Paramyotonia congenita of Von Eulenburg (ORPHA:684)
A rare genetic skeletal muscle ion channel disorder, part of the non-dystrophic myotonias, characterized by exercise and/or cold-exacerbated myotonia.
Epidemiology
The exact prevalence is unknown but is estimated to be < 1/100,000 people in Europe (0.17/100,000 in UK).
Clinical description
Symptoms usually manifest in the first decade of life with an usual onset in early childhood. The major clinical manifestation is episodic muscle stiffness as a consequence of myotonia which, in paramyotonia congenita (PC), is called « paradoxical » because of its worsening with repeated exercice. Muscle stiffness commonly follows severe attacks of stiffness in case of prolonged exercise and/or prolonged cold exposure, it presents an extreme cold sensitivity and can be also exacerbated by other factors, like fasting and some hormonal conditions (menstruation, pregnancy). Myotonia can last seconds to minutes whereas weakness may persist for hours, even if the muscles are rewarmed. Facial, tongue, and hand muscles are predominantly affected whereas the lower limbs are generally only mildly affected.
Etiology
PC is a muscle sodium channelopathy due to missense mutations of the SCN4A gene (17q23.3) encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. Pathological variants of SCN4A lead to an increased membrane excitability. The rapid inactivation phase of the sodium channels, which normally follows muscle contraction, is altered. The sodium channels are prematurely reactivated, and new action potentials are generated, resulting in myotonic bursts.
Diagnostic methods
Diagnosis is based on clinical history, physical exam, electromyographic and genetic tests. EMG records myotonic discharges and reveals specific muscle excitability anomalies after provocative test, showing gradual decrease of compound motor muscle action potential (CMAP) after repeated short exercise tests at room temperature and after cooling. CPK levels vary depending on the myotonia severity. Long exercise test may show progressive and prolonged decrease in the amplitude of CMAPs. Muscle biopsy is not useful for diagnosis. It can reveal a vacuolar myopathy in case of associated attacks of weakness.
Differential diagnosis
The differential diagnosis includes the other non-dystrophic myotonic syndromes such as Thomsen and Becker disease, other sodium channel myotonias, and hyperkalemic periodic paralysis with paradoxical myotonia.
Antenatal diagnosis
Prenatal and preimplantation genetic testing are possible when the pathogenic variant has been identified in an affected family member, but are rarely performed because of the non life-threatening prognosis.
Genetic counseling
PC is transmitted as an autosomal dominant disease with a complete penetrance. Sporadic cases and de novo mutations have been reported. Genetic counseling should be offered to patients informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors (cold exposure, fasting and strenuous/prolonged exercice). Muscle stiffness (myotonia) responds well to sodium channel blockers. Mexiletine or carbamazepine are treatments of choice. Acetazolamide can be useful to prevent attacks of weakness and may also improve myotonia in some cases. Physiotherapy with massages and stretching may be useful against pain and retractions. Close monitoring is necessary during surgery and anesthesia. Depolarizing agents can induce masseter spasms and stiffness of respiratory and other muscles and can therefore impair intubation and mechanical ventilation. Depolarizing muscle relaxants are therefore contraindicated. Myotonic patients are considered to be susceptible to malignant hyperthermia; volatile anesthetics and suxamethonium should be prohibited.
Prognosis
Prognosis is good and symptoms are stable during life. There is no impact on life expectancy. Even if the disease is nonprogressive and not life-threatening, the disability resulting from the symptoms can have a significant functionnal impact on daily life activities, affecting quality of life, personal, social, and professional spheres.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Dr Savine VICART | EURO-NMD* - Dr Nur VILLAR | EURO-NMD*


                                * European Reference Network