Dravet syndrome with SCN1B gene mutation: A rare entity
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_1115_15
Source of Support: None, Conflict of Interest: None
Keywords: Dravet syndrome, early infantile epileptic encephalopathy, SCN1B gene mutation, status epilepticus
Dravet syndrome (DS) is a variant of epileptic encephalopathy that presents in infancy with gradually varying seizure types. Clinical presentation with genetic analysis has increased the awareness regarding DS.
A 7-month old male child was admitted with a history of recurrent convulsions for 4 months. At admission, he was in status epilepticus (SE), which was controlled with intravenous midazolam. He was on phenytoin, leviteracetam, and clonazepam since the previous 2 months because of recurrent seizures. On examination, the baby had global developmental delay. There was no head control or social smile. He did not have any dysmorphic features or neurocutaneous stigmata. The blood pressure was 70/44 mm Hg.
The baby was the first male child, borne out of a consanguineous marriage, born at term by normal vaginal delivery, and had no significant antenatal history. He had cried immediately after birth. By 3 months of age, he had a social smile and could recognize his mother and had developed head control. However, he had an episode of generalized tonic–clonic seizure (GTCS) with fever following DTaP (diphtheria, tetanus, acellular pertussis) vaccination, administered at 3 months of age. The convulsions subsided after the fever was controlled. However, 1 month later, he had another episode of fever with SE that needed hospital admission. His electroencephalography (EEG) was normal. Magnetic resonance imaging (MRI) of the brain was also normal [Figure 1]. He was started on phenobarbitone, which, according to the mother, worsened the seizures. Gradually, leviteracetam, topiramate, and clonazepam were added as he started having recurrent febrile and afebrile seizures.
At our institute, the arterial blood gas, serum lactate, serum ammonia, blood metabolic levels, and ophthalmological examination were normal. He had a maternal uncle who started having seizures from the age of 7 months and had neuro-regression and ultimately died at 5 years of age. As the child was having post-vaccinal convulsions, a possible diagnosis of DS was considered and a genetic analysis was performed for targeted gene sequencing.
A homozygous missense variation in exon 3 of the SCN1B gene (chr19:35524568; C>T) that results in the amino acid substitution of cysteine for arginine at codon 125 (p.R125C; ENST00000415950) was detected. The child was diagnosed as DS. The parents were advised to get a genetic analysis undertaken for the child. However, the high cost of the genetic analysis has prevented the parents from going ahead with the test.
At present, the child is on a regular follow-up. He has recently been started on ketogenic diet. He is receiving leviteracetam at 60 mg/kg/day, sodium valproate at 60 mg/kg/day, topiramate at 10 mg/kg/day, and clonazepam at 1 mg/kg/day. He still has seizures every other day, which are usually generalised tonic clonic and occasionally myoclonic.
Dravet in 1978, first identified epileptic encephalopathy in infants. It is characterized by early onset of seizures in infants (mean age, 5–8 months), presenting as febrile or afebrile seizures, evolving into SE, but with normal developmental parameters., Subsequently, they manifest as myoclonic, atypical absence, or complex partial seizures, usually after 1 year of age. Convulsive SE is more commonly seen in the first year of life. Nonconvulsive SE may manifest as a state of obtundation in patients with DS. These patients have variable myoclonus with impaired consciousness. In our case, the child presented with seizures initially at 3 months of age, and since then, has had a progressive course with varying seizure types.,
Initially, the seizures are triggered by fever, vaccination, illness, or photic stimulation. Thereafter, fever is the most common trigger, as seen in our patient. Even slight variations in temperature are known to trigger seizures in these patients as they grow up.
Majority (75%) of patients with DS have mutations involving the SCN1A (alpha 1 sub unit of voltage gated sodium channel) gene. The remaining patients have mutations in the PCDH19 (commonly in girls), GABRG2, and SCN1B (beta 1 subunit) genes [Table 1].,,,,, Our child had a less common variant with the mutation involving the SCN1B gene. The R125C variant, as seen in our patient, has been once reported previously, caused by a recessive mutation in the SCN1B gene.
Initially, the EEG is found to be normal, as seen in our patient. However, it may show polyspike activity or generalized spike wave pattern later on. MRI brain did not reveal significant abnormalities, as was seen in our patient.
Drugs acting on the sodium channel, such as phenobarbitone and carbamazepine, precipitate seizures in DS, similar to that seen in our patient, whose seizure frequency increased while initially being on phenobarbitone. Valproate and bromide has the maximum efficacy in SCN1A and SCN1B gene mutations, respectively. Seizures are, however, refractory to most drugs. Intellectual impairment is also common.
DS, a variant of epileptic encephalopathy, has an overall poor outcome. The SCN1B mutation has been rarely reported. Genetic mutation analysis should be performed in all family members (affected and unaffected) having an affected child. However, the high cost of the mutation analysis is a hindrance for many parents desirous of investigating their children suspected of having DS.
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