Papers of the Week

Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.

Noh HJ, Ponting CP, Boulding HC, Meader S, Betancur C, Buxbaum JD, Pinto D,
Marshall CR, Lionel AC, Scherer SW, Webber C.

MRC Functional Genomics Unit, University of Oxford, Department of Physiology,
Anatomy, and Genetics, Oxford, United Kingdom.

Autism Spectrum Disorders (ASD) are highly heritable and characterised by
impairments in social interaction and communication, and restricted and
repetitive behaviours. Considering four sets of de novo copy number variants
(CNVs) identified in 181 individuals with autism and exploiting mouse functional 
genomics and known protein-protein interactions, we identified a large and
significantly interconnected interaction network. This network contains 187 genes
affected by CNVs drawn from 45% of the patients we considered and 22 genes
previously implicated in ASD, of which 192 form a single interconnected cluster. 
On average, those patients with copy number changed genes from this network
possess changes in 3 network genes, suggesting that epistasis mediated through
the network is extensive. Correspondingly, genes that are highly connected within
the network, and thus whose copy number change is predicted by the network to be 
more phenotypically consequential, are significantly enriched among patients that
possess only a single ASD-associated network copy number changed gene
(p = 0.002). Strikingly, deleted or disrupted genes from the network are
significantly enriched in GO-annotated positive regulators (2.3-fold enrichment, 
corrected p = 2×10(-5)), whereas duplicated genes are significantly enriched in
GO-annotated negative regulators (2.2-fold enrichment, corrected p = 0.005). The 
direction of copy change is highly informative in the context of the network,
providing the means through which perturbations arising from distinct deletions
or duplications can yield a common outcome. These findings reveal an extensive
ASD-associated molecular network, whose topology indicates ASD-relevant
mutational deleteriousness and that mechanistically details how convergent
aetiologies can result extensively from CNVs affecting pathways causally
implicated in ASD.

PMID: 23754953  [PubMed - in process]

Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway.

Iafrati J, Orejarena MJ, Lassalle O, Bouamrane L, Chavis P.

1] INSERM UMR 901, Marseille, France [2] Aix-Marseille Université, Unité Mixte de
Recherche 901, Marseille, France [3] INMED, Marseille, France.

Defective brain extracellular matrix (ECM) is a factor of vulnerability in
various psychiatric diseases such as schizophrenia, depression and autism. The
glycoprotein reelin is an essential building block of the brain ECM that
modulates neuronal development and participates to the functions of adult central
synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of
early onset, but its synaptic and behavioral functions in juvenile brain circuits
remain unresolved. Here, we found that in juvenile reelin-haploinsufficient
heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to
reduced dendritic spine density and anomalous long-term potentiation in the
prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or
Ro25-6981 to inhibit GluN2B-N-methyl-D-aspartate receptors (NMDARs) restored
normal spine density, synaptic plasticity and converted fear memory to an
erasure-resilient state typical of adult rodents. The functional and behavioral
rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian
target of rapamycin pathway. Finally, we show that fear memory erasure persists
until adolescence in HRM and that a single exposure to ketamine during the
juvenile period reinstates normal fear memory in adolescent mice. Our results
show that reelin is essential for successful structural, functional and
behavioral development of juvenile prefrontal circuits and that this
developmental period provides a critical window for therapeutic rehabilitation
with GluN2B-NMDAR antagonists.Molecular Psychiatry advance online publication, 11
June 2013; doi:10.1038/mp.2013.66.

PMID: 23752244  [PubMed - as supplied by publisher]

The relationship between autism spectrum disorders and attention-deficit/hyperactivity disorder: An overview.

Matson JL, Rieske RD, Williams LW.

Louisiana State University, USA.

The autism spectrum has become a highly studied topic, perhaps the most
researched of all developmental disorders. A host of related topics are being
studied, with one of the most common being comorbidity of autism with other
conditions such as epilepsy, sleep, and anxiety disorders. One of the most
prevalent of these comorbid conditions is attention-deficit/hyperactivity
disorder (AD/HD). A considerable amount of research has appeared on this topic
with respect to symptom expression, prevalence of overlap, type of symptom
overlap, and the effect of these two conditions co-occurrence on other symptoms
and disorders. Given the substantial data base that has accrued, review and
synthesis of these data are in order. This is the purpose of the present
manuscript.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID: 23751293  [PubMed - as supplied by publisher]

Pica in persons with developmental disabilities: Approaches to treatment.

