Tags: dravet syndrome epilepsy SCN1A

Dr Melody Bacon and Dr Michael Yoong

Among epilepsies caused by a single gene mutation, the sodium channel neuronal
type 1α subunit (SCN1A) gene, is the most common. SCN1A seizure disorders
encompass a spectrum that ranges from simple febrile seizures, generalized epilepsy
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 with febrile seizures plus (GEFS+) at the mild end to intractable childhood epilepsy
with generalized tonic-clonic seizures (ICE-GTC) and Dravet syndrome (DS) at the
severe end. The most severe associated condition is Dravet Syndrome, which is
characterized by intractable epileptic seizures and a slowing of the psychomotor
development in the second year of life, resulting in mild to severe intellectual
disability.

Image from https://www.dravetfoundation.org/what-is-dravet-syndrome/

Single-gene epilepsies have a collective minimum incidence of about 1 per 2000 live
births. The incidence of SCN1A related epilepsy is at least 1 per 12,200 live births,
whilst the incidence of Dravet syndrome 1 in 15,500 live births.

Pathophysiology
SCN1A encodes for the α-subunit of a neuronal sodium channel, Nav 1.1.
Pathogenic variants cause a reduction in sodium currents in gamma-aminobutyric
acid (GABA)-ergic inhibitory interneurons, which leads to hyperexcitability of
neuronal networks and the occurrence of seizures. These reduced sodium currents
also impair Purkinje cells, causing motor disorders and contribute to the
development of behavioural problems and cognitive disabilities.

The association of SCN1A pathogenic variants with multiple syndromes can be partly
explained by the consequences of different mutation types: pathogenic variants that
lead to a complete loss of function of the channel are virtually always associated with
severe phenotypes whereas milder disturbances in channel function usually cause
milder phenotypes. However, in clinical practice, it remains difficult to fully predict the
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 effects of all variants on channel function.

Clinical presentation
Sophie is a 5 year old who had her first febrile generalised tonic clonic seizure
following her immunisations at 8 weeks. When she was 6 months old she had an
episode of status epilepticus whilst unwell with bronchiolitis. She is a previously well
child with normal development. Her EEG and MRI brain are normal. Her genetic test
showed SCN1A variant, likely pathogenic. She was initially started on Sodium
Valproate. Following this she had further episodes of status epilepticus and
Stiripentol was added. She then developed myoclonic and focal seizures, mainly
triggered by illness and fever. Since then, Clobazam has been added. School have
recently raised some concerns with her development and she now receives 1:1
support. She has been seizure free for a few months.

Patients with SCN1A-related disease may have a similar presentation at onset despite
having different phenotypes later in life. Below is a table outlining the presentation of
Dravet syndrome.

Age Development Seizure EEG

Febrile tonic-clonic seizure

may be hemiclonic
Usually normal
Birth to Some may Status epilepticus
1 year have mild Usually normal
old learning Fever/illness/Immunisations
disability precipitants

Focal, myoclonic seizures

Increase in seizure frequency,

decrease in status epilepticus
episodes
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 Convulsive seizures – tonic No pathognomonic
clonic, EEG findings.
clonic, hemiclonic
1–5 Mild – severe Polymorphous may
years learning Other seizure types: show background
old disability myoclonic seizures, slowing,
atypical absence seizures, generalised spike
focal seizures, atonic waves, isolated or
seizures, non convulsive in brief bursts
status epilepticus

Developmental of nocturnal
seizures

No pathognomonic
EEG findings.
Multiple seizure types
5 years Moderate to
Polymorphous may
old to profound
Refractory to AED show background
adulthoo learning
slowing,
d disability
Nocturnal seizures generalised spike
waves, isolated or
in brief bursts

Clinical features predicting a worse outcome includes increased frequency convulsive

seizures, status epilepticus, interictal EEG abnormalities in the first year of life, early
appearance of myoclonus/absence seizures/focal seizures, presence of a motor
disorder (including hypotonia, ataxia, spasticity, and dyskinesia), and/or
truncation SCN1A mutations.

When to test for the SCN1A?

Clinical suspicion of SCN1A-related epilepsies / Dravet syndrome may prompt a
clinician to consider sending blood for the SCN1A molecular genetic test. These are:
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 < 12 months old and had prolonged febrile seizure(s)

< 6 months old and had febrile seizure(s)

Normal development prior onset of seizures

Multiple seizures types – especially if hemiclonic

Vaccination associated seizure(s)

Drug resistant epilepsy

85-90% of Dravet syndrome patients will have an

SCN1A mutation identified – most are de novo
(90%). However up to 15% will not!

