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Diagnosing NDM

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

NDM phenotypes

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

Chloride channelopathies

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.

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

References
  • Stunnenberg BC, et al. Muscle Nerve 2020; 62: 430–44.
  • Diaz-Manera J, et al. EMJ Neurol 2021; 6: 37–46.
  • Auranen M, et al. EMJ Neurol 2022;10: 66–77.
  • Morales F, Pusch M. Front Neurol 2020; 10: 1404.
  • Lehmann-Horn F, et al. Acta Myol 2008; 27: 98–113.
  • Wenninger S, et al. Front Neurol 2018; 9: 303.
  • Heatwole C, et al. Neurology 2012 ;79 :348–57.
  • Heatwole C, et al. Neurology 2015; 85: 2136–46.
  • Matthews E, et al. Brain 2010; 133: 9–22.
  • Trivedi JR, et al. Brain 2013 ;136: 2189–200
  • Heatwole CR, et al. Muscle Nerve 2013; 47 :632–48
  • Statland JM, Barohn RJ. Continuum (Minneap Minn) 2013; 19: 1598–614.
  • Hahn C, Salajegheh MK. Iran J Neurol 2016; 15: 46–53.
  • Phillips L, Trivedi JR. Neurotherapeutics 2018; 15: 9549–65.
  • Horga A et al. Neurology 2013; 80: 1472–5.
  • Wang GK, et al. J Physiol 2004; 554: 621–33.
  • Sansone VA, et al. Eur J Neurol 2012; 19: 1470–6.
  • Matthews E, et al. Pract Neurol 2021; 21: 196–204
  • Manousakis G, et al. AANEM Monograph. Available here. Accessed December 2022

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Foods to avoid on a low-potassium diet*

  • Fruit1,2
  • Vegetables1,2
  • Beans/legumes1,3
  • Other1-3
  • Avocado
  • Artichoke
  • Baked beans
  • Bran cereal
  • Apricots
  • Beetroot
  • Kidney beans
  • Dairy (eg yoghurt, milk)†
  • Bananas
  • Brussel sprouts
  • Lentils
  • Nuts
  • Dried fruits eg dates, raisins and prunes
  • Broccoli (cooked)
  • Brown rice
  • Grapefruit
  • Okra
  • Salt substitutes
  • Kiwi
  • Parsnip
  • Wholewheat bread and pasta
  • Mango
  • Potatoes (processed or with skin on)
  • Melons
  • Cooked spinach
  • Nectarines
  • Tomato (concentrated, eg. Tomato puree)
  • Oranges and orange juice
  • Papaya
  • Pomegranate and pomegranate juice

  • Fruit1,2

    Avocado

    Apricots

    Bananas

    Dried fruits eg dates, raisins and prunes

    Grapefruit

    Kiwi

    Mango

    Melons

    Nectarines

    Oranges and orange juice

    Papaya

    Pomegranate and pomegranate juice

  • Vegetables1,2

    Artichoke

    Beetroot

    Brussel sprouts

    Broccoli (cooked)

    Okra

    Parsnip

    Potatoes (processed or with skin on)

    Cooked spinach

    Tomato (concentrated, eg. Tomato puree)

  • Beans/legumes1,3

    Baked beans

    Kidney beans

    Lentils

  • Other1-3

    Bran cereal

    Dairy (eg yoghurt, milk)†

    Nuts

    Brown rice

    Salt substitutes

    Wholewheat bread and pasta

*Meat and fish contain a moderate amount of potassium but they are an important source of protein so shouldn’t be avoided; †Dairy products contain potassium but are an important source of calcium so should be consumed in moderation
References
  • WebMD. Low-potassium diet: what to know? Available at: https://www.webmd.com/food-recipes/low-potassium-diet-foods ; Accessed March 2021
  • St Georges Kidney Patients Association. Eating on a low potassium diet. Available at: https://www.sgkpa.org.uk/main/eating-well-on-a-low-potassium-diet-2 ; Accessed March 2021
  • NHS. Information for people on a low potassium diet. Available at: https://www.nth.nhs.uk/content/uploads/2019/02/PIL1061-Information-for-people-following-a-low-potassium-diet-Final-11.02.19-LP.pdf ; Accessed March 2021
  • NDM type1
  • Symptoms2,3
  • Which type of ion channel? 2,3
  • How is it inherited?2,3

  • Thomsen myotonia congenita

    (also called Thomsen myotonia or autosomal dominant myotonia congenita)
  • Lower limbs tend to be more affected, although can also affect the arms, hands and face. Stiffness may be worse when you first try to move after a period of inactivity, and may ease as you ‘warm up’.
  • Chloride (Cl-)
  • Autosomal dominant

