SYNGAP1 encephalopathy - Neurology · 1/8/2019 · ARTICLE OPEN ACCESS SYNGAP1 encephalopathy A...

ARTICLE OPEN ACCESS

SYNGAP1 encephalopathyA distinctive generalized developmental and epileptic encephalopathy

Danique RM Vlaskamp MD Benjamin J Shaw MD Rosemary Burgess PhD Davide Mei MSc

Martino Montomoli MD Han Xie PhD Candace T Myers PhD Mark F Bennett PhD Wenshu XiangWei BSc

Danielle Williams BappSc Saskia M Maas MD Alice S Brooks MD Grazia MS Mancini MD PhD

Ingrid MBH van de Laar MD Johanna M van Hagen MD PhD Tyson L Ware FRACP

Richard I Webster MBBS MSc FRACP Stephen Malone FRACP Samuel F Berkovic MD FRS

Renate M Kalnins MBBS Federico Sicca MD G Christoph Korenke MD PhD

Conny MA van Ravenswaaij-Arts MD PhD Michael S Hildebrand PhD Heather C Mefford MD PhD

Yuwu Jiang MD PhD Renzo Guerrini MD FRCP and Ingrid E Scheffer MBBS PhD FRACP

Neurologyreg 201992e96-e107 doi101212WNL0000000000006729

Correspondence

Dr Scheffer

schefferunimelbeduau

AbstractObjectiveTo delineate the epileptology a key part of the SYNGAP1 phenotypic spectrum in a large patient cohort

MethodsPatients were recruited via investigatorsrsquo practices or social media We included patients with (likely)pathogenic SYNGAP1 variants or chromosome 6p2132 microdeletions incorporating SYNGAP1 Weanalyzed patientsrsquo phenotypes using a standardized epilepsy questionnaire medical records EEG MRIand seizure videos

ResultsWe included 57 patients (53 male median age 8 years) with SYNGAP1 mutations (n = 53) ormicrodeletions (n = 4) Of the 57 patients 56 had epilepsy generalized in 55 with focal seizures in 7 andinfantile spasms in 1 Median seizure onset age was 2 years A novel type of drop attack was identifiedcomprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure Seizuretypes included eyelid myoclonia with absences (65) myoclonic seizures (34) atypical (20) andtypical (18) absences and atonic seizures (14) triggered by eating in 25 Developmental delaypreceded seizure onset in 54 of 56 (96) patients for whom early developmental history was availableDevelopmental plateauing or regression occurred with seizures in 56 in the context of a developmentaland epileptic encephalopathy (DEE) Fifty-five of 57 patients had intellectual disability which wasmoderate to severe in 50 Other common features included behavioral problems (73) high painthreshold (72) eating problems including oral aversion (68) hypotonia (67) sleeping problems(62) autism spectrum disorder (54) and ataxia or gait abnormalities (51)

ConclusionsSYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy witheyelid myoclonia with absences and myoclonic-atonic seizures as well as a predilection to seizurestriggered by eating

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From the Epilepsy Research Centre (DRMV BJS RB MFB SFB MSH IES) Department of Medicine University of Melbourne Austin Health Australia Departments ofGenetics (DRMV CMAvR-A) and Neurology (DRMV) University Medical Center Groningen University of Groningen the Netherlands Pediatric Neurology Unit and Labo-ratories (DM MM) and Pediatric Neurology (RG) Neurogenetics and Neurobiology Unit and Laboratories A Meyer ChildrenrsquosHospital University of Florence Italy Department ofPediatrics and Pediatric Epilepsy Centre (HX WXW YJ) Peking University First Hospital Beijing China Department of Pediatrics (CTM HCM) Division of Genetic MedicineUniversity of Washington Seattle Population Health and Immunity Division (MFB) Walter and Eliza Hall Institute of Medical Research Melbourne Australia Department of MedicalBiology (MFB) University of Melbourne Australia Caulfield (DW) Melbourne Australia Department of Clinical Genetics (SMM) Academic Medical Centre Amsterdam theNetherlands Department of Clinical Genetics (ASB GMSM IMBHvdL) Erasmus University Medical Centre Rotterdam the Netherlands Department of Clinical Genetics(JMvH) VU University Medical Center Amsterdam the Netherlands Tasmanian Health Service (TLW) Womenrsquos and Childrenrsquos Services Launceston General Hospital TasmaniaAustralia TY Nelson Department of Neurology and Neurosurgery (RIW) and Institute of Neuroscience and Muscle Research (RIW) Childrenrsquos Hospital at Westmead SydneyAustralia Department of Neurosciences (SM) Lady Cilento Childrenrsquos Hospital Brisbane Australia Department of Anatomical Pathology (RMK) Austin Hospital MelbourneAustralia IRCCS Stella Maris Foundation (FS RG) Pisa Italy Klinikum Oldenburg (GCK) Zentrum fur Kinder-und Jugendmedizin Klinik fur Neuropadiatrie u angeboreneStoffwechselerkrankungen Oldenburg Germany Centre of Epilepsy (YJ) Beijing Institute for BrainDisorders China Department of Paediatrics (IES) University ofMelbourne RoyalChildrenrsquos Hospital Australia and Florey Institute of Neurosciences and Mental Health (IES) Parkville Australia

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge was funded by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

e96 Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology

Mutations of the SYNGAP1 gene were first identified in 2009in patients with nonsyndromic intellectual disability (ID) andautism spectrum disorder (ASD) followed in 2013 by rec-ognition of their important role in the developmental andepileptic encephalopathies (DEEs)1ndash3 Most affected indi-viduals have de novo mutations with truncating mutationspredominating although missense mutations chromosomaltranslocations or microdeletions disrupting SYNGAP1 arealso described4ndash8

SYNGAP1 (MIM 603384) on chromosome 6p2132 encodesa synaptic Ras-GTPase-activating protein expressed mainly inthe synapses of excitatory neurons910 SYNGAP1 is a key me-diator in the NMDA receptor activated RAS-signaling cascaderegulating the postsynaptic density and the formation de-velopment and maturation of dendritic spines1112 Loss offunction of SYNGAP1 has major consequences for neuronalhomeostasis and development which are crucial for learning andmemory11 Syngap1-null mice die within a week and Syngap1-heterozygous mutant mice have a lower seizure thresholdlearning and memory deficits and behavioral problems13ndash16

Since our original description of 5 patients with an SYNGAP1-DEE3 2 additional studies have described the epilepsy in 24of 27 patients with SYNGAP1 encephalopathy the specificepilepsy syndrome was described in only 4 of these cases817

SYNGAP1 was originally identified in 38 patients with ID orASD of whom 15 had seizures and only 1 had an epilepsysyndrome diagnosis124ndash718ndash28 We aimed to delineate theepilepsy syndromes within the SYNGAP1 phenotypic spec-trum in a large international cohort of patients with SYN-GAP1 mutations and microdeletions

MethodsStudy cohortWe recruited 66 patients with SYNGAP1 variants via inves-tigatorsrsquo practices in Australia Italy the Netherlands andChina (n = 39) and via the SYNGAP1 Facebook group onwhich parents posted our invitation to participate (n = 27)The pathogenicity of all SYNGAP1 variants was evaluatedwith the use of standard American College of Medical Ge-netics and Genomics guidelines (table e-1 available fromDryad doiorg105061dryadck70sj0)29 We included 57(86) patients with (likely) pathogenic SYNGAP1 variants(n = 53) or chromosome 6p2132 microdeletions includingSYNGAP1 and other genes (n = 4) Five (8) patients witha SYNGAP1 variant of unknown significance were studied

separately Four (6) patients with likely benign SYNGAP1variants were excluded

PhenotypingParents or caregivers of all patients were interviewed witha standardized epilepsy questionnaire30 We analyzed medicalrecords EEGs neuroimaging includingMRI results and whenavailable seizure videos and video-EEG data Seizure types andsyndromes were classified with the 2017 International LeagueAgainst Epilepsy classification3132 The severity of ID wasestablished with IQ scores (when available) or information onthe level of functioning in accordance with the DSM-V33

GenotypingSYNGAP1 mutations were described on the basis of thelongest isoform 1 of SYNGAP1 (NM_00677722)34 andchromosomal microdeletions on the basis of the GenomeReference Consortium Human Reference sequence version37 (GRCh37hg19)

Genotype-phenotype correlationWe examined genotype-phenotype correlations in 4 patientgroups (1) truncating mutations which included nonsenseand frameshift mutations (2) splice-site mutations (3)missense and in-frame insertiondeletion mutations and(4) chromosome 6p2132 microdeletions including SYN-GAP1 and other genes Splice-site mutations were consid-ered separately because their effects on the protein arevariable35

Standard protocol approvals registrationsand patient consentsAll parents or legal representatives of the patients gave writteninformed consent for inclusion and use of photos and videosThis study was approved by the local institutional EthicsCommittee (Austin Health reference No H200702961)

Data availabilityAnonymized data will be shared by request from any qualifiedinvestigator

