Not for duplication or distribution - CLN2 Webinar · •These slides are from a live webinar held...

APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019

Not for duplication or distribution


NOT FOR DUPLICATION OR DISTRIBUTION


About this Enduring Webinar

• These slides are from a live webinar held on 14 November 2019 with Professor Nicola Specchio and Dr Raman Sankar

• Videos are not live in this presentation, and some patient images have been removed for privacy purposes. Images which were once videos will have this symbol

222



Faculty

3

Nicola Specchio, MD, PhDHead of the Epilepsy Unit,

Department of Neuroscience Bambino Gesú Children’s Hospital

Rome, Italy

Raman Sankar, MD, PhDProfessor of Neurology and Pediatrics and Chief of

Pediatric NeurologyDavid Geffen School of Medicine at UCLA

Los Angeles, CA, USA

3



Faculty disclosures

Nicola Specchio, MD, PhD• Consultant: BioMarin Pharmaceutical Inc• Grant / Research support: BioMarin Pharmaceutical Inc

Raman Sankar, MD, PhD• Consulting fee, travel support and honoraria from BioMarin Pharmaceutical Inc

All photos are used with family permission

4



Learning objectives

• Understand benefits of early genetic testing in understanding seizure etiology in pediatric epilepsy patients

• Recognize how genetic research is rapidly advancing our understanding of the underlying causes of epilepsy

• Understand the benefits of epilepsy gene panels in pediatric epilepsy patients to potentially uncover disorders, like CLN2 disease, earlier in the course of the disease

• Understand the urgency to provide a definitive diagnosis to patients, which may enable more precise clinical management and improve patient outcomes

5



Webinar Agenda

Topic Presenter

Welcome & Introductions Nicola Specchio

Epilepsy and Genetics Raman Sankar

CLN2 Disease and the Need for Early Diagnosis Nicola Specchio

Genetic Testing and Actionability of Results Raman Sankar

Case Study Nicola Specchio

Interactive Q&A Session

6


CLN2 Disease

Genetic Testing &

Actionability of Results

Epilepsy and

GeneticsCase Study



Advances In Understanding The Causes of EpilepsyNew research demonstrates increasing genetic basis

8

1. Hauser WA, Kurland LT. Epilepsia. 1975;16:1–66; 2. Thomas RH, Berkovic SF. Nat Rev Neurol. 2014;10:283–292.

19751

Idiopathic

Trauma

Vascular

NeoplasmInfectious

Congenital lesionsBirth anoxia

Other

2014 paradigm2

Epilepsies with complex

inheritance

Single-gene epilepsies: Familial,

de novo

Modifiers and susceptibility

alleles

Trauma

Vascular

NeoplasmInfectious

Congenital lesionsBirth anoxia

Other

Autoimmune Focal epilepsy with MRI-detectable lesions



The History Of Gene Identifications In Epilepsy Research

9

CLN3TPP1

NGS demonstrates the spectrum of phenotypes associated with

genetic epilepsiesCHRNA4 SCN1B

SCN1AGABRG2

Microdeletions

KCNQ2KCNQ3

SLC2A1

GABRA1 LGI1

ARX

CACNA1H

CDKL5

15q13.316p13.1115q11.2

STX1BSLC6A1

GABRA1GABRB3

SIK1KCNA2

ALG13GRIN2B

PURAKCNB1

KCNC1DNM1

HCN1CHD2

SCN2AGRIN2A

DEPDC5KCNT1

PRRT2TBC1D24

STXBP1PCDH19

SCN8A

Channelopathy era Next-generation sequencingDark ages

2011200920072005 2013 2015 2017 201820032001199919971995

TPP1: tripeptidyl peptidase 1.Adapted from: Helbig I et al. Epilepsia. 2016;57:861–868; Sleat DE et al. Science. 1997;277:1802–1805; The International Batten Disease Consortium. Cell. 1995; 82:949–957; Trump N et al. J Med Genet. 2016;53:310–317.



