Sodium Channel Myotonia and a Novel Gly701Asp Mutation in the SCN4A Gene: From an Ophthalmological Symptom to a Familial Disease

ABSTRACT

A six-month-old female child came to an ophthalmology consultation because of a convergent strabismus, myotonia of the orbicularis muscles and difficulty walking in cold environments. Further investigation identified a family history of muscular myotonia in the father, grandmother and uncle. The father also presented with ocular myotonia. The child and family members underwent genetic testing, which was negative for CLCN1 mutations but was positive for a novel heterozygotic Gly701Asp mutation in the SCN4A gene, compatible with sodium channel myotonia. The non-dystrophic myotonias are caused by dysfunction of key skeletal muscle ion channels. Before the advent of DNA sequencing, non-dystrophic myotonias were differentiated based on clinical phenotypes. Sodium channel myotonia disorders are classically of dominant inheritance, in which eye closure myotonia is the most frequent manifestation. Over 40 different mutations have been reported in the SCN4A gene. The Gly701Asp mutation in exon 13 identified in this family has not been described before.

Introduction

The non-dystrophic myotonias are caused by dysfunction of key skeletal muscle ion channels. The worldwide prevalence of non-dystrophic myotonia has been estimated to be 1 in 100 000.¹ The major clinical manifestation of the non-dystrophic myotonias is muscle stiffness and additional common symptoms include pain, weakness and fatigue.^2,3 Myotonia can be demonstrated on examination as delayed muscle relaxation following muscle contraction. Non-dystrophic myotonias are classified as myotonia congenita, caused by mutations in the skeletal muscle chloride channel gene (CLCN1) and inherited in a dominant or in a recessive fashion; paramyotonia congenita and the sodium channel myotonias, characterised by allelic, autosomal dominant disorders caused by mutations in the skeletal muscle sodium channel gene (SCN4A); and hyperkalaemic periodic paralysis, also caused by mutations in SCN4A gene in which episodic paralysis is usually the dominant feature (Table 1).⁴

Table 1.

Summary of non-dystrophic myotonias and their clinical phenotypes.^4.

	Recessive myotonia congenite	Dominant myotonia congenita	Paramyotonia congenita	Sodium channel myotonia
Inheritance	Recessive	Dominant	Dominant	Dominant
Mutated gene	CLCN-1	CLCN-1	SCN4A	SCN4A
Muscle involvement	Preferably lower limbs	Preferably upper limbs. Occasionaly facial muscles	Preferably upper limbs and facial muscles	Preferably upper limbs, facial and extraocular muscles
Cold sensitivity	Minimal	Minimal	Yes	Variable
Warm-up phenomenon	Yes	Yes	No	Sometimes
Eyelid myotonia	Rare	Rare	Common	Common
Muscle hypertrophy	Rare	Common	Infrequent	Common
Muscle weakness	Common transiently	Infrequent transiently	Common and in longer periods	Rare
Pain	Infrequent		Common

Case report

A six-month-old female presented with an intermitent, alternating convergent strabismus and ptosis. On ophthalmological examination she presented with a 15º Hirschberg reflex, and this deviation was variable at subsequent follow-up examinations. Further examination revealed the presence of action myotonia of the orbicularis oculi muscles: after forceful contraction of the orbicularis oculi muscles had been maintained for several seconds she was unable to open her eyelids and compensatory frontalis muscle contraction was needed to open the eyes (Video 1). Her parents reported later at two years of age that the child also had some difficulty walking in cold environments. When she was two-years-old, a retinoscopic examination demonstrated a refractive error of +0.25 + 0.50 x 90º in the right eye and +0.75 + 0.50 x 90º in the left eye. She maintained an alternating and variable angle strabismus, and deviated more frequently the right eye. She started occlusion treatment to prevent the development of amblyopia.

Further investigation identified a family history of muscular myotonia in the father, grandmother and uncle, in which the father and uncle were under investigation by Neurology with a presumptive diagnosis of Thomsen’s myotonia. The father presented with myotonic palpebral and hand phenomena, that improved with warming and exercise (Video 2). Additionally, he had muscle hypertrophy. Her grandmother also presented with similar symptoms. Her uncle had with more severe symptoms with limitation in extension of his limbs, dysphagia and painful myotonia (Figure 1 and Table 2).

Figure 1.

Pedigree of the family diagnosed with sodium channel myotonia, with the mutation c.2102 G > A (p.Gly701Asp) in exon 13 of the SCN4A gene. Pedigree symbols: circles – females; squares – males; closed symbols – affected individuals; arrow – the index patient; asterisk – supplemental data: Videos 1 and 2 showing action myotonia in these patients. Numbers – see Table 2 for clinical manifestations in each affected family member

Table 2.

