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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.

This paper presents detailed recommendations for diagnosis of autism established by a multidisciplinary panel of the Child Neurology Society and the American Academy of Neurology. The paper offers dual-level (general development and specific symptoms) guidelines for diagnosis of autistic disorder, Asperger disorder, childhood disintegrative disorder, atypical autism/pervasive developmental disorder not otherwise specified, and Rett syndrome. (Contains extensive references.) (DB)

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.

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.

Few disorders seem more confusing than autism. Common stereotypes — of a severely withdrawn, mute child with ceaselessly repetitive activities and an averted gaze or a freakish-looking, inept, mathematical prodigy — do not accurately reflect the broad spectrum of autism. Far from being emotionally ill but otherwise normal, persons with autism are now considered to have one of a group of developmental disorders of brain function that have such a broad range of behavioral consequences and severity that they are referred to, collectively, as pervasive developmental disorder (often called PDD) in the fourth edition of the Diagnostic and Statistical Manual . . .

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.

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.

Any person, talented or handicapped, whose social skills have been severely deficient since very early childhood, who started to talk late or whose communicative use of language is inadequate, and who perseverates and lacks cognitive and behavioral flexibility meets the diagnostic criteria for an autistic-spectrum disorder. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), published by the American Psychiatric Association, and the International Classification of Diseases, 10th Revision (ICD-10), published by the World Health Organization, use the term “pervasive developmental disorder” to encompass the broad spectrum of developmental disorders with these characteristics (see Table). Pervasive developmental disorders . . .

Joseph Gleeson and colleagues identify CEP41 mutations as a cause of Joubert syndrome. Their functional studies suggest that CEP41 regulates ciliary entry of TTLL6, an enzyme required for tubulin glutamylation at the cilium. Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function 1 , 2 . However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS) 3 , which we have designated as JBTS15, and identified causative mutations in CEP41 , which encodes a 41-kDa centrosomal protein 4 . We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme 5 . Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.

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.