Clinical, electrophysiological and genetic features of a large Australian family with paramyotonia congenita

To our knowledge, this is the first report of an Australian family with paramyotonia congenita. Paramyotonia congenita is a rare autosomal dominant condition characterised by paradoxical myotonia — impaired relaxation of muscles following muscle contraction, which worsens with repetitive muscle activity.1 It is distinct from other forms of myotonia, which typically improve with repetitive activity (the warm-up phenomenon).4 Paramyotonia is typically exacerbated by exposure to cold, and can be associated with cold-induced paralysis.1 Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A cause paramyotonia congenita,5 and can also cause hyperkalaemic periodic paralysis, potassium-aggravated myotonia, and a small proportion of hypokalaemic periodic paralysis cases.6 Patients carrying an SCN4A mutation may have manifestations of more than one of these allelic disorders.

Our patient’s neurophysiology findings and the clinical features of her affected family members are typical for paramyotonia congenita associated with cold paralysis, and similar to those described in the largest reported case series for this condition.7 In this case series, age of onset was typically during early childhood, and clinical myotonia was evident in 100% of the 56 patients studied. Cold was identified as a precipitant in 91% of patients, and exercise was identified as a precipitant in 46%. Electromyographic evidence for myotonia was seen in 100% of the patients, and 92% had a reduction in compound muscle action potential in response to cold (objective cold paralysis). Forty-nine of the patients (88%) had a mutation of the SCN4A gene. The electromyographic changes evident with cooling in our patient were typical for paramyotonia congenita — cooling initially resulted in abolition of the myotonic discharges, and electrical silence was recorded at lower temperatures.1

The T1313M mutation was identified in our patient and the five affected family members, but not an unaffected family member. This is one of the more common mutations that causes paramyotonia congenita,4,8,9 and has been reported to exclusively cause paramyotonia with the cold-paralysis phenotype.9-13 The hands and face are predominantly affected in patients who carry the T1313M mutation.9-13 A report of French families with paramyotonia congenita noted significant clinical variability in patients carrying the T1313M mutation — in both severity of myotonia and its permanence — and myotonia permanens was evident in six of eight of these patients.9 In our patient, the clawing of the right hand is also likely to reflect myotonia permanens, rather than an interaction between the paramyotonia and multiple sclerosis.

The T1313M mutation has been predominantly described in families with French ancestry, and to a lesser extent in families of English and Japanese background. 5,9,11 One de-novo mutation has been identified in the literature, which occurred in a Japanese man.12 All individuals from the six generations of the family we studied were born in Australia and lived in Australia, but the ancestral origins of the family are unknown.

Present knowledge of SCN4A channel physiology provides insight into the clinical manifestations seen in our patient and the affected members of her family. Voltage-gated sodium channels are heteromultimeric, integral membrane proteins; they are composed of a single large pore-forming α subunit, and 1 or 2 smaller β units.6 There are nine subtypes of α subunit, one of which is expressed in skeletal muscle — SCN4A.6 The α subunit is composed of four structurally homologous domains (D1–D4), with six membrane spanning segments (S1–S6) within each domain.6 The sodium channel is important for generating and propagating action potentials and switches through three functional states: activation (the open-channel state), inactivation, and recovery from inactivation.6

The consequences of the T1313M mutation have been studied by patch-clamp studies using various cell lines. 10,14-17 Overall, the mutation has been shown to slow the rate of channel inactivation, diminish the voltage dependence of inactivation, and increase the rate of recovery from inactivation. 10,14-17 These effects result in increased sodium conductance and prolongation of action potentials, which causes persistent activation of potassium channels, leading to relatively high levels of extracellular potassium.6,10,14-17 Elevated extracellular potassium levels increase the likelihood of afterdepolarisations, which may lead to action potentials on adjacent surface membranes.6 This can result in ongoing muscle contraction and slowed relaxation — the features of paramyotonia.6

Threonine-1313 is a highly conserved residue in the D3–D4 linker; it is important for channel inactivation, and thought to occlude the cytoplasmic portion of the channel.16 The change from the polar hydrophilic threonine to the larger non-polar methionine is thought to impair occlusion of the channel, and therefore impair inactivation.13,16 Although the effects of the mutation have been shown to be potentiated at lower temperatures, as might be expected, no study has shown an increased sensitivity to temperature compared with normal cells.15-17

We have described the clinical, neurophysiological and genetic features of a large Australian family with paramyotonia congenita. The diagnosis of myotonia may be difficult and cause confusion, and the sodium channel disorder described here should be considered in patients with the symptoms described — especially as the symptoms respond to treatments such as acetazolamide and mexiletine, and as there are implications for genetic counselling and prognosis. Clues to the diagnosis include paradoxical myotonia — myotonia that worsens with ongoing exertion — and significant worsening of symptoms in cold conditions.