Since the documented observations of Kanner in 1943, there has been great debate about the diagnoses, the sub-types, and the diagnostic threshold that relates to what is now known as autism spectrum disorder (ASD). Reflecting this complicated history, there has been continual refinement from DSM-III with ‘Infantile Autism’ to the current DSM-V diagnosis. The disorder is now widely accepted as a complex, pervasive, heterogeneous condition with multiple etiologies, sub-types, and developmental trajectories. Diagnosis remains based on observation of atypical behaviors, with criteria of persistent deficits in social communication and restricted and repetitive patterns of behavior. This review provides a broad overview of the history, prevalence, etiology, clinical presentation, and heterogeneity of ASD. Factors contributing to heterogeneity, including genetic variability, comorbidity, and gender are reviewed. We then explore current evidence-based pharmacological and behavioral treatments for ASD and highlight the complexities of conducting clinical trials that evaluate therapeutic efficacy in ASD populations. Finally, we discuss the potential of a new wave of research examining objective biomarkers to facilitate the evaluation of sub-typing, diagnosis, and treatment response in ASD.

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An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options

Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this advancing insight should improve clinical care, at present there is a substantial discrepancy between research knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for the translation of autism genetics knowledge into clinical practice.

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Autism genetics: opportunities and challenges for clinical translation.

The Role of the Immune System in Autism Spectrum Disorder.

Epilepsy is quite common in autism spectrum disorders, and it is increasingly recognized as an additional clinical problem that must be dealt with. The rate of comorbidity varies, depending upon the age and type of disorder, and currently the conservative estimate of comorbidity cases is 20-25% of the whole spectrum. Major risk factors for seizure occurrence are mental retardation and additional neurological disorders, as well as some specific associated medical conditions. Autism with regression has been reported in one-third of children with previously normal or nearly normal development. In an unknown proportion of these subjects, epileptic disorders are concomitant, leading to so-called autistic epileptiform regression. Furthermore, epileptiform abnormalities without seizures are frequent in this population and their role in the development of the nuclear disturbances of autism is controversial. The therapeutic approaches to epilepsy in autism are conventional treatments, yet when seizures are not evident, there is still controversy. Anticonvulsant medications could also potentially interfere with mood and behavioral disturbances frequently observed in ASD. The current understanding of the association between epilepsy and autism is still limited, but from a clinical point of view this association should not be overlooked, and it should be routinely investigated.

Epilepsy in autism spectrum disorders

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations Therefore, ASD has traditionally been framed as a behavioral disorder However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals A majority of these brain tissue studies have been published since 2010 The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders This understanding may lead to new testing and treatment strategies in individuals with ASD

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Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism.

Immunological and autoimmune considerations of Autism Spectrum Disorders

Mitochondrial Encephalomyopathy Associated with a Novel Mutation in the Mitochondrial tRNAleu(UUR)Gene (A3243T)

The Kluver-Bucy syndrome is characterized by psychic blindness or visual agnosia, blunted affect, hypermetamorphosis, hyperorality, bulimia, and sexual behavioral alterations. To date, there have been fewer than 10 reported cases of Kluver-Bucy syndrome in children, most of them irreversible. We describe here a reversible case of the complete Kluver-Bucy syndrome in a child suffering from Shigella encephalopathy.

A reversible case of Klüver-Bucy syndrome in association with shigellosis.

We report a child with HUS complicated by stupor, hemiparesis, expressive aphasia and focal seizures CAT scan of the brain demonstrated 2 large cerebral non-hemorrhagic infarcts Despite the severe neurological involvement the child eventually made a good recovery

Abraham Steinberg

Papers

Immunological and autoimmune considerations of Autism Spectrum Disorders

Mitochondrial Encephalomyopathy Associated with a Novel Mutation in the Mitochondrial tRNAleu(UUR)Gene (A3243T)

A reversible case of Klüver-Bucy syndrome in association with shigellosis.

Stroke in a patient with hemolytic-uremic syndrome with a good outcome