Motor stereotypies in children with autism and other developmental disorders.

The purpose of the study was to count and characterize the range of stereotypies--repetitive rhythmical, apparently purposeless movements--in developmentally impaired children with and without autism, and to determine whether some types are more prevalent and diagnostically useful in children with autism. We described each motor stereotypy recorded during 15 minutes of archived videos of standardized play sessions in 277 children (209 males, 68 females; mean age 4y 6mo [SD 1y 5mo], range 2y 11mo-8y 1mo), 129 with autistic disorder (DSM-III-R), and 148 cognitively-matched non-autistic developmentally disordered (NADD) comparison children divided into developmental language disorder and non-autism, low IQ (NALIQ) sub-groups. The parts of the body involved and characteristics of all stereotypies were scored blind to diagnosis. More children with autism had stereotypies than the NADD comparison children. Autism and, to a lesser degree, nonverbal IQ (NVIQ) <80, especially in females contributed independently to the occurrence, number, and variety of stereotypies, with non-autistic children without cognitive impairment having the least number of stereotypies and children with autism and low NVIQ the most. Autism contributed independently to gait and hand/finger stereotypies and NVIQ <80 to head/trunk stereotypies. Atypical gazing at fingers and objects was rare but virtually limited to autism. Stereotypies are environmentally modulated movement disorders, some highly suggestive, but not pathognomonic, of autism. Their underlying brain basis and genetic correlates need investigation.

Autism: definition, neurobiology, screening, diagnosis.

Autism (ie, the autism spectrum disorders) is now recognized in 1 in 150 children. This article highlights the definition, neurobiology, screening, and diagnosis of autism. The genetics, immunology, imaging, and neurophysiology of autism are reviewed, with particular emphasis on areas that impact pediatricians. Early recognition of the social deficits that characterize autism is key to maximizing the potential of these children.

The autism "epidemic": Ethical, legal, and social issues in a developmental spectrum disorder.

Classic autism has gradually evolved into the concept of a larger "spectrum disorder." The rising prevalence of autism and autism spectrum disorder (autism/ASD) diagnoses can be largely attributed to broader diagnostic criteria, adoption of dimensional assessment strategies, increased awareness, linking of services to diagnosis, and the inclusion of milder neurodevelopmental differences bordering on normality. The spectrum disorder diagnosis raises numerous bioethical issues for individuals and society. Three groups of caregivers have important ethical, legal, and social obligations to individuals with autism/ASD: (1) families and advocates of individuals with autism/ASD; (2) health care and other professionals; and (3) governments. Each group may have different views of autism/ASD diagnostic criteria, screening, testing, and the effectiveness of various interventions. All see timely diagnosis as desirable, but earlier diagnosis may not be better, morally or practically. The growing practice of genetic testing in milder ASD raises ethical questions because of its uncertain scientific validity and limited clinical utility. Individuals with autism/ASD have various kinds of needs but all want acceptance and most deserve better accommodations. Governments struggle to provide a fair allocation of appropriate special education and supportive services. This article examines the evolving dimensions of the autism/ASD diagnosis, outlines certain bioethics principles related to its evaluation and management, reviews relevant laws and disability rights, and emphasizes the societal obligation to recognize neurodevelopmental variation and human neurodiversity. Future directions in the evaluation and care of autism/ASD should attempt to integrate the roles and responsibilities of all agents caring for each unique autistic individual.

Cockayne syndrome in adults: review with clinical and pathologic study of a new case.

Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31(1/2) years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.

Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease.

This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.

Dyscalculia and the Calculating Brain.

