Marvin R. Natowicz

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.

Dravet syndrome patient‐derived neurons suggest a novel epilepsy mechanism

Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage‐gated sodium channel Nav1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that decreased Nav1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient‐specific neurons.

New NBIA subtype Genetic, clinical, pathologic, and radiographic features of MPAN

Objective: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype. Methods: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject. Results: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures. Conclusions: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase–associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.

Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research

This article reviews current evidence for autism spectrum disorder (ASD) interventions for children aged <3 years, based on peer-reviewed articles published up to December 2013. Several groups have adapted treatments initially designed for older, preschool-aged children with ASD, integrating best practice in behavioral teaching methods into a developmental framework based on current scientific understanding of how infants and toddlers learn. The central role of parents has been emphasized, and interventions are designed to incorporate learning opportunities into everyday activities, capitalize on “teachable moments,” and facilitate the generalization of skills beyond the familiar home setting. Our review identified several comprehensive and targeted treatment models with evidence of clear benefits. Although some trials were limited to 8- to 12-week outcome data, enhanced outcomes associated with some interventions were evaluated over periods as long as 2 years. Based on this review, recommendations are proposed for clinical practice and future research.

Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet

Glucose transport protein deficiency due to mutation in the GLUT1 gene is characterized by infantile onset and chronic seizure disorder, microcephaly, global developmental delays, and hypoglycorrhachia. We describe a 10‐year‐old normocephalic male with prominent ataxia, dystonia, choreoathetosis, and GLUT1 deficiency whose motor abnormalities improved with a ketogenic diet. We illustrate the motor abnormalities, at baseline and after ketogenic diet, that characterize this unusual case. This case broadens the phenotype of GLUT1 deficiency and illustrates the importance of cerebrospinal fluid (CSF) evaluation in detecting potentially treatable conditions in children with undiagnosed movement disorders.

Early identification of autism spectrum disorder: Recommendations for practice and research

Early identification of autism spectrum disorder (ASD) is essential to ensure that children can access specialized evidence-based interventions that can help to optimize long-term outcomes. Early identification also helps shorten the stressful “diagnostic odyssey” that many families experience before diagnosis. There have been important advances in research into the early development of ASDs, incorporating prospective designs and new technologies aimed at more precisely delineating the early emergence of ASD. Thus, an updated review of the state of the science of early identification of ASD was needed to inform best practice. These issues were the focus of a multidisciplinary panel of clinical practitioners and researchers who completed a literature review and reached consensus on current evidence addressing the question “What are the earliest signs and symptoms of ASD in children aged ≤24 months that can be used for early identification?” Summary statements address current knowledge on early signs of ASD, potential contributions and limitations of prospective research with high-risk infants, and priorities for promoting the incorporation of this knowledge into clinical practice and future research.

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.

Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder, progressive spastic gait, and peripheral neuropathy. Polyglucosan bodies accumulate in the central and peripheral nervous systems and are often associated with glycogen branching enzyme (GBE) deficiency. To improve clinical diagnosis and enable future evaluation of therapeutic strategies, we conducted a multinational study of the natural history and imaging features of APBD.

Double Outlet Right Ventricle: Aetiologies and Associations

Background: Double outlet right ventricle (DORV), a clinically significant congenital heart defect, occurs in 1–3% of individuals with congenital heart defects. In contrast to other major congenital heart defects, there are no systematic or comprehensive data regarding associations, aetiologies, and pathogenesis of DORV. We analysed reported cases in the medical literature to address these issues. Methods: We queried the PubMed database using key words “double outlet right ventricle” and “DORV” for case reports, epidemiologic analyses and animal studies with this cardiac anomaly. The anatomic subtype of DORV was classified according to criteria of Van Praagh. Results: Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11. DORV was reported in many uncommon or rare non-chromosomal syndromes. Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV. Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis. Conclusions: The large number of genes associated with DORV in both humans and animal models and the different anatomic subtypes seen in specific aetiologies indicate the likelihood of several distinct pathogenetic mechanisms for DORV, including impairment of neural crest derivative migration and impairment of normal cardiac situs and looping.

Early Screening of Autism Spectrum Disorder: Recommendations for Practice and Research.

This article reviews current evidence for autism spectrum disorder (ASD) screening based on peer-reviewed articles published to December 2013. Screening provides a standardized process to ensure that children are systematically monitored for early signs of ASD to promote earlier diagnosis. The current review indicates that screening in children aged 18 to 24 months can assist in early detection, consistent with current American Academy of Pediatrics’ recommendations. We identify ASD-specific and broadband screening tools that have been ev-aluated in large community samples which show particular promise in terms of accurate classification and clinical utility. We also suggest strategies to help overcome challenges to implementing ASD screening in community practice, as well as priorities for future research.