Epilepsy and autism: How does age at seizure onset factor in?

Claude M.J. Braun; Jonathan Elie-Fortier

doi:10.21307/joepi-2021-002

Figures & Tables

Overview of the ensemble of statistical tests (in tables 1-6) of the hypothesis of differences in age at seizure onset between cases with vs without autism.

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with various MRI anomalies

Neurologic morbidity	Number of autistic patients	Number of non-autistic patients	Median age at seizure onset of the autistic patients (days)	Median age at seizure onset of the non-autistic patients (days)	Whole sample coefficient of variation (%)	Mann-Whitney Z (△ between ranks)	p
Abnormal MRI	625	1704	300	720	156	7.4	1.1e-13
Focal temporal lobe damage*	96	299	240	1825	130	7.1	1.1e-12
Cortical dysplasia	187	400	210	730	168	5.7	1.4e-8
Focal frontal lobe damage*	85	196	240	1021	147	4.5	0.000007
Subcortical dysplasia	115	206	330	1020	152	4.4	0.00001
Tumor@	35	114	300	1806	138	4.1	0.00004
Hippocampal sclerosis	18	76	210	1460	118	40.0	0.00007
Nodular periventricular heterotopia	40	53	233	1020	190	3.9	0.0001
Focal parietal lobe damage*	43	142	180	1369	163	3.6	0.0004
Focal occipital lobe damage*	27	121	330	1062	168	3.4	0.001
Thin corpus callosum	81	142	690	150	185	-2.9	0.004
Thick cortex	10	14	195	1460	108	2.7	0.007
Dysembryoplastic neuroepithelial tumor	7	45	730	2993	86	2.6	0.009
Gray/white matter boundary blurring	9	12	300	1004	141	2.5	0.013
Delayed myelination	50	95	270	120	181	-20.0	0.050
Arterovenous malformation¢	11	34	210	695	161	1.5	0.144
Ulegyria	3	9	912	2555	84	1.4	0.165
Cerebellar anomaly+	62	76	635	730	144	1.4	0.172
Double cortex	3	27	1460	2190	56	1.4	0.176
Encephalomalacia	7	12	243	874	120	1.4	0.170
Hypothalamic hamartoma	27	122	365	420	173	1.3	0.194
Central nervous system cyst△	27	63	365	365	173	1.2	0.225
Specific white matter anomaly#	44	92	390	730	126	1.2	0.232
Dilated CSF space(s)	89	176	474	378	163	-1.2	0.856
Chiari or Dandy Walker malformation	14	18	1275	1825	82	0.8	0.447
Cerebral atrophy	146	301	345	360	183	10.0	0.296
Cerebrovascular accident	18	91	315	240	227	-10.0	0.302
Polymicrogyria	7	40	570	1037	129	10.0	0.310
Arachnoid cyst	14	26	195	365	145	10.0	0.320
Gliosis	13	35	1132	1095	145	-0.8	0.403
Encephalomalacia	3	14	365	555	129	0.8	0.432
Any gyral/sulcal malformation	18	94	1186	1095	121	-0.4	0.706
Schizencephaly or porencephaly	3	20	1095	1369	113	0.4	0.714
Hemimegalencephaly	8	8	6	30	350	0.4	0.721
Subependymal giant cell astrocytoma (SEGA)μ	22	24	218	240	143	0.4	0.724
Lissencephaly	4	6	769	105	160	-0.2	0.831
Periventricular leukomalacia	8	25	345	730	107	0.1	0.950
Pachygyria	10	30	1642	1095	114	-00.0	0.963

Tests of a difference between autists and non-autists with regard to age at seizure onset in various epileptic conditions