What does the genetic report mean?

There are over 6,000 places for variants to occur on the SCN1A gene which is
why one child/adult with Dravet Syndrome is unlikely to have exactly the same
mutation as another child/adult and partly why Dravet Syndrome is a spectrum
condition, affecting each individual differently. Of those with an SCN1A mutation 51%
will have truncating phenotypes that leads to a loss of protein function which is
associated with a more severe phenotype. 49% are associated with a missense
mutation which results in a reduced protein function and that is where we get a
range of phenotypes and we don’t know how the phenotype will get affected.

What if the report shows “variant of unknown clinical significance”?

In theses cases it is important to refer to a geneticist. A geneticist may be able to help

determine whether the genetic variant is clinically significant by using other
information available. These are some of the key questions that may help understand
the clinical significance:
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 Is it de novo or inherited from parent? If it is de novo then it is more likely to be
significant than if it was inherited by a parent.

Does this change occur in an important part of the protein? If it does then it is likely
to be more significant.

Is that area conserved in other species? If it is preserved in species then we know

it must be important and thus likely more significant.

Is the change in amino acid similar or completely different? If is completely different

then it is more likely to be significant.

Are functional data available?

For example, in a laboratory setting, you can express a variant in human

embryotic kidney cells. You can then measure the current through that channel
which then gives you an idea how deleterious this mutation may be. This is time
consuming – it can take up to a year on one single variant!

Is it present in population databases? i.e. is there someone else with the same
mutation?

When a variant cannot explain the phenotype, it may be due to the phenomenon of
mosaicism. Mosaicism is present in 7.5% of symptomatic patients with de-novo
pathogenic SCN1A variants.

Investigations (other than genetics)

EEG studies are surprisingly normal in the first 1-2 years of life despite prolonged
and frequent episodes of status epilepticus. From about the age of two years, the EEG
may start to show generalized and multifocal epileptiform activity.

Imaging studies are often normal or may show non-specific abnormalities such as
cerebral atrophy. Hippocampal sclerosis has been observed to a varying degree in
different series ranging from 2% to 70% of cases; it probably occurs in about 30% of
patients overall. Given the well-known association of hippocampal sclerosis with
prolonged febrile status epilepticus, it is perhaps surprising that not all patients with
Dravet syndrome have this acquired lesion.
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 Management
Management can be classified into treatment of Dravet syndrome, and emergency
seizure management. However, beware of treatments to AVOID – sodium channel
blockers: Carbamazepine, Oxcarbamazepine, Lamotrigine, Vigabatrin, Phenytoin (as
daily medication). In individuals with SCN1A mutation, giving sodium channel blockers
may cause more frequent and severe seizures. If given in the first year of life or there
is prolonged use, sodium channel blockers are associated with worse cognitive
outcomes.

Image from
https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16
334

In individuals with SCN1A mutation, giving sodium

channel blocker may cause more frequent and
severe seizures.
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 Image from
https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16
334

Associated features of Dravet Syndrome

Developmental outcomes and associated behavioural difficulties

Development tends to be normal up

until age 1 years age in children with
Dravet syndrome however
development then plateaus and most
will have a degree of learning
disability, ranging from mild to
profound.

Clinical features predicting a worse

developmental outcome included
status epilepticus, interictal EEG
abnormalities in the first year of and
motor disorder. Figure from a prospectively collected data on
a UK cohort of individuals with Dravet
Individuals with Dravet syndrome are syndrome during a 5-year study period and
more likely to have behavioural analysed demographic information based on
problems and acquired autistic UK population and birth figures.
features. Around 46% of individuals
with Dravet syndrome will have some
behavioural problems – two thirds ‘hyperactivity/inattention’ and one third
‘conduct problems’.
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 Motor disorder

Children with Dravet syndrome show progressive gait deterioration in the second
decade of life, with crouch gait and skeletal malalignment comprising increased
femoral neck anteversion, external tibial torsion, and pes valgus.

