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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
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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