Abstract & Commentary
Source: Cannon SC, et al. Neuromuscul Disord. 2002; In press.
Episodic attacks of flaccid muscle weakness is the hallmark of these 4 autosomal dominant disorders involving missense mutations of voltage-gated ion channels. Generalized weakness is the rule during an episode, with sparing of respiratory, ocular, and pharyngeal muscles. Onset is in the first (paramyotonia congenita, hyperkalemic periodic paralysis) or second (hypokalemic periodic paralysis, Anderson’s syndrome) decade with the various forms distinguished by potassium level, myotonia, cardiac arrhythmia, and dysmorphic features. Treatments vary and precise diagnosis is crucial.
Hypokalemic periodic paralysis (HypoPP), though rare (prevalence 1/100,000), is the most common form of periodic paralysis. Rest following exercise, meals rich in carbohydrates, alcohol, and stress precipitate attacks, which usually begin around puberty and may occur daily or rarely. Low-serum potassium (< 3.0 mEq/L) at attack onset and resolution with oral potassium are specific but variable features of HypoPP and their absence does not exclude the diagnosis. Attack duration is the longest of all the periodic paralyses, lasting several hours to days. A fixed proximal myopathy may develop after many episodes, usually in the fourth or fifth decade. Serum creatine kinase is barely elevated if at all, myotonia is never seen on electromyography (EMG), but vacuolar myopathy is present on biopsy. Thyroid function studies are necessary to exclude thyrotoxic periodic paralysis, particularly in Asian men. Linkage analysis and positional cloning have localized HypoPP to a calcium channel gene, CACNLAS, on chromosome 1q31-32, which codes for the a1S subunit of skeletal muscle L-type calcium channel. Three missense mutations have been reported to date. Interestingly, susceptibility to malignant hyperthermia may rarely be associated with the same mutation. In 30% of HypoPP, a CACNLAS mutation is not found. Some of these patients have a sodium channel mutation (SCN4A, see below) and one reported family has a missense mutation involving a potassium channel accessory subunit, MiRP2 (KCNE3).
Hyperkalemic periodic paralysis, despite its appellation, is not always associated with elevated potassium (> 5 mEq/L), though weakness may reliably be provoked by potassium administration, as well as by exercise followed by rest, fasting, muscle cooling, and stress. Onset of HyperPP starts in early childhood with episodes lasting minutes to hours, briefer than in HypoPP. Clinical or electrical myotonia is frequent, while during an attack electrical EMG silence is the sine qua non. Attack frequency tends to diminish with age but a vacuolar myopathy may develop nevertheless. Missense mutations of the adult isoform of the skeletal muscle sodium channel, a subunit gene (SCN4A), on chromosome 17q23 are responsible and 9 different missense mutations have been reported thus far. In some, no mutation is found, possibly due to misdiagnosis or technical limitations of the genetic screen.
Paramyotonia congenita (PMC) affects the same gene as, and shares much clinical overlap with, HyperPP. Myotonic stiffness—which paradoxically worsens with repetitive contractions, hence paramyotonia—is the main feature of PMC, distinguishing it from HyperPP. Cold weather and cold-water immersion worsen the myotonia, in contrast to myotonia congenita, which is insensitive to cold and improves with repetitive contraction. Seven different missense mutations of SCN4A have been reported to date in PMC.
Anderson’s syndrome (AS), a clinical triad of potassium-sensitive periodic paralysis, ventricular arrhythmia, and dysmorphic features, is the only periodic paralysis with extra-muscular manifestations. Serum potassium is usually low, but may be normal or elevated. Myotonia is not a feature, CK is generally normal, but mild fixed weakness is seen in half. Not surprisingly, muscle biopsy is usually myopathic. Various types of ventricular arrhythmias exist and an implantable defibrillator may be necessary in patients with cardiac arrest. Dysmorphic features commonly affect the face and digits, and include low set ears, broad nose, wide set eyes (hypertelorism), small mandible (micrognathia), high-arched palate, clinodactyly, and syndactyly. Nine different mutations of the KCNJ2 gene, coding for the inward rectifying potassium channel, Kir2.1, on chromosome 17q23 (same locus as a sodium and calcium channel), have been reported, 7 missense and 2 with in-frame deletions. No mutation was found in 3 of 16 probands.
Commentary
Missense mutations of the calcium channel gene, CACNLAS, on chromosome 1q31-32, have been found in familial HypoPP. The thyrotoxic form of HypoPP, though clinically comparable, appears not to have these mutations (Clin Endocrinol. 2002;56:367-375). Among 14 patients with thyrotoxic HypoPP, 13 sporadic and 1 with a family history, mutational screening was performed by PCR amplification of the appropriate exons, single-strand conformation polymorphism (SSCP), and further sequencing. None of the thyrotoxic HypoPP patients was found to have the mutations described in HypoPP nor mutation in any of the 4 full S4 voltage-sensing transmembrane segments of the calcium channel gene. However, 2 single nucleotide polymorphisms were found in both familial and sporadic cases with thyrotoxic HypoPP, in higher frequency than in controls, suggesting an association between the two. —Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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