The Era of Targeted Therapy for Genetic Epilepsy

10

Potential for disease-specific management:targeted therapy or clinical trial

Initial empirical AED treatmentno underlying cause yet identified

Genetic assessment: epilepsy gene panel

Old paradigmStepwise approach

Emerging paradigmDirect, accurate, cost-effective

Genetic assessment: chromosomal microarray

AEDFailure

Genetic assessment: epilepsy gene panel

UNINFORMATIVE

Patient withunexplained epilepsy

EpiPM Consortium. Lancet Neurol. 2015;14:1219–1228; Helbig K. A Clinician’s Guide to Genetic Test Selection: Navigating the Wild West. Epilepsygenetics.com. http://epilepsygenetics.net/2016/10/16/a-clinicians-guide-to-genetic-test-selection-navigating-the-wild-west (accessed January 18, 2018).



Reasons For Considering Genetic Testing

11

Genetic testing

Berkovic SF. Epilepsy Curr. 2015;15:192–196.

Genetic testingGenetic

testing

Can impact clinical management e.g. choice of AED1

May avoid unnecessary testing2

Shortens the diagnostic journey for families3

Allows for specific counseling (family planning)4

Opportunity to participate in a clinical study5

Can allow for targeted therapy: precision medicine6

Connect families with each other and advocacy groups7NOT FOR DUPLICATION OR DISTRIBUTION

CLN2 Disease

Genetic Testing &


Epilepsy and

GeneticsCase Study



Features of CLN2 disease

0–1 years• Normal early development1–2 years• May have slow language development2–3 years• Seizures, often polymorphic • Poor mobility• Hospital admissions (seizures)• Increasing medical and developmental

concerns• Referral for diagnostic investigations

3–4 years• Seizures often more troublesome• Developmental stasis• Worsening of mobility and fine motor

skills4–5 years• Further loss of skills• Sleep disorder• Pain and irritability• Increasingly dependent for activities of

daily living

13

CLN2: late-infantile neuronal ceroid lipofuscinosis (NCL) or NCL type 2.



Late stage may be prolonged

>6 years• Gastrostomy dependent• Unsafe swallowing• Loss of communication• Loss of voluntary movement• Chest infections• Ongoing seizures• Myoclonic status• Spasticity and joint contractures• Spinal scoliosis

14

Retain some understanding and

personality



Clinical presentation: Classical late infantile CLN2 disease

Do NOT wait for vision loss to diagnose CLN2

Birth 1 2 3 4 5 6 7 8 9 10 11 12

•Seizures

•Psychomotor d

ecline

•Bedridden

•Blindness •Death

•Ataxia

Age (yr)

• Language delay

15

All photos / videos used with family permission from Bambino Gesù Children’s Hospital.





3 yr old

16


Birth 1 2 3 4 5 6 7 8 9 10 11 12

•Seizures

•Psychomotor d

ecline

•Bedridden


•Ataxia

Age (yr)

• Language delay

Video showing CLN2 patient at 3 years old, who was experiencing some epileptic seizures. This video shows motor development that is still normal





4 yr old

17


3 yr old

Birth 1 2 3 4 5 6 7 8 9 10 11 12

•Seizures

•Psychomotor d

ecline

•Bedridden


•Ataxia

Age (yr)

• Language delay

The same patient after 1 year, who is starting to present with ataxia and other movement disorders





5 yr, 7 mo old

18


4 yr old3 yr old

Birth 1 2 3 4 5 6 7 8 9 10 11 12

•Seizures

•Psychomotor d

ecline

•Bedridden


•Ataxia

Age (yr)

• Language delay

The same patient had a very quick progression of disease – soon suffering continuous myoclonic jerks, is bedridden and almost blind



Clinical scoring for disease severity in late infantile NCL (CLN2): Hamburg scale

Functional categories

Motor function

Language

Visual function

Seizures

Each functional category is scored from 0-3

Normal function = SCORE 3

Slightly abnormal = SCORE 2

Severely abnormal = SCORE 1

No function left = SCORE 0

19NCL, neuronal ceroid lipofuscinoses.Steinfeld R et al. Am J Med Genet. 2002;112:347–354.



(Clinical score)

Sum of MOTORand LANGUAGE

Normal = 3Abnormal = 2Poor = 1No function = 0

(Maximum = 6)

Rapid and predictable neurodegeneration demonstrated by the CLN2 Clinical Rating Scale (N=58)1

CLN2 disease natural history: DEM-CHILD NCL database

20

1. Schulz A. Presented at the 14th International Child Neurology Congress (ICNC); Amsterdam, the Netherlands: May 1 - 5, 2016.