Matson JL, Hattier MA, Belva B, Matson ML.

Louisiana State University, United States. Electronic address:
johnmatson@aol.com.

Pica is a very serious problem in which an individual ingests substances without 
nutrition value, such as paper and paint. As this behavior is often
life-threatening resulting in surgery, pica has received attention from
researchers for several decades. During that time, a number of interventions have
been devised, such as behavioral methods (e.g., aversive stimuli, overcorrection,
time-out, reinforcement) and biological interventions (e.g., pharmacotherapy,
nutritional supplements). This paper is a broad review of the research on
treatment studies for this problem, with a focus on persons with autism and/or
intellectual disability (ID), which constitutes almost all of the published
treatment papers. In addition, strengths and weaknesses of different pica
treatments are discussed. Upon review, applied behavior analysis (ABA) was found 
to have the most robust empirical support to treat this behavior. Most clinicians
are drifting away from aversive techniques and relying on more positive
procedures to guide their treatment plans. The implications of current status and
future directions for research are also addressed.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID: 23747942  [PubMed - as supplied by publisher]

An investigation of self-injurious behaviors in adults with severe intellectual disabilities.

Tureck K, Matson JL, Beighley JS.

Louisiana State University, United States.

Self-injurious behavior (SIB) is commonly observed among individuals with
intellectual disability (ID) living in state-run supports and services centers.
Specific examples of SIB include poking oneself in the eye; harming oneself by
hitting, scratching, or pinching; and pica (i.e., swallowing objects causing
bodily harm). Previous research has focused on SIB in individuals with ID more
generally without focusing on specific levels of ID or taking into account other 
important personal variables. This study examined 45 adults with severe ID living
in two large state-run facilities in the Southeastern United States who were
separated into groups for comparison (ASD and non ASD; verbal and nonverbal).
Data was collected on the presence of SIB using the Autism Spectrum
Disorder-Problem Behavior Adult Version (ASD-PBA). A two-way analysis of variance
(ANOVA) was conducted to determine if there were significant differences between 
groups on rates of SIB. Individuals with ID and ASD exhibited significantly
higher rates of SIB than individuals with only ID, F (1,43)=50.84, p<0.05.
Furthermore, verbal individuals had significantly higher rates of SIB than
nonverbal individuals, F (1,43)=57.612, p<0.05. There was a significant
interaction between the effects of ASD diagnosis and verbal ability on rates of
SIB, F (1,43)=50.84, p<0.05. The implications of these findings in the context of
other research on ID, ASD, SIB, and verbal abilities are discussed.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID: 23747938  [PubMed - as supplied by publisher]

Investigating emotional impairments in adults with autism spectrum disorders and the broader autism phenotype.

Berthoz S, Lalanne C, Crane L, Hill EL.

Institut National de la Santé et de la Recherche Médicale (INSERM U669), Maison
de Solenn-Cochin, Paris, France; Department of Psychiatry, Institut Mutualiste
Montsouris (IMM), Paris, France; Paris-Sud University, Paris, France;
Paris-Descartes University, Paris, France.

There is an increasing interest in the socio-affective atypicalities observed in 
adults with autism spectrum disorder (ASD). The aim of this study was to further 
explore emotional responsiveness in adults with ASD using well-validated
self-reports of alexithymia and to determine whether anhedonic features are part 
of a broader autism phenotype (BAP). Participants comprised 38 adults with ASD,
87 parents of ASD individuals and 47 typical controls. All participants completed
the Autism Spectrum Quotient (AQ), the 20-item Toronto Alexithymia Scale, and the
Bermond-Vorst Alexithymia Questionnaire, as well as the Chapman Physical and
Social Anhedonia Scales. The ASD group differed from controls and parents on most
measures, with the exception of physical and social anhedonia, relative to
parents. Parents differed from controls on social anhedonia, and a higher
proportion of parents were classed as alexithymic, relative to controls. Cluster 
analysis revealed that some parents share more similarities with ASD participants
than with controls. The results suggest that socio-affective impairments
characteristic of ASD are part of the BAP.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

PMID: 23747233  [PubMed - as supplied by publisher]

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits.

Fusco C, Micale L, Augello B, Teresa Pellico M, Menghini D, Alfieri P, Cristina
Digilio M, Mandriani B, Carella M, Palumbo O, Vicari S, Merla G.

Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San
Giovanni Rotondo, Italy.

Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous
deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with
larger and smaller WBS deletion have been reported. They show clinical features
that vary between isolated SVAS to the full spectrum of WBS phenotype, associated
with epilepsy or autism spectrum behavior. Here we describe four patients with
atypical WBS 7q11.23 deletions. Two carry ∼3.5 Mb larger deletion towards the
telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine
3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG)
genes. Other two carry a shorter deletion of ∼1.2 Mb at centromeric side that
excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported
cases, genotype-phenotype correlation in the patients described here further
suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe
neurological and neuropsychological deficits including epilepsy and autistic
traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild 
facial features and moderate neuropsychological deficits. This report highlights 
the importance to characterize additional patients with 7q11.23 atypical
deletions comparing neuropsychological and clinical features between these
individuals to shed light on the pathogenic role of genes within and flanking the
WBS region.European Journal of Human Genetics advance online publication, 12 June
2013; doi:10.1038/ejhg.2013.101.

PMID: 23756441  [PubMed - as supplied by publisher]

Ketogenic Diet Improves Core Symptoms of Autism in BTBR Mice.

Ruskin DN, Svedova J, Cote JL, Sandau U, Rho JM, Kawamura M Jr, Boison D, Masino 
SA.

Neuroscience Program, Trinity College, Hartford, Connecticut, United States of
America ; Department of Psychology, Trinity College, Hartford, Connecticut,
United States of America.

AUTISM SPECTRUM DISORDERS SHARE THREE CORE SYMPTOMS: impaired sociability,
repetitive behaviors and communication deficits. Incidence is rising, and current
treatments are inadequate. Seizures are a common comorbidity, and since the
1920's a high-fat, low-carbohydrate ketogenic diet has been used to treat
epilepsy. Evidence suggests the ketogenic diet and analogous metabolic approaches
may benefit diverse neurological disorders. Here we show that a ketogenic diet
improves autistic behaviors in the BTBR mouse. Juvenile BTBR mice were fed
standard or ketogenic diet for three weeks and tested for sociability,
self-directed repetitive behavior, and communication. In separate experiments,
spontaneous intrahippocampal EEGs and tests of seizure susceptibility (6 Hz
corneal stimulation, flurothyl, SKF83822, pentylenetetrazole) were compared
between BTBR and control (C57Bl/6) mice. Ketogenic diet-fed BTBR mice showed
increased sociability in a three-chamber test, decreased self-directed repetitive
behavior, and improved social communication of a food preference. Although
seizures are a common comorbidity with autism, BTBR mice fed a standard diet
exhibit neither spontaneous seizures nor abnormal EEG, and have increased seizure
susceptibility in just one of four tests. Thus, behavioral improvements are
dissociable from any antiseizure effect. Our results suggest that a ketogenic
diet improves multiple autistic behaviors in the BTBR mouse model. Therefore,
ketogenic diets or analogous metabolic strategies may offer novel opportunities
to improve core behavioral symptoms of autism spectrum disorders.

PMID: 23755170  [PubMed - in process]

Autistic trait interactions underlie sex-dependent facial recognition abilities in the normal population.

Valla JM, Maendel JW, Ganzel BL, Barsky AR, Belmonte MK.

Department of Human Development, Cornell University Ithaca, NY, USA.

Autistic face processing difficulties are either uniquely social or due to a
piecemeal cognitive "style." Co-morbidity of social deficits and piecemeal
cognition in autism makes teasing apart these accounts difficult. These traits
vary normally, and are more separable in the general population, suggesting
another way to compare accounts. Participants completed the Autism Quotient
survey of autistic traits, and one of three face recognition tests: full-face,
eyes-only, or mouth-only. Social traits predicted performance in the full-face
condition in both sexes. Eyes-only males' performance was predicted by a social ×
cognitive trait interaction: attention to detail boosted face recognition in
males with few social traits, but hindered performance in those reporting many
social traits. This suggests social/non-social Autism Spectrum Conditions (ASC)
trait interactions at the behavioral level. In the presence of few ASC-like
difficulties in social reciprocity, an ASC-like attention to detail may confer
advantages on typical males' face recognition skills. On the other hand, when
attention to detail co-occurs with difficulties in social reciprocity, a detailed
focus may exacerbate such already present social difficulties, as is thought to
occur in autism.

PMID: 23755028  [PubMed]

Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice.

Xu P, Grueter BA, Britt JK, McDaniel L, Huntington PJ, Hodge R, Tran S, Mason BL,
Lee C, Vong L, Lowell BB, Malenka RC, Lutter M, Pieper AA.

