powerpoint presentationd2qrtshcpf0x30.cloudfront.net/nodes/58/genetics - friday.pdf · learning...
TRANSCRIPT
NRSP 2019:Genetics & Epilepsy
Douglas M. Smith, MD
Minnesota Epilepsy Group
Minneapolis, MN
Learning Objectives
• At the end of this lecture, you will be able to:• Explore genetic testing involved in the diagnostic work-up
for infants with recurrent seizures
• Differentiate Dravet syndrome from other infantile-onset epileptic encephalopathies, including infantile spasms and Lennox-Gastaut syndrome (LGS).
Lecture Outline
• Historical perspective• From human genome project to 23 & Me• The evolving landscape of epilepsy genes
• High-yield epilepsy syndromes• Dravet syndrome (severe myoclonic epilepsy of infancy)• Cryptogenic West syndrome• Ohtahara / Early myoclonic encephalopathy• Benign familial infantile / neonatal convulsions• Genetic epilepsy with febrile seizures plus (GEFS+)• Early-onset absence epilepsy• Autosomal dominant nocturnal frontal lobe epilepsy• Familial lateral temporal lobe epilepsy• Familial focal epilepsy with variable foci
Lecture Outline
• Practical considerations• Who should we test?
• Variant analysis
• Utility of testing• Treatment implications
• Inheritance
• A glimpse into the future
Historical Perspective
• Human Genome Project (1990-2003)
• 13-year project to sequence the human genome
• Over 200 principal investigators and 20 institutions involved
• Total cost: $3.8 billion
https://web.ornl.gov/sci/techresources/Human_Genome/project/index.shtml
Historical Perspective
• Now, more than half the population of Iceland has had their genome sequenced
• Cost: ~$600 a person
https://www.bbc.com/news/business-49090754
Historical Perspective
Helbig I, et al. Epilepsia. 2016.
High-Yield Epilepsy Syndromes
Dravet Syndrome
• A.k.a. severe myoclonic epilepsy of infancy (SMEI)
• Onset before age 18 months
• Prolonged hemiconvulsive seizures, often with secondary generalization• Obtundation status, myoclonic seizures• Frequent status epilepticus• Often triggered by vaccinations, fever, elevated
temperatures
• Development slows after 1-2 years of age• Ataxia, “crouch gait” later
• Dravet-specific SUDEP rate = 9.32 per 1000 person years
Anwar A, et al. Cureus. 2019; Cooper MS, et al. Epilepsy Research. 2016.
Charlotte Dravet
Dravet Syndrome
Steel D, et al. Epilepsia. 2018.
PCDH19
Depienne C, et al. PLoS Genet. 2009.
Dravet Syndrome
• AVOID SODIUM CHANNEL BLOCKERS• Carbamazepine, oxcarbazepine, lamotrigine, lacosamide
• Avoid phenytoin as maintenance, but may be helpful in status epilepticus
• Reports of worsening of myoclonus with vigabatrin
• Duration of use of contraindicated medications corresponds with negative cognitive outcomes
de Lange IM, et al. Epilepsia. 2018.
Dravet Syndrome
• Preferred treatments:• First-line: valproic acid, clobazam
• Second-line: addition of stiripentol or topiramate or ketogenic diet
• Specific indication• Recent approvals (2018):
• Cannabidiol
• Stiripentol (approved in combination with clobazam)
• In the future: fenfluramine
Anwar A, et al. Cureus. 2019; FDA Prescribing Information.
To the editor of Lancet:
“Sir:- I beg, through your valuable and extensively circulating Journal, to call the attention of the medical profession to a very rare and singular species of convulsion peculiar to young children….”
Dr. William. J. West, in Lancet 1:724, 1841
West Syndrome
Eling P, et al. Neurology. 2002.
West Syndrome
• Combination of infantile spasms, hypsarrhythmia, and developmental regression
• Typical onset 3 to 7 months
• Numerous causes• Perinatal hypoxic-ischemic encephalopathy
• Tuberous sclerosis
• Aicardi syndrome
• Nearly one third of cases have no immediately identifiable cause - cryptogenic
Pellock JM, et al. Epilepsia. 2010.