Classical late infantile CLN2 disease: natural history

2-yr delay

Mean95% CI

2-yrs delay

Rate of decline2.1 units/yr

21CI: confidence intervalFigure adapted from: Nickel M, et al. Presented as poster at the 12th Annual WORLDSymposium; February-March 2016; San Diego, CA, USA. All photos / videos used with family permission from Bambino Gesù Children’s Hospital.

3 yrs old: Average age at 1st seizure

5 yrs old: Average age at diagnosis

Sum

of t

he m

otor

and

lang

uage

scor

e

Age (years)NOT FOR DUPLICATION OR DISTRIBUTION


Delayed diagnosis

• There is a 1- to 4-year delay in achieving an appropriate diagnosis after symptoms have begun to appear•Given the irreparable damage to the brain, early identification is crucial– To improve management, information for families and family planning– To implement disease-specific management options

22

6 yrs 6 yrs 8 mo 7 yrs 6 mo3 yrs 4 yrs 5 yrs 4 mo




Clinical diagnosis of CLN2 Disease

• Developmental history• Seizure history• Examination findings• Initial investigations may provide an

indication– Normal basic “screen”– Brain MRI – disproportionate cerebellar atrophy– EEG – abnormal response to slow rate intermittent

photic stimulation (IPS)

23EEG, electroencephalography; MRI, magnetic resonance imaging.Image from Dr. Specchio, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.



Clues leading to clinical suspicion: MRI findings

• Brain MRI at the age of 3.8 (3.0–5.1) yrs revealed cerebellar atrophy in 100% (14 of 14) of patients

• Alteration of the periventricular white matter signal in the posterior hemispheric region was observed in 79% (11 of 14) patients

24

Specchio N, et al. Epilepsia. 2017;58:1380–1388.



Clues leading to clinical suspicion: EEG findings

• Median delay of 1st IPS from 1st EEG was 4 months (range: 0-23 months)• EEG revealed PPR in 13 out of 14 cases;

PPR from the 1st EEG was seen in 43% of patients• PPR was documented at low frequencies in

9 out of 13 cases with flash-per-flash response evident• Median delay from 1st EEG with IPS and

1st PPR observation was 1.2 months(range: 1.2-16.8 months)

25

Early photosensitivity is a hallmark of CLN2 disease, with PPR typically evident at low frequencies.When it occurs in subjects with seizures and speech delay and/or ataxia,

CLN2 disease should be considered

First EEGFirst IPSFirst PPR

Specchio N, et al. Epilepsia. 2017;58:1380–1388.

Age (years)

Cum

ulat

ive

surv

ival

(%)



Suspicion of NCL disorder• Neuronal ceroid lipofuscinosis (NCL)

gene panel• TPP1/PPT1 enzyme activity

screening tests†

Suspicion of genetic basisof epilepsy• Symptom- or disease-based gene

panel (e.g. epilepsy gene panel)

CLN2 diseasediagnosis confirmed

Diagnostic for CLN2 disease• Deficient TPP1 enzyme

activity in leukocytes‡

• 2 pathogenic mutations in each allele of TPP1 gene§

Suspicion of CLN2 disease• TPP1 enzyme activity test†

• TPP1 molecular test

Presentation of epilepsy• EEG with low frequency IPS (1-2 Hz)*

*Absence of EEG findings should not preclude follow-on testing for epilepsy syndromes, CLN2 disease or other NCLs

Diagnosing patients along the disease continuum; Genetic testing allows for early diagnosis, prior to disease progression

26

*Additional clinical assessments may be warranted, such as brain MRI, OCT/VEP/ERG/FA, EM biopsy; †TPP1 enzyme activity may be measured in sample types such as dried blood spots or saliva. PPT1 enzyme activity (CLN1 disease) is useful to assess with TPP1; ‡TPP1 enzyme activity testing in other sample types can also be diagnostic (see Table 2); §Includes single gene sequencing, gene panels, or whole exome sequencing.Adapted from Fietz et al. Mol Genet Metab. 2016;119:160–167.



