Abstracts

Rationale: To present age dependent dysfunction of neuromuscular junction in severe early onset epileptic encephalopathy. Voltage-gated sodium channels (VGSCs) are responsible for depolarizing currents and signaling between neurons. VGSC α subunit gene SCN8A encodes the transmembrane channel protein Na_v1.6, primarily localized in myelinated axons and in dendrites. Methods: Clinical exam, MR imaging, EEG, electomyoneurography, whole exome sequencing of the proband and both healthy parents. Results: The proband is a boy now at the age of 4 years, from a nonconsanguineous family. First seizures occurred at the age of 3 months, 24 hours after vaccination, and subsequently manifested as recurrent apnoeas, spasms, hemiconvulsions, tonic and generalized tonic-clonic seizures, focal seizures with oral automatisms and status epilepticus. The boy had a severe delay in psychomotor development, no verbal contact, generalized hypotonia, fatiguable muscle weakness, myopathic face with bilateral ptosis,hyperextensible joints anddyskinesias. EEG was normal at onset, and later showed diffuse high voltage, slow activity, with frequent multifocal epileptic discharges. Brain MRI showed delayed myelination. EMNG showed signs of myopathy and low compound muscle action potential (CMAP) amplitude (0,15 mV) on lower extremities. Muscle and nerve biopsy were normal. A prostigmine test was positive. Decremental responseand decrease of the CMAP amplitudes of 15% was obtained on repetitive stimulation. Pyridostigmine therapy resulted in improvement of muscle strength, especially swallowing, and developmental progress.Epileptic seizures decreased on therapy with sodium channel inhibitors and clonazepam.Exome sequencing showed a de novo missense mutation in the SCN8A gene +NM_014191:c.C5401G:p.Q1801E. Conclusions: Functional changes of Nav1.6 at the neuromuscular junction (NMJ) causing age dependent defects in neuromuscular transmission might play a role in the motor endplate maturation in patients with a heterozygous SCN8A mutation and severe early onset epileptic encephalopathy.