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Effect of epilepsy on autism symptoms in Angelman syndrome

Effect of epilepsy on autism symptoms in Angelman syndrome Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1–57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged ≥ 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and ≥ 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months–7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = − 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (β = − 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R = 0.53; F = 10.7; p =0.001). Conclusions: The study provides support for the notion that seizuresthemselvescontributemoretoautismsymptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology. Keywords: Angelman syndrome, Autism spectrum disorder, Epilepsy, Epileptic encephalopathy, Seizure onset Background seizure types and starting in early childhood [7, 8]. High Angelman syndrome (AS) is a neurodevelopmental dis- rates of autistic symptoms are also reported [9–11], with order caused by an absent or non-functioning maternal prevalence estimates of autism spectrum disorder (ASD) allele of chromosome 15q11-q13 [1]. The typical AS ranging from 24 to 81% [6, 10]. AS can be due to phenotype is characterized by intellectual disability (ID), UBE3A mutations, uniparental disomy and imprinting lack of speech, hyperactivity, ataxic gait, microcephaly, defects [1, 12], but deletions are the predominant cause sleep disturbances, frequent laughter/smiling and an and are found in 68–75% of patients. Deletions are also apparently happy demeanour [1–4]. ID ranges from associated with more severe AS-phenotype, and co- moderate to profound, with most individuals functioning deletion of GABA -receptor genes (GABRB3, GABRA5 in the severe to profound range [5, 6]. Epilepsy occurs in and GABRG3) located adjacent to UBE3A gene is sug- 80% or more of cases [2, 7], usually involving multiple gested as a possible explanation for this [1]. Dysfunction of GABRB3 is highly associated with both epilepsy and autism symptoms [13, 14]. * Correspondence: [email protected] NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bakke et al. Molecular Autism (2018) 9:2 Page 2 of 8 A strong association between autism symptoms, epilepsy Association, 115 individuals with AS were identified. Letters and ID has been found in a number of other genetic syn- were sent to the parents/guardians of these individuals, and dromes, such as fragile X and tuberous sclerosis complex they were asked to complete two questionnaires: the Social (TSC), as well as in AS [6, 10]. It is evident, too, that the Communication Questionnaire (SCQ), which measures negative effect of seizures is particularly strong during autism symptoms [38], and a study-specific question- infancy and early childhood [15–18]. Thus, onset of naire assessing epilepsy, medication and developmental seizures during the first year of life is associated with parameters. Written informed consent was given by all increased prevalence and severity of ID and ASD and parents/guardians allowing the researchers access to increased prevalence of brain abnormalities [19, 20]. medical records from all hospitals in Norway (Fig. 1). However, there is a continuing debate [21–24] as to whether autism symptoms, epilepsy and ID are inde- Measures pendent comorbidities [15, 16, 21, 25–27], whether they Clinical information on epilepsy and genetic abnormality are all outcomes of the same underlying pathophysio- Participants’ medical records were used to collect infor- logical/genetic mechanisms [17, 21, 25, 28], or whether mation regarding epilepsy and the nature of the genetic the epilepsy itself contributes to more severe cognitive abnormality. Information on age of epilepsy onset, type and behavioural impairments than might be expected of seizure and treatment with anti-epileptic drugs was from the underlying pathology alone [15, 17, 29, 30], recorded when available. Medical records were not i.e. a so-called encephalopathic effect [30]. comprehensive for all individuals, and formal seizure There are several reasons why AS offers a suitable disease classification was not always performed. model to investigate the association between epilepsy, ID Genetic data were also variable. When information was and autism symptoms. Firstly, the rate of epilepsy in AS available, the genetic abnormality was dichotomised into (> 80%) is as high as or higher than other genetic disorders ‘deletion’ or ‘other’ (i.e.uniparental disomy,imprinting in which epilepsy and autism commonly co-occur (e.g. TSC defects and point mutations). [80–90%]; fragile X syndrome [10–20%]) [29, 31, 32]. Sec- ondly, epilepsy in AS tends to start in very early childhood. Autism symptoms Seizures are also often treatment-resistant and refractory The lifetime version of SCQ was used to assess the number epilepsy has been shown to be an important predictor of of autism symptoms [38]. The SCQ contains 40 items autism symptoms [33]. Thirdly, unlike genetic conditions scored 0 or 1 and was designed to screen for a possible such as TSC, in which the numbers and location of tubers diagnosis of autism in individuals aged 4 years and older are associated with autism symptoms [17, 34], there are no and with a mental age above 2 years [38]. It has also specific structural brain abnormalities in AS that are known frequently been used to measure autistic-type symptoms in to affect the phenotype. Fourthly, knowledge of the specific individuals with genetic syndromes including those with genetic defects that cause AS makes it possible to evaluate AS [9, 11]. We did not classify participants as meeting/not the degree to which the association between epilepsy and meeting the suggested cut-off scores for autism or ASD autism symptoms is a result of the underlying genetic (≥ 22 and ≥ 15, respectively [38]) since the validity of abnormality and to assess the independent contribution of these criteria has not been established for individuals seizures on level of autism symptoms. with genetic disorders associated with severe ID. Never- The aims of the current study were to describe epilepsy theless, SCQ has often been used as the screening tool characteristics and then investigate the relationship in samples with low IQ [39, 40]. between epilepsy, autism symptoms, communication level and genetic