  • Becker myotonia congenita

    (also called Becker myotonia, Becker disease, generalized myotonia, recessive generalized myotonia or autosomal recessive myotonia congenita
  • Lower limbs tend to be more affected, although can also affect the arms, hands and face. Stiffness may be worse when you first try to move after a period of inactivity, or if you are startled, and may ease as you ‘warm up’. Sometimes people with Becker myotonia congenita experience temporary weakness after an episode of myotonia.
  • Chloride (Cl-)
  • Autosomal recessive

  • Paramyotonia congenita

    (Also called Eulenburg disease, paralysis periodica paramyotonia, paramyotonia congenita of von Eulenburg, PMC or von Eulenburg’s disease)
  • Myotonia mainly affects hands and face and gets worse with exercise. Cold is also a key trigger of myotonia, and muscle weakness after an episode of myotonia may last hours or sometimes days.
  • Sodium (Na+)
  • Autosomal dominant

  • Sodium channel myotonia, SCM:

    myotonia permanens and myotonia fluctuans, acetazolamide-responsive myotonia (ARM) previously known as Potassium aggravated myotonias (PAM)
  • Potassium-aggravated myotonia is a rare form of NDM that affects all areas of the body. Myotonia attacks are triggered by eating potassium-rich foods. Symptoms may fluctuate widely from day to day (myotonia fluctuans) or are constant and severe (myotonia permanens).
  • Sodium (Na+)
  • Autosomal dominant

  • Other closely related sodium disorders with myotonia

    (including hyperkalemic paralysis or hyperPP)
  • Myotonia is usually mild, and often involves the eyelids, hands, and tongue. Attacks of weakness can occur at any time and are commonly triggered by rest following exercise, fasting, eating potassium-rich foods or stress.
  • Sodium (Na+)
  • Autosomal dominant
References
  • Stunnenberg B. Muscle Nerve. 2020 Oct; 62(4): 430–444
  • Hahn C, Salajegheh MK. Iran J Neurol 2016;15:46–53
  • Matthews E, et al. Brain 2010:133; 9–22

  • NDM type1

    Thomsen myotonia congenita

    (also called Thomsen myotonia or autosomal dominant myotonia congenita)

    Becker myotonia congenita

    (also called Becker myotonia, Becker disease, generalized myotonia, recessive generalized myotonia or autosomal recessive myotonia congenita

    Paramyotonia congenita

    (Also called Eulenburg disease, paralysis periodica paramyotonia, paramyotonia congenita of von Eulenburg, PMC or von Eulenburg’s disease)

    Sodium channel myotonia, SCM:

    myotonia permanens and myotonia fluctuans, acetazolamide-responsive myotonia (ARM) previously known as Potassium aggravated myotonias (PAM)

    Other closely related sodium disorders with myotonia

    (including hyperkalemic paralysis or hyperPP)

  • Symptoms2,3

    Lower limbs tend to be more affected, although can also affect the arms, hands and face. Stiffness may be worse when you first try to move after a period of inactivity, and may ease as you ‘warm up’.

    Lower limbs tend to be more affected, although can also affect the arms, hands and face. Stiffness may be worse when you first try to move after a period of inactivity, or if you are startled, and may ease as you ‘warm up’. Sometimes people with Becker myotonia congenita experience temporary weakness after an episode of myotonia.

    Myotonia mainly affects hands and face and gets worse with exercise. Cold is also a key trigger of myotonia, and muscle weakness after an episode of myotonia may last hours or sometimes days.

    Potassium-aggravated myotonia is a rare form of NDM that affects all areas of the body. Myotonia attacks are triggered by eating potassium-rich foods. Symptoms may fluctuate widely from day to day (myotonia fluctuans) or are constant and severe (myotonia permanens).

    Myotonia is usually mild, and often involves the eyelids, hands, and tongue. Attacks of weakness can occur at any time and are commonly triggered by rest following exercise, fasting, eating potassium-rich foods or stress.

  • Which type of ion channel? 2,3

    Chloride (Cl-)

    Chloride (Cl-)

    Sodium (Na+)

    Sodium (Na+)

    Sodium (Na+)

  • How is it inherited?2,3

    Autosomal dominant

    Autosomal recessive

    Autosomal dominant

    Autosomal dominant

    Autosomal dominant

References
  • Stunnenberg B. Muscle Nerve. 2020 Oct; 62(4): 430–444
  • Hahn C, Salajegheh MK. Iran J Neurol 2016;15:46–53
  • Matthews E, et al. Brain 2010:133; 9–22