ResultsCohortFifty-seven patients (53 male median age at study 8 years)with (likely) pathogenic SYNGAP1 variants were included 34truncating 8 splice-site and 11 missensein-frame mutationsand 4 microdeletions Forty-six (81) patients have not beenpreviously reported Thirty-nine of these patients had novel

GlossaryAED = antiepileptic drug ASD = autism spectrum disorder DEE = developmental and epileptic encephalopathy DSM-V =Diagnostic and Statistical Manual of Mental Disorders 5th edition EM = eyelid myoclonia EMA = epilepsy with eyelid myocloniawith absences GSW = generalized spike wave ID = intellectual disability MAE = epilepsy with myoclonic-atonic seizuresTCS = tonic-clonic seizures

NeurologyorgN Neurology | Volume 92 Number 2 | January 8 2019 e97

Figure 1 Schematic presentation of SYNGAP1 mutations and microdeletions (A) in patients of our cohort or (B) previously published in the literature

Chromosome 6p2132 microdeletions including SYNGAP1 are presented as gray bars with ltlt and gtgt indicating that their breakpoints were outside the region presented here Truncating (curren) and splice-site (rarr) mutations arepresented above the gene andmissense and in-frame (bull) mutations are shown underneath the gene Bold variants concern recurrent variants that were identified in our cohort but also previously published in the literatureColors of the lines represent the epilepsy syndrome phenotypemoderate to severe developmental and epileptic encephalopathy (red)moderate to severe developmental encephalopathy with epilepsy (orange) moderate tosevere developmental encephalopathy with no epilepsy (blue) mild developmental and epileptic encephalopathy (light green) mild developmental encephalopathy with no epilepsy (dark green) and unknownunclassifiedepilepsy (gray) Chromosomal coordinates were based on National Center for Biotechnology Information Build 37 [hg19] and SYNGAP1 mutations protein domains and exons on the longest isoform 1 (NM_0067722)

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Table 1 Phenotypes in patients with SYNGAP1 mutations and microdeletions

Truncatingmutations

Splice-sitevariants

Missensein-framemutations

Microdeletionsincluding SYNGAP1 Total cohort

(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)

Male 18 (529) 3 (375) 6 (545) 3 (750) 30 (526)

Median age at study (range) 95 y (18 mondash33 y) 95 y (4 y 9 mondash16 y9 mo)

8 y 3 mo (3 y 2mondash18 y 10 mo)

3 y 8 mo (2 y 4 mondash7 y11 mo)

8 y 3 mo (18mondash33 y)

Seizures n () 33 (971) 8 (100) 11 (100) 4 (100) 56 (982)

Median age at seizure onset(range known in n)

2 y (6 mondash7 y3 mo 32)


25 y (4 mondash4 y 11) 20mo (12mondash25 y 4) 2 y (4 mondash7 y3 mo 55)

Multiple seizure types n () 25 (735) 3 (375) 5 (455) 2 (500) 35 (614)

Generalized seizures n () 33 (971) 8 (100) 10 (909) 4 (100) 55 (965)

Any absences n () 33 (971) 8 (100) 8 (727) 4 (100) 53 (930)

EM 26 (765) 4 (500) 6 (545) 1 (250) 37 (649)

EM-myoclonic-atonic 4 (118) 1 (125) mdash mdash 5 (88)

EM-atonic 3 (88) mdash 5 (455) mdash 8 (140)

Atypical absences 5 (147) 4 (500) mdash 2 (500) 11 (193)

Typical absences 3 (88) 2 (250) 3 (273) 2 (500) 10 (175)

Myoclonic absences 2 (59) mdash mdash mdash 2 (35)

Myoclonic 15 (441) 1 (125) 3 (273) mdash 19 (333)

Atonic 5 (147) mdash 2 (182) 1 (250) 8 (140)

Myoclonic-atonic 2 (59) mdash 1 (91) mdash 3 (53)

Unclassified drop attacks 2 (59) mdash mdash mdash 2 (35)

Tonic-clonic seizures n () 11 (324) 1 (125) 2 (182) mdash 14 (246)

Focal seizures n () 6 (176) mdash 1 (91) mdash 7 (123)

Other seizure types spasmstonic n ()

mdash 1 (29) mdash 1 (91) mdash mdash 1 (18) 1 (18)

Photosensitivity (clinical) n () 7 (205) 3 (375) 2 (182) 1 (250) 13 (228)

Photosensitivity (electric) n () 919 (474) 4 (500) 36 (500) 12 (500) 1731 (548)

Reflex seizures n ()a 13 (382) 1 (125) 5 (455) mdash 19 (333)

EEG slow background n () 1531 (484) 4 (500) 49 (444) 3 (750) 2652 (500)

EEG generalized discharges n () 2531 (806) 6 (750) 59 (556) 3 (750) 3952 (750)

EEG (multi)focal discharges n () 1731 (548) 4 (500) 69 (667) 1 (250) 2852 (538)

Seizure- free n ( median agerange known in n)

4 (118 8 y 4 mo3ndash13 y 4)

1 (125 mdash) 6 (545 7 y 5 yndash7 y9 mo 3)

mdash 10 (178 75 y3ndash13 y 7)

Developmental delay n () 3133 (939) 8 (100) 11 (100) 4 (100) 5456 (964)

Sitting (range age knownin n possible in n)

9 mo (4 mondash25 y32 33)

10 mo (5 mondash2 y 1mo 8 8)

12 mo (6ndash20 mo11 11)

19mo (9mondash2 y 1mo4 4)


Walking (range age knownin n possible in n)

2 y (12 mondash6 y 3233)


19 mo (12 mondash25y 10 10)

2 y 9 mo (mdash 1 1) 2 y (12 mondash6 y 5152)

First word (range age knownin n possible in n)

2 y 3 mo (8 mondash11y 24 27)

21mo (12mondash6 y 67)

2 y (18 mondash11 y 99)

2 y 5 mo (20 mondash3 y 1mo 2 2)

2 y (8 mondash9 y 4145)

Two words together (range ageknown in n possible in n)

4 y (16 mondash13 y14 14)

4 y (23 mondash45 y 34)

4 y (2ndash5 y 5 4) 4 y (mdash 1 1) 4 y (16 mondash13 y23 23)

Continued


mutations which included a total of 35 unique mutations be-cause 4 were recurrent The remaining 7 individuals had pre-viously reported mutations Figure 1A depicts the 57SYNGAP1 mutations and microdeletions found in our patientcohort and figure 1B shows the 62 SYNGAP1 variants of allpreviously reported patients who were not included in ourcohort124ndash817ndash28 Inheritance was tested in 53 of 57 patientsand the mutation had arisen de novo in all Table 1 describesthe clinical features for our cohort according to the 4 genotypicgroups More detailed individual genetic and phenotypic aresummarized in tables e-1 and e-2 (available from Dryad doiorg105061dryadck70sj0)

Seizure typesFifty-six of 57 patients had epilepsy with a median age at seizureonset of 2 years (range 4 monthsndash7 years known in 55) Atonset 50 patients had generalized seizures 1 had infantilespasms in the context of West syndrome 3 had possible focalseizures and 2 had unknown seizure types

Absence seizures occurred in 53 of 57 (93) patients eyelidmyoclonia (EM) with absences in 37 atypical absences in11 typical absences in 10 and myoclonic absences in 2Other seizure types included myoclonic (19 of 57 33)atonic (8 of 57 12) myoclonic-atonic (3 of 57 5) andunclassified drop attacks (2 of 57 4) Fourteen (25)

patients had tonic-clonic seizures (TCS) of whom 2 alsohad focal seizures Five patients had focal seizures withoutTCS Four of 57 (7) patients had febrile seizures beforeepilepsy onset

Reflex seizures were seen often occurring in clusters and trig-gered by eating (25) sound (7) or touch (4) Hunger wasalso associated with seizures in 7 Clinical photosensitivityoccurred in 13 (23) patients and EEG photosensitivity in17 of 31 (55) tested Three (5) patients had self-inducedseizures with hyperventilation

Novel seizure type EM-myoclonic-atonic seizuresOf the 36 patients with EM we observed a novel seizure type in13 of 36 (36) in whom the EM evolved to a drop attack Thenature of the drop attack was an EM-myoclonic-atonic seizurein 5 and an EM-atonic seizure in 8 patients (video 1) Ictal EEGshowed generalized spike wave (GSW) discharges coincidingwith the EM followed by a spike-wave complex correlatingwith the myoclonic (spike) and atonic (slowwave) component(figure 2) We also observed that EM seizures were accompa-nied by myoclonic jerks of the limbs in 4 of 36 (11) patientsThese novel seizure types EM-myoclonic-atonic and EM-atonic occurred mainly when EM clustered and at times ofpoor seizure control

Table 1 Phenotypes in patients with SYNGAP1 mutations and microdeletions (continued)

Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)

Intellectual disability (ID )moderate-severe ID ()

