University of Groningen Genotyping and phenotyping epilepsies of childhood Vlaskamp, Danique

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University of Groningen

Genotyping and phenotyping epilepsies of childhood

Vlaskamp, Danique

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Publication date: 2018

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Vlaskamp, D. (2018). Genotyping and phenotyping epilepsies of childhood. Rijksuniversiteit Groningen.

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Chapter 9

Positive effect of sodium channel

blocking anti-epileptic drugs on

neonatal-infantile epilepsy due to a

SCN2A mutation

Translated from the Dutch paper published as:

Chania de Cordt, Danique Vlaskamp, Marrit Hitzert, Roelineke Lunsing, Erica Gerkes, Oebo Brouwer. Gunstig eﬀ ect van natriumkanaal blokkerende anti-epileptica bij neonataal-infantiele epilepsie.

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Chania De Cordt1_{, Danique R.M. Vlaskamp}2,3_{, Marrit Hitzert}3_{, Roelineke J. Lunsing}2_{, Erica}

Gerkes3_{, Oebele F. Brouwer}2

1_{Universiteit Antwerpen, Antwerpen.}2 _{University of Groningen, University Medical Center}

Groningen, Department of Neurology, Groningen, the Netherlands. 3_{University of Groningen,}

University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.

Acknowledgements. We thank Katy McIntyre for her help in translating the manuscript to

English. CHAPTER 9

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Processed on: 29-10-2018 PDF page: 179PDF page: 179PDF page: 179PDF page: 179 Recently, the journal Brain published an article about patients with epilepsy due to a SCN2A

mutation.1_{In this study, Wolﬀ and his colleagues showed a relation between the type of SCN2A}

mutation, the age at onset of seizures, and the eﬀect of sodium channel blocking anti-epileptic drugs. Here we present a case that illustrates this correlation.

CASE

A nine-week-old girl was transferred to our paediatric intensive care because of refractory seizures. She was born at term after an uncomplicated pregnancy and delivery. The parents are not consanguine and the mother has a healthy son and daughter from a previous relationship. At the age of five days, an incident occurred that was interpreted as related to aspiration due to reflux. From the age of six weeks, the girl had seizures with smacking, staring and saturation drops that increased in frequency, as well as generalized tonic-clonic seizures. The administering of levetiracetam and pyridoxine did not have the desired effect on the seizures, and the girl was transferred to the University Medical Center Groningen (UMCG).

On admission, the girl was not alert but responded adequately to pain stimuli. She had normal body body lengths and no evident dysmorphisms. On neurological examination, her fontanel was normal and both her pupils were isocoric and responded to light. She showed little spontaneous motor activity but did show symmetrical motor activity. Reﬂexes were symmetrically present. The results of further physical examination of her heart, lungs and abdomen were normal.

Because of persistent seizures, she was subsequently treated with higher doses of levetiracetam (up to 50/mg/kg/day) and pyridoxine (up to 30mg/kg/day), followed by pyridoxalphosphate (50mg/kg/day) and clobazam (up to 1 mg/kg/day), unfortunately without effect. Two loading doses of phenytoin (up to 30mg/kg/day) were temporarily effective, but no maintenance dose was started. Because of on-going seizures, intravenous midazolam was started (up to 0.3mg/kg/ hour), after which she developed respiratory insufficiency and needed intubation and ventilation. An electroencephalogram (EEG) on the fourth day after admission (Figure 1A) showed a diffuse slow background pattern with epileptiform function disorders, predominantly left temporal and central. A second EEG one week later (Figure 1B) still showed a similar pattern with multifocal epileptiform abnormalities. During ophthalmologic investigation, a small opacity was noticed in both lenses, and in the list of differential diagnoses was a subcapsular cataract or Mittendorf dot. Magnetic resonance imaging (MRI) of the brain showed no abnormalities. Metabolic screening of her blood, liquor and urine, including -aminoadipine semialdehyde (-AASA) showed no abnormalities. The family history revealed that her father also had epilepsy, with an onset at the age of three months. He had focal seizures, sometimes evolving into bilateral tonic-clonic seizures. Phenytoin

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and phenobarbital did not have any eﬀect in his ﬁrst year of life. He became seizure-free at the age of two years after introduction of carbamazepine. He tried to stop carbamazepine twice, once at eight years and once at eleven years. Both times he developed focal clonic seizures, once evolving to a bilateral tonic-clonic seizure. At the age of eleven years, an EEG showed focal epileptiform function disorders, predominantly right frontal.

Figure 1: Electroencephalogram (EEG) the fourth day after admission (A) and on the 11th_{day after}

admission (B).

Figure (A) shows a diﬀuse slow background pattern with epileptiform abnormalities, predominantly left temporal and fronto-central. Figure (B) shows a similar the background pattern with still multifocal epileptiform abnormalities, maximum over the left hemisphere.

After restarting carbamazepine, he became seizure-free again. The father is still on carbamazepine and does not want to stop this treatment. Only with stress or sleep deprivation does he still note subtle phenomena, including uncertainty with walking and diﬃculties with speaking, but without losing consciousness. On admission of his daughter to the UMCG, the father suggested initiating carbamazepine in her as well.