cause in individuals with AS. Based on previ- Communication level ous research on other populations with childhood epilepsy Information about level of development was particularly including TSC [18, 33, 35–37], we hypothesized that age of variable and often very limited. Although many parents onset of epilepsy would be related to the number of autism reported that they had previously been told their child symptoms in AS independent of the effect of the specific had severe to profound intellectual disability (in 7 cases, genetic abnormality. the description was of ‘moderate’ disability), formal test results were rarely recorded, and hence, the validity of Methods these categories was unknown. Although there were no The study was approved by the regional ethics committee adequate data on IQ/developmental level, we did have in Norway (REK 2014/1880). data on communication level. Signing was the major mean of communication for most of the participants; Recruitment procedures the majority had no use of words and no one used more From the records of the Frambu Resource Centre for than 20 words. Categorical ratings of ‘use of signs’ (< 20 Rare Disorders in Norway and the Norwegian Angelman and 20–100 and > 100) were used to divide individuals Bakke et al. Molecular Autism (2018) 9:2 Page 3 of 8 Fig. 1 Recruitment into two groups; those using fewer than 20 signs to com- r). Due to small sample size, Mann-Whitney U test municate and those with more than 20 signs. was used when comparing SCQ in subgroups with/ without epilepsy and when comparing SCQ and age of epilepsy onset in subgroups with/without deletion. Participants Fisher’s exact test was used for categorical data. Due Inclusion criteria to small and unequal sample sizes, Hedges’ g was For the descriptive part of the study (‘Epilepsy characteris- used for effect sizes. Normality of residuals was checked tics’), individuals were included if their parents/guardians using visual inspection of P-P plots. Multiple regression gave their consent to participation/access to medical analysis was conducted to assess the impact of ‘age at records and if their son/daughter had a genetically verified epilepsy onset’and ‘type of genetic aberration’ on SCQ diagnosis of AS. For the second part of the study (‘Relation scores. Due to the combination of dichotomous and between epilepsy and autism symptoms, nonverbal com- continuous covariates, we report the standardized coef- munication level and genetic aberration’), individuals were ficients (β). To correct for multiple comparisons, a sig- required to be at least 4 years of age (i.e. minimum age for nificance level of p ≤ 0.01 was chosen; Bonferroni ‘rule the SCQ). of thumb’ was used to determine appropriate p level Parents/guardians of 56 out of the 115 individuals (p = 0.05/5 = 0.01). identified from the records (49%) consented to par- ticipate; 48 of these individuals (age range 1–57 years; median 14 years 6 months) had a genetically verified AS diagnosis. At the time of questionnaire comple- tion (see Fig. 1), medical records confirmed that 34 in- Table 1 Characteristics of participants with Angelman dividuals had epilepsy and 11 individuals did not. Three syndrome in parts 1 and 2 of study boys (aged 1, 1, and 4 years, respectively) subsequently de- Age Gender Genetics veloped seizures; hence, the 4-year-old was included in Part 1: Range: 1–57 years Male: 30 Deletion: 26 (16 males) the no-epilepsy group in the part 2 of the study. SCQ Epilepsy Mean: 17.1 years Female: 18 UPD: 4 (2 males) characteristics Median: 14.5 years Imprinting: 3 (1 male) questionnaires were completed for 38 of 40 individuals (n=48) Mutation: 2 (1 male) aged 4 years or older (SCQ was not completed for two Unknown: 13 (10 males) participants aged 57 and 40 years). See Table 1 for partici- Part 2: Range: 1–57 years Male: 30 Deletion: 26 (16 males) pants’ characteristics. Relation between Mean: 20.2 years Female: 15 UPD: 2 (2 males) epilepsy and autism Median: 19.1 years Imprinting: 2 (1 male) symptoms, nonverbal Mutation: 2 (1 male) Statistical analysis communication Unknown: 12 (9 males) level and genetic Associations between quantitative measures were ana- aberration (n=40) lyzed by parametric statistics in SPSS (t test, Pearson’s Bakke et al. Molecular Autism (2018) 9:2 Page 4 of 8 Results individuals with and without epilepsy; 19 of 33 (58%) with Part 1: epilepsy characteristics epilepsy and 4 of 7 (57%) (exact p = 1.000) without epilepsy Age of first seizure ranged from 3 months to 7 years used fewer than 20 signs to communicate. Individuals with 10 months (mean 3 years 0 months, SD 2 years 2 months). the deletion weremorelikelytobein the group using <20 Four individuals had their initial seizure during the first year signs to communicate than individuals with other genetic of life; 11 developed epilepsy during the second year. The aberrations (exact p = 0.022). number and type of seizures varied among individuals and Within the epilepsy group, age of epilepsy onset was varied over time in the same individuals. Two individuals lower among individuals using < 20 signs to communicate. (aged 38 and 27 years) had been diagnosed with Lennox- Individuals with the deletion had significantly higher SCQ Gastaut syndrome. One individual had only ‘atypical scores and lower age at epilepsy onset than individuals absence seizures,’ and all others had seizures with ‘jerks’ or with other genetic aberrations. There were no differences ‘convulsions’.Morethanone seizuretypewas recorded in in age between groups (see Table 2 for details). 