Summary of the manifestations of affected family members. Patient 1 – grandmother; Patient 2 – father; Patient 3 – uncle; Patient 4 – index patient

	Patient 1	Patient 2	Patient 3	Patient 4 (Index Patient)
Strabismus	No	No	No	Yes
Ptosis	No	Yes	Yes	Yes
Myotonia of orbicularis oculi	Yes	Yes	Yes	Yes
Muscle hypertrophy	Not known	Yes	Yes	Yes
Myotonic hand phenomena	Not known	Yes	Yes	No
Myotonia of upper limbs	Not known	No	Yes	No
Dysphonia	Not known	No	Yes	Yes
Dysphagia	Not known	No	Yes	No
“Warm-up phenomena”	Not known	Yes	Yes	Yes
Cold sensitivity	Not known	Yes	Yes	Yes
Pain	Not known	No	Yes	No

In collaboration with the Neuro-paediatric department, the child and family members underwent genetic testing, which was negative for CLCN1 mutations but was positive for a heterozygotic mutation in SCN4A, compatible with sodium channel myotonia where the second allele had a c.2102 G > A (p.Gly701Asp) mutation in exon 13.

The girl maintained alternate occlusion until the age of four-years-old, with a best corrected visual acuity of 20/30 in both eyes and she never developed amblyopia. She maintained an alternating ptosis and the myotonic palpebral phenomena, and progressively other symptoms and signs came apparent including dysphonia and hypertrophy of cervical, scapular and dorsal muscles from around three years of age.

Discussion

Before the advent of DNA sequencing, non-dystrophic myotonias were differentiated based on clinical phenotypes that had been loosely matched to a specific ion channel. The ones caused by mutations in the CLCN1 gene cause both Thomsen’s (autosomal-dominant) and Becker’s (autosomal-recessive) myotonia congenita. These chloride ion channelopathies present with myotonia associated with muscle hypertrophy and display a characteristic “warm-up phenomenon”.⁵ The father, grandmother and uncle of the patient in the presented clinical case were initially diagnosed with Thomsen’s myotonia because of the overlapping of the clinical characteristics of the myotonia. The child’s phenotype, in combination with a negative result for a CLCN1 mutation, led to consideration of a sodium channel myotonia diagnosis, which was subsequently confirmed by genetic testing. A previous study screened patients with a clinical diagnosis of Thomsen’s or Becker’s for mutations in both the CLCN1 and SCN4A genes. Approximately 20% of cases were found to have no CLCN1 mutations, and of those all were found to have a SCN4A mutation, showing that sodium channelopathies can mimic the warm-up phenomenon seen with chloride channelopathies.⁶

Sodium channel myotonia disorders are classically of dominant inheritance, that can be distinguished from the chloride channel myotonia disorders by a delayed-onset and exercise-induced myotonia in which muscle contractions induce myotonia after a period of delay. Orbicularis oculi myotonia is more frequent in sodium channel myotonia and many individuals have painful myotonia, with some studies reporting as high as 57% of sodium channelopathies presenting with pain.^7,8

Also, some specific mutations have been reported to be associated with certain phenotypes: the M1476I mutation is associated with severe painful myotonia and a clear warm-up phenomenon.^9,10 The N1297 K mutation was described in a case of a severe neonatal form with oxygen desaturation, early-onset muscle hypertrophy, psychomotor retardation and a fatal outcome at 20 months of age.¹¹ With the L250P mutation myotonia is almost exclusively restricted to the orbicularis oculi muscles.¹²

Over 40 different mutations, including those responsible for periodic paralysis, have been reported in the SCN4A gene. Exons 22 and 24 are recognised as ‘hot spots’ for paramyotonia congenita, particularly the T1313 M mutation and amino acid substitutions at the R1448 position.¹³ The most common sodium channel myotonia mutations are V1589 M and those at the G1306 position.¹⁴

The Gly701Asp identified in this family is a novel mutation. Different family members with this mutation presented with different clinical manifestations and disease severity. The most interesting characteristic was that the child presented with a simple strabismus and ptosis initially, and only on further observations was the myotonic phenomena of the eyelids recognised, which led to neurological investigation by a Neuro-paediatrician and Neurologists. Studies that previously reported ocular myotonia with extraocular muscle involvement identified a V445 M mutation.^15,16 Du et al. described a big family with myotonia congenita in which all affected individuals were diagnosed with esotropia between the ages of three and six, and had at least one surgery in both eyes for strabismus, and additionally eyelid myotonia.¹⁶ It has been speculated that esotropia may be caused by slightly nasally displaced superior and inferior rectus muscles, as well as an inferiorly displaced lateral rectus muscle.⁸

The presentation of the child led to investigation of the family and subsequent diagnosis of the disease. It shows the important role of the Ophthalmologist in identifying these cases and in conjunction with the Neuro-paediatrician, its further investigation.

Declaration of interest statement

There are no conflicts of interest or financial disclosures, as well as no funding was obtained.

Supplemental data

Supplemental data for this article can be accessed online at http://dx.doi.org/10.1080/01658107.2020.1779316.