Dyscalculia, like dyslexia, affects some 5% of school-age children but has received much less investigative attention. In two thirds of affected children, dyscalculia is associated with another developmental disorder like dyslexia, attention-deficit disorder, anxiety disorder, visual and spatial disorder, or cultural deprivation. Infants, primates, some birds, and other animals are born with the innate ability, called subitizing, to tell at a glance whether small sets of scattered dots or other items differ by one or more item. This nonverbal approximate number system extends mostly to single digit sets as visual discrimination drops logarithmically to "many" with increasing numerosity (size effect) and crowding (distance effect). Preschoolers need several years and specific teaching to learn verbal names and visual symbols for numbers and school agers to understand their cardinality and ordinality and the invariance of their sequence (arithmetic number line) that enables calculation. This arithmetic linear line differs drastically from the nonlinear approximate number system mental number line that parallels the individual number-tuned neurons in the intraparietal sulcus in monkeys and overlying scalp distribution of discrete functional magnetic resonance imaging activations by number tasks in man. Calculation is a complex skill that activates both visual and spatial and visual and verbal networks. It is less strongly left lateralized than language, with approximate number system activation somewhat more right sided and exact number and arithmetic activation more left sided. Maturation and increasing number skill decrease associated widespread non-numerical brain activations that persist in some individuals with dyscalculia, which has no single, universal neurological cause or underlying mechanism in all affected individuals.

Autism Spectrum Disorders (ASD) in Blind Children: Very High Prevalence, Potentially Better Outlook.

Autism spectrum disorders affected 19 of 38 unselected children at a school for the blind in Cordoba, Argentina. Autism was linked to total congenital blindness, not blindness' etiology, acquired or incomplete blindness, sex, overt brain damage, or socioeconomic status. Autism "recovery," had occurred in 4 verbal children. Congenital blindness causes profoundly deviant sensory experience and massive reorganization of brain connectivity. Its ≥ 30 times greater prevalence than in sighted children suggests a distinct pathogenesis. Unawareness of autism's high prevalence in blind individuals includes blindness' rarity, misunderstanding of autism as "disease" rather than dimensional behavioral diagnosis, reluctance to diagnose it in blind children, and ignorance of its potentially more favorable outcome. Future investigation may suggest interventions to prevent or mitigate it.

Epilepsy in autism.

There is an increased but variable risk of epilepsy in autism. Three main factors--age, cognitive level, and type of language disorder--account for variability in the reported prevalence of epilepsy. The prevalence is highest in studies that have included adolescents and young adults, individuals with moderate to severe mental retardation and those with motor deficits, and individuals with severe receptive language deficits. The association of autism with clinical or subclinical epilepsy might denote common genetic factors in some cases. Whether subclinical epilepsy has adverse effects on cognition, language, and behaviour is debated, as is the relation of autistic regression with an epileptiform electroencephalogram to Landau-Kleffner syndrome. There is no evidence-based treatment recommendation for individuals with autism, regression, and subclinical epilepsy. Double-blind studies with sufficient power to resolve this issue are urgently needed.

Update on the language disorders of individuals on the autistic spectrum.

Inadequate language is a defining feature of the autism spectrum disorders (autism). Autism is a behaviorally and dimensionally defined developmental disorder of the immature brain that has a broad range of severity and many etiologies, with multiple genes involved. Early studies, which focused on the language of verbal children on the autistic spectrum, emphasized aberrant features of their speech such as unusual word choices, pronoun reversal, echolalia, incoherent discourse, unresponsiveness to questions, aberrant prosody, and lack of drive to communicate. Persistent lack of speech of some individuals was attributed to the severity of their autism and attendant mental retardation rather than possible inability to decode auditory language. Clinical study of unselected children with autism indicated that the language deficits of preschoolers fall into two broad types, perhaps with subtypes, those that involve reception and production of phonology (sounds of speech) and syntax (grammar), and those that do not but involve semantics (meaning) and pragmatics (communicative use of language, processing, and production of discourse). Except for the preschoolers' universally deficient pragmatics and comprehension of speech, many of their language deficits parallel those of non-autistic preschoolers with developmental language disorders. There is now biological support for the clinical observation that young autistic children are language disordered as well as autistic. Recent electrophysiological studies disclose auditory input abnormalities in lateral temporal cortex even in verbal individuals on the autistic spectrum. Severe receptive deficits for phonology enhance the risk for epilepsy. Genetic studies indicate that linkage to chromosome 7q31-33 is limited to families with evidence for phonologic impairment as well as autism. Clearly, social and cognitive disorders alone provide an inadequate explanation for the range of language deficits in autism.

"Auditory neuropathy": physiologic and pathologic evidence calls for more diagnostic specificity.

