Susan L. Hyman

Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

A replication of the Autism Diagnostic Observation Schedule (ADOS) revised algorithms

OBJECTIVE To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282). METHOD Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment. RESULTS Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified. CONCLUSIONS Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.

Head circumference and height in autism : A study by the collaborative program of excellence in autism

Data from 10 sites of the NICHD/NIDCD Collaborative Programs of Excellence in Autism were combined to study the distribution of head circumference and relationship to demographic and clinical variables. Three hundred thirty‐eight probands with autism‐spectrum disorder (ASD) including 208 probands with autism were studied along with 147 parents, 149 siblings, and typically developing controls. ASDs were diagnosed, and head circumference and clinical variables measured in a standardized manner across all sites. All subjects with autism met ADI‐R, ADOS‐G, DSM‐IV, and ICD‐10 criteria. The results show the distribution of standardized head circumference in autism is normal in shape, and the mean, variance, and rate of macrocephaly but not microcephaly are increased. Head circumference tends to be large relative to height in autism. No site, gender, age, SES, verbal, or non‐verbal IQ effects were present in the autism sample. In addition to autism itself, standardized height and average parental head circumference were the most important factors predicting head circumference in individuals with autism. Mean standardized head circumference and rates of macrocephaly were similar in probands with autism and their parents. Increased head circumference was associated with a higher (more severe) ADI‐R social algorithm score. Macrocephaly is associated with delayed onset of language. Although mean head circumference and rates of macrocephaly are increased in autism, a high degree of variability is present, underscoring the complex clinical heterogeneity of the disorder. The wide distribution of head circumference in autism has major implications for genetic, neuroimaging, and other neurobiological research.

Discovery of allelic variants of HOXA1 and HOXB1 : Genetic susceptibility to autism spectrum disorders

BACKGROUND Family studies have demonstrated that the autism spectrum disorders (ASDs) have a major genetic etiologic component, but expression and penetrance of the phenotype are variable. Mice with null mutations of Hoxa1 or Hoxb1, two genes critical to hindbrain development, have phenotypic features frequently observed in autism, but no naturally occurring variants of either gene have been identified in mammals. METHODS By sequencing regions of genomic DNA of patients with autism spectrum disorders, we detected a substitution variant at HOXA1 and an insertion variant at HOXB1, both in coding regions of the genes. Fifty-seven individuals ascertained for a diagnosis of an ASD, along with 166 of their relatives, were typed for these variants. Two non-ASD populations were typed, and the frequency of the newly identified alleles was determined in all groups. The genotypes of the ASD families were tested for conformation to Hardy-Weinberg proportions and Mendelian expectations for gene transmission. RESULTS The frequency of the variants was 10-25% in persons of European or African origin. In the ASD families, there was a significant deviation from the HOXA1 genotype ratios expected from Hardy-Weinberg proportions (P = 0.005). Among affected offspring, a significant deviation from Mendelian expectation in gene transmission (P = 0.011) was observed. No statistically significant effects were detected when the same analyses were applied to the HOXB1 locus, but there was evidence of an interaction between HOXA1, HOXB1, and gender in susceptibility to ASDs. CONCLUSIONS The results support a role for HOXA1 in susceptibility to autism, and add to the existing body of evidence implicating early brain stem injury in the etiology of ASDs.

Early Regression in Social Communication in Autism Spectrum Disorders: A CPEA Study

In a multisite study of 351 children with autism spectrum disorders, 21 children with developmental delays, and 31 children with typical development, this study used caregiver interviews (i.e., the Autism Diagnostic Interview-Revised) at the time of entry into other research projects and follow-up telephone interviews designed for this project to describe the childrens early acquisition and loss of social-communication milestones. Children who had used words spontaneously and meaningfully and then stopped talking were described by their caregivers as showing more gestures, greater participation in social games, and better receptive language before the loss and fewer of these skills after the loss than other children with autism spectrum disorders. A significant minority of children with autism without word loss showed a very similar pattern of loss of social-communication skills, a pattern not observed in the children with developmental delays or typical development.

