SUPPLEMENTARY INFORMATION - Neurology · Resume of all 147 STXBP1-mutations reported to date p.2 Table e-3: Overview of the clinical characteristics of 147 reported patients with

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SUPPLEMENTARY INFORMATION

STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy

Legend table e-1:

Detailed clinical description of 45 new patients with STXBP1-E p.2

Legend table e-2:

Resume of all 147 STXBP1-mutations reported to date p.2

Table e-3:

Overview of the clinical characteristics of 147 reported patients with STXBP1-E p.2-11

Figure e-1 :

STXBP1 truncating mutations. p.12

Supplemental methods and results:

Statistical analyses p.13-16

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Supplementary tables:

Table e-1 (separate excel table) legend: Detailed clinical description of 45 new patients with STXBP1-E.

Glossary: ACTH, adrenocorticotropic hormone; AED, anti-epileptic drugs; B6, pyridoxine; BS, Burst

supression; CBZ, carpabamazepine; CC, corpus callosum; CLB, clobazam; CLN, clonazepam; CS,

corticosteroids; d, day(s); ESX, ethosuximide; FS, focal seizures; FDS, focal dyscognitive seizures; GTC,

generalized tonic clonic; GBP, gabapentine; HC, head circumference; HS, hypsarrhythmia; IED,

intermittent epileptic discharges; KD, ketogenic diet; LCM, lacosamide; LEV, levetiracetam; LTG,

lamotrigine; mo, month(s); NTZ, nitrazepam; NREM, non-REM (rapid eye movement) sleep; OXC,

oxcarbamazepine; PB, phenobarbital; PER, Perampanel; PHT, phenytoin; PRM, primidon; PVL,

periventricular leukomalacia; R, R; RFM, rufinamide; SE, Status Epilepticus; SLT, sulthiam; STP,

stiripentol; SW, spike-waves; sz(s), seizure(s); TPM, topiramate; VGB, vigabatrin; VNS, vagal nerve

stimlator; VPA = valproic acid; wk, week(s); WM, white matter; yr, year(s); ZNS, zonisamide

NA= data not available

Table e-2 (separate excel table) legend: Resume all 147 STXBP1-mutations reported to date.

Glossary: d, days; EME, Early Myoclonic Encephalopathy; EOEE, Early onset Epilepsy and

Encephalopathy; ID, Intelectual Disability; LGS, Lennox-Gastaut syndrome; OS, Ohtahara Syndrome;

mo, months; NSE, Non Syndromic Epilepsy; sz, seizure(s); wk, weeks

NA= data not available

Table e-3 (below): Summary of the phenotypic characteristics of 147 patients with STXBP1 mutations

reported in literature (including present study).

Diagnosis refers to diagnosis at onset. A diagnosis of West was only made if there was a clear description

of a combination of epileptic spasms and hypsarrhythmia from onset. Early onset epilepsy and

encephalopathy (EOEE) was diagnosed in case of epilepsy onset < 2 years with development delay

without arguments for Ohtahara/West syndrome at onset. A diagnosis of Intellectual disability and Non-

Syndromic Epilepsy (ID+NSE) was made in case of developmental delay from birth and epilepsy onset

beyond 2 years of age.

Modified or hemi- HS was classified as HS in the table.

EEG results of patients who did not have seizures were not included in calculations.

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Table e-3: Summary of the phenotypic characteristics of 147 patients with STXBP1 mutations reported in literature (including present study).