Departments of Neuroscience and Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, TX 75390.

Compulsive behavior is a debilitating clinical feature of many forms of
neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive
spectrum disorders, eating disorders, and autism. Although several studies link
striatal dysfunction to compulsivity, the pathophysiology remains poorly
understood. Here, we show that both constitutive and induced genetic deletion of 
the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic
inhibition of MC4R signaling, normalize compulsive grooming and striatal
electrophysiologic impairments in synapse-associated protein 90/postsynaptic
density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human
obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores 
normal weight and metabolic features of MC4R-null mice, a model of human obesity.
Our findings offer insights into the pathophysiology and treatment of both
compulsive behavior and eating disorders.

PMID: 23754400  [PubMed - as supplied by publisher]

Do politics affect prevalence? An overview and the case of cerebral palsy.

Dalembert G, Brosco JP.

Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, 
FL.

: Many factors must be considered when assessing estimates of prevalence,
including research methods and quality of the work by the research team. Broad
social and political forces also influence estimates of prevalence, as seen in
the case of autism and intellectual disability. Indeed, researchers themselves
may be influenced by broader sociopolitical factors in ways that they do not
recognize. To further explore the relationship of prevalence to sociopolitical
factors, we reviewed the historical prevalence of cerebral palsy (CP) (as a proxy
for physical disability) in the late 20th century. We hypothesized that increased
awareness of physical impairments associated with the disability rights movement 
of the 1970s would increase the prevalence of CP, primarily because of changes in
case definition. Although prevalence of CP did rise slightly in the 1980s, we
conclude that this change is better explained by increased survival of low birth 
weight infants, which is only indirectly related to the disability rights
movement.

PMID: 23751888  [PubMed - in process]

Adult rats treated with risperidone during development are hyperactive.

Bardgett ME, Franks-Henry JM, Colemire KR, Juneau KR, Stevens RM, Marczinski CA, 
Griffith MS.

Department of Psychological Science.

Risperidone is an antipsychotic drug approved for use in children, but little is 
known about the long-term effects of early-life risperidone treatment. In
animals, prolonged risperidone administration during development increases
forebrain dopamine receptor expression immediately upon the cessation of
treatment. A series of experiments was performed to ascertain whether early-life 
risperidone administration altered locomotor activity, a behavior sensitive to
dopamine receptor function, in adult rats. One additional behavior modulated by
forebrain dopamine function, spatial reversal learning, was also measured during 
adulthood. In each study, Long-Evans rats received daily subcutaneous injections 
of vehicle or 1 of 2 doses of risperidone (1.0 and 3.0 mg/kg per day) from
postnatal Days 14 to 42. Weight gain during development was slightly yet
significantly reduced in risperidone-treated rats. In the first 2 experiments,
early-life risperidone administration was associated with increased locomotor
activity at 1 week postadministration through approximately 9 months of age,
independent of changes in weight gain. In a separate experiment, it was found
that the enhancing effect of early-life risperidone on locomotor activity
occurred in males and female rats. A final experiment indicated that spatial
reversal learning was unaffected in adult rats administered risperidone early in 
life. These results indicate that locomotor activity during adulthood is
permanently modified by early-life risperidone treatment. The findings suggest
that chronic antipsychotic drug use in pediatric populations (e.g., treatment for
the symptoms of autism) could modify brain development and alter neural set
points for specific behaviors during adulthood. (PsycINFO Database Record (c)
2013 APA, all rights reserved).

PMID: 23750695  [PubMed - in process]

The Autism Impact Measure (AIM): Initial Development of a New Tool for Treatment Outcome Measurement.

Adjusting Head Circumference for Covariates in Autism: Clinical Correlates of a Highly Heritable Continuous Trait.

Chaste P, Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ,
Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C,
Mane SM, Lese Martin C, Martin DM, Morrow EM, Walsh CA, Sutcliffe JS, State MW,
Devlin B, Cook EH Jr, Kim SJ.

Department of Psychiatry (PC, LK, BD), University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania; FondaMental Foundation (PC), Créteil, France.