Suspicion of NCL disorder• Neuronal ceroid lipofuscinosis (NCL)

gene panel• TPP1/PPT1 enzyme activity

screening tests†

Suspicion of genetic basisof epilepsy• Symptom- or disease-based gene

panel (e.g. epilepsy gene panel)

Diagnosing patients along the disease continuum; Genetic testing allows for early diagnosis, prior to disease progression

27

*Additional clinical assessments may be warranted, such as brain MRI, OCT/VEP/ERG/FA, EM biopsy; †TPP1 enzyme activity may be measured in sample types such as dried blood spots or saliva. PPT1 enzyme activity (CLN1 disease) is useful to assess with TPP1; ‡TPP1 enzyme activity testing in other sample types can also be diagnostic (see Table 2); §Includes single gene sequencing, gene panels, or whole exome sequencing.Adapted from Fietz et al. Mol Genet Metab. 2016;119:160–167.

Disease progression

Suspicion of CLN2 disease• TPP1 enzyme activity test†

• TPP1 molecular test



Age of onset of various epileptic encephalopathies and CLN2 Disease

Age of onset years

Different epilepsy syndromes may be considered in young children presenting with new-onset of seizures at late infantile age

ESES/LKS, electrical status epilepticus in sleep/Landau-Kleffner syndrome; FIRES, febrile infection-related epilepsy syndrome; ABPE, atypical benign partial epilepsy; MPSI, migrating partial seizures of infancy.Adapted from Helbig I and Tayoun A. Mol Syndromol., 2016;(4):172-181.

28



Early Diagnosis is Critical for Timely Disease-Specific Management

29

Genetic testing

Berkovic SF. Epilepsy Curr. 2015;15:192–196.

Genetic testingGenetic

testing

Can impact clinical management e.g. choice of AED1

May avoid unnecessary testing2

Shortens the diagnostic journey for families3

Allows for specific counseling (family planning)4

Opportunity to participate in a clinical study5

Can allow for targeted therapy: precision medicine6

Rapid progression after age ± 3 yrs (CLN2-specific) 7NOT FOR DUPLICATION OR DISTRIBUTION

APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019EEG: Specchio N, et al. Presented at the ICNC Symposium, May 2016, Amsterdam, Netherlands; MRI: Image from Dr. Specchio, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.

Summary

Earlierdiagnosis

Involve the parents:

Is there a delay in language

development

Request an enzymatic test or

a disease/symptom-based gene panel

which includes the TPP1/CLN2 gene

Perform an EEG with IPS at low frequency (1Hz):

Look for PPR

Request an MRI:Atrophy of the cerebellum

and cortex & occasional white matter anomalies in periventricular areas may

point to CLN2 disease

30


CLN2 Disease

Genetic Testing &


Epilepsy and

GeneticsCase Study



Which Genetic Testing Tools Should You Use?Types and benefits of various genetic testing tools

Chromosomal microarray Gene panels Whole exome sequencing

What is it?Detects duplications and deletions1 Test a wide set of epilepsy-associated

genes;1 number of genes tested may vary (<20 to up to 554)5

Comprehensive testing, simultaneously sequences coding regions of all known genes1

UtilityUsed for pts with epilepsy and developmental delay1,2,3

No specific-disease suspicion needed,efficiently tests for many conditions fitting a clinical phenotype6

Sequencing of exons, beyond known epilepsy associated genes

Yield Low diagnostic yield (~5%)1 High diagnostic yield (up to ~50%4) High diagnostic yield (17%–72%6)

Pros

• Broad insurance coverage • Efficient way to reach an early molecular diagnosis1

• Consistent, reliable, effective & automated• May include deletions, duplications1

• May identify new etiologies for epilepsy-related genes6

• Re-analysis is possible, as more genes discovered

Cons

• Not inclusive of exon level analysis3 • Detection of most variants/interpretation of VUS

• Historic (improving)– Cost – Turn-around time (2–6 weeks)

• Access/availability

• Detection of most variants/interpretation of VUS– Larger deletions/duplications not

usually detected1

• Comparatively higher cost• Turnaround time (8–12 weeks)• Limited insurance coverage

VUS, variant of unknown significance.1. Helbig K. A Clinician’s Guide to Genetic Test Selection: Navigating the Wild West. http://epilepsygenetics.net/2016/10/16/a-clinicians-guide-to-genetic-test-selection-navigating-the-wild-west/ (accessed January 18, 2018). 2. Miller DT et al. Am J Hum Genet. 2010;86(5):749–764. 3. Trakadis Y and Shevell M. Dev Med Child Neurol. 2011;53:994–999. 4. Tucker T et al. Eur J Human Genet. 2014;22:792–800; 5. MNG Laboratories. Improved epilepsy panel portfolio. https://mnglabs.com/improved-epilepsy-panel-portfolio (accessed May 8, 2018). 6. Mei D et al. Mol Diagn Therap. 2017;21:357–373.