Epileptic condition	Number of autistic patients	Number of non-autistic patients	Median age at seizure onset of the autistic patients (days)	Median age at seizure onset of the non-autistic patients (days)	Whole sample coefficient of variation (%)	Mann-Whitney Z (Δ between ranks)	P
Intractable epilepsy+	1146	2923	272	730	147	12.0	2.9e-33
Temporal lobe focus #	128	639	546	1825	112	7.7	1.4e-14
Partial seizure	187	828	300	1095	141	7.1	1.4e-12
Generalized tonic/clonic seizure	621	1603	365	660	146	5.7	1.1 e-8
Frontal lobe focus #	132	384	610	1460	114	5.3	1.2e-7
Focal seizure (not further specified)	283	861	330	1095	133	5.0	5.3e-7
Absence seizure	177	507	700	1278	106	4.5	0.000006
Status epilepticus awake	154	299	240	330	154	2.9	0.003
ESES/CSWSS	67	439	1277	1642	70	2.7	0.007
Non-refractory epilepsy	260	999	390	600	165	2.4	0.018
Lennox-Gastaut syndrome	61	152	395	815	116	2.3	0.020
Parietal lobe focus #	12	39	375	1825	168	2.3	0.023
Infantile spasm	234	364	120	150	183	2.2	0.027
Febrile seizure	175	436	270	365	136	2.2	0.028
Occipital lobe focus #	51	175	730	1095	100	2.2	0.030
Tonic seizure	101	236	300	232	158	-1.9	0.064
Dravet/SMEI syndrome	136	235	180	180	249	1.8	0.071
West syndrome/hypsarrhythmia	107	186	128	150	205	1.7	0.092
Atonic (drop) seizure	87	172	450	720	101	1.6	0.114
Gastroenteritis-triggered seizure onset	4	178	1225	570	108	-1.2	0.238
Ohtahara syndrome/suppression burst	25	60	5	3	265	1.0	0.930
Idiopathic epilepsy *	320	1539	1460	1463	106	0.9	0.384
Myoclonic seizure	211	497	330	365	140	0.8	0.400
Vaccine-contiguous seizure onset	31	36	180	180	123	0.3	0.800

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with a mutation defined only by cytogenetic location (involving several candidate genes)

Cytogenetic location of the mutation	Number of autistic patients	Number of non-autistic patients	Median age at seizure onset of the autistic patients (days)	Median age at seizure onset of the non-autistic patients (days)	Whole sample coefficient of variation (%)	Mann-Whitney Z (△ between ranks)	p
22q11.2 mutation	9	39	1460	330	131	-1.6	0.114
Ring20 mutation	7	52	3285	2008	71	-1.4	0.151
7q11.23 mutation	8	22	270	495	146	1.3	0.188
9q21.13 mutation	8	5	1607	1278	74	-0.8	0.419
16p11.2 mutation	7	43	240	180	254	0.6	0.519
2q24.3 mutation	10	10	38	17	287	-0.5	0.593
Xp22.31 mutation	3	11	3650	2190	66	-0.5	0.640
Trisomy-21	10	8	225	236	85	0.4	0.655
15q13.3 mutation	5	30	3285	3468	64	0.1	0.906

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with a mutation of a single gene located on the X chromosome

Mutated gene and its cytogenetic location	Number of autistic patients	Number of non-autistic patients	Median age at seizure onset of the autistic patients (days)	Median age at seizure onset of the non-autistic patients (days)	Whole sample coefficient of variation (%)	Mann-Whitney Z (△ between ranks)	p
PCDH19/Xq22.1 mutation	130	192	270	315	127	3.1	0.002
SLC6A8/Xq28 mutation	18	13	1278	2555	75	1.3	0.185
MECP2/Xq28 mutation	13	11	1095	730	101	-10.0	0.361
KIAA2022/Xq13.3 mutation	8	4	420	605	110	10.0	0.368
FMR1/Xq27.3 mutation	10	16	1460	913	79	-0.9	0.354
SYN1/Xp11.3 mutation	3	8	1450	3103	123	0.9	0.376
CNKSR2/Xp22.12 mutation	3	16	730	1077	78	0.9	0.392
WDR45/Xp11.23 mutation	3	15	780	450	116	-0.8	0.426
ARX/Xp21.3 mutation	5	10	30	120	286	0.4	0.664
CDKL5/Xp22.13 mutation	63	35	42	45	343	0.3	0.747
PIGA/Xp22.2 mutation	5	5	180	150	106	-0.3	0.750
IQSEC2/Xp11.22 mutation	16	10	730	730	111	0.2	0.811
SPTAN1/9q34.11 mutation	14	5	528	540	141	0.1	0.888
SLC9A6/Xq26.3 mutation	14	5	529	540	136	0.1	0.888

