New mutation of the Na channel in the severe form of potassium‐aggravated myotonia

Abstract

Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF-hand calcium-binding motif in the intracellular C-terminus. A functional analysis of the mutant channel using the voltage-clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C-terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666-673, 2009.

Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis

“…For example, the same mutation has been described to cause either a PMC or an SCM phenotype in different pedigrees [22]. A number of new mutations have been identified in the last year, including a severe form of PAM with onset in infancy [25] and a very mild mutation causing isolated eyelid myotonia [26].…”

Flecainide-Responsive Myotonia Permanens With SNEL Onset: A New Case and Literature Review

“…These types of sodium channel myotonias do not produce muscle weakness, but they do share some overlapping clinical features (eg, muscle stiffness, hypertrophy). [1][2][3][4] They can affect either children or adult patients; newborns may manifest with severe neonatal episodic laryngospasm (SNEL) characterized by muscle hypotonia and recurrent episodes of laryngospasm, followed by apnea. SNEL exhibits a spontaneous decrease in frequency and duration; this clinical phase is usually followed by myotonia (ie, myotonia permanens or paramyotonia congenita).…”

Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca 2+ -dependent regulation of polycystin-2 channel activity

“…A potassium-aggravated myotonia associated mutation in the assumed EF-hand in Na V 1.4 disrupts fast channel inactivation (9), and bestrophin Cl − and BK channels have been proposed to contain EF-hands which, when mutated, abolish Ca 2þ sensitivity (10,11). In polycystin-2-like-1 (polycystin-L), a protein related to PC2, an EF-hand within the C-terminal tail may attenuate channel overstimulation (12).…”