These age-related changes have a significant impact

on mobility and independence in the community
setting. Crouch gait is not specific to patients with
Dravet syndrome or sodium-channel mutations, but
the high frequency in patients with Dravet syndrome
and the characteristic progression during 2 decades
of life in this now well-defined epileptic
encephalopathy suggest that there may be a specific
pathogenesis to unveil.

Functionally, a crouch gait is inefficient, requires

higher energy cost, increases the stress on joints
(especially knees). Many children over the age of 13 need a walker or wheelchair for
longer distance mobility.

Treatment options are aimed at managing consequences of gait rather than

preventative measures. Children may benefit from orthotics, physiotherapy, spasticity
treatments – baclofen, L-dopa and some may even require multi-level orthopaedic
surgery.

Sleep problems

Many children with severe developmental and epileptic encephalopathies experience

significant sleep disturbance, causing a major disruption to the family’s quality of life.
>70% of individuals with Dravet syndrome have sleep problems. Difficulty initiating
and maintaining sleep was most common, particularly in those older than 20 years.
Second-most common were sleep-wake transition disorders, affecting more than
50% of those younger than 5 years. Sleep breathing disorders were a frequent
problem in all age groups.
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 Other co-morbidities include: growth and nutrition issues, frequent infections,
dysautonomia – of varying extent

Mortality

Dravet syndrome is associated with an increased mortality. It is estimated 10% of

children with DS die of SUDEP before their 20th birthday. Dravet specific mortality is
9.32 per 1000-person-year.

Beware of the Dravet mimics

This illustration looks at Dravet mimics and it highlights other genetic disorders that
present in similar way to Dravet syndrome. As you can see, the majority are caused by
SCN1A, but there are other number of genes that may present like Dravet. Notably
PCDH19, presents mainly in girls with clusters of febrile seizures early on.

Image from:
https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.13889

Gene therapy
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 We are moving into a new era in genetic epilepsies, where we have opportunities for
precision medicine – gene therapy. The aim of gene therapy is to restore the
deficient SCN1A protein production. In theory this can be done by supplying a new
copy of SCN1A via use of a virus: adeno-associated virus (AAV) or Lentivirus however
inserting a gene into specific populations of neurons in the brain is neither possible
nor proven safe and effective in humans yet. Further complicating this potential
solution is the fact that the safe and effective methods of transport in gene therapy
are too small to fit SCN1A, a relatively large gene. Direct editing of the mutation
in SCN1A is not possible in humans yet, either.

The aim of gene therapy is to restore the deficient

SCN1A protein production.

However, there are other genetic approaches that, while not altering the DNA directly,
capitalize on steps in the gene-to-protein pathway cells naturally use therefore
increasing more functional sodium channel proteins. Stoke Therapeutics was the first
company to publicly announce their research for a treatment for Dravet syndrome.
Their treatment is called “Targeted Augmentation of Nuclear Gene Output” or TANGO.
The idea is you inject intrathecally antisense oligonucleotides (ASOs) that bind to pre-
mRNA to up-regulate – protein production. This trial is open for recruitment and has
enrolled their first patient in August 2020.

Another company, Encoded Therapeutics, is using a slightly different approach to

arrive at the same solution: more healthy sodium channels. They do this not by
focusing on increasing the cell’s processing efficiency, but rather by upregulating the
reading of the gene in the first place. A trial is expected to start in 2021.

What we don’t know though is what the effect of over-expression of SCN1A may have
on patients?
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 Take home messages

Consider sending blood for the SCN1A molecular genetic test in any infant who
presents with features suggestive of Dravet syndrome.

Dravet syndrome is the most well-recognized epilepsy phenotype associated

with SCN1A.

Avoid sodium channel blockers in individuals with SCN1A related epilepsy / Dravet
syndrome.

Dr Melody Bacon, paediatric registrar with special interest in neurology, Royal

London Hospital. Consultant review by Dr Michael Yoong, paediatric neurology
consultant, Royal London Hospital

Further Reading

1. Dravet Syndrome UK

2. Dravet Syndrome Foundation

3. Scheffer I. E. Diagnosis and long-term course of Dravet syndrome, Journal of the

European Paediatric Neurology Society, 2012, 16; S5-S8 DOI
10.1016/j.epjpn.2012.04.007

4. McDonald C. L, BS, Russell P et al, Focal Seizures in Patients with SCN1A

Mutations: Response to Treatment, Journal of Child Neurology 2017, 32(2) 170-
1746, DOI 10.1177/0883073816672379

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