32



Benefits of Gene Panels: UtilityIncrease understanding of genetic heterogeneity

Many epilepsy syndromes reveal genetic heterogeneity1

33

Phenotype Implicated Genes

Autosomal dominant nocturnal frontal lobe epilepsy DEPDC5, KCNT12

Benign familial neonatal epilepsy KCNQ2,1 KCNQ3,1 SCN2A2

Early infantile epileptic encephalopathy KCNT1, SCN2A, STXBP12

Epilepsy of infancy with migrating focal seizures KCNT1, SCN2A, SNC8A2

Early-onset epileptic encephalopathy SCN2A, STXBP12

West syndrome FOXG1, GRIN2A, GRIN2B, KCNT1, MEF2C, SCN2A, SCN8A, ARX, CDKL52

Gene panels can help elucidate the genetic heterogeneity associated with epilepsy phenotypes

1. Scheffer IE et al. Epilepsia. 2017;58:512–521; 2. Mei D et al. Mol Diagn Therap. 2017;21:357–373.



Benefits of Gene Panels: UtilityAssist in characterizing phenotypic heterogeneity

Many variants are found in cases where the phenotype is either not easily distinguishable from that caused by a number of other genes or is atypical for the previously reported phenotype(s)1– In only 15% of cases, physicians correctly identified the mutated gene, prior to genetic testing1

Pathogenic variants in a specific gene can manifest in a spectrum comprising both severe and mild spectrum comprising both severe and mild epilepsies2

• SCN2A– Initially associated with BFNIS3

– Subsequently associated with EIMFS and other less well delineated forms of epileptic encephalopathy3

• KCNQ2– Initially associated with BFNS3

– Subsequently associated with early-onset epileptic encephalopathy3

34

BFNIS, benign familial neonatal-infantile seizures; BFNS, benign familial neonatal seizures; EIMFS, epilepsy with migrating focal seizures in infancy.1. Trump N et al. J Med Genet. 2016;53:310–317; 2. Scheffer IE et al. Epilepsia. 2017;58:512–521; 3. Mei D et al. Mol Diagn Therap. 2017;21:357–373.



STXBP1 encephalopathyA neurodevelopmental disorder including epilepsy

53%

21%

1%

10%

2%

7%

6%

Spectrum of STXBP1-associated phenotypes

EOEE

OS

EME

West

Dravet

ID, no epilepsy

NSE + IDOS

35

Stamberger H et al. Neurology. 2016;86(10):954-962.

EOEE

West

Example of Extreme Phenotypic Pleiotropy



Benefits of Gene Panels: No Disease-Specific Suspicion NeededSimultaneously detect both common and rare seizure disorders

36

56 genes with <10 pts diagnosed

A total of 67 pathogenic genes were identified in 348 patients

0

10

20

30

40

50

60

70

SCN1A

SCN2A

STXB

P1CD

KL5

KCNQ2

SCN8A

CHD2

SYNGA

P1PC

DH19

KCNT1

MEC

P2FO

XG1

GABR

B3MEF2C

UBE

3AGA

BRA2

PNPO

TCF4

GABR

A1GN

AO1

HNRN

PUIQSEC2

KCNB1

PNKP

PRRT

2SLC2

A1SPTA

N1

ATP1

A3CA

SJGR

IN1

GRIN2A

HCN1

KCNA2

KCNJ10

MBD

5PIGA

POLG

SLC2

5A22

SLC9

A6 TPP1

ALDH

7A1

ARHG

EF9

ARX

ATP1

A2CA

CNA1

ACN

TNAP

2CP

A6 DCX

DEPD

C5DL

G3EEF1A2

EHMT1

FARS2

GPHN

KCNA1

KCNQ3

KCTD

7LG

I1MFSD8

PDHA

1SLC1

3A5

SLC9

A6SM

SSTX1

BTB

C1D2

4WDR

45ZEB2

11 genes with ≥10 pts

diagnosed

Many pts present with few genetic diagnoses

Few pts present with many distinct genetic diagnoses

Mei D et al. Mol Diagn Ther. 2017;21:357–373.