33 individuals. Seizures resembling generalized tonic-clonic Age at epilepsy onset was highly correlated with SCQ seizures (sometimes described as generalized convulsions) score (r = − 0.61, p = 0.0004). A linear regression was were reported in 29 individuals. Seizures resembling conducted with SCQ as the dependent variable and age atypical absence seizures were seen in 17 individuals, at seizure onset and type of genetic abnormality as the myoclonic seizures in 10 and atonic seizures in 13. covariates (forced entry). Age at onset of seizures had an Focal seizures were seen in four individuals. Sixteen independent contribution when entering the type of individuals had their first seizure during a febrile episode, genetic aberration as a covariate. The type of genetic and 10 participants were reported to have epileptic seizures aberration did not have an independent contribution in that were aggravated by fever. EEGs were recorded this model (see Table 3 and Fig. 2). As a supplementary repeatedly in several participants, and findings were analysis, we included level of nonverbal communication typical of those reported in AS [2]. When EEGs were as a third covariate. Age of epilepsy onset was significant recorded prior to first seizure, delta waves but no also in this model (β = − 0.81, p= 0.007). epileptiform activity were often reported. More epilepti- form discharges in EEGs were recorded during periods of Discussion seizure aggravation. Seizures were commonly reported to This study explored the relationship between age of be resistant to anti-epileptic drugs and drug resistance epilepsy onset, autism symptomatology, type of genetic was particularly marked before 6 years of age, and 21 indi- aberration and nonverbal communication level in a viduals had received benzodiazepine as emergency treat- Norwegian sample of individuals with AS. Among the ment. Three individuals had been treated with only one 56 individuals with AS identified from the available anti-epileptic drug, and all others had tried two or more databases, 48 (86%) had genetically verified AS. This is anti-epileptic drugs. Valproate was the most frequently in line with other reports noting that no genetic abnor- prescribed anti-epileptic drug (31 participants), followed mality can be identified in 10–15% of individuals with by nitrazepam (18) and clonazepam (16). AS [4]. Other clinical findings were similar to those of previous studies of AS. Thus, deletions were the most Part 2: the relation between epilepsy and autism symptoms, common genetic cause identified [1, 4]. With regard to nonverbal communication level and genetic aberration epilepsy, the prevalence in this study was 77%, some- Mean SCQ was 16.3 (SD = 5.9 range: 0–27). SCQ scores what lower than the rates of ≥ 80% commonly reported were higher in individuals with epilepsy (n = 31) than in [4, 7, 8, 41]. However, our sample included several very those without (n = 7), but the difference was not significant young participants who may not yet have had their first (see Table 2). SCQ and age were not correlated (p = 0.12). seizure. We also excluded individuals in whom the Level of nonverbal communication did not differ between cause of AS was unknown and there is some indication Table 2 SCQ scores and age at onset of epilepsy according to communication level and genetic aberration Epilepsy No epilepsy Epilepsy and level of nonverbal Epilepsy and type of genetic (N = 31) (N =7) communication (n = 31) aberration (n = 23) p value < 20 signs ≥ 20 signs p value Deletion Other genetic p value [Hedges’ g] (n = 17) (n = 14) [Hedges’ g] (n = 18) aberration (n =5) [Hedges’ g] SCQ mean (SD) 17.0 (5.6) 13.6 (6.7) 0.354 [0.59] 19.4 (4.4) 14.1 (5.7) 0.007 [1.05] 18.7 (5.0) 10.8 (6.6) 0.007 [1.48] Age at onset of 36.6 months na na 30.2 months 44.4 months 0.160 [0.56] 25.2 months 79.0 months < 0.001 [3.60] epilepsy mean (SD) (26.0) (18.5) (32.1) (13.7) (19.3) Age (SD) 20.0 years (9.7) 13.0 years (9.6) 0.170 [0.72] 21.4 years (10.6) 18.2 years (8.6) 0.57 [0.33] 16.6 years (5.2) 17.4 years (9.5) 0.104 [0.13] SCQ Social Communication Questionnaire score, na not applicable Bakke et al. Molecular Autism (2018) 9:2 Page 5 of 8 Table 3 Statistical results of regression model with SCQ as to the number of autism symptoms reported. Although dependent outcome the lack of an independent effect of type of genetic aberra- Standardized Unstandardized coefficients tion is likely due to the low number of causes other than coefficients deletion, it should be noted that the slope of the regres- Covariate β pB Standard 95% confidence sion lines is similar for both genetic subgroups, thus error interval supporting the importance of age at seizure onset across Model with two covariates R = 0.53; F = 10, 7; p = 0.001 the sample. These findings from AS parallel evidence from Age at epilepsy onset − 0.90 0.006 − 0.21 0.07 − 0.35/− 0.07 studies in other rare disorders such as TSC; although both Genetic aberration − 0.22 0.45 − 3.24 4.23 − 12.01/5.61 early seizures and encephalopathy are highly associated with type of genetic abnormality, early seizures may con- tribute to a worsening of developmental outcome [17, 43]. that individuals with AS of unknown cause may have the Similarly, from fragile X syndrome, research indicates that highest prevalence of seizures [7]. Epilepsy characteristics males with the FMR1 premutation are more likely to have with early-onset epilepsy, multiple seizure types, a ASD and ID if seizures occur in childhood [29, 44]. tendency to have seizures during febrile episodes and Although individuals with epilepsy had more autism commonly treatment-resistant seizures, particularly in symptoms than those without epilepsy, and despite a early childhood, are also in line with the findings reported moderate to large effect size, this difference was not by others [2, 7, 8, 41, 42], and the use of anti-epileptic significant [15]. This may be due to the rarity of non- drugs is comparable to other studies [7, 8, 41]. epilepsy cases among individuals with AS and hence the The main focus of the study was the association very small size of the no-epilepsy group. However, the between age of epilepsy onset and extent of autism findings also point towards the importance of viewing symptomatology when type of genetic abnormality was epilepsy as a spectrum disorder rather than a dichotomy controlled for. Our findings from this study of individuals [15]. Hence, the comorbidity between autism symptoms with AS provide support for the notion that seizures and epilepsy may be related both to the underlying themselves contribute more to autism symptoms than pathology and to the effect of seizures. The high risk of might be expected from the underlying pathology alone ASD in populations with early-onset epilepsy has been [15–17, 21]. As anticipated, individuals with a deletion of used to support the encephalopathy hypothesis, i.e. that 15q11-q13 had substantially more autism symptoms than seizures may cause ASD [16, 25]. Others have argued individuals with other genetic aberrations (g =1.48). How- against this because the relationship is bi-directional ever, when entered into a regression model with epilepsy and individuals with