32 (941) 30 (882) 8 (100) 7 (875) 11 (100) 9 (818) 4 (100) 4 (100) 55 (965) 50 (877)

Regression ( median age rangeknown in n)

1533 (455 2 y 6mondash18 y 11)

6 (750 5 y 4 mo 4 y9 mondash6 y 2)

7 (636 13 mo 9mondash18 mo 9)

4 (100 18 mo 12mondash7 y 4)

3256 (571 2 y 6mondash18 y 19)

Autism spectrum disorder n () 20 (588) 5 (625) 5 (455) mdash 30 (526)

Severe behavioral problems n () 2833 (848) 5 (625) 6 (545) 4 (100) 4156 (732)

High pain thresholds n () 2733 (818) 57 (714) 410 (400) 23 (667) 3954 (722)

Eating problems n ()b 23 (676) 6 (625) 7 (636) 4 (100) 39 (684)

Hypotonia n () 22 (647) 4 (500) 8 (727) 4 (100) 38 (667)

Sleep problems n () 2033 (606) 57 (714) 6 (545) 3 (750) 3455 (618)

Ataxia andor gaitabnormalities n ()

2034 (588) 5 (625) 4 (364) mdash 29 (509)

Orthopedic issues n () 10 (294) 3 (375) 3 (273) mdash 16 (281)

Other features tremormicrocephaly nN ()

3 (88) 032 (minus) 1 (125) 17 (143) mdash 1 (250) mdash 5 (88) 154 (19)

Abbreviations EM = eyelid myoclonia with or without absences ID = intellectual disabilityIf patients had missing information a denominator is given that represents the number of patients with known information on this variable If no de-nominator is given there was information on all patientsa Reflex seizures include seizures triggered by eating sound or touchb Eating problems included a poor intake uncontrolled eating with gorging eating inedible objects difficulties with transition from fluids to solid food in earlychildhood and difficulties with chewing and swallowing

e100 Neurology | Volume 92 Number 2 | January 8 2019 NeurologyorgN

Neurodevelopment and behavioral issuesDevelopmental delay was identified soon after birth in 55 of56 (96) patients and preceded seizure onset in all De-velopment regressed or plateaued with seizure onset in 56patients Language was severely impaired with 12 patientsbeing nonverbal at age 2 to 33 years ID was present in 55 of57 patients being moderate to severe in 50 and mild in 5

Behavioral problems were seen in 41 of 56 (73) patients andwere often severe with oppositional and defiant behavior withaggression self-injury and tantrums ASD was diagnosed in30 (53) patients

Other featuresAn interesting observation was that the families of 39 of 54(72) patients noted that they had a high pain thresholdPatients did not respond to painful events such as a fracturedbone surgical incision of a lesion or a foreign object lodged intheir foot

Difficulties with eating were a major problem in 39 (68)patients Twenty-three patients had a poor intake because theywere fussy about food type color texture and temperature(16) or had oral aversion (5) oral hypersensitivity (3) andpoor appetite (3) Four patients needed a nasogastric tube

because of the severity of their eating problems In contrast7 patients had uncontrolled eating with gorging and 3 wouldeat inedible objects Eleven of 55 patients had difficultieswith transition from fluids to solid food in early childhoodSeventeen of 56 patients had chewing and swallowingdifficulties

Sleep was disturbed in 34 of 55 (62) patients with diffi-culties initiating (n = 19) and maintaining (n = 29) sleepImproved seizure control led to better sleep in 12 patientsThere was no clear correlation with EEG features therewas an increase in epileptiform activity in sleep in 9 of 23(39) patients with sleep difficulties which was also ob-served in 6 of 12 (50) without sleep difficulties Sleep alsoimproved with melatonin (n = 10) clonidine (n = 5) andtrazodone (n = 1)

Examination findingsPhotographs of 31 of 57 patients were available (figure 3) andrevealed subtle dysmorphic features not present in allpatients These included full slightly prominent eyebrowswith medial flaring in some hypertelorism full nasal tipslightly upturned nasal tip in younger children short phil-trum cupid bow upper lip broad mouth with diastemata ofthe upper teeth and small pointed chin

Figure 2 Ictal EEG registration during eyelid myocloniandashmyoclonicndashatonic seizure

Red arrows indicate the different phases of theseizure associated with a generalized spikewave (eyelid myoclonia) and a further spikewave correlating with themyoclonic (spike) andatonic (wave) components


Neurologic examination showed hypotonia in 38 (67) ataxiaor an unsteady gait in 29 (51) tremor in 5 (9) and mi-crocephaly in 1 (2) of 54 Orthopedic abnormalities includedfoot or spine deformities in 16 (28) including pes planus (7)pronated feet (4) scoliosis (3) pes cavus (1) congenital hipdislocation (1) or congenital hip dysplasia (1)

EEG findingsEEG results were available for 52 of 57 patients from whentheir epilepsy was active Many children did not have fur-ther EEGs because of severe behavioral problems GSWand generalized poly-spike wave were reported in 39 of 52(75) patients Focal or multifocal epileptiform dischargeswere seen in 28 of 52 (54) often in addition to GSW orgeneralized poly-spike wave (21 of 39 54) Slow back-ground activity was seen in 26 of 52 (50) patients

NeuroimagingMRI was reported as normal in 37 of 53 (70) patients Onepatient had a left frontal subcortical nodular heterotopia The15 remaining patients had nonspecific findings thin corpus

callosum (3 2 of 3 also had a thin chiasma opticum) enlargedventricles or subarachnoid spaces (3) hyperintense T2 signalsin the white matter (3) posterior centrum semiovale (2) orfasciculus longitudinalis medialis (1) patent cavum vergae(1) atypical white matter abnormalities (1) mega cisternamagna fossa posterior (1) discrete hippocampal tissue loss(1) or a pineal cyst (1)

Brain pathologyBrain pathology was available from patient 14 a 33-year-oldnonverbal woman with a de novo SYNGAP1 nonsense mu-tation (video 2) who died of aspiration pneumonia Thepathology showed cerebellar Purkinje cell loss with associatedastrocytosis (figure 4A) Astrocytosis was found pre-dominantly in the superficial cortical layer but also in thehippocampi and deep gray nuclei (figure 4B) Macroscopicevaluation showed a low brain weight (1194 g minus32 SD) withwidely but moderately distributed leptomeningeal fibrosismost evident over the frontal lobes (figure 4C) Corticalneurons did not show evidence of anoxic ischemic injury (datanot shown)

Figure 3 SYNGAP1 dysmorphology

Portrait photographs from 31 of 56 patients with SYNGAP1mutations or microdeletions including SYNGAP1 (A) Patient 4 (B) patient 6 (C) patient 7 (D) patient 8(siblingof patient 9) (E) patient 9 (siblingofpatient 8) (F) patient 12 (G) patient 13 (H) patient 14 (I) patient 16 (J) patient 18 (K) patient 19 (L) patient 20 (M) patient21 (N) patient 23 (O) patient 25 (P) patient 27 (Q) patient 28 (R) patient 29 (S) patient 31 (T) patient 32 (U) patient 33 (V) patient 34 (W) patient 35 (X) patient 37(Y) patient 45 (Z) patient 47 (AA) patient 50 (AB) patient 51 (AC) patient 52 (AD) patient 54 (monozygotic twin with patient 55) and (AE) patient 55 (monozygotictwin with patient 54)


Epilepsy syndromeA distinctive generalized epilepsy phenotype emerged combin-ing features of 2 well-described syndromes epilepsy with eyelidmyoclonia with absences reported by Jeavons36 and epilepsywith myoclonic-atonic seizures described by Doose et al37 Theoverall gestalt in 56 of 57 patients was a spectrum of severity ofgeneralized DEE with multiple seizure types including EMmyoclonic and atonic (and combinations of all 3) TCS werefairly frequent whereas focal seizures occurred in aminority Themajority of patients had a severe outcome with moderate tosevere ID (49 of 56 88) while 7 of 56 (12) had a milderoutcome with normal intellect or mild ID One child with a mildoutcome had West syndrome The remaining patient with noseizures but epileptiform abnormalities on EEG had a (static)developmental encephalopathy with a severe outcome Anotherdistinctive feature of SYNGAP1 seen in a quarter of cases wasthe presence of reflex seizures triggered by eating

Epilepsy treatment and outcomeOverall 20 different antiepileptic drugs (AEDs) were started(table e-3 available from Dryad doiorg105061dryadck70sj0) Valproate and lamotrigine were most commonlyprescribed (n = 45 and n = 22) with ongoing prescription oflamotrigine for 77 of patients and valproate for 64patients Of the 6 patients who had received cannabidiol 5 of6 (833) remained on it

