Robert M. Joseph

CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism

Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

Holistic and part-based face recognition in children with autism.

BACKGROUND There is substantial evidence that children with autism are impaired in face recognition. Although many researchers have suggested that this impairment derives from a failure of holistic face processing and a tendency to represent and encode faces on a part-by-part basis, this hypothesis has not been tested directly. METHOD Holistic face processing was assessed by comparing childrens ability to recognize a face part (eyes, nose, or mouth) in the context of the whole face in which it was learned with their ability to recognize the same face part in isolation. RESULTS In Study 1, as expected, typically developing 9-year-olds (n = 27) and 11-year-olds (n = 30) were significantly better at recognizing face parts presented in the whole than in the part test condition, and this effect was limited to upright faces and not found for inverted faces. Consistent with prior findings, typically developing children were most accurate when face recognition depended on the eyes. In Study 2, high-functioning children with autism (n = 22) evidenced a whole-test advantage for mouths only, and were markedly deficient when face recognition depended on the eyes. Their pattern of performance diverged from age- and IQ-matched comparison participants (n = 20), who performed similarly to the typically developing children in Study 1. CONCLUSIONS These findings suggest that face recognition abnormalities in autism are not fully explained by an impairment of holistic face processing, and that there is an unusual significance accorded to the mouth region when children with autism process information from peoples faces.

Cognitive profiles and social-communicative functioning in children with autism spectrum disorder

BACKGROUND Whether there is an unusual degree of unevenness in the cognitive abilities of children with autism spectrum disorder (ASD) and whether different cognitive profiles among children with ASD might index etiologically significant subgroups are questions of continued debate in autism research. METHOD The Differential Ability Scales (DAS) and the Autism Diagnostic Observation Schedule (ADOS) were used to examine profiles of verbal and nonverbal abilities and their relationship to autistic symptomatology in 120 relatively high-functioning children with ADI-confirmed diagnoses of autism. RESULTS Discrepancies between verbal and nonverbal ability scores occurred at a significantly higher rate than in the DAS normative sample (30%) in both a younger group of 73 children (56%) with a mean age of 5;5 and an older group of 47 children (62%) with a mean age of 8;11. Discrepancies were mainly in favor of nonverbal ability in the younger group, but occurred equally in favor of verbal and nonverbal abilities in the older group. Comparison of the two age groups suggested a growing dissociation between verbal and nonverbal (and particularly visual processing) skills with age. In the older group, children with discrepantly higher nonverbal abilities demonstrated significantly greater impairment in social functioning, as measured on the ADOS, independent of absolute level of verbal and overall ability. CONCLUSIONS These findings demonstrate a high rate of uneven cognitive development in children with ASD. Indications of a dissociation between verbal and visual-perceptual skills among the older children, and the specific association of discrepantly high nonverbal skills with increased social symptoms suggest that the nonverbal > verbal profile may index an etiologically significant subtype of autism.

Activation of the fusiform gyrus when individuals with autism spectrum disorder view faces

Prior imaging studies have failed to show activation of the fusiform gyrus in response to emotionally neutral faces in individuals with autism spectrum disorder (ASD) [Critchley et al., Brain 124 (2001) 2059; Schultz et al., Arch. Gen. Psychiatry 57 (2000) 331]. However, individuals with ASD do not typically exhibit the striking behavioral deficits that might be expected to result from fusiform gyrus damage, such as those seen in prosopagnosia, and their deficits appear to extend well beyond face identification to include a wide range of impairments in social perceptual processing. In this study, our goal was to further assess the question of whether individuals with ASD have abnormal fusiform gyrus activation to faces. We used high-field (3 T) functional magnetic resonance imaging to study face perception in 11 adult individuals with autism spectrum disorder (ASD) and 10 normal controls. We used face stimuli, object stimuli, and sensory control stimuli (Fourier scrambled versions of the face and object stimuli) containing a fixation point in the center to ensure that participants were looking at and attending to the images as they were presented. We found that individuals with ASD activated the fusiform face area and other brain areas normally involved in face processing when they viewed faces as compared to non-face stimuli. These data indicate that the face-processing deficits encountered in ASD are not due to a simple dysfunction of the fusiform area, but to more complex anomalies in the distributed network of brain areas involved in social perception and cognition.