ASD are at increased risk of future onset, genetic aberration made no significant contribution epilepsy and seizures may occur in adolescence or Fig. 2 Scatterplot of age at onset of epilepsy and SCQ. Fit-lines are shown according to the type of genetic abnormality Bakke et al. Molecular Autism (2018) 9:2 Page 6 of 8 adulthood [21, 22, 45, 46]. This study highlights the number of autism symptoms is highly related to severity importance of considering the additive effects of the of ID [11]. Thus, high rates of autism symptoms were to underlying genetic aetiology and seizures contributing be expected in this sample of individuals with AS [9, 10]. to autism symptoms in AS, which may be relevant also The severity of ID in AS is the main limitation when using for other conditions [15, 29]. The encephalopathic effect this disorder as a disease model for studying the relation may be greater when seizures start early. Early-life seizures between autism symptoms and epilepsy. may result in molecular changes which impact neural It is clear that information from a larger sample of network structure, and the hippocampal region may be of individuals with AS, with a larger range of genetic causes particular importance. Molecular changes may also influ- other than deletions, and detailed information on devel- ence the expression of genes involved in autism symptoms opmental level is needed to increase confidence in the and genetic syndromes such as GABRB3, FMR1, TSC1 current findings. More details of the genetic aberration, and TSC2 [16, 29]. Moreover, research suggests that such as size and exact break points of the deletions, are effectsof seizureson GABA -receptor expression are also needed. Finally, further studies in this area should age-dependent, a finding that further supports the notion investigate which autism symptoms are particularly that early seizures are particularly harmful [16]. vulnerable to early seizures and which are less affected. There was no difference in the level of nonverbal com- Such knowledge may be of relevance for better under- munication between the epilepsy group and no–epilepsy standing of the biology of ASD. group. Age of first seizure however, was associated with nonverbal communication (g = 0.56) and individuals with Conclusions the lowest level of nonverbal communication had earlier This study provides support for the notion that, in indi- seizure onset than those who used more signs to com- viduals with AS, seizures themselves contribute more municate. A number of other studies has found that to autism symptoms than expected from the underlying earlier age of seizure onset is associated with poorer genetic pathology. This study demonstrates how a rare cognitive outcome [18, 33, 35–37, 47, 48]. Our study condition may illuminate core issues in research on did not include a measure of development, only a measure developmental disorders. Individuals with Angelman of nonverbal communication. However, supplemental syndrome show limited variation in genetic aetiology, analysis showed that age of epilepsy remained significant and the condition is therefore a suitable one in which also when nonverbal communication was entered as a to investigate the relation between epilepsy and autism covariate. This suggests that the number of autism symp- symptoms. toms was not explained only by the level of nonverbal Abbreviations communication. AS: Angelman syndrome; ASD: Autism spectrum disorder; ID: Intellectual disability; Although the findings of this exploratory study have SCQ: Social Communication Questionnaire; TSC: Tuberous sclerosis complex potentially important implications for understanding the Acknowledgements complex links between autism symptoms and epilepsy, We are thankful to the participants in the study and the Norwegian there are a number of limitations that must be taken Angelman Society. We are thankful to Bjørg Hoem for sending out the into account in the interpretation of the data. Firstly, the questionnaires. This study is part of the BUPgen study group and the research network NeuroDevelop. sample size was small and the age of participants was very wide, ranging from infancy to adulthood. In addition, Funding we did not have data on the level of ID, only an estimate This study was funded by NevSom, University Hospital of Oslo. of nonverbal communication was available. There were Availability of data and materials also few individuals with a genetic cause other than the The datasets used and analyzed during the current study are available from 15q11 deletion, and we lacked data on size of deletions. the corresponding author on reasonable request. Furthermore, information from medical records was often incomplete and formal seizure classification, except for Authors’ contributions KAB, ØJK, AH and TN planned and designed the study. KAB collected the tonic-clonic seizures, was rarely performed. Hence, some clinical information from the medical records, and LR and AH collected the individuals may have had more types and higher frequency genetic data. KAB, PH and TN analysed the data and interpreted the results. of seizures than reported (particularly those of short dur- KAB wrote the first draft of the manuscript. All authors contributed to the manuscript and have read and approved the final manuscript. ation or less severe such as absences and myoclonic seizures). Finally, there was no clinical assessment of Ethics approval and consent to participate autism, and rather than a categorical distinction between The study was approved by the regional ethics committee in Norway (REK 2014/1880). Written informed consents were given by parents/guardians ASD/non-ASD, we focused on the frequency of autism allowing the researchers access to medical records from all hospitals in Norway. symptoms as measured by the SCQ. While this avoided the problems of misdiagnosing ASD in a population with Consent for publication severe developmental delay, it is well established that the Not applicable Bakke et al. Molecular Autism (2018) 9:2 Page 7 of 8 Competing interests 18. Capal JK, Bernardino-Cuesta B, Horn PS, Murray D, Byars AW, Bing NM, et al. The authors declare that they have no competing interests. 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Effect of epilepsy on autism symptoms in Angelman syndrome

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2018 The Author(s).
