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NDM is challenging to recognise because symptoms are often non-specific, transient and highly variable. Diagnosis is usually confirmed in a specialist neuromuscular clinic and is based on history, neuromuscular examination, the presence of electrical myotonia on electromyography (EMG) and genetic testing.1 However, people impacted by NDM often first present at primary or general medical clinics where these tests are unavailable and an NDM diagnosis may not even be considered due to its rarity. Consequently, there is a need to alert all healthcare professionals to the key signs and symptoms of NDM – particularly myotonia and myalgia – to expedite referral to an appropriate specialist. Together, we can help shorten the long diagnostic delays experienced by those affected.2,3
NDMs are ultra-rare genetic neuromuscular disorders characterised by skeletal muscle stiffness (myotonia), which is caused by mutations in sodium or chloride ion channels in muscle cell membranes.4 NDMs are divided into two genotypes depending on whether the pathogenic variant occurs in the chloride (CLCN1) or sodium channel gene (SCN4A). These channelopathies are then further subdivided into distinct phenotypes based on mode of inheritance, clinical or electrophysiological features.
It is important to correctly identify the type of NDM to ensure patients receive appropriate treatment advice.
The mytonic disorders and periodic paralyses
In the chloride channelopathies (Becker myotonia congenita and Thomsen myotonia congenita), mutations in the CLCN1 gene affect the function, conductivity or number of chloride ion channels, which lead to delayed repolarisation, impaired development of resting potential, muscle cell membrane hyperexcitability and delayed muscle relaxation.4,9
Symptoms of chloride channelopathies tend to manifest at approximately 10 years of age.1,9,10 Some signs of Becker myotonia congenita and Thomsen myotonia congenita are similar, such as myotonia improving after a ‘warm-up’ period, but myalgia, muscle hypertrophy, transient weakness, and upper limb involvement, are more common in Becker myotonia congenita, while in Thomsen myotonia congenita, lower limbs are more likely to be affected. Chloride channelopathies may respond better to higher doses of the Class IB antiarrhythmic drug, mexiletine, than is needed for a response in sodium channelopathies.
In the sodium channelopathies, mutations in the SCN4A gene lead to delays in sodium ion gate closure after movement, which slows muscle relaxation.4
Symptoms of sodium channelopathies manifest earlier than chloride channelopathies at approximately 5 years of age.1 Symptoms include facial muscle stiffness (often involving eyelid myotonia), pain, and episodic weakness, which are all exacerbated in cold weather.
As seen in the chloride channelopathies, symptoms can vary across the sodium channelopathies. In paramyotonia congenita (PMC), myotonia may worsen after repetitive contractions, while potassium-rich food and drink can also trigger myotonia related to some sodium channelopathies.1,2
Differential diagnosis of NDM
NDM can be challenging to diagnose. Myotonia is the key symptom shared by all NDMs and may be described by patients as their muscles cramping, locking up, being stiff, stuck, or aching.1,2,17,18
Investigation for NDM begins with a patient history describing age of symptom onset, family history and exacerbating factors, eg. exercise, cold, menstruation, dietary potassium.1,2
Neurological examinations and ‘bedside’ tests of motor function, including observations of stiffness level when initiating movement and muscle relaxation after a contraction form the key initial assessments for myotonia.1,2 Eyelid and hand grip myotonia may be checked for in the clinic by asking patients to repeatedly open and close their eyes and to make and release a fist, respectively.18 Leg myotonia may be observed as a patient rises from their seat in the waiting room.18
Suspected myotonia can be confirmed by EMG. Definite NDM must then be differentiated from other myotonic disorders based on the presence of a CLCN1 or SCN4A pathogenic variant.1 NDM subtypes are identified by responses to exercise testing and clinical features.
Differential diagnosis of NDM1,19
Possible, probable and definite NDM
More than 200 CLCN1 and 65 SCN4A gene mutations have so far been linked with NDM.4 If genetic testing reports a variant of uncertain significance (VUS), then this can be considered probable NDM, and if no variant is found, it may still be considered possible NDM in the presence of a positive history and EMG.1 If genetic testing does not identify a known pathogenic mutation, or if genetic testing is unavailable, then further diagnostic work up is recommended.1
Possible, probable and definite NDM1
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- Diaz-Manera J, et al. EMJ Neurol 2021; 6: 37–46.
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- Matthews E, et al. Pract Neurol 2021; 21: 196–204
- Manousakis G, et al. AANEM Monograph. Available here. Accessed December 2022