Benefits of Gene Panels: No Disease-Specific Suspicion NeededSimultaneously detect both common and rare seizure disorders

37

56 genes with <10 pts diagnosed

A total of 67 pathogenic genes were identified in 348 patients

0

10

20

30

40

50

60

70

SCN1A

SCN2A

STXB

P1CD

KL5

KCNQ2

SCN8A

CHD2

SYNGA

P1PC

DH19

KCNT1

MEC

P2FO

XG1

GABR

B3MEF2C

UBE

3AGA

BRA2

PNPO

TCF4

GABR

A1GN

AO1

HNRN

PUIQSEC2

KCNB1

PNKP

PRRT

2SLC2

A1SPTA

N1

ATP1

A3CA

SJGR

IN1

GRIN2A

HCN1

KCNA2

KCNJ10

MBD

5PIGA

POLG

SLC2

5A22

SLC9

A6 TPP1

ALDH

7A1

ARHG

EF9

ARX

ATP1

A2CA

CNA1

ACN

TNAP

2CP

A6 DCX

DEPD

C5DL

G3EEF1A2

EHMT1

FARS2

GPHN

KCNA1

KCNQ3

KCTD

7LG

I1MFSD8

PDHA

1SLC1

3A5

SLC9

A6SM

SSTX1

BTB

C1D2

4WDR

45ZEB2

11 genes with ≥10 pts

diagnosed

Many pts present with few genetic diagnoses

Few pts present with many distinct genetic diagnosesPanels detect both common and rare seizure disorders

Mei D et al. Mol Diagn Ther. 2017;21:357–373.



Benefits of Gene Panels: Reduction in Healthcare CostsHigh diagnostic yield expedites diagnosis and reduces costs

38

Clinical features

Metabolic testingof CSF

Metabolic testing of urine/plasma

Brain MRI

Chromosome microarray Muscle/skin biopsy

Repeated testing (EEG / MRI) can have a higher than cost of molecular

testing

• Late diagnosis costs more

Diagnosis of epileptic encephalopathy patients (N=31)

Epilepsy panel:

• High diagnostic yield**• Efficient way to potentially reach an

early molecular diagnosis*

Gen

etic

cau

ses w

ere

iden

tifie

d in

28%

(31

of 1

10) p

atie

nts s

tudi

ed

Data are from a large retrospective cohort study (N=110) of diagnostic yield in patients with epileptic encephalopathy conducted at a single epilepsy genetics clinic at an academic pediatric health science center. *Percentage of patients who obtained a genetic diagnosis by targeted next-generation sequencing epileptic encephalopathy panels**Targeted next-generation sequencing identified a genetic cause in 12.7% of the 110 patients.CSF, cerebrospinal fluid; EEG, electroencephalography; MRI, magnetic resonance imaging.Mercimek-Mahmutoglu S et al. Epilepsia. 2015;56:707–716.



Gene Panels In Patients With Epilepsy

39

SNV, single nucleotide variants; CNVs, copy number variants. Mei D et al. Mol Diagn Therap. 2017;21:357–373); Helbig K. A Clinician’s Guide to Genetic Test Selection: Navigating the Wild West. Epilepsygenetics.com; Chambers C, et al. J Genet Couns. 2016 Apr;25(2):213-7; Berg AT et al. JAMA Pediatr. 2017;171:863–871; MNG Laboratories. Improved epilepsy panel portfolio. https://mnglabs.com/improved-epilepsy-panel-portfolio (accessed May 8, 2018).