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10.1186/s13229-017-0185-1
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Abstract

Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1–57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged ≥ 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and ≥ 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months–7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = − 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (β = − 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R = 0.53; F = 10.7; p =0.001). Conclusions: The study provides support for the notion that seizuresthemselvescontributemoretoautismsymptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology. Keywords: Angelman syndrome, Autism spectrum disorder, Epilepsy, Epileptic encephalopathy, Seizure onset Background seizure types and starting in early childhood [7, 8]. High Angelman syndrome (AS) is a neurodevelopmental dis- rates of autistic symptoms are also reported [9–11], with order caused by an absent or non-functioning maternal prevalence estimates of autism spectrum disorder (ASD) allele of chromosome 15q11-q13 [1]. The typical AS ranging from 24 to 81% [6, 10]. AS can be due to phenotype is characterized by intellectual disability (ID), UBE3A mutations, uniparental disomy and imprinting lack of speech, hyperactivity, ataxic gait, microcephaly, defects [1, 12], but deletions are the predominant cause sleep disturbances, frequent laughter/smiling and an and are found in 68–75% of patients. Deletions are also apparently happy demeanour [1–4]. ID ranges from associated with more severe AS-phenotype, and co- moderate to profound, with most individuals functioning deletion of GABA -receptor genes (GABRB3, GABRA5 in the severe to profound range [5, 6]. Epilepsy occurs in and GABRG3) located adjacent to UBE3A gene is sug- 80% or more of cases [2, 7], usually involving multiple gested as a possible explanation for this [1]. Dysfunction of GABRB3 is highly associated with both epilepsy and autism symptoms [13, 14]. * Correspondence: [email protected] NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bakke et al. Molecular Autism (2018) 9:2 Page 2 of 8 A strong association between autism symptoms, epilepsy Association, 115 individuals with AS were identified. Letters and ID has been found in a number of other genetic syn- were sent to the parents/guardians of these individuals, and dromes, such as fragile X and tuberous sclerosis complex they were asked to complete two questionnaires: the Social (TSC), as well as in AS [6, 10]. It is evident, too, that the Communication Questionnaire (SCQ), which measures negative effect of seizures is particularly strong during autism symptoms [38], and a study-specific question- infancy and early childhood [15–18]. Thus, onset of naire assessing epilepsy, medication and developmental seizures during the first year of life is associated with parameters. Written informed consent was given by all increased prevalence and severity of ID and ASD and parents/guardians allowing the researchers access to increased prevalence of brain abnormalities [19, 20]. medical records from all hospitals in Norway (Fig. 1). However, there is a continuing debate [21–24] as to whether autism symptoms, epilepsy and ID are inde- Measures pendent comorbidities [15, 16, 21, 25–27], whether they Clinical information on epilepsy and genetic abnormality are all outcomes of the same underlying pathophysio- Participants’ medical records were used to collect infor- logical/genetic mechanisms [17, 21, 25, 28], or whether mation regarding epilepsy and the nature of the genetic the epilepsy itself contributes to more severe cognitive abnormality. Information on age of epilepsy onset, type and behavioural impairments than might be expected of seizure and treatment with anti-epileptic drugs was from the underlying pathology alone [15, 17, 29, 30], recorded when available. Medical records were not i.e. a so-called encephalopathic effect [30]. comprehensive for all individuals, and formal seizure There are several reasons why AS offers a suitable disease classification was not always performed. model to investigate the association between epilepsy, ID Genetic data were also variable. When information was and autism symptoms. Firstly, the rate of epilepsy in AS available, the genetic abnormality was dichotomised into (> 80%) is as high as or higher than other genetic disorders ‘deletion’ or ‘other’ (i.e.uniparental disomy,imprinting in which epilepsy and autism commonly co-occur (e.g. TSC defects and point mutations). [80–90%]; fragile X syndrome [10–20%]) [29, 31, 32]. Sec- ondly, epilepsy in AS tends to start in very early childhood. Autism symptoms Seizures are also often treatment-resistant and refractory The lifetime version of SCQ was used to assess the number epilepsy has been shown to be an important predictor of of autism symptoms [38]. The SCQ contains 40 items autism symptoms [33]. Thirdly, unlike genetic conditions scored 0 or 1 and was designed to screen for a possible such as TSC, in which the numbers and location of tubers diagnosis of autism in individuals aged 4 years and older are associated with autism symptoms [17, 34], there are no and with a mental age above 2 years [38]. It has also specific structural brain abnormalities in AS that are known frequently been used to measure autistic-type symptoms in to affect the phenotype. Fourthly, knowledge of the specific individuals with genetic syndromes including those with genetic defects that cause AS makes it possible to evaluate AS [9, 11]. We did not classify participants as meeting/not the degree to which the association between epilepsy and meeting the suggested cut-off scores for autism or ASD autism symptoms is a result of the underlying genetic (≥ 22 and ≥ 15, respectively [38]) since the validity of abnormality and to assess the independent contribution of these criteria has not been established for individuals seizures on level of autism symptoms. with genetic disorders associated with severe ID. Never- The aims of the current study were to describe epilepsy theless, SCQ has often been used as the screening tool characteristics and then investigate the relationship in samples with low IQ [39, 40]. between epilepsy, autism symptoms, communication level and genetic cause in individuals with AS. Based on