The term "auditory neuropathy" is being used in a rapidly increasing number of papers in the audiology/otolaryngology literature for a variety of individuals (mostly children) who fulfill the following criteria: (1) understanding of speech worse than predicted from the degree of hearing loss on their behavioral audiograms; (2) recordable otoacoustic emissions and/or cochlear microphonic; together with (3) absent or atypical auditory brain stem responses. Because of the general lack of anatomic foundation for the label "auditory neuropathy" as currently used, we review the anatomy of the auditory pathway, the definition of neuropathy and its demyelinating, axonal, and mixed variants. We submit that the diagnostic term "auditory neuropathy" is anatomically inappropriate unless patients have documented evidence for selective involvement of either the spiral ganglion cells or their axons, or of the 8th nerve as a whole. In view of biologic differences between peripheral nerves and white matter tracts in the brain, the term "auditory neuropathy" is inappropriate for pathologies affecting the central auditory pathway in the brainstem and brain selectively. Published reports of patients with "auditory neuropathy" indicate that they are extremely heterogeneous in underlying medical diagnosis, age, severity, test results, and that only a small number have undergone the detailed investigations that would enable a more precise diagnosis of the locus of their pathologies. The electrophysiology of peripheral neuropathies and the deficits expected with pathologies affecting the hair cells, spiral ganglion cells and their axons (auditory neuropathy sensu stricto), and brain stem relays are reviewed. In order to serve patients adequately, including potential candidates for cochlear implants, and to increase knowledge of auditory pathologies, we make a plea for more comprehensive evaluation of patients who fulfill the currently used audiologic criteria for "auditory neuropathy" in an effort to pinpoint the site of their pathologies. We suggest that the term auditory neuropathy be limited to cases in which the locus of pathology is limited to the spiral ganglion cells, their processes, or the 8th nerve, and that the term neural hearing loss be considered for pathologies that affect all higher levels of the auditory pathway, from the brainstem to the auditory cortex.

Classification of behaviorally defined disorders: biology versus the DSM.

Three levels of investigation underlie all biologically based attempts at classification of behaviorally defined developmental and psychiatric disorders: Level A, pseudo-categorical classification of mostly dimensional descriptions of behaviors and their disorders included in the 2013 American Psychiatric Association's Fifth Edition of the Diagnostic and Statistical Manual (DSM-5); Level C, mostly categorical classification of genetic and environmental causes (etiologies) of Level A disorders; and Level B, the pathophysiologic--both categorical and dimensional--biologic mechanisms underlying Level A "diagnoses" which comprise hierarchically interacting molecular, cellular, and neural networks and major brain pathways orchestrated by Level C etiologies. Besides modest numbers of effective psychotropic medications and their derivatives, major advances in treatment have addressed the behavioral symptoms of Level A-defined developmental and psychiatric disorders. The National Institute of Mental Health proposes support for a new biologically based Research Domain Criteria (RDoC) classification; its goal is to apply to behaviorally defined Level A developmental and psychiatric disorders the biologically based Level C and Level B research strategies that have greatly accelerated treatment and prevention of medical disorders. It plans to supplement effective educational and behavioral symptom-based interventions with faster, more potent and specific biologic therapies and, hopefully, to discover how effective behavioral interventions alter brain function. This commentary raises the question of whether a hybrid nosology that maps biology onto behavior is attainable. At a minimum, such a nosologic effort requires greater in-depth and better informed dialog between investigators of behavior and biology than occurs typically, and more realistic communication of the implications of research results to the public.

Abnormalities of joint mobility and gait in children with autism spectrum disorders.

AIMS: Abnormalities of gross motor function in children with autism are well known to clinicians but have not received much empirical documentation and, with the exception of stereotypies, are not among its diagnostic criteria. We recorded the characteristics of gait and prevalence of toe walking, the range of passive joint mobility, and age at walking in children with DSM IV autism spectrum disorders (ASDs) and in age- and gender-matched typically developing peers (mean age 4years 6months, range 22months-10years 9months). METHODS: We evaluated maximum range of mobility at the elbow, wrist, metacarpo-phalangeal, and ankle joints and videoed children walking and running. Two neurologists blind to diagnosis independently scored features of gait clinically. RESULTS: Children with ASDs had significantly greater joint mobility (p<.002), more gait abnormalities (p<.0001), and on average walked 1.6months later than their non-autistic peers. INTERPRETATION: This study indicates that attention should be directed to motor abnormalities as well as sociability, communication, and restricted and repetitive behaviors in individuals with ASDs. Motor deficits add to children's other handicaps. They indicate that ASDs affect a broader range of central nervous system circuitry than often appreciated.

