Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Here, the authors describe homozygous or compound heterozygous SCN4A mutations in 11 individuals from six unrelated families with congenital myopathy. The affected cases had clinical phenotypes ranging from severe foetal hypokinesia resulting in early lethality to ‘classical’ congenital myopathy that improved clinically over time. Functional assessment of the mutant Nav1.4 channels in HEK293 cells revealed full and partial loss-of-function effects constituting a novel molecular pathomechanism associated with SCN4A mutations.