previ- Communication level ous research on other populations with childhood epilepsy Information about level of development was particularly including TSC [18, 33, 35–37], we hypothesized that age of variable and often very limited. Although many parents onset of epilepsy would be related to the number of autism reported that they had previously been told their child symptoms in AS independent of the effect of the specific had severe to profound intellectual disability (in 7 cases, genetic abnormality. the description was of ‘moderate’ disability), formal test results were rarely recorded, and hence, the validity of Methods these categories was unknown. Although there were no The study was approved by the regional ethics committee adequate data on IQ/developmental level, we did have in Norway (REK 2014/1880). data on communication level. Signing was the major mean of communication for most of the participants; Recruitment procedures the majority had no use of words and no one used more From the records of the Frambu Resource Centre for than 20 words. Categorical ratings of ‘use of signs’ (< 20 Rare Disorders in Norway and the Norwegian Angelman and 20–100 and > 100) were used to divide individuals Bakke et al. Molecular Autism (2018) 9:2 Page 3 of 8 Fig. 1 Recruitment into two groups; those using fewer than 20 signs to com- r). Due to small sample size, Mann-Whitney U test municate and those with more than 20 signs. was used when comparing SCQ in subgroups with/ without epilepsy and when comparing SCQ and age of epilepsy onset in subgroups with/without deletion. Participants Fisher’s exact test was used for categorical data. Due Inclusion criteria to small and unequal sample sizes, Hedges’ g was For the descriptive part of the study (‘Epilepsy characteris- used for effect sizes. Normality of residuals was checked tics’), individuals were included if their parents/guardians using visual inspection of P-P plots. Multiple regression gave their consent to participation/access to medical analysis was conducted to assess the impact of ‘age at records and if their son/daughter had a genetically verified epilepsy onset’and ‘type of genetic aberration’ on SCQ diagnosis of AS. For the second part of the study (‘Relation scores. Due to the combination of dichotomous and between epilepsy and autism symptoms, nonverbal com- continuous covariates, we report the standardized coef- munication level and genetic aberration’), individuals were ficients (β). To correct for multiple comparisons, a sig- required to be at least 4 years of age (i.e. minimum age for nificance level of p ≤ 0.01 was chosen; Bonferroni ‘rule the SCQ). of thumb’ was used to determine appropriate p level Parents/guardians of 56 out of the 115 individuals (p = 0.05/5 = 0.01). identified from the records (49%) consented to par- ticipate; 48 of these individuals (age range 1–57 years; median 14 years 6 months) had a genetically verified AS diagnosis. At the time of questionnaire comple- tion (see Fig. 1), medical records confirmed that 34 in- Table 1 Characteristics of participants with Angelman dividuals had epilepsy and 11 individuals did not. Three syndrome in parts 1 and 2 of study boys (aged 1, 1, and 4 years, respectively) subsequently de- Age Gender Genetics veloped seizures; hence, the 4-year-old was included in Part 1: Range: 1–57 years Male: 30 Deletion: 26 (16 males) the no-epilepsy group in the part 2 of the study. SCQ Epilepsy Mean: 17.1 years Female: 18 UPD: 4 (2 males) characteristics Median: 14.5 years Imprinting: 3 (1 male) questionnaires were completed for 38 of 40 individuals (n=48) Mutation: 2 (1 male) aged 4 years or older (SCQ was not completed for two Unknown: 13 (10 males) participants aged 57 and 40 years). See Table 1 for partici- Part 2: Range: 1–57 years Male: 30 Deletion: 26 (16 males) pants’ characteristics. Relation between Mean: 20.2 years Female: 15 UPD: 2 (2 males) epilepsy and autism Median: 19.1 years Imprinting: 2 (1 male) symptoms, nonverbal Mutation: 2 (1 male) Statistical analysis communication Unknown: 12 (9 males) level and genetic Associations between quantitative measures were ana- aberration (n=40) lyzed by parametric statistics in SPSS (t test, Pearson’s Bakke et al. Molecular Autism (2018) 9:2 Page 4 of 8 Results individuals with and without epilepsy; 19 of 33 (58%) with Part 1: epilepsy characteristics epilepsy and 4 of 7 (57%) (exact p = 1.000) without epilepsy Age of first seizure ranged from 3 months to 7 years used fewer than 20 signs to communicate. Individuals with 10 months (mean 3 years 0 months, SD 2 years 2 months). the deletion weremorelikelytobein the group using <20 Four individuals had their initial seizure during the first year signs to communicate than individuals with other genetic of life; 11 developed epilepsy during the second year. The aberrations (exact p = 0.022). number and type of seizures varied among individuals and Within the epilepsy group, age of epilepsy onset was varied over time in the same individuals. Two individuals lower among individuals using < 20 signs to communicate. (aged 38 and 27 years) had been diagnosed with Lennox- Individuals with the deletion had significantly higher SCQ Gastaut syndrome. One individual had only ‘atypical scores and lower age at epilepsy onset than individuals absence seizures,’ and all others had seizures with ‘jerks’ or with other genetic aberrations. There were no differences ‘convulsions’.Morethanone seizuretypewas recorded in in age between groups (see Table 2 for details). 