dr. Hannah Stamberger ://nvavg.nl/wp-content/uploads/2016/03/De-Jonge-en-Stamberge… · epilepsy approximately 95% of patients most frequent seizure types are epileptic spasms (65.3%),

Epilepsie & ernstige mentale retardatie: (nieuwe) genen en genotype-fenotype correlatie

dr. Hannah Stamberger prof. dr. Peter De Jonghe

Neurogenetics group, DMG, VIB

http://www.molgen.vib-ua.be

Disclosures

No disclosures to report.

Outline

1. Introduction – epileptic encephalopathies

2. Monogenetic epilepsy syndromes

3. Copy number variants

4. Research & diagnostics

5. What about therapy?

A brief history

• 1995: CHRNA4 and ADNFLE (Steinlein et al. 1995) Large families, Linkage, Sanger sequencing

• 2002: de novo mutations in SCN1A - Dravet syndrome (Claes et al. 2002)

• 2005: Next generation Sequencing (NGS) becomes commercially available

• 2009: first gene ‘discovery’ with WES: DHODH - Miller syndrome (Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13.)

• Anno 2016:

• Third generation seq/ Massive parallel seq?

• > 60 genes associated with epilepsy (OMIM 2015: 32 ‘known’ genes for EIEE)

> 40 different epilepsy syndromes

Epileptic encephalop.

Classification (Berg et al 2010)

• Berg et al. 2010: “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time”

• Revision on the way?

Epileptic encephalopathy

Thomas, R. H. & Berkovic, S. F. (2014) , Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.62

Aetiology of epilepsy

Outline






Autosomal dominant (large families)

Autosomal recessive

Dominant de novo X-linked

Mendelian inheritance

STXBP1: syntaxin binding protein 1

• 2008: Saitsu et al.: LoF mutations STXBP1 - Ohtahara syndrome

• 2008- current: • phenotypic expansion : West, Dravet, Non syndromic

epilepsy + intelectual disability (ID), ID without epilepsy (!), autism

• Study- 2015 – 45 newly diagnosed patients

– 132 reported patients

> 150 patients discribed in literature

. Parisi et al. Italian Journal of

Pediatrics 2011 37:58 doi:10.1186/1824-7288-37-58

Figure 1: Spectrum of STXBP1-associated phenotypes (Dx at onset)

epilepsy approximately 95% of patients most frequent seizure types are epileptic spasms (65.3%), focal seizures

(57.9%) and tonic seizures (41.3%) seizure freedom is achieved in more than 1 in 3 patients, almost 1 in 3

remain therapy resistant

EEG > 60% focal or multifocal epileptic activity burst-suppression (35.9%) and hypsarrhythmia (40%) are frequent EEG

findings

intellectual disability all patients, majority has severe to profound ID (88.4%)

behavioral problems autism or autistic features are seen in almost 1 in 5 patients

motor features (axial) hypotonia, ataxia or ataxic gait, (intentional) tremor, spasticity and dyskinesia and/or dystonia are frequently seen

imaging (brain MRI) normal in almost 1/2 cerebral atrophy (33.3%), thin corpus callosum (16.2 %) and

hypomyelination or delayed myelination (16.2%) are frequent (age related) findings

Table 1: Summary of clinical features of STXBP1-E

• No clear correlation between age at seizure onset, seizure duration or age when seizure free and cognitive outcome

• Prognosis – 1/3 seizure free

Pharmacotherapeutic response: LEV? VGB? VPA?

– 88 % severe - profound ID

• Future: Disease modifying therapy? > Protein-protein interaction inhibition (Hussain et al.2014)

STXBP1- encephalopathy

Case 1: 27 year old female

• Negative family history

• Age 18 mo: first seizures, fever sensitive

• Development slowed, refractory szs

• MRI: negative

• FU in UZA since 2010: multiple hospital admissions (SE!!, aspiration pneumonia, anemia,.. )

• Dravet-like?

Genetic work up • SCN1A seq negative

• 2014: Gene panel with > 50 genes for DS/MAE : negative

• WES...

KCNT1 (Slack, chr.9)

Heron et al, Nature Genetics 2012

• 2012: first mutations described in ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy) and MMFSI (malignant migrating focal seizures of infancy)

• 2012 – current: expansion of phenotype to EOEE, focal epilepsies and cardiac arrythmias

Mutation effect: GoF?

Millegan et al, Ann, Neurol. 2014 Apr;75(4):581-90. doi: 10.1002/ana.24128. Epub 2014 Apr 14.

Precision medicine: Quinidine?

Millegan et al, Ann, Neurol. 2014 Apr;75(4):581-90. doi: 10.1002/ana.24128. Epub 2014 Apr 14.