West Syndrome
• Genetic testing is high-yield in cryptogenic spasms• Causal abnormality in 23.5% of cases
• VUS in 14.8% of cases
• Metabolic causes• ALDH7A1, PNPO (pyridoxine-responsive epilepsy)
• POLG1 (and other mitochondrial causes)
• Single-gene epilepsy disorders• STXBP1, CDKL5, KCNQ3
• Genetic-structural causes• TSC1/2, ARX
• Chromosomal microduplications & deletions
Wirrell EC, et al. Epilepsia. 2015; Pellock JM, et al. Epilepsia. 2010.
West Syndrome
Wirrell EC, et al. Epilepsia. 2015.
Early Infantile Encephalopathies
Ohtahara syndrome Myoclonic Encephalopathy
• Onset first month of life
• Myoclonic seizures predominate
• Burst suppression on EEG
• Onset first month of life
• Tonic seizures predominate
• Rare myoclonic seizures
• Burst suppression on EEG
Beal JC, et al. Pediatr Neurol. 2012.
Early Infantile Encephalopathies
• Overlapping genetic causes
• Rule out metabolic causes first• Pyridoxine-responsive epilepsy, mitochondrial
encephalopathies
• Positive genetic testing in 30-50% of cases• KCNQ2, SCN2A, SCN8A, STXBP1, ARX, PIGA, PRRT2
Olson HE, et al. Ann Neurol. 2017;Ostrander BEP, et al. NPJ Genom Med. 2018..
Infantile Epileptic Encephalopathies
• Ohtahara Syndrome / Early Myoclonic Encephalopathy• Onset around 1 month• Burst suppression on EEG• Tonic & myoclonic seizures
• West Syndrome• Onset around 5-6 months• Hypsarrhythmia on EEG• Infantile spasms
• Dravet syndrome• First seizures around 6 months, worst seizures 9-12 months• Focal or generalized epileptiform discharges on EEG• Myoclonic & hemiclonic seizures, febrile status epilepticus
Beal JC, et al. Pediatr Neurol. 2012; Pellock JM, et al. Epilepsia. 2010; Anwar A, et al. Cureus. 2019.
Benign Familial Convulsions
• Neonatal – First month of life• A.k.a. “fifth day fits”
• Diagnosis of exclusion
• KCNQ2, KCNQ3
• Infantile – First year of life (typically 4-6 months)• Associated with paroxysmal kinesiogenic dyskinesia
• PRRT2, SCN2A, KCNQ2, KCNQ3
Al Yazidi G, et al. Child Neurol Open. 2017; Ebrahimi-Fakhari D, et al. Brain. 2015.
Genetic Epilepsy with Febrile Seizures Plus (GEFS+)
• Familial inheritance pattern• Diagnosis is not for the individual
• Combination of family members with febrile seizures and epilepsy
• High yield – in this particular study, 23% with pathological genetic findings• SCN1A, SCN1B, GABRG2, PCDH19
• Note these are also Dravet genes!
• Also chromosome 7q21 deletions, CACNA1H?
Afawi Z, et al. Neurology. 2016.
Early-Onset Absence Epilepsy
• Absence seizures +/- GTCs before 3 years of age
• Often associated with a movement disorder
• Glut-1 deficiency due to SLC2A1 mutation
Pong AW, et al. Epilepsia. 2012.
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
• It’s all in the name
• Often normal interictal EEG
• Onset between infancy and adulthood• Usually during childhood
• DDx – parasomnias• Parasomnias usually first third of evening
• Genetics – CHRNA2, CHRNA4, CHRNB2 (nicotinic acetylcholine receptor)• Can treat with carbamazepine, zonisamide, nicotine,
fenofibrate?• Rare phenotype of KCNT1, DEPDC5
Willoughby JO, et al. Epilepsia. 2003;Kurahashi H, Hirose S. GeneReviews. 2018.
