De novo SCN1A mutations are seen in Dravet syndrome, a severe form of childhood epilepsy with a high incidence of sudden unexpected death. We describe the case of a patient with a homozygous SCN1A mutation who presented following an out of hospital arrest.
Case Report: A 17-month-old girl presented following an out of hospital arrest with return of circulation after 12 minutes of resuscitation. Her collapse was filmed by her mother and in the video, she is seen to become distressed after a noise stimulus before her gaze deviated, posture became decorticate and cyanosis developed.
The patient had no other known medical conditions except an admission to hospital aged 2 months with an apparent life-threatening event after becoming stiff and unresponsive with no preceding cry or pallor. Following this she was investigated by the neurology team for further episodes which involved a brief cry followed by deep inspiration, colour change and loss of consciousness. In addition, she also had blank spells with behavioural arrest. Outpatient investigations included a normal ECG, brain MRI, standard and 24-hour video EEG and these events were diagnosed as breath-holding attacks.
There was a significant family history of the patient’s older half-sibling passing away suddenly in her cot aged 28 months following a short history of coryza and a family history of hemiplegic migraine.
During their admission, the patient continued to have multiple events usually precipitated by distress, before appearing to breath hold and become cyanotic and dystonic before progressing to needing ventilatory support. All cardiology investigations including ECG, echocardiogram and 24-hour tape were all normal. A loop recorder has been fitted.
All serum and urine metabolic investigations were normal including a muscle biopsy for mitochondrial respiratory chain defects.
A genetics panel returned positive for a homozygous SCN1A mutation. Unusually our patient has a homozygous mutation which raises the question of consanguinity.
Discussion: Dravet syndrome (DS) is a severe form of epilepsy characterised by seizures, developmental delay, ataxia and an increased risk of sudden death. Around 10–20% of patients die before adulthood. The condition is known as a SCN1A-related seizure disorder as the majority are due to a mutation in the SCN1A gene. This gene codes for neuronal voltage-gated sodium channels, the sodium channel Nav 1.1 is expressed in the brain whereas Nav 1.5 is expressed in cardiac muscle.
A study in 2013 by Auerbach using mouse models found a twofold increase in the peak transient and persistent sodium transmembrane current density in cardiac myocytes in mice who were heterozygous for SCN1A. Myocytes in these mice demonstrated QT prolongation and ventricular arrhythmias. This is supported by a study in 2018 which reported a 1.5-fold increase in transient sodium channel current density in skin biopsies of patients with DS compared to controls.
Data on this subject is limited. Mutations in the Nav 1.1 sodium channel have been linked with seizures, but there are no reports of arrhythmias linked to Nav 1.5 channel mutations in humans. Recent animal and in vitro studies in heterozygous cases suggest that the increased sodium current density in these patients may be responsible for cardiac arrhythmias underlying the increased risk of sudden death in DS patients. Our patient was homozygous for this mutation and we suggest that perhaps a homozygous state can cause a more significant predisposition to cardiac arrhythmias in humans.