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.

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Abnormal activation of the social brain during face perception in autism.

ASD involves a fundamental impairment in processing social‐communicative information from faces. Several recent studies have challenged earlier findings that individuals with autism spectrum disorder (ASD) have no activation of the fusiform gyrus (fusiform face area, FFA) when viewing faces. In this study, we examined activation to faces in the broader network of face‐processing modules that comprise what is known as the social brain. Using 3T functional resonance imaging, we measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing nonemotional faces. We replicated our original findings of significant activation of face identity‐processing areas (FFA and inferior occipital gyrus, IOG) in ASD. However, in addition, we identified hypoactivation in a more widely distributed network of brain areas involved in face processing [including the right amygdala, inferior frontal cortex (IFC), superior temporal sulcus (STS), and face‐related somatosensory and premotor cortex]. In ASD, we found functional correlations between a subgroup of areas in the social brain that belong to the mirror neuron system (IFC, STS) and other face‐processing areas. The severity of the social symptoms measured by the Autism Diagnostic Observation Schedule was correlated with the right IFC cortical thickness and with functional activation in that area. When viewing faces, adults with ASD show atypical patterns of activation in regions forming the broader face‐processing network and social brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging to the mirror neuron system are involved in the face‐processing disturbances in ASD. Hum Brain Mapp, 2007.

Autism Spectrum Disorders According to DSM-IV-TR and Comparison With DSM-5 Draft Criteria: An Epidemiological Study

OBJECTIVE The latest definitions of autism spectrum disorders (ASDs) were specified in DSM-IV-TR in 2000. DSM-5 criteria are planned for 2013. Here, we estimated the prevalence of ASDs and autism according to DSM-IV-TR, clarified confusion concerning diagnostic criteria, and evaluated DSM-5 draft criteria for ASD posted by the American Psychiatry Association (APA) in February 2010. METHOD This was an epidemiological study of 5,484 eight-year-old children in Finland, 4,422 (81%) of them rated via the Autism Spectrum Screening Questionnaire by parents and/or teachers, and 110 examined by using a structured interview, semi-structured observation, IQ measurement, school-day observation, and patient records. Diagnoses were assigned according to DSM-IV-TR criteria and DSM-5 draft criteria in children with a full-scale IQ (FSIQ) ≥50. Patient records were evaluated in children with an FSIQ <50 to discover diagnoses of ASDs. RESULTS The prevalence of ASDs was 8.4 in 1,000 and that of autism 4.1 in 1,000 according to DSM-IV-TR. Of the subjects with ASDs and autism, 65% and 61% were high-functioning (FSIQ ≥70), respectively. The prevalence of pervasive developmental disorder not otherwise specified was not estimated because of inconsistency in DSM-IV-TR criteria. DSM-5 draft criteria were shown to be less sensitive in regard to identification of subjects with ASDs, particularly those with Aspergers syndrome and some high-functioning subjects with autism. CONCLUSIONS DSM-IV-TR helps with the definition of ASDs only up to a point. We suggest modifications to five details of DSM-5 draft criteria posted by the APA in February 2010. Completing revision of DSM criteria for ASDs is a challenging task.

The relationship of theory of mind and executive functions to symptom type and severity in children with autism

Although neurocognitive impairments in theory of mind and in executive functions have both been hypothesized to play a causal role in autism, there has been little research investigating the explanatory power of these impairments with regard to autistic symptomatology. The present study examined the degree to which individual differences in theory of mind and executive functions could explain variations in the severity of autism symptoms. Participants included 31 verbal, school-aged children with autism who were administered a battery of tests assessing the understanding of mental states (knowledge and false belief) and executive control skills (working memory, combined working memory and inhibitory control, and planning) and who were behaviorally evaluated for autism severity in the three core symptom domains. Whereas theory of mind and executive control abilities explained the significant variance beyond that accounted for by language level in communication symptoms, neither explained the significant variance in reciprocal social interaction or repetitive behaviors symptoms. These findings are discussed in terms of a proposed distinction between higher level, cognitive-linguistic aspects of theory of mind and related executive control skills, and more fundamental social-perceptual processes involved in the apprehension of mental state information conveyed through eyes, faces, and voices, which may be more closely linked to autistic deficits in social reciprocity.