Study Present Saitsu 2008 Tohyama 2008

Hamdan 2009 Deprez 2010 Saitsu 2010 Otsuka 2010 Hamdan 2011 Mignot 2011 Milh 2011

Inclusion criteria and number of patients in screening cohort

45 patients with a STXBP1 mutation

1 de novo deletion 13 patients with OS

95 patients with ID (25/95 + epilepsy) (+190 controls and 142 ASD pat)

106 patients with EE (incl 10 OS, 32 West, 14 MMPSI, 2EME)

29 patients with cryptogenic OS, 54 patients with West

86 patients with various forms of epilepsy (incl 10 OS, 43 West, 2 LGS)

50 patients with NSID

29 with EE (syndromic and non-syndromic), 1 patient with EE screened with array-CGH

52 patients with various forms of EE (38 OS, 7 EME, 7 EOEE)

No. (% of screening cohort) of patients with STXBP1 mutation

45 4 (31%) + 1 deletion

2 (2%) (0 % in controls and ASD)

6 (6%) 9/29 (31%), 0/54 2 (2%) 1 (2%) 2 (7%) + 1 de novo deletion

5 (10 %)

Mean age at sz onsetb(range)

11.5 mo

(1 d – 12 yr) 34.4 d (4 d – 2 mo)

17.4 mo (6wk - 2yr 9 mo)

1.7 mo (3d – 4.5 mo)

19.1 d (0d – 2 mo)

3.5 mo (1 - 6 mo)

- 3.5 mo (2 -6 mo)

8 d (16 h – 5 wk)

Mean age at inclusion (range)

9.6 yr (1 – 56 yr)

NA

21 yr (15-27 yr)

9.7 yr (6-11 yr)

2.8 yr (6mo -10 yr)

1.9 yr (1 y 11m – 2yr)

21 yr 12.5 yr (5.5-22 yr)

3.8 yr (2-7 yr)

Clinical diagnosis at onset (%)

OS 5 (100) 9 (100) 1 (50) 5 (100)

EME

West at onset 5 (11) 1 (17) 1 (50)

EOEE 30 (67) 1 (50) 5 (83) 3 (100)

ID + NSE 5 (11) 1 (50)

ID without epilepsy 4 + 1 +possible szs) (11)

1 (100)

DS

Sz type at onset (%) -

FS 3 (8)

T 7 (18) 3 (60) 1 (17) 1 (11)

C 7 (18) 1 (20) 1 (17) 2 (22) 1 (33) 2 (40)

TC 4 (10) 1 (20) 1 (11)

ES 7 (18) 1 (20) 3 (50) 2 (22) 2 (100) 3 (100) 3 (60)

HC 1 (3) 1 (11)

M 4 (10) 2 (33)

AS/ drop attacks 1(3)

Foc.szs (/FDS) +/- sec. gen 14 (36) 1 (20) 2 (100) 2 (33) 2 (22) 1 (33)

Absences

SE 2 (5)

Additional sz types (%) -

FS

T 19 (49) 1 (50) 2 (33) 1 (11) 1 (33) 2 (40)

C 1 (3) 1 (20)

TC 11 (28) 1 (20)

ES 10 (26) 4 (80) 7 (78) 2 (40)

HC 1 (3)

M 5 (13) 1 (20) 3 (33) 2 (40)

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AS/drop attacks 4 (10) 1 (50)

Foc. szs (/FDS) +/- sec. gen 11(28) 2* (22) 5 (100)

Absences 4 (10)

SE 2 (5)

Seizure free (+/-AED) at time of publication (range age at sz freedom)

14/39 (1mo – 4yr)

1/5 (3 mo)

0/2 4/6 (5 wk-8 mo)

3/9 (NA)

1/1a (after surgery at 1 yr 1 mo)

- 2/3 (ca 4 - 10 mo)

5/5 (6 – 18 mo)

EEG -

BS 6/38a 5/5 0/2 0/6 9/9 1/2 0/3 5/5

HS 15/38a 4/5 0/2 4/6 NA 1/2 1/3 1/5

focal/multifocal 29/38 a 1/5 2/2 2/6 8/9 0/2 2/3 2/5

Imaging (MRI) NA ***

Normal 25/43 1/5 1/1a 3/6 2/9 1/2 a

Atrophic changes 8/43 4/5 1/6 5/9 2/2 1/2 a 4/4a

Thin Corpus callosum 4/43 1/5 2/2 4/4a

Hypomyelination/ delayed myelination

7/43 3/5 1/6 1/9 2/2

Other 10/43 2/6 3/9

Other eurological features (nr)