Studies confirm utility of NGS panels

Panel testing is becoming increasingly accessibleand efficient

Panels continue to become more comprehensive

Not all panels arecreated equal3

• High diagnostic yield (up to ~50%1)

• Yield varies by population, many studies produced yields of ~20%2

• Variants of Uncertain Significance still pose interpretation challenges3

• Costs vary by country, but are declining overall

• Turnaround time continues to improve

• Additional genes continually added as new genetic etiologies are identified

• In addition to SNV, short and long indels, exon level deletions / duplications (CNVs), structural rearrangements and triplet repeat expansions can be studied in some modern NGS panels

• Turnaround time varies

• Number of genes <20 –approximately 5544


APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 20191. http://www.omim.org/search/?index=clinicalSynopsis&start=1&limit=10&search=%22seizure%22+ AND%22ataxia%22&sort=score+desc%2C+prefix_sort+desc (accessed Aug 2017).

When to Use a Gene Panel for Epilepsy Diagnosis

40

Gene panel• Testing for many conditions

fitting the clinical picture• Efficient way to reach an early

molecular diagnosis

Patient X• Non-specific symptoms– Seizures– Ataxia (motor disturbance)– Language development delay

Diagnosis?

• >500 possible diagnoses1

• Each condition is unlikely • Testing one-by-one = inefficient• Rarely biochemical test available



Genetic Epilepsies May Be Hiding Behind Non-Specific SignsConsider testing when you see language development delay and/or motor disturbance

• In an evaluation of results from an industry-sponsored, no-cost testing program:– Language delay, motor disturbance: the best predictors of genetic testing outcome• Language delay and/or motor disturbance symptoms were associated with most (92/133) genes on this panel

0

20

40

60

80

100

Language delay or motor disturbance reported

P<0.01

(n=11)(n=114) (n=8)

49%

100% No genetic diagnosisAny genetic diagnosis

Clinical presentation by outcome group

Total number of orders where clinicians indicated presence or lack of presence of clinical feature for each outcome group. Non-responders not included in total. Review of 176 Invitae Epilepsy Panel (125 genes) tests in children ages 2 to 4, who had their first unprovoked seizure after the age of 2. There were 2 outcomes groups: no genetic diagnosis or any genetic diagnosis in a gene included in the Invitae Epilepsy Panel. Adapted from Miller N et al. Behind the Seizure™: A no-cost, 125-gene epilepsy panel for pediatric seizure onset between 2-4 years. Poster session presented at: The ACMG Annual Clinical Genetics Meeting; April 10-14, 2018; Charlotte, NC.

41



GLUT1: glucose transporter type 1; SCN1A: sodium voltage-gated channel alpha subunit 1.Adapted from Poduri A, et al. Nat Rev Neurol. 2014;10:293-299.1. Fulgent Genetics. Actionable Epilepsy NGS Panel. https://www.fulgentgenetics.com/actionable-epilepsy (accessed May 8, 2018).

Identifying a seizures’ underlying etiology can enable more precise treatment • Many genes are actionable: Gene panels increasingly help tailor the approach to treatment – more than 20 genes1

have been linked to specific treatment strategies

GLUT1 deficiency

SCN1A

Ketogenic diet should be tried

SLC2A1

Avoidance of certain sodiumchannel agents

Early diagnosis is critical

Dravet syndrome

Even if there is no known therapy for a detected variant, the knowledge can help modify clinical management, including evaluating patient for clinical trial enrollment or determining additional tests to pursue

42


CLN2 Disease

Genetic Testing &


Epilepsy and

GeneticsCase Study



AGE (YEARS)

CLN

2 D

ISEA

SE C

LIN

ICA

L R

ATI

NG

SC

ALE

SC

OR

E (M

OTO

R A

ND

LA

NG

UA

GE)

6

5

4

3

2

1

00 1 2 3 4 5 6 7 8 9 10 1211

Loss of voluntary movements/bedridden

Death

Blindness

Dysphagia Tube feeding

Visual decline

Cognitive decline Loss of cognitive functions/dementia

Myoclonus/spasticity/dystonia

Ataxia Loss of ambulation

New-onset seizures Drug-resistant seizures

Language delay

Language decline Loss of language

1. Schulz A, et al. Biochim Biophys Acta. 2013;1832:1801-1806; 2 Mole S, et al. Gene Reviews [online]. 2013; 3. Nickel M et al. Lancet Child Adolesc Health. 2018;2(8):582–590.

