Myotonia

Myotonia is a failure of muscle cell relaxation manifesting clinically as impaired relaxation after voluntary muscle contraction (e.g., grip myotonia, Video 100.1) or prolonged reflexive contraction during specific neurological examination testing (e.g., percussion myotonia, Video 100.2). The latter is most frequently evaluated by gently percussing the thenar eminence with a reflex hammer and assessing for sustained thumb abduction. Myotonia may be described as “stiffness” but is not typically associated with significant pain. This distinguishes it from muscle cramping, in which pain is prominent. Myotonic discharges can be seen during electromyography (EMG) and are characterized by spontaneous waxing and waning muscle cell discharges with variable amplitude and frequency (unlike cramping, which is due to spontaneous motor-unit firing). Clinical myotonia is most commonly associated with myotonic dystrophies and skeletal muscle channelopathies; myotonia seen on EMG is less specific and may be seen in other chronic disorders of muscle, particularly metabolic myopathies.

A.

Periodic paralysis in the setting of myotonia is typically associated with mutations in the SCN4A gene, resulting in hyperkalemic periodic paralysis. Andersen-Tawil syndrome (ATS), a rare disorder associated with periodic paralysis, cardiac arrhythmias, and developmental abnormalities, should be considered in any patient manifesting at least two of these issues. Two-thirds of patients with ATS have mutations in the KCNJ2 gene. Hypokalemic and thyrotoxic periodic paralysis are not addressed here, as these disorders are not associated with myotonia but should be considered in any patient presenting with episodes of periodic paralysis.
B.

The pattern of weakness associated with clinical myotonia can be helpful in distinguishing myotonic dystrophy type 1, which typically causes facial and hand grip weakness, from other myotonic disorders, which are usually—though not invariably—associated with proximal weakness.
C.

Myotonic muscular dystrophy, type 1 (DM1) is the most common myotonic disorder. It is an autosomal dominant condition caused by a trinucleotide (CTG) repeat expansion in the 3′ untranslated region of the dystrophica myotonia type-1 protein kinase ( DMPK ) gene. DM1 may present from infancy (congenital DM1) to adulthood. Distal muscles are typically affected first, particularly in the upper extremities. The neck flexors and facial muscles are commonly involved. The classic facial appearance of DM1 patients is due to the combination of atrophy of the temporalis muscles, weakness of the muscles of jaw closure, and ptosis. Dysphagia is common. DM1 can be associated with other systemic issues including cardiac arrhythmias, cataracts, and intellectual impairment.
D.

When prominent proximal weakness is present, myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy, is most likely. DM2 is an autosomal dominant disorder caused by a tetranucleotide (CCTG) repeat expansion in intron 1 of the CNBP gene. DM2 patients tend to have milder systemic features than are seen in DM1 and there is no congenital form. In the setting of proximal weakness and myotonia seen only on EMG, other chronic myopathic disorders, particularly metabolic myopathies like acid maltase deficiency and debranching enzyme deficiency, should be considered. McArdle disease, a disorder of glycogen metabolism, can be difficult to distinguish from a myotonic disorder clinically due to increasing muscle stiffness with exertion seen in this disorder, which may resemble a paramyotonic pattern.
E.

Chloride channelopathies, also known as myotonia congenita, are the result of mutations in the CLCN1 gene. They may be inherited in an autosomal dominant (Thomsen disease) or recessive (Becker disease) pattern. These patients have classic myotonia with initial impairment of muscle relaxation, which improves with repeated movements. Mutations do not appear to cause systemic effects or weakness, and patients have a normal life span. On occasion, DM2 can present without notable proximal muscle weakness, so this should be considered if testing for myotonia congenita is negative.
F.

Most myotonia improves with exercise; patients who experience myotonia that worsens with exercise have “paradoxical myotonia” or paramyotonia. Symptoms are typically exacerbated by cold. Paramyotonia congenita is caused by mutations in the SCN4A gene. Paramyotonia congenita and hyperkalemic periodic paralysis are allelic disorders, and some families demonstrate clinical features of both.
G.

Genetic testing panels are a useful tool in diagnosing myotonic disorders; however, it is important to recognize that DM1 and DM2 are nucleotide repeat disorders that are not effectively studied by large genetic muscular dystrophy next-generation sequencing panels.