Complementary and Alternative Medicine Treatments for Children with Autism Spectrum Disorders

Complementary and alternative medical (CAM) treatments are commonly used for children with autism spectrum disorders. This review discusses the evidence supporting the most frequently used treatments, including categories of mind-body medicine, energy medicine, and biologically based, manipulative, and body-based practices, with the latter two treatments the most commonly selected by families. Clinical providers need to understand the evidence for efficacy (or lack thereof) and potential side effects. Some CAM practices have evidence to reject their use, such as secretin, whereas others have emerging evidence to support their use, such as melatonin. Most treatments have not been adequately studied and do not have evidence to support their use.

Plasma Amino Acids Profiles in Children with Autism: Potential Risk of Nutritional Deficiencies

The plasma amino acid profiles of 36 children with autism spectrum disorders were reviewed to determine the impact of diet on amino acid patterns. Ten of the children were on gluten and casein restricted diets administered by parents, while the other 26 consumed unrestricted diets. No amino acid profile specific to autism was identified. However, children with autism had more essential amino acid deficiencies consistent with poor protein nutrition than an age/gender matched control group. There was a trend for children with autism who were on restricted diets to have an increased prevalence of essential amino acid deficiencies and lower plasma levels of essential acids including the neurotransmitter precursors tyrosine and tryptophan than both controls and children with autism on unrestricted diets. These data indicate that larger, more focused studies of protein nutrition in children with autism are needed in order to determine the extent to which restricted diets might place the developing brains of children with autism at risk from protein malnutrition. The high rate of tryptophan and tyrosine deficiency in this group is also of concern given their role as neurotransmitter precursors.

Nutrient Intake From Food in Children With Autism

OBJECTIVE The impact of abnormal feeding behaviors reported for children with autism spectrum disorders (ASDs) on their nutritional status is unknown. We compared nutrient intake from food consumed by children with and without ASD and examined nutrient deficiency and excess. METHODS Prospective 3-day food records and BMI for children (2–11 years) with ASD participating in the Autism Treatment Network (Arkansas, Cincinnati, Colorado, Pittsburgh, and Rochester) were compared with both the National Health and Nutrition Examination Survey data and a matched subset based on age, gender, family income, and race/ethnicity (N = 252 analyzed food records). RESULTS Children with ASD and matched controls consumed similar amounts of nutrients from food. Only children with ASD aged 4 to 8 years consumed significantly less energy, vitamins A and C, and the mineral Zn; and those 9 to 11 years consumed less phosphorous. A greater percentage of children with ASD met recommendations for vitamins K and E. Few children in either group met the recommended intakes for fiber, choline, calcium, vitamin D, vitamin K, and potassium. Specific age groups consumed excessive amounts of sodium, folate, manganese, zinc, vitamin A (retinol), selenium, and copper. No differences were observed in nutritional sufficiency of children given restricted diets. Children aged 2 to 5 years with ASD had more overweight and obesity, and children 5 to 11 years had more underweight. CONCLUSIONS Children with ASD, like other children in America, consume less than the recommended amounts of certain nutrients from food. Primary care for all children should include nutritional surveillance and attention to BMI.

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism

BACKGROUND The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.

Early environmental factors in autism

Genetic and environmental influences are not mutually exclusive as causes of birth defects. Rather, both contribute to the etiology of many congenital anomalies. Recent results from studies of autism in twins argue that this is the case for autism spectrum disorders. Thus, even after the genetic causes of autism are known, it will be necessary to identify environmental factors that contribute to the expression of the symptoms. The first half of this review describes what has been learned from research on exogenous influences in autism, discussing studies of infections, inoculations, general pre- and perinatal factors, family histories, and drug and chemical exposures. The second discusses gene-environment interactions in other birth defects and the methods by which teratogens have been discovered. The role of known genetic syndromes in the etiology of autism is discussed with attention to whether their associations with the disorder are genetic or teratologic in nature. MRDD Research Reviews 1998;4:121–128.