Ion channels are membrane proteins that allow rapid, passive, but selective passage of ions. The dynamic interaction of ion channels is critical for the regulation of membrane excitability and the function of excitable cells, such as nerve and muscle. Indeed, modern molecular techniques have led to the successful identification of mutations in genes encoding both voltage-gated and ligand-gated ion channels in numerous human neuromuscular disorders, collectively termed channelopathies. Channelopathies include periodic paralysis, episodic ataxia, congenital myasthenic syndromes, hereditary hyperekplexia, rare epilepsies, cardiac arrhythmias, and migraine syndromes that share similarities in their episodic nature, precipitating factors, therapeutic responses, and long-term degenerative features. Understanding the phenotypic expression of these rare, monogenic channelopathies may shed light on similar mechanisms in the more common, likely polygenic and multifactorial, paroxysmal neurologic disorders, such as migraine and epilepsy. See Table 204-1 for MIM and GenBank numbers.
Familial periodic paralyses are the prototypical channelopathies. These are autosomal dominant disorders characterized by episodes of weakness or by paralysis precipitated by stress or fatigue, with residual myopathy. Some patients respond well to acetazolamide, a carbonic anhydrase inhibitor. Hyperkalemic periodic paralysis, so named because an oral potassium load can precipitate an attack, is associated with muscle sodium channel mutations. Paramyotonia congenita, characterized by myotonia paradoxically worsened by repeated muscle action, is also associated with muscle sodium channel mutations. Hypokalemic periodic paralysis, characterized by episodic weakness without myotonia precipitated by lowering of serum potassium, is associated with muscle calcium channel mutations. Myotonia congenita, with prominent muscle hyperexcitability inherited dominantly or recessively, is another group of muscle disorders associated with ion channel mutations, specifically muscle chloride channels.
Episodic ataxia is an autosomal dominant disorder characterized by attacks of gait imbalance and clumsiness precipitated by stress and fatigue and often dramatically responsive to acetazolamide. While most patients have no interictal neurologic deficits, some may experience a slow decline in baseline function with evidence of cerebellar atrophy. Episodic ataxia type 1 (with myokymia) is associated with mutations in a potassium channel gene widely expressed in the nervous system. Episodic ataxia type 2 (with interictal nystagmus) is associated with mutations in a calcium channel gene prominently expressed in the cerebellum and the neuromuscular junction. Other mutations in the same calcium channel gene may cause hemiplegic migraine or severe progressive ataxia in addition to attacks of imbalance.
Congenital myasthenic syndromes are nonimmune mediated disorders of neuromuscular transmission characterized by weakness, fatigability, and progressive muscle atrophy. Mutations in the α, β, or ε subunit of the nicotinic acetylcholine receptor channel resulting in abnormal channel kinetics or assembly appear to be the cause in many cases of congenital myasthenic syndromes. Slow channel congenital myasthenic syndrome is an autosomal dominant disorder caused by mutations that prolong nicotinic acetylcholine receptor channel opening, which contributes to inappropriate endplate depolarization and potential excitotoxicity. Heteroallelic mutations in the ε subunit gene cause congenital myasthenic syndromes through two different mechanisms: lack of ε subunit leading to deficiency of acetylcholine receptor channels (with partial phenotypic rescue by the expression of the fetal γ subunit), or altered agonist binding and channel kinetics resulting in the low-affinity fast channel syndrome.
Hereditary hyperekplexia, characterized by an exaggerated startle response and hypertonia, is an autosomal dominant condition associated with mutations in a glycine receptor channel gene. The role of the inhibitory glycine receptors in the brainstem and spinal cord is not completely understood. Benzodiazepines markedly reduce the severity of startle-induced spasms in some individuals.
Other paroxysmal neurologic disorders share features with known channelopathies. Mutations in ion channels or related proteins likely underlie familial dystonias, migraine, and epilepsy. Indeed, mutations in both ligand- and voltage-gated channels have been identified in several pedigrees with rare, monogenic epilepsies.