tremor (17), ataxic gait (5), ataxia (10), dystonia (5), dyskinesia(7), choreatic movements (4), EPS (2+2 with EP features), , pyramidal signs (6), hypotonia (21), spasticity (4), myoclonus (1), jerks (1)

choreoathetosis (1), spasticity (3), hypotonia (2)

tremor (2) , hypotonia (2)

ataxia (3), dyskinesia (2), (axial) hypotonia (2),

spasticity (8) hypotonia (2) tremor (1) tremor (3), myoclonus (1), dyskinesia(1), extrapyramidal rigidity (1), pyramidal signs (1)

jerks (4), dyskinesia (3), tremor (2), pedaling (1), dystonia (1), ataxic gait (2)

Degree of ID/DD (%) ***

learning difficulties

Mild 3 (7)

Moderate 5 (11) 1 (11)

Severe 33 (75) 2 (100) 3 (50) 1 (100) 3 (100) 3 (60)

Profound 3 (7) 5 (100) 3 (50) 8 (89) 1 (20)

not specified/NA 1 (2) 2 (100) 1 (20)

Behavioral/ autistic features reported (nr)

autistic traits/ autism (14), stereotypies (14), hyperact.(3), acting out/aggress. (3), hypervent. (3)

hypervent. (1) hyperactivity (3), stereotypies (2)c

attention disorder (1)

hypervent.(1), stereotypies (3)

autistic features (3), stereotypies (2),

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Table e-3 (part 2):

Study Saitsu 2011 Saitsu 2012 Vatta 2012 Campbell 2012 Rauch 2012 Weckhuysen 2013

Mastrangelo 2013

Sampaio 2013 Kim 2013


1 case report arrey CGH study on 28 patients with OS

1 case report 10 patients with 9q34.11 del.

51 patients with NSID (history of szs in 17)

160 patients with various forms of EOEE (6 OS, 65 West, 64 EOEE, LGS, EME)

1 case report

2 case reports 1 new case report (2 previously reported)

No. (% of screening cohort) of patients with STXBP1 mutation

1 2 (7%) 1 6/10 (60%) involved STXBP1, 1 involved only STXBP1

3 (6%) 6 (4%) 1 2 1

Mean age at sz onset(range)

37 d 19.5 d (1 wk – 32d)

2 wk 19.4 mo

(neonatal – 6yr) 30 mo 26.7 d

(2d – 3 mo) 2 mo 4 wk

(2wk – 6wk) 6 wk


1 yr NA 8 mo 6.3 yr (2-13 yr)

6.4 yr (2.5 yr -10.25 yr)

8.1 yr (20 mo – 20 yr 9 mo)

24 mo 5 yr (2– 8yr)

10 yr

Clinical diagnosis

OS 1 2 (100) (DD:EME) 2 (33)

EME

West at onset 1 (17) 1 (17) BS without szs West

EOEE 1 2 (33) 3 (50) 2 (100) 1

ID + NSE 1 (17) 1 (33)

ID without epilepsy 2 (33) 2 (67) (1 + EEG aberrations)

DS

Sz type at onset (%) NA no sz at onset, only BS on EEG

FS

T 1 (50) 1 (17)

C

TC 1 (50)

ES 1 1 (50) 1 (33)a 1 (17) 1 (50)

HC 1

M 1 (50) 1 1 (17) 1 (50)

AS/ drop attacks

Foc. szs (/FDS) +/- sec. gen 1 1 2 (67)a 3 (50) 2 (100)

absences

SE

Additional sz types (%)

FS

T 1 (17)

C

TC 1 (17) 1

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ES 1 4 (67) 1 1 (50) 1

HC 1 (17)

M 2 (67)a 3 (50) 1

AS/ drop attacks 1 (33)a 1 (17)

Foc. szs (/FDS) +/- sec. gen 1 3 (50) 1 1

absences

SE 1 (17)

Seizure free (+/-AED) at time of publication (range)

0/1 NA 1/1 (before 8 mo)

