life without pain? Hedonists take note'
Francis Galton and contemporary eugenics
Gene therapy and performance enhancement
Pain sensitivity and voltage-gated sodium channels
The neurological basis of the emotional dimension of pain

and further reading

BLTC Research
Utopian Surgery?
The Good Drug Guide
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
MDMA: Utopian Pharmacology
Critique of Huxley's Brave New World