does the nature of a scn1a mutation influence the temporal … · 2020. 9. 11. · onset in first...
TRANSCRIPT
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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
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► 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
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SCN1A associated phenotypes
► GEFS+
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SCN1A associated phenotypes
► GEFS+
► Dravet
syndrome
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SCN1A associated phenotypes
Charlotte Dravet
► GEFS+
► Dravet
syndrome
► FHM3
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SCN1A associated phenotypes
Charlotte Dravet
► GEFS+
► Dravet
syndrome
► FHM3
► EOEE
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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
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Spectrum of SCN1A related epilepsies
Severe
Dravet
syndrome
Mild
GEFS+
FS+
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► 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
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► 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)
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RSodium channel alpha 1 subunit (SCN1A)
Ion Channel
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Dravet syndrome – a channelopathy
R
Brunklaus & Zuberi (2014) Epilepsia 55(7):979-984
Nabbout et al. (2013) Orphanet J Rare Dis.13;8:176
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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
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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
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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
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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
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► Phenotypical differences between truncating and missense variants
Neurology 2011;76:594-600
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► Impact on rate of cognitive decline
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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?
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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
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Genome Res. 2020 Jan;30(1):62-71.
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Conventional pathogenicity modelling
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Whole-cell current as a marker of function for
missense variants
Brunklaus & Schorge et al. Hum Mutat. 2020 Feb;41(2):363-374.
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Sci Transl Med. 2020 Aug 12;12(556):eaay6848
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+
+
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
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Inhibitory n.
Excitatory n.
Corticospinal n.
Brunklaus and Lal, DMCN 2020
Model of sodium channel disorders
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Variant location as surrogate for function
Brunklaus et al. Epilepsia. 2020 Mar;61(3):387-399
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Epilepsia. 2018 Mar;59(3):690-703.
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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.
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Evidence Based Treatments
Cross et al. Epilepsia. 2019 Dec;60 Suppl 3:S39-S48.
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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
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Future opportunities for precision treatment
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Ana Mingorance, Dracaena consulting
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University of Cologne,
Germany
Eduardo PerezBroad Institute Harvard & Cleveland clinic, USDennis Lal
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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