33 individuals. Seizures resembling generalized tonic-clonic Age at epilepsy onset was highly correlated with SCQ seizures (sometimes described as generalized convulsions) score (r = − 0.61, p = 0.0004). A linear regression was were reported in 29 individuals. Seizures resembling conducted with SCQ as the dependent variable and age atypical absence seizures were seen in 17 individuals, at seizure onset and type of genetic abnormality as the myoclonic seizures in 10 and atonic seizures in 13. covariates (forced entry). Age at onset of seizures had an Focal seizures were seen in four individuals. Sixteen independent contribution when entering the type of individuals had their first seizure during a febrile episode, genetic aberration as a covariate. The type of genetic and 10 participants were reported to have epileptic seizures aberration did not have an independent contribution in that were aggravated by fever. EEGs were recorded this model (see Table 3 and Fig. 2). As a supplementary repeatedly in several participants, and findings were analysis, we included level of nonverbal communication typical of those reported in AS [2]. When EEGs were as a third covariate. Age of epilepsy onset was significant recorded prior to first seizure, delta waves but no also in this model (β = − 0.81, p= 0.007). epileptiform activity were often reported. More epilepti- form discharges in EEGs were recorded during periods of Discussion seizure aggravation. Seizures were commonly reported to This study explored the relationship between age of be resistant to anti-epileptic drugs and drug resistance epilepsy onset, autism symptomatology, type of genetic was particularly marked before 6 years of age, and 21 indi- aberration and nonverbal communication level in a viduals had received benzodiazepine as emergency treat- Norwegian sample of individuals with AS. Among the ment. Three individuals had been treated with only one 56 individuals with AS identified from the available anti-epileptic drug, and all others had tried two or more databases, 48 (86%) had genetically verified AS. This is anti-epileptic drugs. Valproate was the most frequently in line with other reports noting that no genetic abnor- prescribed anti-epileptic drug (31 participants), followed mality can be identified in 10–15% of individuals with by nitrazepam (18) and clonazepam (16). AS [4]. Other clinical findings were similar to those of previous studies of AS. Thus, deletions were the most Part 2: the relation between epilepsy and autism symptoms, common genetic cause identified [1, 4]. With regard to nonverbal communication level and genetic aberration epilepsy, the prevalence in this study was 77%, some- Mean SCQ was 16.3 (SD = 5.9 range: 0–27). SCQ scores what lower than the rates of ≥ 80% commonly reported were higher in individuals with epilepsy (n = 31) than in [4, 7, 8, 41]. However, our sample included several very those without (n = 7), but the difference was not significant young participants who may not yet have had their first (see Table 2). SCQ and age were not correlated (p = 0.12). seizure. We also excluded individuals in whom the Level of nonverbal communication did not differ between cause of AS was unknown and there is some indication Table 2 SCQ scores and age at onset of epilepsy according to communication level and genetic aberration Epilepsy No epilepsy Epilepsy and level of nonverbal Epilepsy and type of genetic (N = 31) (N =7) communication (n = 31) aberration (n = 23) p value < 20 signs ≥ 20 signs p value Deletion Other genetic p value [Hedges’ g] (n = 17) (n = 14) [Hedges’ g] (n = 18) aberration (n =5) [Hedges’ g] SCQ mean (SD) 17.0 (5.6) 13.6 (6.7) 0.354 [0.59] 19.4 (4.4) 14.1 (5.7) 0.007 [1.05] 18.7 (5.0) 10.8 (6.6) 0.007 [1.48] Age at onset of 36.6 months na na 30.2 months 44.4 months 0.160 [0.56] 25.2 months 79.0 months < 0.001 [3.60] epilepsy mean (SD) (26.0) (18.5) (32.1) (13.7) (19.3) Age (SD) 20.0 years (9.7) 13.0 years (9.6) 0.170 [0.72] 21.4 years (10.6) 18.2 years (8.6) 0.57 [0.33] 16.6 years (5.2) 17.4 years (9.5) 0.104 [0.13] SCQ Social Communication Questionnaire score, na not applicable Bakke et al. Molecular Autism (2018) 9:2 Page 5 of 8 Table 3 Statistical results of regression model with SCQ as to the number of autism symptoms reported. Although dependent outcome the lack of an independent effect of type of genetic aberra- Standardized Unstandardized coefficients tion is likely due to the low number of causes other than coefficients deletion, it should be noted that the slope of the regres- Covariate β pB Standard 95% confidence sion lines is similar for both genetic subgroups, thus error interval supporting the importance of age at seizure onset across Model with two covariates R = 0.53; F = 10, 7; p = 0.001 the sample. These findings from AS parallel evidence from Age at epilepsy onset − 0.90 0.006 − 0.21 0.07 − 0.35/− 0.07 studies in other rare disorders such as TSC; although both Genetic aberration − 0.22 0.45 − 3.24 4.23 − 12.01/5.61 early seizures and encephalopathy are highly associated with type of genetic abnormality, early seizures may con- tribute to a worsening of developmental outcome [17, 43]. that individuals with AS of unknown cause may have the Similarly, from fragile X syndrome, research indicates that highest prevalence of seizures [7]. Epilepsy characteristics males with the FMR1 premutation are more likely to have with early-onset epilepsy, multiple seizure types, a ASD and ID if seizures occur in childhood [29, 44]. tendency to have seizures during febrile episodes and Although individuals with epilepsy had more autism commonly treatment-resistant seizures, particularly in symptoms than those without epilepsy, and despite a early childhood, are also in line with the findings reported moderate to large effect size, this difference was not by others [2, 7, 8, 41, 42], and the use of anti-epileptic significant [15]. This may be due to the rarity of non- drugs is comparable to other studies [7, 8, 41]. epilepsy cases among individuals with AS and hence the The main focus of the study was the association very small size of the no-epilepsy group. However, the between age of epilepsy onset and extent of autism findings also point towards the importance of viewing symptomatology when type of genetic abnormality was epilepsy as a spectrum disorder rather than a dichotomy controlled for. Our findings from this study of individuals [15]. Hence, the comorbidity between autism symptoms with AS provide support for the notion that seizures and epilepsy may be related both to the underlying themselves contribute more to autism symptoms than pathology and to the effect of seizures. The high risk of might be expected from the underlying pathology alone ASD in populations with early-onset epilepsy has been [15–17, 21]. As anticipated, individuals with a deletion of used to support the encephalopathy hypothesis, i.e. that 15q11-q13 had substantially more autism symptoms than seizures may cause ASD [16, 25]. Others have argued individuals with other genetic aberrations (g =1.48). How- against this because the relationship is bi-directional ever, when entered into a regression model with epilepsy and individuals with ASD are at increased risk of future onset, genetic aberration made no