1/4 NA 2/6 (3-13 mo)

1/1 (NA)

2/2 (6-10 mo))

0/1

EEG NA

BS 1/1 2/2 0/1 0/4 2/6 1/1 2/2** 1/1

HS 0/1 0/2 0/1 1/4 3/6 1/1 1/2** 0/1

focal/multifocal 0/1 0/2 1/1 3/4 6/6 1/1 0/2 0/1

Imaging (MRI)

Normal 1/1 1/2 1/1 4/6 normal CT/MRI

1/3 1/2a 2/2 1/1

Atrophic changes 1/2 1/3 1/2a

Thin corpus callosum 1/2 1/1


other 2/6 1/3

Other neurological features (nr)

spasticity (1) spasticity (1) NA ataxia (3), tremor(1), dyskinesia (1), pyramidal signs (1), hypotonia (6)

ataxia (3), tremor (2), dystonia (1), hypotonia (1)

spasticity (1) , tremor (1), ataxic gait (1), ataxia (1), hypotonia (2)

jerks (1), axial hypotonia (1)

spasticity (1), ataxia (1), tremor (1), dystonia (1), hypotonia (1)

dyskinesia

Degree of ID/DD

learning difficulties

mild

moderate 1 (17)

severe 4 (67) 3 (100) 4 (67) 1 2 (100)

profound 1 1 (50) 1 (17) 2 (33) 1

not specified/NA 1 (50) 1 (100)


autism(2) autistic features (1)

autistic features (1)b, stereotypies (1)

stereotypies

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Table e-3 (part 3):

Study Epi 4 K consortium 2013

Barcia 2013 Romaniallo 2014 Barcia 2014 Tso 2014 Carvill 2014 Michaud 2014 Matsumoto 2014 Keogh 2014


WES on 264 patient-parent trio’s with LGS or IS

1 case report

1 case report 3 new patients with STXBP1 mutations (4 pat. previously reported by Milh 2011)

1 case report 80 SCN1A negative DS patients (WES + targeted resequencing)

44 patients with IS (8 targ.seq. STXBP1, 18 WES)

1 case report 1 case report

No.(%) of patients with STXBP1 mutation

5 (2%) 1 1 3 1 3 (4%) 2 (5%)

1 1

Mean age at sz onset (range)

3 moa (2 – 4mo)

5 mo 8 mo 1.4 mo (8d -3 mo)

3 d 9.7 mo (6-12 mo)

NA 4 mo 5 d


NA 7 yr 3 yr 5.7 yr (2-12yr)

24 mo 12.7 yr (6-21 yr)

NA 5 yr NA

Clinical diagnosis

OS 1 (33) 1

EME

West at onset 1 (20) 1 (33)

EOEE 4 (80) 1 1 1 (33) 2 (100) 1 1

ID + NSE

ID without epilepsy

DS 3 (100)

Sz type at onset (%) NA NA (gen.szs)

FS 2 (67)

T

C

TC 1 1 (33)

ES 3 (60) 3 (100) 1 1

HC

M

AS/ drop attacks

Foc. szs (/FDS) +/- sec. gen 2 (40) 1

Absences

SE

Additional sz types (%) NA NA

FS 1 fever sensitivity reported in all patients

T 1 (20) 1c 1 2 (67) 1

C

TC 2 (67)

ES 1 (20) 1 2 (100)

HC 1 (33)

M 1 3 (100)

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AS/ drop attacks 2 (67)

Foc. szs (/FDS) +/- sec. gen 1 (20) 1 2 (67) 2 (100) 1

Absences 2 (67)

SE 1 1 (33)


NA 1/1 0/1 2/3 (26mo-NA)

1/1 NA NA 0/1 0/1

EEG

BS 2/5 0/1 0/1 1/3 1/1 0/3 0/2 1/1 0/1

HS 3/5 0/1 0/1 2/3 0/1 0/3 0/2 0/1 0/1

focal/multifocal 4/5 1/1 1/1 1/3 1/1 2/3 2/2 0/1 1/1

Imaging (MRI)

