T. Nicole Takahashi

Facial phenotypes in subgroups of prepubertal boys with autism spectrum disorders are correlated with clinical phenotypes

BackgroundThe brain develops in concert and in coordination with the developing facial tissues, with each influencing the development of the other and sharing genetic signaling pathways. Autism spectrum disorders (ASDs) result from alterations in the embryological brain, suggesting that the development of the faces of children with ASD may result in subtle facial differences compared to typically developing children. In this study, we tested two hypotheses. First, we asked whether children with ASD display a subtle but distinct facial phenotype compared to typically developing children. Second, we sought to determine whether there are subgroups of facial phenotypes within the population of children with ASD that denote biologically discrete subgroups.MethodsThe 3dMD cranial System was used to acquire three-dimensional stereophotogrammetric images for our study sample of 8- to 12-year-old boys diagnosed with essential ASD (n = 65) and typically developing boys (n = 41) following approved Institutional Review Board protocols. Three-dimensional coordinates were recorded for 17 facial anthropometric landmarks using the 3dMD Patient software. Statistical comparisons of facial phenotypes were completed using Euclidean Distance Matrix Analysis and Principal Coordinates Analysis. Data representing clinical and behavioral traits were statistically compared among groups by using χ2 tests, Fishers exact tests, Kolmogorov-Smirnov tests and Students t-tests where appropriate.ResultsFirst, we found that there are significant differences in facial morphology in boys with ASD compared to typically developing boys. Second, we also found two subgroups of boys with ASD with facial morphology that differed from the majority of the boys with ASD and the typically developing boys. Furthermore, membership in each of these distinct subgroups was correlated with particular clinical and behavioral traits.ConclusionsBoys with ASD display a facial phenotype distinct from that of typically developing boys, which may reflect alterations in the prenatal development of the brain. Subgroups of boys with ASD defined by distinct facial morphologies correlated with clinical and behavioral traits, suggesting potentially different etiologies and genetic differences compared to the larger group of boys with ASD. Further investigations into genes involved in neurodevelopment and craniofacial development of these subgroups will help to elucidate the causes and significance of these subtle facial differences.

Lack of association between Rh status, Rh immune globulin in pregnancy and autism.

Though causes of autism are considered largely genetic, considerable concern remains that exposure to Rh immune globulin (RhIg), which until 2001 in the United States contained the preservative thimerosal, can cause autism. To determine whether mothers of children with autism are more likely to be Rh negative (Rh−) or to have received RhIg preserved with thimerosal, which is 49.6% ethyl mercury, we surveyed families of children with an autism spectrum disorder (ASD) ascertained through a University‐based autism clinic considered free of ascertainment biases related to type of autism or severity. Between 2004 and 2006, 305 mothers of 321 children with an ASD agreed to participate in a telephone interview. Analysis of complete records including the blood group status and RhIg exposure of 214 families showed that Rh− status is no higher in mothers of children with autism than in the general population, exposure to antepartum RhIg, preserved with thimerosal is no higher for children with autism and pregnancies are no more likely to be Rh incompatible. This was also true for autism subgroups defined by behavioral phenotype, gender, IQ, regressive onset, head circumference, dysmorphology, birth status, essential, or complex phenotype. These findings support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism. These data are important not only for parents in this country but also for the international health community where thimerosal continues to be used to preserve multi‐dose vials which in turn makes vaccines affordable.

Autism Families with a High Incidence of Alcoholism

To determine the significance of neuropsychiatric disorders in autism families, we analyzed 167 pedigrees ascertained through an autistic child; 39% had alcoholism in patterns consistent with transmission of a genetic trait. Children from high alcoholism families were more likely to have the onset of their autistic behavior occur with a loss of language (52.5% vs. 35.8%, p = 0.04). This occurred primarily in families where the mother was alcoholic (80% vs. 40%, p = 0.05), suggesting an association between maternal alcoholism and regressive onset autism. Children from high alcoholism families were less likely to be macrocephalic (14.7% vs. 40.6%, p = 0.0006). Children from high alcohol and low alcohol families did not differ in dysmorphology status, IQ, sex ratio or sib recurrence risk.

Predicting Responsiveness to Treatment of Children With Autism A Retrospective Study of the Importance of Physical Dysmorphology

This retrospective study examined predictors of outcome for children With autism folloWing 6 and 12 months of early intensive behavioral intervention. Potential predictor variables included pretreatment functioning, age at onset of treatment, treatment intensity, family involvement, and physical characteristics (e.g., brain abnormalities, dysmorphology). For the 19 study participants, presence of dysmorphic features Was the only variable that predicted response to treatment after 6 months (R 2 = .58). Dysmorphology Was associated With Worse outcomes. After 12 months, both dysmorphology and a history of regression predicted poorer response to treatment (R 2 = .67). Children Who made the most progress in treatment had pretreatment language skills and normal physical features. Dysmorphic features in children With autism may represent abnormalities in prenatal development that are associated With poorer child outcomes.

Facial structure analysis separates autism spectrum disorders into meaningful clinical subgroups.

Varied cluster analysis were applied to facial surface measurements from 62 prepubertal boys with essential autism to determine whether facial morphology constitutes viable biomarker for delineation of discrete Autism Spectrum Disorders (ASD) subgroups. Earlier study indicated utility of facial morphology for autism subgrouping (Aldridge et al. in Mol Autism 2(1):15, 2011). Geodesic distances between standardized facial landmarks were measured from three-dimensional stereo-photogrammetric images. Subjects were evaluated for autism-related symptoms, neurologic, cognitive, familial, and phenotypic variants. The most compact cluster is clinically characterized by severe ASD, significant cognitive impairment and language regression. This verifies utility of facially-based ASD subtypes and validates Aldridge et al.’s severe ASD subgroup, notwithstanding different techniques. It suggests that language regression may define a unique ASD subgroup with potential etiologic differences.

