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This chapter provides a clinicians' guide to the key clinical, genetic, and treatment aspects of the main single-gene neurological channelopathies. It considers the major skeletal muscle channelopathies followed by the main CNS channelopathies. The periodic paralyses (PP) are disorders in which patients experience focal or generalized episodes of muscle weakness of variable duration. Hypokalemic periodic paralysis can also be caused by missense mutations in the voltage sensor of domain 2 of SCN4A. Expression studies indicate that the SCN4A mutations associated with hypo-PP cause loss of function of the channel. Many studies indicate a strong genetic contribution to the risk of developing idiopathic generalized epilepsy, as well as febrile seizures. Inherited variability in the coding sequence of the GABRD gene, encoding the subunit of GABAA receptors, has also been suggested to act as a susceptibility factor for generalized epilepsy.
The developmental/congenital disorders are a gray area between core idiopathic and core acquired epilepsies, and their inclusion under the term symptomatic epilepsy reflects the inevitably artificial nature of all classification schemes. This chapter talks about epilepsy syndromes, temporal characteristics of acquired epilepsy, and provoked epilepsies. The term 'acquired' is used to refer to symptomatic epilepsies excluding the predominately genetic or developmental causes. The main reason for considering epilepsy a symptom is that there are so many different causes, and it is therefore perhaps ironical to note that the current classifications of epilepsy pay no heed to etiology at all, focused as they are on clinical and electrographic semiology. It is clear that the distinctive natures of the underlying pathological and physiological processes underlying symptomatic epilepsy after acute brain insults are very different from those underlying idiopathic epilepsy, and so are the clinical, therapeutic, and prognostic features.
Neurofibromatosis 1 (NF1) is a common autosomal dominant disease with an estimated birth incidence of 1 in 2500 and a prevalence of 1 in 4000 (Huson et al., 1991). The principal and defining clinical features are café au lait patches, skinfold freckling, cutaneous neurofibromas (benign peripheral nerve sheath tumours), iris Lisch nodules (hamartomas) and characteristic bony dysplasia (Huson et al., 1988; National Institutes of Health Consensus Development Conference, 1988) (Table 1). The majority of patients are diagnosed by the age of three years. NF1 arises as a spontaneous mutation in 50% of individuals and there is a wide variety of disease expression in patients with NF1, even within families. Neurofibromatosis 1 is clinically and genetically distinct from the rare condition neurofibromatosis 2, which is characterized by bilateral vestibular schwannomas (benign tumours of the eighth cranial nerve), schwannomas involving other cranial nerves, spinal nerve roots and peripheral nerves and by central nervous system meningiomas and gliomas (Evans et al., 1992).
The gene for NF1 has been identified on chromosome 17q11.2 by positional cloning (Viskochil et al., 1990; Wallace et al., 1990) and the protein product is neurofibromin, which has high levels of expression in the brain and acts as a tumour suppressor (Gutmann et al., 1991). Neurofibromin reduces cell proliferation by promoting the inactivation of the protooncogene p21RAS, which has a major role in mitogenic intracellular signalling pathways.
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