Thirty-five of 56 (63) patients had refractory epilepsy withongoing seizures after 2 AEDs Six became seizure-free on thethird to sixth AED In total 10 of 56 (18) patients becameseizure-free at 7 years of age (median range 3ndash13 years) Ofthese seizures were controlled on monotherapy with valproate(3) levetiracetam (1) or steroids (1 for infantile spasms)Polytherapy combinations resulting in seizure freedom in-cluded levetiracetam and topiramate (1) valproate and lamo-trigine (1) and cannabidiol valproate and lamotrigine (1)Two were seizure-free on no treatment Four patients had noseizures for a period of 6 months to 7 years while treated withcarbamazepine (1) lamotrigine (1) valproate (1) or valproatelamotrigine and clobazam but seizures recurred

Genotype-phenotype correlationThe phenotypes of patients with truncating splice-site ormissensein-framemutations andmicrodeletions were similaroverall except that 4 patients with microdeletions all had anearlier seizure onset (20 months compared with 2 years in theremaining cohort table 1) All 4 patients had microdeletionsthat included additional genes (4ndash13 genes) In terms of theoutcome all 4 cases had severe ID consistent with the rest ofthe cohort Given their similar epileptology and other features(high pain threshold in 2 poor oral intake in 2 seizurestriggered by hunger and photosensitivity in 1 and dysmorphicfeatures in 2) we included them in the total cohort

For evaluating genotype-phenotype correlations we separatedSYNGAP1 encephalopathies into 2 groups based on severitydetermined by their intellect Milder phenotypes included

Figure 4 Brain pathology in a patient with an SYNGAP1mutation

(A) Glial fibrillary acidic protein (GFAP)ndashstained section of the cerebellarcortex showing a single surviving Purkinje cell (arrow points toward this cell)in a field of Purkinje cell loss and mild internal granular layer and cerebellarmolecular layer astrocytosis (B) GFAP staining of dentate gyrus showing noneuronal loss but mild reactive astrocytosis in the dentate granular layerand the dentate molecular layer of the hippocampus (C) Vertex view of thecerebral hemispheres showing leptomeningeal fibrosis


normal intellect or mild ID severe phenotypes referred tomoderate to severe ID Of the 7 patients with a milder pheno-type (green mutations figure 1A) 5 had a truncating or splice-site mutation of which 4 were located in exons 1 to 4 Two otherpatients had amissense variant in exons 6 and 11 Five previouslyreported patients also had a milder phenotype (green and darkgreen mutations figure 1B) with 3 of 5 having mutations inexons 1 to 4 In the combined cohort of our and previouslyreported patients milder phenotypes were significantly moreoften observed in patients with mutation or deletions in exons 1to 4 (50 n = 6 of 12) compared to exons 5 to 19 (7 6 of 85 p= 0001 Fisher exact test) No significant differences were ob-served in outcome between patients with different mutationtypes (data not shown)

Patients with SYNGAP1 variants of unknownsignificance (n = 5)Not included in our cohort of 56 patients were 5 individualswith an SYNGAP1 variant of unknown significance Tables e-1and e-2 (available from Dryad doiorg105061dryadck70sj0) show details of their pathogenicity predictions andassociated phenotypes Three patients who had variantsreported in gnomAD or ExAC and for whom inheritance oftheir SYNGAP1 variant was unavailable had phenotypes thatwere consistent with our large cohort38 Two had generalizedDEE and 1 had mild ID with EM Their presence in pop-ulation databases is difficult to explain although EM can besubtle and easily missed It remains to be determined whethertheir SYNGAP1 variant has a role in their presentation The

Figure 6 Comorbidities of SYNGAP1 encephalopathy

The figure shows the percentage of each comorbidity associated with SYNGAP1 encephalopathy in our cohort Dark red denotes moderate to severeintellectual disability light red denotes mild intellectual disability

Figure 5 SYNGAP1 encephalopathy

This conceptual diagram highlights that the mostcommon epilepsy phenotype in our cohort was anoverlapping syndrome combining the features of 2well-recognized epilepsy syndromes epilepsy witheyelid myoclonia with absences (EMA) and epilepsywith myoclonic-atonic seizures (MAE) About one-thirdof the cohort did not fit into either of these syndromesand had nonsyndromic developmental and epilepticencephalopathy (DEE) One case had West syndromeOther individuals with SYNGAP1 encephalopathy mayhave developmental encephalopathy (intellectual dis-ability) without epilepsy


remaining 2 had variants with lower conservation and path-ogenicity prediction scores and had focal epilepsy with orwithout ID so their phenotype was quite different

DiscussionSYNGAP1 is an important gene for the DEEs present in 1 ofour original cohort of patients with unsolved DEEs3817 havingbeen first identified as a gene for ID1 Here we describe a dis-tinctive generalized DEE phenotype for SYNGAP1 combiningsyndromic features of epilepsy with eyelid myoclonia withabsences (EMA) and epilepsy with myoclonic-atonic seizures(MAE) (figure 5) SYNGAP1 encephalopathy was associatedwith a spectrumofmild (8) to severe (88) ID and a range ofother comorbid conditions (figure 6) Seizures were oftentriggered by eating The 1 patient without a DEE had a staticdevelopmental encephalopathy without seizures but had epi-leptiform abnormalities on EEG

SYNGAP1-DEE shares many of the striking features of thesyndrome of EMA39 The key seizure type absences withEM together with photosensitivity was found in the ma-jority (64 and 55 respectively) of our cohort The onsetof EM was earlier for SYNGAP1-DEE (lt3 years) comparedwith the classic syndrome of EMA (peak onset 6ndash8 years)39

In addition EMA is often associated with better cognitiveoutcome with individuals being of normal intellect or havingmild ID An earlier age at onset (lt3 years) of EM is asso-ciated with poorer intellectual outcome and perhaps someof these individuals have SYNGAP1 mutations40ndash43 How-ever there is debate as to whether the diagnosis of EMAallows for the presence of additional seizures types40 OurSYNGAP1-DEE cohort with EM also had myoclonic (33)and atonic (8) seizures We speculate that the more severecases of EMA may be explained by SYNGAP1 mutationsespecially those individuals with earlier onset of EM ormyoclonic or atonic seizures

SYNGAP1-DEE also resembles the syndrome of MAE (for-merly called myoclonic-astatic epilepsy) as reported in 3 of 11patients in a previous series8 Drop attacks are the hallmark ofMAE due to atonic seizures myoclonic seizures and MAEEleven of 57 patients had features consistent with myoclonic-atonic seizures but with a more severe overall outcome com-pared with the variable outcome described in MAE374445

Furthermore severe developmental delay before the onset ofseizures in all but 2 patients together with focal and multifocalepileptiform activity in 57 of cases mitigates against theclassic features of MAE374445

SYNGAP1 encephalopathy often combines the features ofthese 2 epilepsy syndromes EMA and MAE An overlappingdiagnosis of MAE and EMA was present in 35 of our cohort(figure 5) Bringing the 2 syndromic concepts together wealso identified a novel distinctive seizure type a drop attackbeginning with EM followed by a myoclonic-atonic compo-nent (EM-myoclonic-atonic) or simply an atonic component

(EM-atonic) We considered EM-myoclonic-atonic and EM-atonic as overlapping seizure types because the myocloniccomponent could be easily missed (video 1) We distin-guished EM-(myoclonic)-atonic seizures from atypicalabsences which may also include myoclonic and atoniccomponents First the myoclonic jerks and atonic seizureswere more abrupt and pronounced than in atypical absenceseizures in which subtle jerks and loss of tone can occurSecond the frequency of GSW was faster (gt3 Hz) comparedwith atypical absences (lt25 Hz) One reported patient hadseizures with blinking followed by a head drop and fall withirregular GSW27 suggestive of our SYNGAP1 seizure type

One patient in our cohort had West syndrome which has notbeen associated with SYNGAP1 before (figure 5) Althoughatypical absences present in 20 of our cohort may suggesta diagnosis of Lennox-Gastaut syndrome other diagnosticcriteria such as tonic seizures and generalized paroxysmal fastactivity on EEG were absent Only 1 patient had nocturnaltonic seizures (patient 19)46

We observed a DEE in all but 1 of our 57 patients while only55 of the previously published patients had a DEE (figures1ndash5)61722 The remaining patients in the literature had a mildto severe developmental encephalopathy with (20) or with-out (25) seizures it was not possible to determine whethersome of these patients may have had a DEE Our findings thatsuch a high proportion of patients with SYNGAP1 encepha-lopathy had a DEE may be due to ascertainment bias becauseperhaps parents from the SYNGAP1 Facebook group partici-pated in the study only if they were concerned that their childhad seizures Equally EM seizures can be very subtle andmisinterpreted as a behavioralmannerism For example patient24 was a 9-year-old boy in whom the parents recognized thathis eyelid fluttering was seizure activity only after an SYNGAP1mutation was identified Patient 16 had frequent eyelid flut-tering from the age of 1 year but her first EEG was notperformed until the age of 10 years and showed frequentepileptiform abnormalities Her seizures and behavioral andsleep problems all improved after she started AEDs In 8patients developmental regression occurred 2 months to gt3years before the recognition of seizures Diagnosis of seiz-ures in SYNGAP1 encephalopathy is thus crucial becauseappropriate management may potentially improve outcome

