Clinical Characteristics of Children with Autism Spectrum Disorder and Co-Occurring Epilepsy

Objectives: To estimate the prevalence of epilepsy in children with Autism Spectrum Disorder (ASD) and to determine the demographic and clinical characteristics of children with ASD and epilepsy in a large patient population. Methods: Cross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. The prevalence of epilepsy was estimated from a population-based sample. Children with and without epilepsy were compared on demographic and clinical characteristics. Multivariate logistic regression was used to examine the association between demographic and clinical characteristics and epilepsy. Results: The average prevalence of epilepsy in children with ASD 2–17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. The association between epilepsy and the majority of these characteristics appears to be driven by the lower IQ of participants with epilepsy. In a multivariate regression model, only age and cognitive ability were independently associated with epilepsy. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001). Conclusion: This is among the largest studies to date of patients with ASD and co-occurring epilepsy. Based on a representative sample of children with ASD, the average prevalence of epilepsy is approximately 12% and reaches 26% by adolescence. Independent associations were found between epilepsy and older age and lower cognitive ability. Other risk factors, such as poor language and developmental regression, are not associated with epilepsy after controlling for IQ. These findings can help guide prognosis and alert clinicians to patients with ASD who are at increased risk for epilepsy

A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+)/H(+) Exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, ages 4 to 19) with mutations in NHE6 were administered standardized research assessments and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants (SNVs), 2 indels and 1 CNV deletion. All mutations were protein-truncating or splicing mutations. We identified two recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, seven of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical and behavioral symptoms. All CS participants were non-verbal and had intellectual disability, epilepsy and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%) and MRI evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%) and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy and regression

Epilepsy Diagnosis by Gender and Age among Individuals with Autism Spectrum Disorder.

<p>Abbreviations: NSCH, 2007 National Survey of Children’s Health; Wt. %, weighted percentage; CI, confidence interval.</p>a<p>Genetic Collaborative Samples (AGRE, SSC, and AC) combined.</p>b<p>Unweighted number of children.</p

Prevalence of Epilepsy by Age among Individuals with Autism Spectrum Disorder, All Studies.

<p>The percentage of children with epilepsy by age group by study sample. The prevalence is higher in older children than younger children. Abbreviations: AGRE, the Autism Genetic Resource Exchange; SSC, the Simons Simplex Collection; AC, the Autism Consortium; NSCH, 2007 the National Survey of Children’s Health.</p

Logistic Regression Modeling the Odds of an Epilepsy Diagnosis by Demographic and Clinical Characteristics, Combined Genetic Collaborative Sample^a.

<p>Abbreviations: OR, odds ratio; CI, confidence interval; FSIQ, full scale IQ score.</p>a<p>Genetic Collaborative Samples (AGRE, SSC, and AC) combined.</p><p>Model 1: Individual models for each variable.</p><p>Model 2: Individual models for each variable, adjusted for full scale IQ score only.</p><p>Model 3: Single model adjusted for all variables.</p><p>Odds ratios for full scale IQ score and adaptive behavior composite score represent the odds of epilepsy for a one standard deviation increase.</p

Distribution of Epilepsy among Individuals with Autism Spectrum Disorder by Study Sample.

<p>Abbreviations: AGRE, the Autism Genetic Resource Exchange; SSC, the Simons Simplex Collection; AC, the Autism Consortium; NSCH, the 2007 National Survey of Children’s Health; Wt. %, weighted percentage; CI, confidence interval.</p>a<p>Genetic Collaborative Samples (AGRE, SSC, and AC) combined.</p>b<p>Unweighted number of children.</p

Summary of Samples and Measures.

<p>Abbreviations: ASD, Autism Spectrum Disorder; ADI-R, Autism Diagnostic Interview–Revised.</p