How Can Genetic Information Impact Management?

Dec 3, 2012

Samuel F Berkovic MD FRS

Epilepsy Research Centre

University of Melbourne

American Epilepsy Society | Annual Meeting

Disclosure

Name of Commercial Interest

UCB Sanofi-Aventis

SciGen Bionomics Inc

(holds SCN1A patent)

American Epilepsy Society | Annual Meeting 2012

Type of Financial Relationship

Research Support, Speaker

Research Support, Speaker

Research Support

Research Support

Learning Objectives

• To appreciate the expanding understanding of genetics in the causation of epilepsies. • To understand how genetic knowledge can be applied in everyday clinical practice

American Epilepsy Society | Annual Meeting 2012

Outline

• How important is genetics in Epilepsy Causation? Genetic Epidemiology

“Hidden” Genetics of Epilepsy

• Role in daily Practice Closure to causation; avoid unnecessary investigation

What tests and when?

Genetic Knowledge that alters treatment

Genetic Knowledge that alters genetic counseling

American Epilepsy Society | Annual Meeting 2012

Doctor...….

What is wrong with my child?

Can you cure it?

What caused it?

➤ Clinically, cause is very important

➤ Much of the causation of epilepsy is genetic

The Transfiguration

Raphael

Traditional View of Epilepsy Causation

Rochester Study Hauser et al 1975

Genetic Epidemiology

1. FAMILIAL AGGREGATION STUDIES Recurrence risk ratio Compare frequency in particular relatives to controls Epilepsy overall 2.5 in first degree relatives

Generalized epilepsy 4 - 9 Partial epilepsy 2 - 3 Febrile seizures 3 - 5

Constance Absence

Onset 6 yr

Kathryn Absence

Onset 6 yr

Twins of William Lennox, 1949

2003: Seizure free since teenage 8

Slide Unavailable

Genetic Epidemiology

2. TWIN STUDIES

Generalised (n = 99) 0.73 0.33 p = 0.0001

Focal (n = 103) 0.34 0.04 p = 0.002

Febrile (n = 180) 0.60 0.14 p = 0.0001

Unclassified (n = 36) 0.43 0.13 p = 0.1

Case-wise concordance

Syndrome Monozygous Dizygous

Berkovic et al Ann Neurol 1998 Vadlamudi and Berkovic 2012 (in preparation)

Genetic Generalized Epilepsy (Helbig et al 2008)

10

Slide Unavailable

MULTIPLEX FAMILY STUDIES Select for families with two or more affecteds - bias Source of most gene discoveries to date

• AD Nocturnal Frontal Lobe Epilepsy

• First epilepsy gene

• Nicotinic receptor (1995)

• Epilepsy channelopathies

single

gene

epilepsies

epilepsies with

polygenic

inheritance

epilepsies with a major

acquired cause trauma,

infections, vascular etc.

Structural/Metabolic Genetic

The Neurobiological Spectrum of the

Epilepsies

12 Modified from Helbig et al 2008

Genes for Epilepsies: Big picture 2012

Ion channel subunits

Voltage-gated (Sodium, Potassium)

Ligand-gated (Nicotinic, GABA)

Non-ion channel genes (LGI1, GLUT1, PRRT2 etc)

Genetic heterogeneity for rare monogenic disorders

Pleiotropic expression of individual genes

Complex Epilepsies (majority of cases)

Common variants (GWAS) – few identified

Rare variants – some identified (CNVs, ion channels, others)

Monogenic Epilepsies (largely dominant, rare)

Genes for Epilepsies: Big picture 2012

• Under-ascertainment of family history

• Obvious family history not expected in a complex disorder

Not expected – Importance of de novo mutagenesis Severe childhood encephalopathies

Dravet syndrome (sodium channel SCN1A)

Other single gene disorders

Copy Number Variants (CNVs)

Milder epilepsies

GLUT-1 deficiency in early onset absence

CNV 15q13.3 in GGE

Hidden Genetics of ‘Sporadic’ Epilepsy

Febrile Seizures Dravet syndrome

*SCN1A mutation

Monozygosity confirmed

Dravet syndrome – Discordant MZ twins

15

What is the Mechanism for Discordance?