BACKGROUND: Brain development follows a different trajectory in children with
autism spectrum disorders (ASD) than in typically developing children. A proxy
for neurodevelopment could be head circumference (HC), but studies assessing HC
and its clinical correlates in ASD have been inconsistent. This study
investigates HC and clinical correlates in the Simons Simplex Collection cohort. 
METHODS: We used a mixed linear model to estimate effects of covariates and the
deviation from the expected HC given parental HC (genetic deviation). After
excluding individuals with incomplete data, 7225 individuals in 1891 families
remained for analysis. We examined the relationship between HC/genetic deviation 
of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic
ancestry, and ASD status were significant predictors of HC (estimate of the ASD
effect = .2 cm). HC was approximately normally distributed in probands and
unaffected relatives, with only a few outliers. Genetic deviation of HC was also 
normally distributed, consistent with a random sampling of parental genes.
Whereas larger HC than expected was associated with ASD symptom severity and
regression, IQ decreased with the absolute value of the genetic deviation of HC. 
CONCLUSIONS: Measured against expected values derived from covariates of ASD
subjects, statistical outliers for HC were uncommon. HC is a strongly heritable
trait, and population norms for HC would be far more accurate if covariates
including genetic ancestry, height, and age were taken into account. The
association of diminishing IQ with absolute deviation from predicted HC values
suggests HC could reflect subtle underlying brain development and warrants
further investigation.

Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.

PMID: 23746936  [PubMed - as supplied by publisher]

Mutations in the C-terminus of CDKL5: proceed with caution.

Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism.

Pizzarelli R, Cherubini E.

Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati
Trieste, Italy.

Autism Spectrum Disorders (ASDs) comprise an heterogeneous group of
neuro-developmental abnormalities, mainly of genetic origin, characterized by
impaired social interactions, communications deficits, and stereotyped behaviors.
In a small percentage of cases, ASDs have been found to be associated with single
mutations in genes involved in synaptic function. One of these involves the
postsynaptic cell adhesion molecule neuroligin (NL) 3. NLs interact with
presynaptic neurexins (Nrxs) to ensure a correct cross talk between post and
presynaptic specializations. Here, transgenic mice carrying the human R451C
mutation of Nlgn3, were used to study GABAergic signaling in the hippocampus
early in postnatal life. Whole cell recordings from CA3 pyramidal neurons in
slices from NL3(R451C) knock-in mice revealed an enhanced frequency of Giant
Depolarizing Potentials (GDPs), as compared to controls. This effect was probably
dependent on an increased GABAergic drive to principal cells as demonstrated by
the enhanced frequency of miniature GABAA-mediated (GPSCs), but not AMPA-mediated
postsynaptic currents (EPSCs). Changes in frequency of mGPSCs were associated
with an acceleration of their decay kinetics, in the absence of any change in
unitary synaptic conductance or in the number of GABAA receptor channels, as
assessed by peak scaled non-stationary fluctuation analysis. The enhanced
GABAergic but not glutamatergic transmission early in postnatal life may change
the excitatory/inhibitory balance known to play a key role in the construction
and refinement of neuronal circuits during postnatal development. This may lead
to behavioral deficits reminiscent of those observed in ASDs patients.

PMID: 23761734  [PubMed - in process]

Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene.

Aldinger KA, Plummer JT, Levitt P.

BACKGROUND: Several proteins involved in epigenetic regulation cause syndromic
neurodevelopmental disorders when human genes are mutated. More general
involvement of epigenetic mechanisms in neurodevelopmental phenotypes is unclear.
METHODS: In an attempt to determine whether DNA methylation differentiates
clinical subgroups, profiling was performed on bisulfite converted DNA from
lymphoblastoid cell lines (LCLs) in discovery (n = 20) and replication (n = 40)
cohorts of females with Rett syndrome (RTT; n = 18), autism (AUT; n = 17),
seizure disorder (SEZ; n = 6), and controls (CTL; n = 19) using Illumina
HumanMethylation27 arrays. TAC1 CpGs were validated using a Sequenom EpiTYPER
assay and expression was measured in LCLs and postmortem brain. Chromatin
immunoprecipitation was performed in HEK cells. Cells were treated with valproic 
acid and MeCP2 binding was assessed. RESULTS: Two female-only cohorts were
analyzed. DNA methylation profiling in a discovery cohort identified 40 CpGs that
exhibited statistically significant differential methylation (>=15%) between
clinical groups (P <0.01). Hierarchical clustering and principal components
analysis suggested neurodevelopmental groups were distinct from CTL, but not from
each other. In a larger and more heterogeneous replication cohort, these 40 CpG
sites suggested no clear difference between clinical groups. Pooled analysis of
DNA methylation across all 60 samples suggested only four differentially
methylated CpG sites (P <0.0005), including TAC1. TAC1 promoter CpG
hypermethylation was validated in AUT and SEZ (P <0.005). Analyzed for the first 
time in postmortem brain, TAC1 expression was reduced in cingulate cortex in RTT 
and AUT+SEZ (P = 0.003). However, no significant difference in TAC1 promoter CpG 
methylation was detected in RTT and AUT+SEZ brains. Additional molecular analyses
revealed that MeCP2 binds directly to the TAC1 promoter and is sensitive to
antiepileptic drug treatment. CONCLUSION: These data suggest that DNA methylation
is not widely altered in RTT, consistent with subtle changes in gene expression
previously observed. However, TAC1 may be an important target for further
functional analyses in RTT. Studies of larger sample cohorts using primary cells 
that also consider shared clinical features and drug treatments may be required
to address apparent subtle disruptions of DNA methylation in neurodevelopmental
disorders.