We found that a quarter of patients in our cohort had the dis-tinctive feature that their reflex seizures were triggered by eatingobserved previously in a single patient with seizures triggered bychewing8 The underlying pathophysiologic mechanism for thisis unknown Eating problems with poor intake or gorging werealso found in more than half of our cohort

From our historical data we could not reliably evaluate theefficacy of the prescribed AEDs Further studies are warrantedto explore the efficacy of the drugs particularly those thatappear of benefit such as lamotrigine valproate and canna-bidiol for SYNGAP1-DEE


SYNGAP1-DEE is associated with 4 main comorbid con-ditions ID behavioral problems a high pain threshold andataxia (figure 6) ID was moderate to severe in 88 of patientswith only 2 exhibiting borderline intellect We might haveunderestimated the prevalence of milder phenotypes due toascertainment bias given our recruitment via Facebook Severebehavioral problems with oppositional behavior tantrumsaggression and self-injury were present in almost three-quarters of patients as previously observed One of our mostfascinating findings was that three-quarters of the familiesreported a high pain threshold in their child often leading toa delay in diagnosis of injuries and inflammation Parker et al17

also reported a high pain threshold as an anecdotal observationby some families This finding of a high pain threshold maysuggest a role for SYNGAP1 in sensory processing

The neuropathologic study of the brain of a woman witha truncating SYNGAP1 mutation identified a clear loss of cere-bellar Purkinje cells and associated astrocytosis (figure 4A) Anunsteady or ataxic gait was identified in 51 of our patientsincluding this patient Ataxia or gait abnormalities were alsoobserved in 7 of 10 and 10 of 17 patients reported by Parkeret al17 andMignot et al8 respectively highlighting that cerebellarfeatures are a key part of the SYNGAP1-DEE phenotype817

Truncating and splice-site mutations occur throughoutSYNGAP1 while missense mutations mainly cluster in theprotein domains8 A milder outcome of SYNGAP1-DEE wasobserved significantly more frequently in patients withmutations in exons 1 to 4 compared with those with muta-tions in exons 5 to 198 In line with this Mignot et al8 alsoshowed that patients with mutations in exons 4 and 5 weremore pharmacosensitive compared to those with mutations inexons 6 to 198 SYNGAP1 has several isoforms in humanswith different promoter sites and alternative splicing thesemay explain the variation in phenotypic severity becausevariants early within the gene transcript often lead to com-plete loss of the gene product due to nonsense-mediateddecay Further studies on the presence and function of dif-ferent human isoforms of SYNGAP1 are warranted to explainthe correlation between mutation location and phenotypeOther environmental and genetic factors may also contributeto phenotypic variability We identified concordant pheno-types in monozygotic twins (patients 53 and 54) similarphenotypes in 2 siblings (patients 8 and 9) yet variablephenotypes in individuals sharing the same mutation(patients 3 and 4 6 and 7 24 and 25 28 and 29 37 and 38)

We describe SYNGAP1-DEE as a predominantly generalizedDEE with ID behavioral problems a high pain threshold andataxia SYNGAP1-DEE combines features of both EMA andMAE In SYNGAP1-DEE we observed a novel type of dropattack with EM evolving into a myoclonic-atonic or an atonicseizure Furthermore a quarter of patients had seizures trig-gered by eating Recognition of seizures in the context ofSYNGAP1-DEE can be challenging but is crucial to optimizingantiepileptic therapy and improving long-term outcome

Author contributionsDRM Vlaskamp drafting and revising manuscript dataanalysis acquisition of data BJ Shaw acquisition of data RBurgess data analysis D Mei M Montomoli H Xie and WXiangWei acquisition of data and data analysis CT MeyersandMF Bennett analysis of SYNGAP1 variants DWilliamsinitiative of study study design SM Maas AS BrooksGMS Mancini IMBH van de Laar JM van Hagen TWare R Webster S Malone SF Berkovic acquisition ofdata RM Kalnins analysis of brain pathology F Sicca ac-quisition of data GC Korenke data analysis CMA vanRavenswaaij-Arts analysis of dysmorphology acquisition ofdata MS Hildebrand HC Mefford supervision of analysisof SYNGAP1 variants Y Jiang study supervision revisemanuscript data acquisition R Guerrini study supervisionrevise manuscript acquisition of data IE Scheffer co-writingmanuscript data analysis study design

AcknowledgmentThe authors thank all patients and their families for theirparticipation They are grateful for the support of theSYNGAP1 parent support group They thank the VictorianInstitute of Forensic Medicine Dr Angelika Riess DrMarjolaine Willems Dr Einar Bryne and Dr Ferdinant Kokfor providing clinical information and Dr Zhixian Yang andDr Xiaoyan Liu for EEG review

Study fundingDanique RM Vlaskamp has received an unrestricted travelgrant from the Dutch Society of Child Neurology Jo KolkFoundation and the Research School of Behavioural andCognitive Neurosciences Han Xie is supported by the NationalNatural Science Foundation of China (Youth Foundation)(grant 81501123) Mark F Bennett is supported by the Victo-rian State Government Operational Infrastructure Support andAustralian Government National Health and Medical ResearchCouncil Independent Research Institute Infrastructure SupportScheme Yuwu Jiang is supported by the Chinese National KeyResearch Project (2016YFC1306200 2016ndash2020) This workwas supported in part by a grant from the EU SeventhFramework Programme FP7 under the project DESIRE(grant agreement 602531) to Renzo Guerrini Ingrid EScheffer is supported by a National Health and MedicalResearch Council Program Grant (1091593 2016ndash2020)and Senior Practitioner Fellowship (1104831 2016ndash2020)

DisclosureD Vlaskamp B Shaw and R Burgess report no disclosuresrelevant to the manuscript D Mei has received scientificadvisory board honoraria from BioMarin Pharmaceutical MMontomoli H Xie C Myers M Bennett W XiangWei DWilliams S Maas A Brooks G Mancini I van de Laar J vanHagen T Ware and R Webster report no disclosures relevantto the manuscript S Malone has received scientific advisoryboard honoraria from UCB and BioMarin S Berkovic RKalnins F Sicca G Korenke C van Ravenswaaij-Arts and MHildebrand report no disclosures relevant to themanuscript H


Mefford is funded by NIH grant National Institute of Neuro-logical Disorders and Stroke 1R01NS069605 Y Jiang reportsno disclosures relevant to the manuscript R Guerrini serves onthe editorial boards of Neurologyreg and Seizure has receivedspeaker and consultancy fees from Eisai Inc Novartis ZogenixBioMarin UCB Pharma and GW Pharma receiveshas re-ceived research support from the European Community theItalian Ministry of Health the Mariani Foundation the ItalianEpilepsy Federation Telethon the Tuscany Region the PisaFoundation and the Italian Ministry of University and Re-search I Scheffer serves on the editorial boards of Neuro-logyregeand Epileptic Disorders may accrue future revenue ona pending patent regarding a therapeutic compound has re-ceived speaker honoraria fromAthena Diagnostics UCB GSKEisai and Transgenomics has received scientific advisoryboard honoraria from Nutricia UCB and GSK has receivedfunding for travel from Athena Diagnostics UCB and GSKand receiveshas received research support from the NationalHealth and Medical Research Council Australian ResearchCouncil NIH Health Research Council of New ZealandMarch of Dimes the Weizmann Institute Citizens United forResearch in Epilepsy US Department of Defense and thePerpetual Charitable Trustees Go to NeurologyorgN for fulldisclosures

Publication historyReceived byNeurologyMarch 5 2018 Accepted in final form August 272018

References1 Hamdan FF Gauthier J Spiegelman D et al Mutations in SYNGAP1 in autosomal

nonsyndromic mental retardation N Engl J Med 2009360599ndash6052 Pinto D Pagnamenta AT Klei L et al Functional impact of global rare copy number

variation in autism spectrum disorder Nature 2010466368ndash3723 Carvill GL Heavin SB Yendle SC et al Targeted resequencing in epileptic ence-

phalopathies identifies de novo mutations in CHD2 and SYNGAP1 Nat Genet 2013451ndash16

4 Klitten LL Moslashller RS Nikanorova M Silahtaroglu A Hjalgrim H Tommerup N Abalanced translocation disrupts SYNGAP1 in a patient with intellectual disability speechimpairment and epilepsy with myoclonic absences (EMA) Epilepsia 201152190ndash193

5 Krepischi ACV Rosenberg C Costa SS Crolla JA Huang S Vianna-Morgante AM Anovel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chro-mosome 6 associatedwithmental retardation Am JMedGenet A 2010152A2365ndash2378

6 Zollino M Gurrieri F Orteschi D Marangi G Leuzzi V Neri G Integrated analysis ofclinical signs and literature data for the diagnosis and therapy of a previously unde-scribed 6p213 deletion syndrome Eur J Hum Genet 201119239ndash242