• Study DNA from multiple tissues

– Blood lymphocytes

– Hair

– Buccal cells

– Skin fibroblasts

– Neural cells

Posterior septum and

superior turbinate

Olfactory (nasal) epithelium - source of neural tissue

Contains neuronal precursor cells 16

Heterozygous mutation in all tissues

No mutation in any tissue of co-twin

17

Vadlamudi et al NEJM 2010 18

Post-zygotic Mutations and Mosaicism

Hemimegalencephaly Post-zygotic mutations in 30% in the PIK3CA, AKT3 or mTOR genes Lee at al Nat Genet 2012; Poduri et al Neuron 2012

Genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling

Linear nevus sebaceous Post-zygotic KRAS HRAS mutations Groesser et al. Nat Genet 2012

Can cause severe and lateralized epilepsies

Post-zygotic Mutations and Mosaicism

Can cause mild epilepsies

Somatic mutations in SCN1A Mild GEFS+ phenotype

Discovered in parents of Dravet children

Important because of recurrence risk in children

Is this a common phenomenon? Usual in cancer where tumor is examined

Why not in epilepsies?

Challenging, but not impossible hypothesis to test!

Doctor - What caused it?

The Transfiguration

Raphael

Unknown

Idiopathic

Congenital

Trauma Stroke

Others

Mostly Genetic!!

Role in Daily Practice

‘Closure’ of diagnosis is very important Patients/Families stop searching

Allows families to focus on the problem

Empowers families to advocate (eg Dravet foundation)

Avoids unnecessary testing

multiple MRIs

inappropriate pre-surgical work-up

intracranial electrodes

Role in Daily Practice What tests and when?

Before thinking tests..

Proper family history!

Precise clinical syndromic diagnosis if possible

Testing

Landscape is rapidly changing

Individual gene testing often costly and low yield but still

appropriate in some cases

Multiple new genes being discovered

Low cost technology for screening multiple genes evolving

Interpretation of tests is an issue

Genetic literacy of Neurologists!

High Yield Tests in Appropriate Settings

Copy Number Variation (Array CGH; SNP arrays)

“Epilepsy +“ (see Dr Mefford’s talk)

+ Intellectual Disability

or Autistic Spectrum Disorder

or Congenital Anomalies

or Brain Malformations

Epileptic Encephalopathies

Consider in pediatric and adult clinics

High Yield Tests in Appropriate Settings

SLC2A1 sequencing (GLUT1 deficiency)

Classic GLUT1 encephalopathy (De Vivo)

Early-onset Absence Epilepsy (10% cases)

Myoclonic-atonic Epilepsy (5% cases)

Epilepsy and Paroxysmal Exercise induced Dyskinesia

Presentation can be in adolescents and adults!

Treatment implication – ketogenic diet if refractory

High Yield Tests in Appropriate Settings

SCN1A Testing Suspected Dravet syndrome

Diagnostic evolution in children well known

Normal infant

Onset 6 months hemi-clonic seizures

Intellectual slowing/regression in 2nd year

Multiple seizure types

Harder to recognize in adults

Gait is a big clue (Rodda et al Arch Neurol 2012)

Treatment implication – avoid sodium channel blockers

High Yield Tests in Appropriate Settings

PCDH19 testing – Girls only epilepsy

Familial or sporadic

Onset usually < 3 years

Clusters of febrile seizures every 1-3 months

Focal or generalized convulsive seizures

Many seizures / day for few days

Intellectual disability in 2/3; Regress or never normal

Prominent psychiatric features

ASD, aggression, depression, psychosis

Outcome quite variable

High Yield Tests in Appropriate Settings

PCDH19 which girls to test

Female only family history

Sporadic cases in girls

SCN1A negative Dravet

Typical pattern: onset < 3, clusters, psychiatric features

Management implication – counseling a special challenge

Males are unaffected but transmit gene to daughters

Impact on Clinical Care and Practice Role of genetics in epilepsy under-estimated

- Mendelian epilepsies uncommon - Familial aggregation modest – complex inheritance - De novo mutagenesis emerging as very important - Genetics may explain much of the 75% of ‘unknown’

causes

Genetics in daily Practice - Closure to causation; avoid unnecessary investigation - Directly alter treatment: GLUT1, SCN1A mutations - Diagnosis essential for counseling Recurrence risk of de novo mutations Unusual inheritance patterns - Female-limited epilepsy Prenatal diagnosis