Sorting the phenotypic heterogeneity of autism spectrum disorders: A hierarchical clustering model

Autism spectrum disorder (ASD) is characterized by notable phenotypic heterogeneity, which is often viewed as an obstacle to the study of its etiology, diagnosis, treatment, and prognosis. Heterogeneity in ASD is multidimensional and complex including variability in phenotype as well as clinical, physiologic, and pathologic parameters. We apply a hierarchical clustering model suited to dealing with datasets of mixed data types to stratify children with ASD into more homogeneous subgroups in line with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 model. The results of this cluster analysis will provide a better understanding the complex issue of ASD phenotypic heterogeneity and identify subgroups useful for further ASD genetic studies. Our goal is to provide insight into viable phenotypic and genotypic markers that would guide further cluster analysis of ASD genetic data. We suggest that analyzing the clusters in a hierarchical structure is a well-suited and meaningful model to unravel the complex heterogeneity of this disorder.

Ensemble statistical and subspace clustering model for analysis of autism spectrum disorder phenotypes

Heterogeneity in Autism Spectrum Disorder (ASD) is complex including variability in behavioral phenotype as well as clinical, physiologic, and pathologic parameters. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) now diagnoses ASD using a 2-dimensional model based social communication deficits and fixated interests and repetitive behaviors. Sorting out heterogeneity is crucial for study of etiology, diagnosis, treatment and prognosis. In this paper, we present an ensemble model for analyzing ASD phenotypes using several machine learning techniques and a k-dimensional subspace clustering algorithm. Our ensemble also incorporates statistical methods at several stages of analysis. We apply this model to a sample of 208 probands drawn from the Simon Simplex Collection Missouri Site patients. The results provide useful evidence that is helpful in elucidating the phenotype complexity within ASD. Our model can be extended to other disorders that exhibit a diverse range of heterogeneity.

Atypical pupillary light reflex in 2–6-year-old children with autism spectrum disorders

The purpose of this study was to investigate pupillary light reflex (PLR) in 2–6‐years‐old children with autism spectrum disorders (ASD). A total of 117 medication‐free 2–6‐year‐old boys participated in this study. Sixty participants were diagnosed with ASD (the “ASD group”) and the other 57 were in the control group of typical development (the “TD group”). A questionnaire was completed by the parent/guardian for assessing potential dysfunctions in the autonomic nervous system (ANS). The base pupil radius, PLR latency, and constriction time showed a significant age‐related trend in both the ASD and TD groups. The base pupil size increased with age in the typically developing children, but not in the ASD group. The ASD group showed more symptoms related to ANS dysfunctions. An association between abnormal sweating with base pupil radius and PLR constriction was observed in the TD group but not the ASD group. The different association of PLR parameters with ANS dysfunction may suggest disrupted autonomic controls in children with ASD. Autism Res 2017, 10: 829–838.

Reply to Bernard et al. “Re: Miles and Takahashi Paper on RhIg and Autism”

Our study used Rh status as a surrogate for exposure to prenatal thimerosal and found no difference in rates of Rh status between mothers of childrenwith autism and controls. We assiduously recorded the brand and lot number of RhIg from prenatal records collected from the 29 Rh mothers who were treated during their pregnancy. In cases where there was any question, as when the lot number was not recorded, we called the administering obstetrical office or hospital to determine which product was used. This confirmed that the surrogate was valid in the locality of our study, that is, all Rh mothers were in fact exposed to an RhIg which contained thimerosal. Since it is very reasonable that on a local or regional basis, one brand can predominate, invoking an estimated US market share is irrelevant for our Missouri population. Moreover, SafeMinds market share argument is spurious, based on 1996–2000 numbers and an erroneous assumption that our study group were all pregnant within that period. More than half (15/29) of our Rh study pregnancies occurred prior to 1996 before the introduction of thimerosal free RhIg (BayRho) by Bayer Corporation. During this time which product was used is immaterial since both products contained thimerosal; in fact, the Bayer product contained either an equivalent or a greater concentration of thimerosal than RhoGam (0.01% vs. 0.003% after 1986). And, the 14 pregnancies after 1995, were not randomly distributed; 5 were in 1996, 1 in 1998, 3 in 1999, 3 in 2000, and 2 in 2001. Finally, let us point out that the use of unvalidated IMS data with an unspecified rate of error, unknown variance, and no demonstrated applicability to local or regional utilization rates plus an uninterpretable extrapolation methodology is devoid of any statistical or scientific merit. To answer the second question, we recognized that we could access an optimal population in which to test our study hypothesis. Families evaluated in our multidisciplinary autism clinic, partially supported by theMissouri Department of Mental Health, came only because of some question about autism, not because of a bias of the clinic toward a specific therapy or type of autism. Thus, the design of our study was hypothesis driven and prescribed by our study population of families who had generously agreed to be contacted and to participate in research designed to learn more about the causes and treatments of autism. Being a simple study not likely to attract NIH funding but requiring many months collecting records, we submitted an unsolicited research proposal to Johnson and Johnson, the manufacturers of RhoGam, who agreed to fund the project. The intent of this study was to provide one more piece of evidence regarding the causes of autism spectrum disorders, contributing to research aimed at understanding both the genetic and environmental factors that lead to these disorders.