Normal 3/5 1/1 1/3 1/1 1/2a 1/1

Atrophic changes 1/5 1/1 2/3 1/2a 2/2 1/1

Thin Corpus callosum 1/1 2/3 1/1


1/1 1/3 1/2

other 2/5 1/1 2/2

Other neurological features (nr)

cerebral palsy (1) axial hypotonia, dystonia, myoclonus

axial hypotoniac dyskinesia (1), ataxic gait (1), axial hypotonia (2)

hypotonia NA NA dystonia, axial hypotonia

ataxia, dystonia , EPS, pyramidal signs

Degree of ID/DD

learning difficulties 1 (33)

mild

moderate 2 (100)

severe 3 (60) 1 1 2 (67) 1 2 (67) 1

profound 1 (33) 1

not specified/NA 2 (40)


PDD (1), stereotypies (1)a

transient episodes of agitation with self harmc , stereotypiesc

stereotypies (1) NA NA stereotypies

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Table e-3 (part 4):

Study Boutry –Kryza 2014

Nicita 2015 Romaniello 2015

Mercimek-Mahmutoglu 2015

Olson 2015 Kwong 2015 Dilena 2015 Yamamoto 2015

Naele 2012, Kodera 2013, Carvill 2013, Tucker 2014

Total (%)


73 patients with IS, array-CGH + seq.

1 case report 1 case report 110 patients with EE

WES study on 11 patients with Rett features

26 patients with IEE

1 case report 42 patients with EE

Large NGS studies, no/little phenotypic information

39 different studies

No.(%) of patients with STXBP1 mutation

2 new (in total 3, 4%)

1 1 3 (3%) 1 (9%) 2 (8%) 1 4 (10%) 13 147 patients with STXBP1 mutations

Mean age at sz onset (range)

23 d (1d – 1.5 mo)

5 wk 2 mo 3.5 mo (2wk – 9.5 mo)

29 d 0.5 mo (0.5 mo)

1 mo 33 d (2 d- 3 mo)

NA 6.1 mo , median 42 d (1d – 12 yr)


7.5 yr (4 – 11yr)

15 mo 9 yr 4.7 yr (4-5 yr) 8 yr 4.5 yr (3-6 yr)

33 mo 4.4 yr (2.5 yr – 8 yr)

NA 7.7 yr, median 5 yr 9 mo (6 mo – 56 yr)

Clinical diagnosis NA Information available for 134 pat.

OS 1 28 (20.9)

EME 1 1 (0.7)

West at onset 1 13 (9.7)

EOEE 2 (100) 1 3 1 2 1 2 71 (53)

ID + NSE 8 (6)

ID without epilepsy 9 (6.7) +1 pat + 2 possible sz

DS 3 (2.2)

Sz type at onset (%) NA NA Information available for 116 pat.

FS 5 (4.3)

T 1 (33)a 15 (12.9)

C 1 (50) 1 16 (13.8)

TC 9 (7.8)

ES 1 (50) 1 (33)a 36 (31)

HC 3 (2.6)

M 1 11 (9.5)

AS/ drop attacks 1 (0.9)

Foc. szs (/FDS) +/- sec. gen 1 (50) 1 1 1 (50) 1 (33)a 39 (33.6)

Absences 0 (0)

SE 2 (1.7)

Additional sz types (%) NA Information available for 121 pat.

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FS 1 (33) 3 (2.5)

T 1 (33) 1 35 (28.9)

C 2 (1.7)

TC 1 (33) 17 (14)

ES 2 (100) 1 1 1 (33) 1 1 (50)a 1(33)a 43 (35.5)

HC 3 (2.5)

M 1 (50)a 25 (20.7)

AS/ drop attacks 9 (7.4)

Foc. szs (/FDS) +/- sec. gen 1 (50) 1 1(33)a 31 (25.6)

Absences 6 (5)

SE 5 (4.1)


1/2 0/1 1/1 (5 mo)

NA NA 0/2 1/1 (2-3 mo)

