Periodic Paralysis and Other Channelopathies



Periodic Paralysis and Other Channelopathies


Comana M. Cioroiu

Lewis P. Rowland



INTRODUCTION

Muscle channelopathies comprise a heterogeneous group of diseases of skeletal muscle that include both syndromes of episodic weakness (periodic paralyses) and muscle fiber hyperexcitability (nondystrophic myotonias). The clinical phenotype depends on the particular channel mutation involved, and attacks can vary in severity, duration, and constellation of symptomatic triggers (Table 93.1). Most of these disorders are inherited in an autosomal dominant fashion, although sporadic mutations do exist. Changes in neuronal membrane depolarization secondary to various ion channel mutations can either lead to sustained depolarization and resultant overt muscle weakness or to a more mild constant depolarization (or reduced repolarization) leading to myotonia and stiffness. On occasion, there is overlap between the two, and some patients may have episodes of both myotonia and paralysis. There are three main types of periodic paralysis: hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome (periodic paralysis with cardiac arrhythmia and dysmorphic features). The nondystrophic myotonic disorders are primarily composed of myotonia congenita, paramyotonia congenita, as well as a subgroup of potassium aggravated myotonic disorders. Electrodiagnostic testing is important in helping to identify particular patterns and make a correct diagnosis. Needle electromyogram (EMG) is needed to detect myotonic discharges or other abnormal spontaneous activity. In addition to routine nerve
conduction studies, short and long exercise tests are uniquely used to help characterize specific patterns. In short exercise testing, the patient is asked to exercise a muscle (typically the abductor digiti minimi), and a compound muscle action potential (CMAP) is recorded every 10 seconds thereafter and compared to a baseline. In the long exercise test, the patient is asked to exercise the muscle for an extended amount of time (usually 5 minutes), and CMAPs are recorded every 2 minutes thereafter for about 1 hour and compared to baseline. Changes in CMAP amplitude in both short and long exercise testing can be used to differentiate between the various channelopathies. For instance, CMAP amplitudes typically increase in the periodic paralyses and decrease in the myotonias. Different electrodiagnostic patterns diagnostic of each particular disease were described in 2004 by Emmanuel Fournier and are still used today and are known as Fournier patterns. Targeted confirmatory genetic testing is often done thereafter to confirm the diagnosis. Although patients with these diseases have a normal life expectancy, they may struggle with persistent pain or progressive weakness causing significant functional impairment.








TABLE 93.1 Clinical Features of Hereditary Periodic Paralysis and Nondystrophic Myotonias



















































































Hypokalemic Periodic Paralysis


Hyperkalemic Periodic Paralysis


Andersen-Tawil Syndrome


Paramyotonia Congenita


Myotonia Congenita


Gene


CACN1AS or SCN4A


SCN4A


KCNJ2


SCN4A


CLCN-1 (AD) or SCN4A (AR)


Age of onset


Usually second or latter part of first decade


First decade


First or second decade


First decade


First decade


Sex


Male preponderance


Equal


Equal


Equal


Male preponderance


Frequency of paralytic episodes


Daily to yearly


Hourly to daily


Daily to yearly


May not be present; otherwise, weekly to monthly


Usually not present, variable frequency in AR form


Degrees of paralysis


Tends to be severe


Tends to be mild but can be severe


Variable


Tends to be mild but can be severe


Lasting seconds to minutes in AR form, usually not present in AD form


Effect of cold


May induce an attack


May induce an attack


May induce an attack


Tends to induce an attack


No effect


Oral potassium


Relieves or prevents an attack


Precipitates an attack


May relieve or prevent an attack


May precipitate an attack


No effect


Myotonia


Absent


May be present


Absent


Present


Present


Precipitants


Carbohydrate-rich food, cold


Fasting, stress, rest after exercise, K-rich foods


Carbohydrate-rich food, rest after exercise


Fasting, stress, cold, rest after exercise


Exercise


Exercise testing


Increase in CMAP with gradual decline with long exercise testing; short exercise testing normal (Fournier V)


Increase in amplitudes with gradual decrease in both short and long exercise testing (Fournier IV)


Unknown


Prominent drop in amplitudes with cooling in both long and short exercise testing; PEMPs present (Fournier I)


AD: drop in amplitude on short exercise testing, less drop with repeated testing


AR: drop in amplitude with slow recovery (Fournier II)


AD, autosomal dominant; AR, autosomal recessive; K, potassium; CMAP, compound muscle action potential; PEMP, postexercise myotonic potential. Modified from Hudson AJ. Progressive neurological disorder and myotonia congenita with paramyotonia. Brain. 1963;86:811.



HYPOKALEMIC PERIODIC PARALYSIS


EPIDEMIOLOGY AND PATHOBIOLOGY

Hypokalemic periodic paralysis (hypoKPP) is the most common of the periodic paralyses, yet it is still rare, affecting only about 1.7 per 1,000,000 people in England. Clinical onset is usually within the first 2 years of life (although it may be delayed into the sixth decade) and is more prevalent in men than women in a ratio of about 2:1. Most of these patients have mutations in either the CACN1AS gene (CaV1.1, chromosome 1q31-32) encoding an L-type calcium channel or less commonly, the SCN4A sodium channel gene (NaV1.4, chromosome 17q23). In the presence of these mutations, muscle fibers become depolarized and electrically inexcitable, leading to weakness. Just how these mutations cause persistent depolarization is unknown; however, one mouse model of such a calcium channel mutation proposed a possible explanation via a “gating pore current,” described as an anomalous inward current at the resting potential triggered by low extracellular potassium content, leading to depolarization and sodium channel inactivation. At the structural level, mutations in the calcium channel lead to a vacuolar myopathy, whereas sodium channel mutations are associated with the development of transverse tubular aggregates and less vacuolization.


Jul 27, 2016 | Posted by in NEUROLOGY | Comments Off on Periodic Paralysis and Other Channelopathies
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