Paramyotonia Congenita: Clinical Features, Diagnosis, and Management
Overview and Pathophysiology
Paramyotonia congenita is an autosomal dominant skeletal muscle sodium channelopathy caused by missense mutations in the SCN4A gene, which encodes the α subunit (NaV1.4) of the voltage-gated sodium channel, resulting in cold-induced myotonia and episodic weakness that paradoxically worsens with continued muscle activity. 1, 2
Clinical Features
Characteristic Symptoms
Cold-induced muscle stiffness (myotonia) affecting primarily the eyelids, hands, face, and jaw, which paradoxically worsens with repeated muscle contraction rather than improving (the "paradoxical" feature distinguishing it from other myotonias) 3
Episodic weakness triggered by cold exposure and exercise, though some patients present with stiffness alone without weakness episodes 4
Symptom onset in childhood, typically manifesting in early years with lifelong persistence but non-progressive course 3
Temperature sensitivity as the defining feature, with symptoms provoked by cold exposure (cold water immersion, cold weather) and improving with warming 2, 5
Distribution Pattern
Predominantly affects distal muscles initially (hands, eyelids) before potentially involving proximal limb muscles 3
Facial muscles including eyelids and jaw muscles are characteristically involved 3, 4
Diagnosis
Clinical Examination
Percussion myotonia at the thenar eminence is typically demonstrable on physical examination 3
Family history revealing autosomal dominant inheritance pattern supports the diagnosis 3
Electrophysiological Testing
Electromyography (EMG) shows generalized myotonic discharges with characteristic high-frequency runs 3
Short exercise test following cold exposure demonstrates a pathognomonic decrease in compound motor action potential (CMAP) amplitude after exercise, even in patients without clinical weakness episodes 4
Repetitive nerve stimulation after ice bath immersion reveals a decrement pattern that confirms the diagnosis 4
Molecular Genetic Testing
Direct DNA sequencing of the SCN4A gene is the definitive diagnostic test, identifying specific missense mutations 1, 2
Most common mutations occur at position T1313 (threonine to methionine or alanine) in the DIII-DIV cytoplasmic loop, and at R1448 (arginine to cysteine, histidine, proline, or serine) in the DIV-S4 segment 1, 3, 5
The DIII-DIV cytoplasmic loop is the critical region that pivots during membrane depolarization to inactivate the channel; mutations here disrupt fast inactivation, causing persistent sodium current and membrane hyperexcitability 1
Functional Consequences of Mutations
Mutations cause gain-of-function changes with impaired fast inactivation: slowed kinetics, reduced voltage sensitivity, accelerated recovery from inactivation, and temperature-sensitive alterations 2, 5
At cold temperatures, mutant channels show hyperpolarizing shift in activation and depolarizing shift in fast inactivation, creating a window for persistent sodium current that triggers myotonia 2, 5
Treatment
Preventive Measures
Avoid cold exposure as the primary management strategy, including cold water, cold weather, and air conditioning 3
Precautions during general anesthesia are essential due to risk of diaphragm myotonia and respiratory complications 3
Pharmacological Management
Mexiletine (membrane-stabilizing antiarrhythmic agent) is the first-line medication, demonstrating objective improvement in both clinical symptoms and electrophysiological abnormalities on short exercise testing 4
Tocainide (another membrane-stabilizing antiarrhythmic) can be used as an alternative 3
Acetazolamide (carbonic anhydrase inhibitor) may be beneficial in some patients, though evidence is less robust than for mexiletine 3
Prognosis
Non-progressive disorder with stable symptoms throughout life, distinguishing it from degenerative neuromuscular diseases 3
No cardiac involvement is expected, unlike myotonic dystrophy, as paramyotonia congenita affects only skeletal muscle sodium channels 3
Quality of life can be significantly improved with appropriate cold avoidance and mexiletine therapy when symptoms are bothersome 4
Key Clinical Pitfalls
Do not confuse with myotonic dystrophy, which has multisystem involvement including cardiac conduction defects, cataracts, and progressive weakness—paramyotonia congenita is purely a skeletal muscle disorder 3
The paradoxical worsening with exercise (rather than warm-up phenomenon) is pathognomonic and distinguishes paramyotonia from myotonia congenita 3
Genetic testing is essential for definitive diagnosis and genetic counseling, as clinical overlap exists among sodium channelopathies 2