Outline






Deletion Duplication

Insertion Translocation

• Important risk factor for epilepsy

• Array-CGH (whole genome oligonucleotide array comparative genomic hybridization) is often included in the evaluation of patients when a genetic aetiology is suspected

• Recent epilepsy studies show that CNVs are detected in up to 6% of patients

• Established syndromes associated with epilepsy

• Hotspots predisposing to epilepsy: 1q21.1, 15q11.2, 15q13.3, 15q11-q13, 16p11.2, 16p13.11

Copy number variants (CNVs)

Olsen et al, Ann Neurol. 2014

Outline






Genetic discoveries associated with epilepsy Ion channels

•SCN1A, SCN2A, SCN8A, SCN9A

•KCNQ2, KCNQ3, KCNT1, KCNH1

•CACNA1A, CACNA1H, CACNB4

•HCN1

•…

Synaptic transport

•ARHGEF9 STXBP1

•DNM1 SV2A

•GPHN SYNGAP1

•NECAP1 TBC1D14

•PCDH19 STX1B

•PRRT2 …

•SNAP25 •…

Transcription regulators/ Signal transduction

•ARX GNAO1

•CDKL5 WWOX

•CHD2 …

•FOXG1

•MECP2

•QARS

•…

Neurotransmitter receptors

•GRIN2A, GRIN2B

•GABRA1

•GABBRG2, GABBRB3

•CHRNA2, CHRNA4,

•…

Metabolic

•ALG13 SLC25A22

•ALDH7A1 SLC2A1

•PNKP …

•PNPO

•SLC12A5

•SLC13A5

CNV hotspots

•1q21.1,

•15q11.2

•15q13.3

•15q11-q13,

•16p11.2,

•16p13.11

•…

Genetic overlap

autism

intelectual disability schizophrenia

childhood epilepsies

Li J. et al. Mol. Psychiatry (2015)

Genetic testing in epilepsy

Case 2: 10 yr old boy

• Born 40 wk, normal neonatal development • Age 5 mo: febrile szs • Development slowed, refractory sz: myoclonic, tonic

clonic, atypical absences, temperature sensitive • Worsening of szs with LTG • MRI: negative • EEG: slow background, unilateral and generalized SWC

Genetic work-up?

Q: Which genetic test would you ask first?

A. Array CGH

B. Diagnostic panel (ca 20 genes)

C. Whole exome/genome sequencing

D. SCN1A sequencing

Thomas, R. H. & Berkovic, S. F. (2014), Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.62

Whole exome sequencing/ whole genome sequencing

Q: Which parameters would you take into account when classifying a variant as pathogenic?

A. Absent in ‘control’ population (ExAC, 1000 genomes, dbSNP..)

B. Should already be reported as pathogenic (clinvar)

C. de novo occurence (when phenotype is isolated)

D. There should be functioal evidence (e.g. electrophysiology)

E. …

F. Combination

benign pathogenic

‘likely benign’ uncertain significance ‘likely pathogenic’

Guidelines?

Patient

•Counseling

•Treatment strategy

Community

•Research

•Data curation

Importance of genetic testing

Recessive ¼ (2 parents carrier) 1 x ‘carrier frequency’ x ¼ (1 parent carrier) Dominant ½ De novo no recurrence risk? CAVE: germline mosaicism

Counseling - recurrence risk

• Clinvar (NCBI)

• SCN1A SCN1A Variant Database (DMG, VIB)

SCN1A mutation database (Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou 510260, China.)

The SCN1A infobase (UC Davis Medical Center, Department of Neurology)

• KCNQ2/3: http://www.rikee.org/ (collaboration Baylor College of Medicine, USA; University of Molise, Italy; University of Antwerp, Belgium)

• Future initiatives: STXBP1, Epilepsiome,…?

epilepsygenetics.net

Patient registries

Outline






Symptomatic, supportive – anti-epileptic drugs – fysiotherapy, logotherapy, counseling…

Precision medicine – mutation oriented: – existing & new compounds – gene therapy?

+ search for good biomarkers to monitor treatment effect GOAL: ‘disease modifying therapy’

Therapeutic options

e.g. mTOR pathway

mTOR inhibitors - everolimus - sirolimus

DEPDC5 NPRL2 NPRL3 …

Take home messages

• The aetiology of about 40% of all epilepsies is assumed to have a major genetic contribution

• Genetic epilepsies are heterogeneous disorders with significant genetic overlap with other developmental diseases

• Next generation sequencing is available in research and diagnostic centers, a simple blood sample can do the trick

• A genetic diagnosis has consequences for both patient and community

Acknowledgements

Neurogenetics group: Peter De Jonghe Sarah Weckhuysen Jonathan Baets Tania Djémié Inès Mademan Jolien Roovers Willem De Ridder Tine Deconinck Katia Hardies Rik Hendrickx

Patients and families Collaborators

dr. Hannah Stamberger ://nvavg.nl/wp-content/uploads/2016/03/De-Jonge-en-Stamberge… · epilepsy approximately 95% of patients most frequent seizure types are epileptic spasms (65.3%),

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