7 Writzl K Knegt AC 6p213 Microdeletion involving the SYNGAP1 gene in a patientwith intellectual disability seizures and severe speech impairment Am JMedGenet A2013161A1682ndash1685

8 Mignot C Stulpnagel CV Nava C et al Genetic and neurodevelopmental spectrumof SYNGAP1-associated intellectual disability and epilepsy J Med Genet 201653511ndash522

9 Chen HJ Rojas-Soto M Oguni A Kennedy MB A synaptic Ras-GTPase activatingprotein (p135 SynGAP) inhibited by CaM kinase II Neuron 199820895ndash904

10 Kim JH Liao D Lau LF Huganir RL SynGAP a synaptic RasGAP that associateswith the PSD-95SAP90 protein family Neuron 199820683ndash691

11 Jeyabalan N Clement JP SYNGAP1 mind the gap [online serial] Front CellNeurosci 2016101ndash16

12 Tidyman WE Rauen KA Expansion of the RASopathies Curr Genet Med Rep 2016457ndash64

13 Kim JH Lee HK Takamiya K Huganir RL The role of synaptic GTPase-activatingprotein in neuronal development and synaptic plasticity J Neurosci 2003231119ndash1124

14 Komiyama NH Watabe AM Carlisle HJ et al SynGAP regulates ERKMAPK sig-naling synaptic plasticity and learning in the complex with postsynaptic density 95and NMDA receptor J Neurosci 2002229721ndash9732

15 Guo X Hamilton PJ Reish NJ Sweatt JD Miller CA Rumbaugh G Reduced ex-pression of the NMDA receptor-interacting protein SynGAP causes behavioral ab-normalities that model symptoms of schizophrenia Neuropsychopharmacology2009341659ndash1672

16 Clement JP Aceti M Creson TK et al Pathogenic SYNGAP1 mutations impaircognitive development by disrupting the maturation of dendritic spine synapses Cell2013151709ndash723

17 Parker MJ Fryer AE Shears DJ et al De novo heterozygous loss-of-functionmutations in SYNGAP1 cause a syndromic form of intellectual disability Am J MedGenet A 2015167A2231ndash2237

18 Vissers LE de Ligt J Gilissen C et al A de novo paradigm for mental retardation NatGenet 2010421109ndash1112

19 Hamdan FF Gauthier J Araki Y et al Excess of de novo deleterious mutations ingenes associated with glutamatergic systems in nonsyndromic intellectual disabilityAm J Hum Genet 201188306ndash316

20 de Ligt J Willemsen MH van Bon BWM et al Diagnostic exome sequencing inpersons with severe intellectual disability N Engl J Med 20123671921ndash1929

21 Rauch A Wieczorek D Graf E et al Range of genetic mutations associated withsevere non-syndromic sporadic intellectual disability an exome sequencing studyLancet 20123801674ndash1682

22 Berryer MH Hamdan FF Klitten LL et al Mutations in SYNGAP1 cause intellectualdisability autism and a specific form of epilepsy by inducing haploinsufficiencyHuman Mutat 201334385ndash394

23 von Stulpnagel C Funke C Haberl C et al SYNGAP1 mutation in focal and gen-eralized epilepsy a literature overview and a case report with special aspects of theEEG Neuropediatrics 201546287ndash291

24 Redin C Gerard B Lauer J et al Efficient strategy for the molecular diagnosis ofintellectual disability using targeted high-throughput sequencing J Med Genet 201451724ndash736

25 Dyment DA Tetreault M Beaulieu CL et al Whole-exome sequencing broadens thephenotypic spectrum of rare pediatric epilepsy a retrospective study Clin Genet20158834ndash40

26 OrsquoRoak BJ Stessman HA Boyle EA et al Recurrent de novo mutations implicatenovel genes underlying simplex autism risk Nat Commun 201455595

27 Prchalova D Havlovicova M Sterbova K Stranecky V Hancarova M Sedlacek ZAnalysis of 31-year-old patient with SYNGAP1 gene defect points to importance ofvariants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype case report BMC Med Genet 20171862

28 McRae JF Clayton S Fitzgerald TW et al Prevalence and architecture of de novomutations in developmental disorders Nature 2017542433ndash438

29 Richards S Aziz N Bale S et al Standards and guidelines for the interpretation ofsequence variants a joint consensus recommendation of the American college ofmedical genetics and genomics and the association for molecular pathology GenetMed 201517405ndash424

30 Reutens TC Howell RA Gebert KE Berkovic SF Validation of a questionnaire forclinical seizure diagnosis Epilepsia 1992331065ndash1071

31 Fisher RS Cross JH French JA et al Operational classification of seizure types by theInternational League Against Epilepsy [online serial] Epilepsia 20171ndash9 Availableat ilaeorg Accessed January 17 2018

32 Scheffer IE Berkovic S Capovilla G et al ILAE classification of the epilepsiesposition paper of the ILAE Commission for Classification and Terminology[online serial] Epilepsia 20171ndash10 Available at ilaeorg Accessed January 172018

33 American Psychiatric Association Diagnostic and Statistical Manual of Mental Dis-orders DSM-V Washington DC American Psychiatric Association 2013

34 Bateman A Martin MJ OrsquoDonovan C et al UniProt a hub for protein informationNucleic Acids Res 201543D204ndashD212

35 Krawczak M Riess J Cooper DN The mutational spectrum of single base-pairsubstitutions in mRNA splice junctions of human genes causes and consequencesHum Genet 19929041ndash54

36 Jeavons PM Nosological problems of myoclonic epilepsies in childhood and ado-lescence Dev Med Child Neurol 1977193ndash8

37 Doose H Gerken H Leonhardt R Volzke E Volz C Centrencephalic myoclonic-astatic petit mal clinical and genetic investigation Neuropadiatrie 1970259ndash78

38 Lek M Karczewski KJ Minikel EV et al Analysis of protein-coding genetic variationin 60706 humans Nature 2016536285ndash291

39 Striano S Capovilla G Sofia V et al Eyelid myoclonia with absences (Jeavons syn-drome) a well-defined idiopathic generalized epilepsy syndrome or a spectrum ofphotosensitive conditions Epilepsia 20095015ndash19

40 Striano S Eyelid myoclonia with absences an overlooked epileptic syndromeNeurophysiol Clin 200232287ndash296

41 Caraballo RH Fontana E Darra F et al A study of 63 cases with eyelid myocloniawith or without absences type of seizure or an epileptic syndrome Seizure 200918440ndash445

42 Sadleir LG Vears D Regan B Redshaw N Bleasel A Scheffer IE Family studies ofindividuals with eyelid myoclonia with absences Epilepsia 2012532141ndash2148

43 Fournier-Goodnight AS Gabriel M Perry MS Preliminary neurocognitive outcomesin Jeavons syndrome Epilepsy Behav 201552260ndash263

44 Stephani U The natural history of myoclonic astatic epilepsy (Doose syndrome) andLennox-Gastaut syndrome Epilepsia 200647(suppl 2)53ndash55

45 Oguni H Hayashi K Awaya Y Fukuyama Y Osawa M Severe myoclonic epilepsy ininfants a review based on the Tokyo Womenrsquos Medical University series of 84 casesBrain Dev 200123736ndash748

46 Arzimanoglou A French J Blume WT et al Lennox-Gastaut syndrome a consensusapproach on diagnosis assessment management and trial methodology LancetNeurol 2009882ndash93


DOI 101212WNL0000000000006729201992e96-e107 Published Online before print December 12 2018Neurology

Danique RM Vlaskamp Benjamin J Shaw Rosemary Burgess et al encephalopathy

encephalopathy A distinctive generalized developmental and epilepticSYNGAP1

This information is current as of December 12 2018

ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2018 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

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Disputes amp Debates Editorsrsquo ChoiceSteven Galetta MD FAAN Section Editor

Reader response Patient-reported outcomes across cerebrovascularevent types More similar than differentAndrew R Spector (Durham NC)

Neurologyreg 201993905 doi101212WNL0000000000008482

Katzan et al1 looked at an important question but the conclusions are difficult to support withthe studymethods applied Without premorbid data to indicate the rates of pain fatigue anxietydepression and sleep disturbances before the cerebrovascular events we have no way to knowthat the symptoms noted on the follow-up questionnaire were outcomes of the events As theauthors admit it is likely that severalmdashif not manymdashof the TIAs were not ischemic in etiologySymptoms such as pain anxiety and depression are potentially causes of these transientneurologic symptoms in a manner that would not apply to the stroke subtypes Therefore itwould be inappropriate to call them outcomes Although the data indicating that the 3 strokesubtypes have similar symptoms on follow-up are useful the TIA data must be interpreted verycautiously

1 Katzan IL Schuster A Newey C Uchino K Lapin B Patient-reported outcomes across cerebrovascular event types more similar thandifferent Neurology 201891e2182ndashe2191