Children experience a dramatic loss of function as symptoms compound with age1,2†

44

†Age ranges depicted are averages for the classic late-infantile phenotype. Atypical phenotypes of CLN2 disease can vary in age of onset, rate of progression, and disease manifestation.

Two hallmark presenting

symptoms of CLN2

disease are early

language delay and

new-onset seizures3



Age of onset of various epileptic encephalopathies and CLN2 Disease

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Age of onset years

Different epilepsy syndromes may be considered in young children presenting with new-onset of seizures at late infantile age

ESES/LKS, electrical status epilepticus in sleep/Landau-Kleffner syndrome; FIRES, febrile infection-related epilepsy syndrome; ABPE, atypical benign partial epilepsy; MPSI, migrating partial seizures of infancy.Adapted from Helbig I et al. Epilepsia. 2016;57:861–868.

CLN2 Disease



Traditional vs genomic diagnosis

• Male, 7 yrs (currently 12 yrs)• Onset: 2 yrs 8m, focal seizure, Status epilepticus• EEG: diffuse abnormalities • VPA, PB, PHT, LEV• 3 brain MRI, multiple hospital admission, ataxia, cognitive regression, repetitive

myoclonus• Genetic tests: Karyotype → CGH array → SCN1A → NGS panel → CLN2 diagnosis• Limited disease-specific management• Time for diagnosis: 5 years

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• Female, 3 yrs (currently 5 yrs)• Onset: 2 yrs 6, focal seizures, repetitive

seizures• EEG: PPR and diffuse abnormalities• VPA, LEV (then withdrawn)• 1 brain MRI; lumbar puncture, only one

hospital admission for repetitive seizures• Genetic test: NGS panel → CLN2 diagnosis• Early evaluation of disease-specific

management• Time for diagnosis: 2 monthsNOT FOR DUPLICATION OR DISTRIBUTION


Video showing CLN2 patient running, chasing a ball without any motor disturbance

Video showing patient drawing, talking and interacting with parents

These are videos of the female Case Study on previous slide. In very early stages of CLN2 disease, it may be difficult to diagnose without an epilepsy gene panel, as motor disturbance may not be immediately apparent.


Genetic epilepsies may be hiding behind non-specific signsGene panels are an efficient way to expedite earlier diagnosis



Genetic epilepsies may be hiding behind non-specific signsGene panels are an efficient way to expedite earlier diagnosis

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Video showing patient walking unassisted, with no motor disturbance

Video showing running and playing soccer with a sibling - with no motor disturbance



January 2019 – EEG

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This same patient’s EEG at a similar time as the videos were taken – showing normal brain function with some spikes over the frontal bilateral regions.



Conclusion

• Careful evaluation of symptoms of disease onset• Look at seizure semiology, EEG findings and other possible associated symptoms• Early use of epilepsy gene panels including genes for NCLs• Evolution of disease• Refer patients to specialized centers for genetic counseling and better management• Avoid AEDs with potential negative impact on seizures (i.e. sodium channel blockers)

and on motor and cognitive development (i.e. barbiturates)• Evaluation of the disease stage in order to better prescribe the right drug

(i.e. anti-dystonic, anti-cholinergic, muscle relaxant)• Ask to parents to film children time to time, in order to document the progression

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Take-home messages

• Genetic research is rapidly advancing our understanding of the underlying causes of epilepsy

• Gene panels are an efficient way to expedite diagnosis• CLN2 disease is rapidly progressing, fatal neurodegenerative disorder. Early diagnosis

is critical• When there is a suspicion of genetic basis of epilepsy, a symptom or disease based

gene panel can allow for early diagnosis, prior to progression of disease • Identifying the genetic etiology in patients with early-onset epilepsy can impact

clinical management • Genetic epilepsies may be hiding behind non-specific signs• Language development delay and/or motor disturbance were found to be common

predictors of genetic testing outcome*

51*Based on review of 176 Invitae Epilepsy Panel (125 genes) tests in children ages 2 to 4, who had their first unprovoked seizure after the age of 2.



Thank you

Thank you for participating!

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For more information about diagnostic testing programs available through BioMarin, ask your local BioMarin representative or send a request to [email protected]

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http://bmrn.com



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Not for duplication or distribution - CLN2 Webinar · •These slides are from a live webinar held...

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