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Processed on: 29-10-2018 PDF page: 181PDF page: 181PDF page: 181PDF page: 181 Because of the positive family history and the lack of any other obvious cause for her epilepsy,

genetic testing was performed. A Single Nucleotide Polymorphism microarray (SNP-array) was normal. Whole Exome Sequencing (WES) with trio-analysis (father-mother-child) showed a few heterozygous missense variants of unknown signiﬁcance (VUS). The variant found in SCN2A (c.3973G>A, p.Val1325Ile) was inherited from her father. After investigations in the fathers’ parents, who both had no epilepsy based on history, it turned out that the variant had risen

de novo in the father. The variant has not been reported before and is likely pathogenic given

its segregation with epilepsy in the family and the compatible phenotypes reported for other pathogenic variants in SCN2A. Furthermore, the amino acid change is in a conserved region and prediction programs predict it to have a likely pathogenic eﬀect. The missense variant has not been described in databases of healthy controls.

The girl commenced carbamazepine treatment (15mg/kg/day), and became seizure-free within ﬁve days and was more alert. She was soon transferred to a general hospital. At follow-up at the age of six months, she smiled and babbled interactively, but only followed visual stimuli brieﬂy and did not yet grab. She thus had some developmental delay. In the meantime, she had had a few seizures, but these disappeared after increasing the carbamazepine dose to 18.8mg/kg/ day. On ophthalmological examination, no abnormalities were seen anymore. Given her young age, no conclusions can be made regarding her developmental course and movement disorders, although there was a mild developmental delay at six months.

DISCUSSION

The clinical picture of this case ﬁts within the known SCN2A phenotypic spectrum. Howell and her colleagues divided SCN2A phenotypes into four groups: three neonatal-infantile phenotypes with subcategories based on the severity of the epilepsy, possibly associated developmental problems and movement disorders, and one later onset phenotype.2_{The phenotype of our case}

can be classiﬁed as one of the neonatal-infantile variants. SCN2A is the abbreviation for Sodium

Voltage-Gated Channel Alpha subunit 2. The SCN2A gene codes for a voltage sensitive sodium

channel, Na_v1.2, that plays an important role in initiating action potentials. On the functional level a distinction is made between gain-of-function and loss-of-function mutations in SCN2A. Gain-of-function mutations cause increased activity of the sodium channel, leading to an increased duration or height of sodium inﬂux. Loss-of-function mutations result in reduced activation of the sodium channel. Both mutation types can cause epilepsy.

Functional studies on missense mutations in a cohort of children with a neonatal-infantile onset of epilepsy (younger than three months) performed by Wolﬀ and colleagues suggest that this cohort has gain-of-function mutations. In the patient cohort with later-onset epilepsy (older than three months), mutations were shown to result in a loss of function, presumably because these mutations

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need a more mature brain to disturb the channels. Even though the missense variant in our case has not yet been studied and its functional effect is unknown, we can hypothesize that it probably concerns a gain-of-function mutation given the above-mentioned genotype-phenotype correlation. Wolff and colleagues also showed a correlation between the type of mutation and the effect of sodium-channel-blocking anti-epileptic drugs. Sodium channel blockers result in a reduction of seizures or even seizure freedom in neonatal-infantile epilepsy with gain-of-function mutations, while other anti-epileptic drugs are often less effective. In children with seizures after the age of three months, the opposite is true and sodium channel blockers can even lead to a higher seizure frequency. This is a nice example of personalized medicine, where treatment with drugs is optimized based on the specific underlying aetiology.

Our case supports the conclusion in the recent article of Wolff and his colleagues. In our patient, there was also a positive effect of the sodium-channel-blocker carbamazepine with complete seizure freedom in a neonatal-infantile epilepsy that was difficult to treat. Carbamazepine was commenced because of the therapy resistance and the positive effect of this drug in her father. Later, the positive effect was explained by the observed SCN2A mutation. An adequate family history for epilepsy, including the effect of treatment, and genetic testing can be very important in the choice of treatment.

Currently, there are no standardized guidelines in the Netherlands for the treatment of neonatal-infantile seizures. In a previous study by Sands and colleagues, they concluded that carbamazepine was a safe and eﬀective drug in benign familial neonatal epilepsy (BFNE).3_{This study included a}

few patients with mutations in genes other than SCN2A, namely KCNQ2 and KCNQ3. Mutations in these potassium-channel-coding genes are also associated with benign familial neonatal seizures. From a neurophysiological point of view, it is understandable that sodium channel blockers can have a similar positive effect in patients with a loss-of-function mutation in KCNQ2 and KCNQ3. Our case confirms that carbamazepine can also be recommended in epilepsy with neonatal-infantile onset. In the study of Wolff and colleagues, phenytoin was the most effective sodium channel blocker. In our patient, a loading dose of phenytoin had effect. In her father, this effect was retrospectively not present, but it was not known if there was a temporary effect or if therapeutic levels of phenytoin were ever reached.

CONCLUSION

Our case illustrates the possible positive eﬀect of sodium channel blockers in neonatal-infantile seizures associated with a SCN2A mutation. A precise family history and careful interpretation of genetic testing results can be an important guideline for making the right diagnosis and initiating eﬀective treatment.

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REFERENCES

1. Wolﬀ M, Johannesen KM, Hedrich UBS et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017. doi:10.1093/brain/awx054

2. Howell KB, McMahon JM, Carvill GL, et al. SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015; 85: 958– 66.

3. Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia 2016; 57: 2019–2030.

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