PMID: 23759142  [PubMed - as supplied by publisher]

Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.

Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, Frank Y, Wang AT,
Cai G, Parkhomenko E, Halpern D, Grodberg D, Angarita B, Willner JP, Yang A,
Canitano R, Chaplin W, Betancur C, Buxbaum JD.

BACKGROUND: 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a
neurodevelopmental disorder characterized by intellectual disability, hypotonia, 
delayed or absent speech, and autistic features. SHANK3 has been identified as
the critical gene in the neurological and behavioral aspects of this syndrome.
The phenotype of SHANK3 deficiency has been described primarily from case
studies, with limited evaluation of behavioral and cognitive deficits. The
present study used a prospective design and inter-disciplinary clinical
evaluations to assess patients with SHANK3 deficiency, with the goal to provide a
comprehensive picture of the medical and behavioral profile of the syndrome.
METHODS: A serially ascertained sample of patients with SHANK3 deficiency (n =
32) was evaluated by a team of child psychiatrists, neurologists, clinical
geneticists, molecular geneticists and psychologists. Patients were evaluated for
autism spectrum disorder using the Autism Diagnostic Interview-Revised and the
Autism Diagnostic Observation Schedule-G. RESULTS: Thirty participants with
22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants
with de novo SHANK3 mutations were included. The sample was characterized by high
rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum
disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe
to profound intellectual disability and only five (19%) used some words
spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance,
recurring upper respiratory tract infections, gastroesophageal reflux and
seizures were also common. Analysis of genotype-phenotype correlations indicated 
that larger deletions were associated with increased levels of dysmorphic
features, medical comorbidities and social communication impairments related to
autism. Analyses of individuals with small deletions or point mutations
identified features related to SHANK3 haploinsufficiency, including ASD, seizures
and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI,
gastroesophageal reflux, and certain dysmorphic features. CONCLUSIONS: This study
supports findings from previous research on the severity of intellectual, motor, 
and speech impairments seen in SHANK3 deficiency, and highlights the predominance
of autism spectrum disorder in the syndrome. Limitations of existing evaluation
tools are discussed, along with the need for natural history studies to inform
clinical monitoring and treatment development in SHANK3 deficiency.

PMID: 23758760  [PubMed - as supplied by publisher]

SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders.

Autism, processing speed, and adaptive functioning in preschool children.

A comparison of tantrum behavior profiles in children with ASD, ADHD and comorbid ASD and ADHD.

Goldin RL, Matson JL, Tureck K, Cervantes PE, Jang J.

Louisiana State University, United States. Electronic address: rgoldi3@lsu.edu.

The present study was conducted to compare rates of tantrum behaviors in children
with autism spectrum disorders (ASD) (n=255), attention-deficit/hyperactivity
disorder (ADHD) (n=40) and children with comorbid ASD and ADHD (n=47).
Parents/guardians of children aged 3-16 years were surveyed about their
children's behaviors using the Autism Spectrum Disorders-Comorbidity for Children
(ASD-C-C). Children with ADHD alone differed from children with ASD alone and
children with comorbid ASD and ADHD on rates of tantrum behaviors. Examination of
individual tantrum behavior items indicated that children with comorbid ASD and
ADHD have a more similar symptom presentation to children with ASD than children 
with ADHD. This study adds to the literature on the presentation of common
co-occurring behaviors of ASD when there is comorbid ADHD. The implications of
these findings may aid in the assessment and treatment of tantrum behaviors in
children with comorbid ASD and ADHD.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID: 23764824  [PubMed - as supplied by publisher]