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with medical diagnoses not primarily based on MRI or in subsamples not receiving surgery for intractable epilepsy

Neurologic morbidity	Number of autistic patients	Number of non-autistic patients	Median age at seizure onset of the autistic patients (days)	Median age at seizure onset of the non-autistic patients (days)	Whole sample coefficient of variation (%)	Mann-Whitney Z (△ between ranks)	p
Epilepsy surgery	168	595	210	1095	138	9.2	2.4e-20
Angelman syndrome phenotype	91	54	730	1630	106	3.2	0.001
Tuberous sclerosis phenotype	162	238	180	210	246	3.1	0.002
Vagus nerve stimulation	61	199	365	1095	124	2.6	0.009
Neonatal adenylosuccinate lyase deficiency	22	8	84	1460	114	2.1	0.032
Kabuki syndrome	4	13	195	1095	87	20.0	0.045
Maternal diabetes	6	6	273	730	77	1.9	0.053
Neonatal pyridoxin deficiency	13	104	14	2	660	-1.9	0.057
Neonatal/infantile hypoglycemia	13	51	180	730	100	1.9	0.059
Hypotonia documented at birth	45	49	540	330	143	-1.9	0.062
KBG syndrome	8	10	2738	468	84	-1.8	0.074
Bainbridge-Ropers syndrome	5	5	2190	730	154	-1.8	0.074
Various metabolic syndromes #	18	24	278	730	141	1.6	0.117
Hydrocephaly	8	24	210	727	143	1.5	0.127
Encephalitis	26	69	695	1450	110	1.5	0.137
Low Apgar score (<7)	4	17	90	453	140	1.4	0.150
Microcephaly (OFC)@	170	254	365	270	162	-1.4	0.174
Intellectual deficiency	950	1475	360	365	146	1.2	0.219
Temple-Baraitser syndrome	3	9	985	270	134	-1.2	0.226
Cerebrovascular accident	18	91	315	240	227	-10.0	0.302
Rett syndrome phenotype	49	26	960	730	112	-10.0	0.330
Cornelia De Lange syndrome	11	19	1333	150	128	-10.0	0.331
Neonatal folate deficiency	10	17	635	132	133	-0.9	0.393
Congenital hyperbilirubinemia	11	9	300	1095	133	0.8	0.403
Nicolaides-Baraitser syndrome	12	19	638	540	118	-0.8	0.428
Any severe fetal distress or at birth	155	262	450	365	151	-0.9	0.372
Williams-Beuren syndrome	6	16	303	635	138	0.9	0.376
Phelan-McDermid syndrome	25	12	2555	2008	66	-0.6	0.569
Asphyxia/anoxia at birth	28	54	387	348	144	-0.5	0.649
Autoimmune encephalitis*	3	22	1934	2445	60	0.3	0.738
Periventricular leukomalacia	8	16	345	1004	103	0.3	0.787
Macrocephaly (OFC)@	40	52	365	870	144	0.2	0.822
Various mitochondrial syndromes	18	8	450	1095	123	0.2	0.845
Head trauma	6	33	2463	2555	114	00.0	0.969

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with a mutation of a single gene on an autosome