Disorders of nucleotide excision repair.

Deficient repair of ubiquitous errors in the genome risks faulty transcription or replication. Its direct and indirect phenotypic consequences are rare, complex, dementing, lethal disorders of children with inadequately understood overlapping genotypes and variable severity. Mutations of CSA or CSB responsible for impaired transcription-coupled repair cause Cockayne syndrome (CS). Its characteristics are (1) profound growth deficiency affecting all tissues, including the brain, (2) premature aging marked by cachexia, vascular disease, exocrine deficiency, and osteopenia, but not cancer, and (3) a selective degenerative disorder of central and peripheral myelin and by neuronal loss in the retina and inner ear, and in the cerebellum and basal ganglia where it is associated with calcification. Xeroderma pigmentosum (XP) can arise from mutations of at least eight genes involved in global genomic repair. Severe XPA and XPC cause innumerable carcinomas and melanomas in light-exposed eyes and skin, and enhanced risk of visceral cancers. XPA and XPD and others can cause childhood XP neurological disease with widespread neuronal loss, axonal sensorimotor neuropathy, and dwarfing. Four genes, including XPD, can cause trichothiodystrophy (TTD) with sulfur-deficient, brittle, tiger-tail hair, and growth and developmental inadequacy. CSB or XPD can cause the severe congenital cerebro-oculofacioskeletal (COFS) CS-like syndrome with joint contractures, cataracts, and early death. Three XP genes can also cause XP/CS complex. Much more needs to be learned about these and other disorders of DNA repair to enable prevention and treatment.

Motor stereotypies and volumetric brain alterations in children with Autistic Disorder.

Motor stereotypies are defined as patterned, repetitive, purposeless movements. These stigmatizing motor behaviors represent one manifestation of the third core criterion for an Autistic Disorder (AD) diagnosis, and are becoming viewed as potential early markers of autism. Moreover, motor stereotypies might be a tangible expression of the underlying neurobiology of this neurodevelopmental disorder. In this study, we videoscored stereotypies recorded during semi-structured play sessions from school age children with AD. We examined the effect of severity and persistence over time of stereotypies on brain volumetric changes. Our findings confirmed that the brain volume of school age children with AD is, on average, larger than that of age-matched typically developing children. However, we have failed to detect any sign of volumetric differences in brain regions thought to be particularly linked to the pathophysiology of stereotypies. This negative finding may suggest that, at least with respect to motor stereotypies, functional rather than structural alterations might be the underpinning of these disruptive motor manifestations of autism.

Neurobiological basis of autism.

Autism (autism spectrum disorders) is a complex, strongly genetically influenced, behaviorally defined disorder of the immature brain associated with very uneven intellectual abilities. Among its most salient and potentially treatable neurologic features that this article focuses on are epilepsy, disorganized sleep patterns, and sensory and motor deficits. Its many causes and wide range of severity means that there is no symptom, no pathology, imaging, electroencephalography, or other biologic feature, and no biologic treatment that is universal or diagnostic of this developmental syndrome.

Brief report: life history and neuropathology of a gifted man with Asperger syndrome.

Despite recent interest in the pathogenesis of the autism spectrum disorders (pervasive developmental disorders), neuropathological descriptions of brains of individuals with well documented clinical information and without potentially confounding symptomatology are exceptionally rare. Asperger syndrome differs from classic autism by lack of cognitive impairment or delay in expressive language acquisition. We examined the 1,570 g brain of a 63 year old otherwise healthy mathematician with an Autistic Spectrum Disorder of Asperger subtype. Except for an atypical gyral pattern and megalencephaly, we detected no specific neuropathologic abnormality. Taken together, the behavioral data and pathological findings in this case are compatible with an early neurodevelopmental process affecting multiple neuroanatomic networks, but without a convincing morphologic signature detectable with routine neuropathologic technology.