significant contribution epilepsy and seizures may occur in adolescence or Fig. 2 Scatterplot of age at onset of epilepsy and SCQ. Fit-lines are shown according to the type of genetic abnormality Bakke et al. Molecular Autism (2018) 9:2 Page 6 of 8 adulthood [21, 22, 45, 46]. This study highlights the number of autism symptoms is highly related to severity importance of considering the additive effects of the of ID [11]. Thus, high rates of autism symptoms were to underlying genetic aetiology and seizures contributing be expected in this sample of individuals with AS [9, 10]. to autism symptoms in AS, which may be relevant also The severity of ID in AS is the main limitation when using for other conditions [15, 29]. The encephalopathic effect this disorder as a disease model for studying the relation may be greater when seizures start early. Early-life seizures between autism symptoms and epilepsy. may result in molecular changes which impact neural It is clear that information from a larger sample of network structure, and the hippocampal region may be of individuals with AS, with a larger range of genetic causes particular importance. Molecular changes may also influ- other than deletions, and detailed information on devel- ence the expression of genes involved in autism symptoms opmental level is needed to increase confidence in the and genetic syndromes such as GABRB3, FMR1, TSC1 current findings. More details of the genetic aberration, and TSC2 [16, 29]. Moreover, research suggests that such as size and exact break points of the deletions, are effectsof seizureson GABA -receptor expression are also needed. Finally, further studies in this area should age-dependent, a finding that further supports the notion investigate which autism symptoms are particularly that early seizures are particularly harmful [16]. vulnerable to early seizures and which are less affected. There was no difference in the level of nonverbal com- Such knowledge may be of relevance for better under- munication between the epilepsy group and no–epilepsy standing of the biology of ASD. group. Age of first seizure however, was associated with nonverbal communication (g = 0.56) and individuals with Conclusions the lowest level of nonverbal communication had earlier This study provides support for the notion that, in indi- seizure onset than those who used more signs to com- viduals with AS, seizures themselves contribute more municate. A number of other studies has found that to autism symptoms than expected from the underlying earlier age of seizure onset is associated with poorer genetic pathology. This study demonstrates how a rare cognitive outcome [18, 33, 35–37, 47, 48]. Our study condition may illuminate core issues in research on did not include a measure of development, only a measure developmental disorders. Individuals with Angelman of nonverbal communication. However, supplemental syndrome show limited variation in genetic aetiology, analysis showed that age of epilepsy remained significant and the condition is therefore a suitable one in which also when nonverbal communication was entered as a to investigate the relation between epilepsy and autism covariate. This suggests that the number of autism symp- symptoms. toms was not explained only by the level of nonverbal Abbreviations communication. AS: Angelman syndrome; ASD: Autism spectrum disorder; ID: Intellectual disability; Although the findings of this exploratory study have SCQ: Social Communication Questionnaire; TSC: Tuberous sclerosis complex potentially important implications for understanding the Acknowledgements complex links between autism symptoms and epilepsy, We are thankful to the participants in the study and the Norwegian there are a number of limitations that must be taken Angelman Society. We are thankful to Bjørg Hoem for sending out the into account in the interpretation of the data. Firstly, the questionnaires. This study is part of the BUPgen study group and the research network NeuroDevelop. sample size was small and the age of participants was very wide, ranging from infancy to adulthood. In addition, Funding we did not have data on the level of ID, only an estimate This study was funded by NevSom, University Hospital of Oslo. of nonverbal communication was available. There were Availability of data and materials also few individuals with a genetic cause other than the The datasets used and analyzed during the current study are available from 15q11 deletion, and we lacked data on size of deletions. the corresponding author on reasonable request. Furthermore, information from medical records was often incomplete and formal seizure classification, except for Authors’ contributions KAB, ØJK, AH and TN planned and designed the study. KAB collected the tonic-clonic seizures, was rarely performed. Hence, some clinical information from the medical records, and LR and AH collected the individuals may have had more types and higher frequency genetic data. KAB, PH and TN analysed the data and interpreted the results. of seizures than reported (particularly those of short dur- KAB wrote the first draft of the manuscript. All authors contributed to the manuscript and have read and approved the final manuscript. ation or less severe such as absences and myoclonic seizures). Finally, there was no clinical assessment of Ethics approval and consent to participate autism, and rather than a categorical distinction between The study was approved by the regional ethics committee in Norway (REK 2014/1880). Written informed consents were given by parents/guardians ASD/non-ASD, we focused on the frequency of autism allowing the researchers access to medical records from all hospitals in Norway. symptoms as measured by the SCQ. While this avoided the problems of misdiagnosing ASD in a population with Consent for publication severe developmental delay, it is well established that the Not applicable Bakke et al. Molecular Autism (2018) 9:2 Page 7 of 8 Competing interests 18. Capal JK, Bernardino-Cuesta B, Horn PS, Murray D, Byars AW, Bing NM, et al. The authors declare that they have no competing interests. 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Journal

Molecular Autism – Springer Journals

Published: Dec 1, 2018

Keywords: neurology; neurosciences; neuropsychology; psychiatry; pediatrics; human genetics

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