Copyright copy 2019 American Academy of Neurology

Editorsrsquo note Patient-reported outcomes across cerebrovascularevent types More similar than differentIn ldquoPatient-reported outcomes across cerebrovascular event types More similar than dif-ferentrdquo Katzan et al retrospectively reviewed patient-reported measures in multipledomains over a 2-year period for 2181 patients with ischemic stroke TIA intracerebralhemorrhage (ICH) and subarachnoid hemorrhage (SAH) at a single institution Afteradjustment patients with TIA had worse scores for pain fatigue anxiety depression andsleep than patients with the various forms of stroke Spector notes that although the data forischemic stroke ICH and SAH are interesting the TIA results must be interpreted withcaution because (1) there were no premorbid data on these domains so it is unclearwhether symptoms can be attributed to the TIA and (2) some of the TIAs likely were noteven ischemic Katzan et al agree with both of these limitations Both Katzan et al andSpector feel that further research of the impact of TIA on the aforementioned domains isneeded

Ariane Lewis MD and Steven Galetta MD


NeurologyorgN Neurology | Volume 93 Number 20 | November 12 2019 905

Author disclosures are available upon request (journalneurologyorg)

Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Author response Patient-reported outcomes across cerebrovascularevent types More similar than differentIrene L Katzan (Cleveland) and Brittany Lapin (Cleveland)


We appreciate Dr Spectorrsquos interest in our article1 We agree that because we do not havepremorbid scores for the patients with stroke we cannot attribute the scores to the direct effectof the stroke events rather the study demonstrated the degree to which 8 domains of health(termed patient-reported outcomes) are affected across types of cerebrovascular events Wetried to be careful about the wording used in the article but thank Dr Spector for highlightingthis point We also agree with the comment that patients with the clinical diagnosis of TIA mayhave not truly had ischemia as the mechanism for their symptoms This reiterates the pointsdiscussed in our article1 TIA is a subjective diagnosis that is known to have at best modestinterrater reliability As we suggested in the article1 diagnosis of TIA may have been inaccuratein some patients which could also partly explain previous reports by others of reduced qualityof life in patients with TIA We believe that further evaluation is warranted to better understandthe impact of TIA on patientsrsquo health status

1 Katzan IL Schuster A Newey C Uchino K Lapin B Patient-reported outcomes across cerebrovascular event types More similar thandifferent Neurology 201891e2182ndashe2191


Editorsrsquo note Continuous EEG is associated with favorablehospitalization outcomes for critically ill patientsIn ldquoContinuous EEG is associated with favorable hospitalization outcomes for critically illpatientsrdquo Hill et al retrospectively reviewed national inpatient hospitalization data overa 10-year period and found that continuous EEG (cEEG) use increased gt10-fold from 2004to 2013 but that it was still only used for 03 of critically ill patients They noted thatalthough patients evaluated with cEEG appeared more ill its use was associated with lowerin-hospital mortality for critically ill patients prompting them to conclude that cEEG maybe underused At a single institution Sethi found that cEEG use increased gt5-fold from2005 to 2011 but he notes that in some cases cEEG was unnecessary and a 30-minuteemergent EEGwould have been sufficient He comments that better guidelines are neededon the indications for cEEG vs 30-minute EEG in critically ill patients Hill et al agree that itis necessary to further evaluate which subgroups of critically ill patients benefit from cEEGthe most to ensure that resources are allocated appropriately



906 Neurology | Volume 93 Number 20 | November 12 2019 NeurologyorgN



Reader response Continuous EEG is associated with favorablehospitalization outcomes for critically ill patientsNitin K Sethi (New York)


I read with interest the Hill et al1 article on continuous EEG (cEEG) use in critically ill patientsand its association with favorable outcomes (lower in-hospital mortality) in their studiedcohort except the seizurestatus epilepticus subgroup The authors concluded that continuedexpansion of cEEG use may be warranted My colleagues and I performed an audit of the long-term cEEG monitoring in our neurologic-neurosurgical intensive care unit over 7 years(2005ndash2011) and found a substantial increase in cEEG use2 Studies were frequently ordered byintensivists and residents in training for indications where a 30-minute emergent EEG (rEEG)would suffice This included sudden change in the sensorium of a patient sudden change inneurologic examination a patient not waking up after recent neurosurgical intervention anda patient admitted after a single seizure who then became encephalopathic after receiving IVlorazepam in the emergency department2 The American Epilepsy Society and the AmericanClinical Neurophysiology Society need to better define clinical indications for cEEG vs rEEGmonitoring in critically ill patients before a call for continued expansion of its use in this patientgroup can be justified

1 Hill CE Blank LJ Thibault D et al Continuous EEG is associated with favorable hospitalization outcomes for critically ill patientsNeurology 201992e9ndashe18

2 Sethi NK Rapaport BS Solomon GE An audit of continuous EEG monitoring in the neurological-neurosurgical intensive care unitJ Clin Neurophysiol 201431416ndash417


Author response Continuous EEG is associated with favorablehospitalization outcomes for critically ill patientsChloe E Hill (Ann Arbor MI) and Leah J Blank (New York)


We appreciate Dr Sethirsquos thoughtful response to our article1 We agree that better definition ofclinical utility through development of a stronger evidence base is key Although our worksuggested that continuous EEG (cEEG) is underused at present we need to understand whichsubgroups of critically ill patients benefit most from the application of cEEG Furthermorerigorous assessment of study length (ie routine EEG vs cEEG) such as Dr Sethirsquos study2 andthe prospective trial of cEEG vs routine EEG in adults with impaired consciousness3 will bevery important in informing proper allocation of resources going forward



3 Rossetti AO Schindler K Alvarez V et al Does continuous video-EEG in patients with altered consciousness improve patient outcomeCurrent evidence and randomized controlled trial design J Clin Neurophysiol 201835359ndash364





CORRECTIONS

When Should We Treat Periodic Lateralized EpileptiformDischarges (PLEDS) (P5061)Neurologyreg 201993908 doi101212WNL0000000000008489

In the abstract ldquoWhen ShouldWeTreat Periodic Lateralized EpileptiformDischarges (PLEDS)(P5061) by Yusuf Solaiman et al1 first published in the April 2014 Supplement the authorrsquosname should read Ahmad Yusuf Solaiman The authors regret the error

Reference1 Yusuf Solaiman A Memon A Basha M et al When Should We Treat Periodic Lateralized Epileptiform Discharges (PLEDS) (P5061)

Neurology 201482(10 Supplement)P5061

SYNGAP1 encephalopathyA distinctive generalized developmental and epileptic encephalopathyNeurologyreg 201993908 doi101212WNL0000000000008352

In the article ldquoSYNGAP1 encephalopathy A distinctive generalized developmental and epi-leptic encephalopathy by Vlaskamp et al1 first published online December 12 2018 insupplemental table 1 the cnotation for the mutation identified in patient 21 should readldquog33408547GgtGGCTGC c1718_1719insGCTGC pGlu578Alafs74rdquo The supplementaldata were corrected after publication The authors regret the error

Reference1 Vlaskamp DRM Shaw BJ Burgess R et al SYNGAP1 encephalopathy a distinctive generalized developmental and epileptic en-

cephalopathy Neurology 201992e96ndashe107




Mutations of the SYNGAP1 gene were first identified in 2009in patients with nonsyndromic intellectual disability (ID) andautism spectrum disorder (ASD) followed in 2013 by rec-ognition of their important role in the developmental andepileptic encephalopathies (DEEs)1ndash3 Most affected indi-viduals have de novo mutations with truncating mutationspredominating although missense mutations chromosomaltranslocations or microdeletions disrupting SYNGAP1 arealso described4ndash8

SYNGAP1 (MIM 603384) on chromosome 6p2132 encodesa synaptic Ras-GTPase-activating protein expressed mainly inthe synapses of excitatory neurons910 SYNGAP1 is a key me-diator in the NMDA receptor activated RAS-signaling cascaderegulating the postsynaptic density and the formation de-velopment and maturation of dendritic spines1112 Loss offunction of SYNGAP1 has major consequences for neuronalhomeostasis and development which are crucial for learning andmemory11 Syngap1-null mice die within a week and Syngap1-heterozygous mutant mice have a lower seizure thresholdlearning and memory deficits and behavioral problems13ndash16

Since our original description of 5 patients with an SYNGAP1-DEE3 2 additional studies have described the epilepsy in 24of 27 patients with SYNGAP1 encephalopathy the specificepilepsy syndrome was described in only 4 of these cases817

SYNGAP1 was originally identified in 38 patients with ID orASD of whom 15 had seizures and only 1 had an epilepsysyndrome diagnosis124ndash718ndash28 We aimed to delineate theepilepsy syndromes within the SYNGAP1 phenotypic spec-trum in a large international cohort of patients with SYN-GAP1 mutations and microdeletions