3/4 NA 46/105 of whom information was available (43.8)

EEG NA NA

BS NA 1/1** 0/1 0/3 0/1 0/1 1/4 42/117 (35.9)

HS 2/2 0/1 1/1 0/3 1/1 0/1 3/4 44/110 (40)

focal/multifocal NA 1/1 0/1 1/3 1/1 1/1 1/4 75/117 (64.1)

Imaging (MRI) NA NA NA

Normal 1/3 1/1 55/117 (47)

Atrophic changes 3/4 39/117 (33.3)

Thin Corpus callosum 1/1 1/1 19/117 (16.2)


1/1 1/4 19/117 (16.2)

Other 2/3 25/117 (21.4)

Motor features (nr) ataxia (1) dystonia tremor, ataxia, dyskinesia

hypotonia (1) spasticity, ataxic gait

dystonia (2) (axial) hypotonia

NA NA hypotonia (39), ataxia/ataxic gait (34), spasticity (20), tremor (31), dyskinesia (17); dystonia (14), choreatic movements/ choreoatetosis (5), extrapyramidal signs (6), pyramidal signs (9), ‘jerks’ (6), myoclonus (3)

Degree of ID/DD Information available for 121 pat.

learning difficulties 1 (0.8)

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Glossary: AED, anti-epileptic drugs; AS, atonic seizures; ASD, Autism spectrum Disorder; C, clonic seizures; d, day(s); DD, development delay; DS, Dravet syndrome; EE, epileptic encephalopathy; EOEE, Early Onset Epilepsy and

Encephalopathy; EME, Early myoclonic encephalopathy; EPS, extrapyramidal symptoms; ES, epileptic spasms; FS, febrile seizures; Foc szs, focal seizures; FDS, focal dyscognitive seizures; HC, hemiclonic seizures; HS,

hypsarrhythmia; ID, Intellectual disability; IEE, infantile EE; M, myoclonic seizures; mo, month(s); MMPSI, Malignant migrating partial seizures of infancy; NSE, Non Syndromic Epilepsy; OS, Ohtahara syndrome; PDD, pervasive

developmental disorder; BS, burst suppression; SE, status epilepticus; sz, seizure(s); T, tonic seizures; TC, tonic clonic seizures; yr, year(s);

NA: data not available, “-“ : not applicable a: data not available for all patients, b: later reported by Young et al. c: Information obtained after communication with treating physician

*: 1 versive sz after hypoxia at 2 yr, **: only reported during sleep, ***: additional info reported later by Barcia et al.2014

Mild 4 (3.3)

Moderate 9 (7.4)

Severe 2 (100) 1 2/2 1 1/2a 77 (63.6)

Profound 1 1/2a 30 (24.8)

not specified/NA 3 (100) 1 13 (100) 26 (21.5)


autistic features (2), aggressive behavior (incl. self-aggressive) (1), stereotypies (2)

autistic features, stereotypies

autism (1) self-injurious, stereotypies

NA NA autism/ autistic traits (25), stereotypies (31), hyper-activity (6) acting out/ (self) aggressive (5), self-injurious (1), hyper-ventilation (5), attention disorder (1), PDD (1)

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Figure e-1: STXBP1 truncating mutations.

Truncating mutations in STXBP1-E with their location on protein level. The blue bars represent the previously unreported mutations, the red bars the already

published mutations and the red and blue bars the mutations seen in newly diagnosed and previously reported patients. The grey bars represent the ExAC

missense variants reported once, the black bars the ones reported more than once . All STXBP1 truncating mutations are located within the 3 domains of the

protein whereas all ExAC truncating mutations are outside and in the very last part of the gene.

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Supplementary methods and results: Statistical analyses

To identify possible genotype-phenotype correlations, we looked for a statistical correlation between mutation

type (truncating mutations versus missense mutations) and cognitive outcome (learning disabilities-moderate

ID versus severe-profound ID) and between mutation type and seizure outcome (seizure free versus not seizure

free). We also investigated if there was a difference in age at seizure onset and age when seizure free between

the groups with missense and truncating mutations.