Mutated gene and its cytogenetic location	Number of autistic patients	Number of non-autistic patients	Median age at seizure onset of the autistic patients (days)	Median age at seizure onset of the non-autistic patients (days)	Whole sample coefficient of variation (%)	Mann-Whitney Z (△ between ranks)	p
DEPDC5/22q12.2-q12.3 mutation	8	27	51	1095	116	3.9	0.00009
CNTNAP2/7q35-q36 mutation	10	17	270	730	187	3.2	0.001
UBE3A/15q11.2 mutation	81	33	730	1825	108	2.6	0.010
SCN1A/2q24.3 mutation	126	277	180	180	188	1.9	0.053
ASXL3/18q12. 1 mutation	5	5	730	2190	154	1.8	0.074
SLC6A1/3p25.3 mutation	15	23	1085	540	66	-1.7	0.082
SCN2A/2q24.3 mutation	15	23	6	240	279	1.7	0.083
PTEN/10q23.31 mutation	5	10	42	2373	132	1.7	0.085
HCN1/5p12 mutation	6	29	225	270	119	1.7	0.095
FOLR1/11q13.4 mutation	4	8	1577	41	148	-1.7	0.109
EEF1A2/20q13.33 mutation	5	15	120	90	178	-1.6	0.114
PNPO/17q21.32 mutation	5	31	5	1	385	-1.6	0.207
HNRNPU/1q44 mutation	6	10	318	392	82	1.5	0.125
KCNA2/1p13.3 mutation	4	14	180	293	207	1.5	0.134
ANKRD11/16q24.3 mutation	7	8	1095	365	98	-1.5	0.143
KCNB1/20q13.13 mutation	12	23	378	270	82	-1.4	0.151
Miscellaneous mutations*	167	455	547	720	146	1.4	0.163
ALDH7A1/5q23.2 mutation	5	25	2	270	223	1.3	0.195
KCNT1/9q34.3 mutation	7	10	270	913	227	1.2	0.221
TSC1/9q34.13 mutation	6	21	215	540	103	1.1	0.316
PACS2/14q32.33 mutation	4	9	34	4	257	-1.1	0.330
CUX2/12q24.11-q24.12 mutation	4	7	273	180	200	-10.0	0.412
SETD1B/12q24.31 mutation	9	3	990	180	95	-0.9	0.354
STXBP1/9q34/mutation	26	39	44	30	152	-0.9	0.355
MEF2C/5q14.3 mutation	16	16	345	300	71	-0.9	0.395
GABRA1/5q34 mutation	6	26	330	240	198	-0.7	0.465
NF1/17q11.2 mutation	4	42	1004	1789	116	0.7	0.486
CHD2/15q26.1 mutation	23	35	730	875	94	0.6	0.528
TSC2/16p13.3 mutation	46	50	180	150	267	-0.5	0.605
NBEA/13q13.3 mutation	9	6	720	720	139	0.5	0.607
GABRG2/5q34 mutation	4	8	405	660	82	0.4	0.669
MBD5/2q23.1 mutation	8	12	560	986	116	0.4	0.670
FOXG1/14q12 mutation	3	12	150	180	255	-0.3	0.770
SPTAN1/9q34.11 mutation	4	23	195	120	211	-0.3	0.756
KCNQ3/8q24.22 mutation	8	8	900	1004	90	0.3	0.792
SCN8A/12q13.13 mutation	16	57	180	165	140	-0.3	0.794
KCNQ2/20q13.33 mutation	13	60	4	3	282	-0.2	0.838
SYNGAP1/6p21.32 mutation	26	34	900	785	75	-0.2	0.840
GRIN2A/16p13.2 mutation	13	48	1460	1460	497	0.2	0.880
GABRB3/15q12 mutation	8	4	180	270	226	0.1	0.898
POGZ/1q21.3 mutation	6	9	1186	912	69	-0.1	0.906
DNM1/9q34.11 mutation	5	15	210	210	58	0.1	0.930
SHANK3/22q13.33 mutation	7	13	2555	2555	68	00.0	10.0

Epilepsy and autism: How does age at seizure onset factor in?

Figures & Tables

Figure 1.

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with various MRI anomalies

Tests of a difference between autists and non-autists with regard to age at seizure onset in various epileptic conditions

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with a mutation defined only by cytogenetic location (involving several candidate genes)

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with a mutation of a single gene located on the X chromosome

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with medical diagnoses not primarily based on MRI or in subsamples not receiving surgery for intractable epilepsy

Tests of a difference between autists and non-autists regarding age at seizure onset in subsamples with a mutation of a single gene on an autosome

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