Genotype-phenotype correlation studies and tailored

treatment for the most common monogenic epilepsies:

SCN1A

Dr Andreas Brunklaus MD

Consultant Paediatric Neurologist

Royal Hospital for Children, Glasgow

Honorary Clinical Senior Lecturer

Institute of Health and Wellbeing, University of Glasgow

► I have received honoraria for speaking at educational symposia and

attending advisory boards from Biocodex, Zogenix, GW Pharma, Nutricia

and Encoded Therapeutics.

► My institution has received funding from GW Pharma and Zogenix for

undertaking research trials.

Declaration of Interest

SCN1A associated phenotypes

► GEFS+

SCN1A associated phenotypes

► GEFS+

► Dravet

syndrome

SCN1A associated phenotypes

Charlotte Dravet

► GEFS+

► Dravet

syndrome

► FHM3

SCN1A associated phenotypes

Charlotte Dravet

► GEFS+

► Dravet

syndrome

► FHM3

► EOEE

Dravet Syndrome

► Onset in first year of life with febrile seizures

► Prolonged unilateral or generalized clonic seizures

► Other seizure types evolve by 1- 4 years

► Presumed normal early development

► Psychomotor slowing > 1 year

► Developmental & epileptic encephalopathy

Spectrum of SCN1A related epilepsies

Severe

Dravet

syndrome

Mild

GEFS+

FS+

► 241 individuals (1 to 42 years)

► Analysis of UK birth cohort from

2003 – 2007 (n=88)

► Incidence of Dravet syndrome at

least 1 per 40,900

– now 1 per 15,000

► Incidence of SCN1A related

epilepsy at least 1 per 12,200

Symonds & Zuberi et al. (2019) Brain. 2019 Aug 1;142(8):2303-2318

► Voltage-gated sodium channel

►Widespread expression in CNS

► NaV1.1 channels are primarily

localized in cell bodies

► Role in the generation of action

potentials

► NaV1.1 expression is first detectable

postnatally and increases thereafter

Sodium channel alpha 1 subunit (SCN1A)

RSodium channel alpha 1 subunit (SCN1A)

Ion Channel

Dravet syndrome – a channelopathy

R

Brunklaus & Zuberi (2014) Epilepsia 55(7):979-984

Nabbout et al. (2013) Orphanet J Rare Dis.13;8:176

Dravet syndrome – a channelopathy

R

Yu et al (2006) Nat Neurosci;9:1142-1149

Brunklaus & Zuberi (2014) Epilepsia 55(7):979-984

Nabbout et al. (2013) Orphanet J Rare Dis.13;8:176

Dravet syndrome – a channelopathy

R

Ogiwara et al (2007) J Neurosci;27:5903-14

Brunklaus & Zuberi (2014) Epilepsia 55(7):979-984

Nabbout et al. (2013) Orphanet J Rare Dis.13;8:176

Dravet syndrome – a channelopathy

R

Han et al. (2012) Nature;489:385-90

Bender et al. (2013) Neurobiol Dis;doi:10.1016/j.nbd.2012.12.021

Brunklaus & Zuberi (2014) Epilepsia 55(7):979-984

Nabbout et al. (2013) Orphanet J Rare Dis.13;8:176

Variant classes

Missense

(49%)

Insert/Deletion (2%)

Rearrangements (5%)

Splicesite (9%)

Frame-

shift (18%)

Nonsense (17%)

Truncating

(51%)

Loss of

protein

function

?phenotype

Severe

phenotype

? altered

protein

function

Zuberi & Brunklaus et al (2011) Neurology;76:594-600

► Phenotypical differences between truncating and missense variants

Neurology 2011;76:594-600

► Impact on rate of cognitive decline

Background – SCN/NaV1 neurodevelopmental disordersgnomAD vs pathogenic missense burden (variants from the general population)

Mis

se

nse

Bu

rde

n

Courtesy of Perez-Palma & Lal

Grey

Polymorphisms

How do missense variants from the general population differ from those found in patients?

Background – SCN/NaV1 neurodevelopmental disordersgnomAD vs pathogenic missense burden (variants from the general population)

Mis

se

nse

Bu

rde

n

How do missense variants from the general population differ from those found in patients?

Grey

Polymorphisms

Blue

Disease causing variants

Courtesy of Perez-Palma & Lal

Genome Res. 2020 Jan;30(1):62-71.

Conventional pathogenicity modelling

Whole-cell current as a marker of function for

missense variants

Brunklaus & Schorge et al. Hum Mutat. 2020 Feb;41(2):363-374.

Sci Transl Med. 2020 Aug 12;12(556):eaay6848

+

+

6

Evolution of voltage-gated ion channels

CO-+H3N

‘lasd;

lsj;fljs;ljfGoldin et al. (2000). Neuron 28:365-8 Brunklaus et al. J Med Genet 2014;51:650-658

Inhibitory n.

Excitatory n.

Corticospinal n.

Brunklaus and Lal, DMCN 2020

Model of sodium channel disorders

Variant location as surrogate for function

Brunklaus et al. Epilepsia. 2020 Mar;61(3):387-399

Epilepsia. 2018 Mar;59(3):690-703.

Appropriate treatment is important

► Early contraindicated medication use has negative impact on cognitive outcome in

Dravet syndrome

de Lange et al. Epilepsia. 2018 Jun;59(6):1154-1165.

Evidence Based Treatments

Cross et al. Epilepsia. 2019 Dec;60 Suppl 3:S39-S48.

Genotype-phenotype Treatment Considerations

► 137 Dravet syndrome patients with pathogenic SCN1A variants subdivided by missense or

truncating variant

► Response to antiepileptic therapies did not differ by genotype with regard to medication class.

► Need for prospective natural history data to evaluate

treatment effects on seizure burden and development

Future opportunities for precision treatment

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Ana Mingorance, Dracaena consulting

University of Cologne,

Germany

Eduardo PerezBroad Institute Harvard & Cleveland clinic, USDennis Lal

Andreas.Brunklaus@nhs.net

Royal Hospital for Children,

Glasgow

Ismael Ghanty

Felix Steckler

Ben Dunwoody

Sameer Zuberi

Joseph Symonds

Kirsty Stewart

Sarah Gardiner

AcknowledgementsInternational Collaborators

Acknowledgements

University College

London, UK

Stephanie Schorge

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