We further looked for a possible correlation between seizure characteristics and cognitive outcome. We

verified whether there was a correlation between seizure outcome and cognitive outcome. We also looked if

there was a difference in age at seizure onset, age at seizure freedom or duration of seizures between the

group with learning disabilities to moderate ID at the one hand, and the group with severe to profound ID on

the other hand. Duration of seizures was calculated as the time between seizure onset and seizure freedom for

the patients in which this was known. For the patients who were not seizure free we calculated the time

between seizure onset and age at inclusion.

A Chi square test was used to compare mutation type (missense versus truncating) and cognitive outcome

(mild to moderate ID versus severe to profound) and cognitive outcome and seizure outcome (seizure free

versus not seizure free). A Fisher’s exact test was used in case any of the cells had an expected count below 5.

A nonparametric Mann Whitney U test was used to look for a difference in age at seizure onset, age when

seizure free and duration of seizures between different groups regarding mutation type and cognitive

outcome. Statistical analyses were performed with SPSS Statistics 22 (IBM). As indicated in the summary

below, none of these comparisons showed a statistically significant correlation.

To make sure we had comparable groups we also investigated if there was a significant age difference between

the different groups that were compared, since seizures are usually more frequent and more severe at younger

age. As shown in the resume below there was no significant difference.

Statistical power was calculated with G*Power 3.1.9.2 (http://www.gpower.hhu.de/)1 . Despite the fact that we collected and reviewed a large group of patients, all analyses were significantly underpowered (power ranging from 5.0 to 45.4 %). However, we believe that these analyses are important and strengthen our hypothesis based on case reviews that there is no obvious genotype-phenotype correlation and no clear correlation between seizures and cognitive outcome. We recognize that much larger sample size would be necessary to make definite statements based on statistics, but the rarity of the disorder hampers such studies.

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Summary of results:

* Mean age at seizure freedom lower than mean age at seizure onset because this information was available for less patients

Figure e-2: Age at seizure freedom (in days), missense vs truncating mutations

The central line in the boxplot represents the median of the age when patients became seizure free, with the bottom and top

of the box representing the first and third quartile. The whiskers are defined by 1.5 times the IQR (inter-quartile range).

Outliers are represented with a star/dot.

Missense mutations Truncating mutations Two-sided P Test

LD-mild-moderate ID,

N (%)

4/45 (8.8) 10/76 (13.2) 0.478 Chi square

severe profound ID, N

(%)

41/45 (91.1) 66/76 (86.8)

seizure free,

N (%)

12/35 (34.3) 35/70 (50) 0.127 Chi square

age seizure onset

(mean)

288.9 days

(SD: 782.4)

118.9 days

(SD: 303.4)

0.333 Mann-Whitney-U

age seizure freedom

(mean)

223.6 days*

(SD: 189.4)

305.6 days

(SD: 279.6)

0.225

Mann-Whitney-U

age at inclusion (mean) 7.7 years

(SD: 6.4)

7.7 years

(SD: 7.8)

0.944

Mann-Whitney-U

LD-Moderate ID Severe-Profound ID Two-sided P

seizure free (%) 5/9 (55.6) 37/91 (40.7) 0.486 Fisher’s exact

age seizure onset

(mean)

120.8 days

(SD: 131.5)

199.8 days

(SD: 583.3)


age seizure freedom

(mean)

285.0 days

(SD: 133.0)

284.4 days

(SD: 280.3)


seizure duration

(mean)

3690.9 days

(SD: 6950.7)

1786.7 days

(SD: 2154.6)


age at inclusion (mean) 9.0 years

(SD: 15.2)

8.0 years

(SD: 6.1)


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Figure e-3: Age at seizure freedom (in days): mild to moderate ID vs severe to profound ID

References:

1. Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175-191.

Documents

SUPPLEMENTARY INFORMATION - Neurology · Resume of all 147 STXBP1-mutations reported to date p.2 Table e-3: Overview of the clinical characteristics of 147 reported patients with