Familial Lateral Temporal Lobe Epilepsy
• A.k.a. autosomal dominant partial epilepsy with auditory features• But only about half have auditory features
• Autosomal dominant inheritance with 54% penetrance
• Highly variable age of presentation (~18 years)
• Genetics: LGI1• Rarely DEPDC5
Ottman R, et al. Neurology. 2004.
Familial Focal Epilepsy with Variable Foci
Scheffer IE, et al. Ann Neurol. 1998; epilepsygenetics.net.
• All in the name
• May have FCD
• mTOR pathway genes
• DEPDC5, NPRL2, NPRL3
Practical Considerations
Who Shouldn’t Get Tested
• A different cause has been proven
• Abnormal MRI• (With a few exceptions)
• Well controlled seizures• (With a few exceptions)
• Febrile seizures only• (With a few exceptions)
• Certain epilepsy syndromes• Juvenile myoclonic epilepsy (JME), typical childhood or
juvenile absence epilepsy (CAE or JAE), Jeavon syndrome
Who Should Be Tested
• Unexplained refractory epilepsy
• “Epilepsy plus”• Intellectual disability• Other unexplained rare problems
• Seizures under age 2
• Certain epilepsy syndromes• West syndrome, Dravet syndrome, Generalized Epilepsy
with Febrile Seizures Plus (GEFS+)
• Seizures “run in the family”
• Thinking about having kids/having more kids
Variant Analysis
• Step 1: Does the inheritance make sense?
• Step 2: Does the phenotype make sense?
• Step 3: Is it inherited or de novo?
• Step 4: Higher level analysis by genetic counselors• Grantham, SIFT, PANTHER, PolyPhen scores
• How much does this gene normally tolerate variation?
• In-silica, in-vitro, or in-vivo modeling of mutations
Benefits of Testing
• May help predict future challenges• Higher risk of SUDEP (SCN1A, SCN8A)
• Risk of movement disorder (SLC2A1, PRRT2)
• Additional testing – e.g. check overnight EEG (GRIN2A)
• Explains behavior challenges
• Anticipate future seizure types
• May help predict seizure pattern• Seizures worst when infant (KCNQ2, KCNQ3, PRRT2)
• Seizures worst in early childhood (SCN1A, PCDH19)
• Importance of management of seizure clusters (CACNA1A, PCDH19)
• Inheritance pattern & family planning
Benefits of Testing
• Guides antiseizure medication selection• SCN1A & Dravet – clobazam, valproic acid,
ketogenic diet, cannabidiol, stiripentol, fenfluramine• AVOID sodium channel drugs
• SLC2A1 – ketogenic diet, triheptanoin
• KCNQ2, KCNQ3 – oxcarbazepine / carbamazepine, ezogabine
• SCN8A – sodium channel blockers, high-dose
• SCN2A – sodium channel blockers, zonisamide
• PCDH19 – clobazam
Benefits of Testing
• Guides antiseizure medication selection• CHRNA3, CHRNB2, CHRNA4 – oxcarbazepine /
carbamazepine, zonisamide, nicotine
• TSC1/2 – everolimus, vigabatrin, cannabidiol
• KCNT1 – quinidine
• POLG1 – avoid valproic acid
• TPP1 – cerliponase alfa
Benefits of Testing
Areas of Active Research
• Genotype / phenotype prediction
• Antiseizure medication profiles
• Gene discovery• Re-analysis of clinical whole exomes
• Gene-specific RCTs
• Novel pathogenic mechanisms• Whole genome sequencing
Areas of Active ResearchGene-Specific RCTs: SCN2A
Wolff M, et al. Brain. 2017.
Novel Pathogenicity Mechanisms
Ishiura H, et al. Nat Genet. 2018.
A Glimpse into the Future
• Modifier genes• Polygenic inheritance
• Personalized mutation modeling
• Gene discovery of “benign” epilepsy syndromes
• Exomes as common as MRI in seizure evaluation
Any questions?Thanks for listening!