MethodsStudy cohortWe recruited 66 patients with SYNGAP1 variants via inves-tigatorsrsquo practices in Australia Italy the Netherlands andChina (n = 39) and via the SYNGAP1 Facebook group onwhich parents posted our invitation to participate (n = 27)The pathogenicity of all SYNGAP1 variants was evaluatedwith the use of standard American College of Medical Ge-netics and Genomics guidelines (table e-1 available fromDryad doiorg105061dryadck70sj0)29 We included 57(86) patients with (likely) pathogenic SYNGAP1 variants(n = 53) or chromosome 6p2132 microdeletions includingSYNGAP1 and other genes (n = 4) Five (8) patients witha SYNGAP1 variant of unknown significance were studied

separately Four (6) patients with likely benign SYNGAP1variants were excluded

PhenotypingParents or caregivers of all patients were interviewed witha standardized epilepsy questionnaire30 We analyzed medicalrecords EEGs neuroimaging includingMRI results and whenavailable seizure videos and video-EEG data Seizure types andsyndromes were classified with the 2017 International LeagueAgainst Epilepsy classification3132 The severity of ID wasestablished with IQ scores (when available) or information onthe level of functioning in accordance with the DSM-V33

GenotypingSYNGAP1 mutations were described on the basis of thelongest isoform 1 of SYNGAP1 (NM_00677722)34 andchromosomal microdeletions on the basis of the GenomeReference Consortium Human Reference sequence version37 (GRCh37hg19)

Genotype-phenotype correlationWe examined genotype-phenotype correlations in 4 patientgroups (1) truncating mutations which included nonsenseand frameshift mutations (2) splice-site mutations (3)missense and in-frame insertiondeletion mutations and(4) chromosome 6p2132 microdeletions including SYN-GAP1 and other genes Splice-site mutations were consid-ered separately because their effects on the protein arevariable35

Standard protocol approvals registrationsand patient consentsAll parents or legal representatives of the patients gave writteninformed consent for inclusion and use of photos and videosThis study was approved by the local institutional EthicsCommittee (Austin Health reference No H200702961)

Data availabilityAnonymized data will be shared by request from any qualifiedinvestigator

ResultsCohortFifty-seven patients (53 male median age at study 8 years)with (likely) pathogenic SYNGAP1 variants were included 34truncating 8 splice-site and 11 missensein-frame mutationsand 4 microdeletions Forty-six (81) patients have not beenpreviously reported Thirty-nine of these patients had novel

GlossaryAED = antiepileptic drug ASD = autism spectrum disorder DEE = developmental and epileptic encephalopathy DSM-V =Diagnostic and Statistical Manual of Mental Disorders 5th edition EM = eyelid myoclonia EMA = epilepsy with eyelid myocloniawith absences GSW = generalized spike wave ID = intellectual disability MAE = epilepsy with myoclonic-atonic seizuresTCS = tonic-clonic seizures




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Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)

Male 18 (529) 3 (375) 6 (545) 3 (750) 30 (526)





Seizures n () 33 (971) 8 (100) 11 (100) 4 (100) 56 (982)







Any absences n () 33 (971) 8 (100) 8 (727) 4 (100) 53 (930)

EM 26 (765) 4 (500) 6 (545) 1 (250) 37 (649)






Myoclonic 15 (441) 1 (125) 3 (273) mdash 19 (333)

Atonic 5 (147) mdash 2 (182) 1 (250) 8 (140)














4 (118 8 y 4 mo3ndash13 y 4)


mdash 10 (178 75 y3ndash13 y 7)





12 mo (6ndash20 mo11 11)




2 y (12 mondash6 y 3233)


19 mo (12 mondash25y 10 10)



2 y 3 mo (8 mondash11y 24 27)


2 y (18 mondash11 y 99)


2 y (8 mondash9 y 4145)


4 y (16 mondash13 y14 14)

4 y (23 mondash45 y 34)


Continued









Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)


32 (941) 30 (882) 8 (100) 7 (875) 11 (100) 9 (818) 4 (100) 4 (100) 55 (965) 50 (877)


1533 (455 2 y 6mondash18 y 11)

6 (750 5 y 4 mo 4 y9 mondash6 y 2)

7 (636 13 mo 9mondash18 mo 9)

4 (100 18 mo 12mondash7 y 4)

3256 (571 2 y 6mondash18 y 19)





Hypotonia n () 22 (647) 4 (500) 8 (727) 4 (100) 38 (667)

Sleep problems n () 2033 (606) 57 (714) 6 (545) 3 (750) 3455 (618)


2034 (588) 5 (625) 4 (364) mdash 29 (509)

































































































































Errata





Reprints











































CORRECTIONS














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Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)

Male 18 (529) 3 (375) 6 (545) 3 (750) 30 (526)





Seizures n () 33 (971) 8 (100) 11 (100) 4 (100) 56 (982)







Any absences n () 33 (971) 8 (100) 8 (727) 4 (100) 53 (930)

EM 26 (765) 4 (500) 6 (545) 1 (250) 37 (649)






Myoclonic 15 (441) 1 (125) 3 (273) mdash 19 (333)

Atonic 5 (147) mdash 2 (182) 1 (250) 8 (140)














4 (118 8 y 4 mo3ndash13 y 4)


mdash 10 (178 75 y3ndash13 y 7)





12 mo (6ndash20 mo11 11)




2 y (12 mondash6 y 3233)


19 mo (12 mondash25y 10 10)



2 y 3 mo (8 mondash11y 24 27)


2 y (18 mondash11 y 99)


2 y (8 mondash9 y 4145)


4 y (16 mondash13 y14 14)

4 y (23 mondash45 y 34)


Continued









Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)


32 (941) 30 (882) 8 (100) 7 (875) 11 (100) 9 (818) 4 (100) 4 (100) 55 (965) 50 (877)


1533 (455 2 y 6mondash18 y 11)

6 (750 5 y 4 mo 4 y9 mondash6 y 2)

7 (636 13 mo 9mondash18 mo 9)

4 (100 18 mo 12mondash7 y 4)

3256 (571 2 y 6mondash18 y 19)





Hypotonia n () 22 (647) 4 (500) 8 (727) 4 (100) 38 (667)

Sleep problems n () 2033 (606) 57 (714) 6 (545) 3 (750) 3455 (618)


2034 (588) 5 (625) 4 (364) mdash 29 (509)

































































































































Errata





Reprints











































CORRECTIONS













Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)

Male 18 (529) 3 (375) 6 (545) 3 (750) 30 (526)





Seizures n () 33 (971) 8 (100) 11 (100) 4 (100) 56 (982)







Any absences n () 33 (971) 8 (100) 8 (727) 4 (100) 53 (930)

EM 26 (765) 4 (500) 6 (545) 1 (250) 37 (649)






Myoclonic 15 (441) 1 (125) 3 (273) mdash 19 (333)

Atonic 5 (147) mdash 2 (182) 1 (250) 8 (140)














4 (118 8 y 4 mo3ndash13 y 4)


mdash 10 (178 75 y3ndash13 y 7)





12 mo (6ndash20 mo11 11)




2 y (12 mondash6 y 3233)


19 mo (12 mondash25y 10 10)



2 y 3 mo (8 mondash11y 24 27)


2 y (18 mondash11 y 99)


2 y (8 mondash9 y 4145)


4 y (16 mondash13 y14 14)

4 y (23 mondash45 y 34)


Continued









Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)


32 (941) 30 (882) 8 (100) 7 (875) 11 (100) 9 (818) 4 (100) 4 (100) 55 (965) 50 (877)


1533 (455 2 y 6mondash18 y 11)

6 (750 5 y 4 mo 4 y9 mondash6 y 2)

7 (636 13 mo 9mondash18 mo 9)

4 (100 18 mo 12mondash7 y 4)

3256 (571 2 y 6mondash18 y 19)





Hypotonia n () 22 (647) 4 (500) 8 (727) 4 (100) 38 (667)

Sleep problems n () 2033 (606) 57 (714) 6 (545) 3 (750) 3455 (618)


2034 (588) 5 (625) 4 (364) mdash 29 (509)

































































































































Errata





Reprints











































CORRECTIONS



















Truncatingmutations

Splice-sitevariants



(n = 34) (n = 8) (n = 11) (n = 4) (n = 57)


32 (941) 30 (882) 8 (100) 7 (875) 11 (100) 9 (818) 4 (100) 4 (100) 55 (965) 50 (877)


1533 (455 2 y 6mondash18 y 11)

6 (750 5 y 4 mo 4 y9 mondash6 y 2)

7 (636 13 mo 9mondash18 mo 9)

4 (100 18 mo 12mondash7 y 4)

3256 (571 2 y 6mondash18 y 19)





Hypotonia n () 22 (647) 4 (500) 8 (727) 4 (100) 38 (667)

Sleep problems n () 2033 (606) 57 (714) 6 (545) 3 (750) 3455 (618)


2034 (588) 5 (625) 4 (364) mdash 29 (509)

































































































































Errata





Reprints











































CORRECTIONS







































































































































Errata





Reprints











































CORRECTIONS



















































CORRECTIONS












SYNGAP1 encephalopathy - Neurology · 1/8/2019 · ARTICLE OPEN ACCESS SYNGAP1 encephalopathy A...

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