1. Barman A, Richter S, Soch J, Deibele A, Richter A, Assmann A, Wustenberg T, Walter H, Seidenbecher CI, Schott BH. {{Gender-specific modulation of neural mechanisms underlying social reward processing by Autism Quotient}}. {Social cognitive and affective neuroscience}. 2015 May 4.
Autism spectrum disorder (ASD) refers to a neurodevelopmental condition primarily characterized by deficits in social cognition and behavior. Subclinically, autistic features are supposed to be present in healthy humans and can be quantified using the Autism Quotient (AQ). Here we investigated a potential relationship between AQ and neural correlates of social and monetary reward processing, using functional magnetic resonance imaging (fMRI) in young, healthy participants. In an incentive delay task with either monetary of social reward, reward anticipation elicited increased ventral striatal activation, which was more pronounced during monetary reward anticipation. Anticipation of social reward elicited activation in the default mode network (DMN), a network previously implicated in social processing. Social reward feedback was associated with bilateral amygdala and fusiform face area (FFA) activation. The relationship between AQ and neural correlates of social reward processing varied in a gender-dependent manner. In women and, to a lesser extent men, higher AQ was associated with increased posterior DMN activation during social reward anticipation. During feedback, we observed a negative correlation of AQ and right amygdala activation in men only. Our results suggest that social reward processing might constitute an endophenotype for autism-related traits in healthy humans that manifests in a gender-specific way.
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2. Bitton JY, Demos M, Elkouby K, Connolly M, Weiss SK, Donner EJ, Whiting S, Ronen GM, Bello-Espinosa L, Wirrell EC, Mohamed IS, Dooley JM, Carmant L. {{Does treatment have an impact on incidence and risk factors for autism spectrum disorders in children with infantile spasms?}}. {Epilepsia}. 2015 May 5.
OBJECTIVE: Infantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. METHODS: Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule-Generic (ADOS-G). RESULTS: Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). SIGNIFICANCE: ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome.
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3. Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, Kang JX. {{Autistic children exhibit decreased levels of essential Fatty acids in red blood cells}}. {International journal of molecular sciences}. 2015;16(5):10061-76.
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p < 0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n = 20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism.
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4. Du RY, Yiu CC, Wong VC, McGrath CP. {{Autism Developmental Profiles and Cooperation with Oral Health Screening}}. {J Autism Dev Disord}. 2015 May 7.
To determine the associations between autism developmental profiles and cooperation with an oral health screening among preschool children with autism spectrum disorders (ASDs). A random sample of Special Child Care Centres registered with the Government Social Welfare Department in Hong Kong was selected (19 out of 37 Centres). All preschool children with ASDs were invited to participate in the oral health survey and 347 children agreed to participate (among 515 invited). A checklist of autism developmental profiles: (1) level of cognitive functioning, (2) social skills development, (3) communication skills development, (4) reading skills and (5) challenging behaviours was ascertained. Feasibility of conducting oral health screening in preschool children with ASDs was associated with their cognitive functioning (p = 0.001), social skills development (p = 0.002), communication skills development (p < 0.001), reading skills (p < 0.001) and challenging behaviours (p = 0.06). In regression analyses accounting for age (in months) and gender, inability to cooperate with an oral health screening was associated with high level of challenging behaviours (OR 10.50, 95 % CI 2.89-38.08, p < 0.001) and reduced cognitive functioning (OR 5.29, 95 % CI 1.14-24.61, p = 0.034). Age (in months) was positively associated with likelihood of cooperative behaviour with an oral health screening (OR 1.06, 95 % CI 1.03, 1.08, p < 0.001). Feasibility of conducting population-wide oral health screening among preschool children with ASDs is associated with their developmental profiles; and in particular levels of cognitive functioning, and challenging behaviours.
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5. Frye RE, Rose S, Slattery J, MacFabe DF. {{Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome}}. {Microbial ecology in health and disease}. 2015;26:27458.
Autism spectrum disorder (ASD) affects a significant number of individuals worldwide with the prevalence continuing to grow. It is becoming clear that a large subgroup of individuals with ASD demonstrate abnormalities in mitochondrial function as well as gastrointestinal (GI) symptoms. Interestingly, GI disturbances are common in individuals with mitochondrial disorders and have been reported to be highly prevalent in individuals with co-occurring ASD and mitochondrial disease. The majority of individuals with ASD and mitochondrial disorders do not manifest a primary genetic mutation, raising the possibility that their mitochondrial disorder is acquired or, at least, results from a combination of genetic susceptibility interacting with a wide range of environmental triggers. Mitochondria are very sensitive to both endogenous and exogenous environmental stressors such as toxicants, iatrogenic medications, immune activation, and metabolic disturbances. Many of these same environmental stressors have been associated with ASD, suggesting that the mitochondria could be the biological link between environmental stressors and neurometabolic abnormalities associated with ASD. This paper reviews the possible links between GI abnormalities, mitochondria, and ASD. First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut-brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction.
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6. Frye RE, Slattery J, MacFabe DF, Allen-Vercoe E, Parker W, Rodakis J, Adams JB, Krajmalnik-Brown R, Bolte E, Kahler S, Jennings J, James J, Cerniglia CE, Midtvedt T. {{Approaches to studying and manipulating the enteric microbiome to improve autism symptoms}}. {Microbial ecology in health and disease}. 2015;26:26878.
There is a growing body of scientific evidence that the health of the microbiome (the trillions of microbes that inhabit the human host) plays an important role in maintaining the health of the host and that disruptions in the microbiome may play a role in certain disease processes. An increasing number of research studies have provided evidence that the composition of the gut (enteric) microbiome (GM) in at least a subset of individuals with autism spectrum disorder (ASD) deviates from what is usually observed in typically developing individuals. There are several lines of research that suggest that specific changes in the GM could be causative or highly associated with driving core and associated ASD symptoms, pathology, and comorbidities which include gastrointestinal symptoms, although it is also a possibility that these changes, in whole or in part, could be a consequence of underlying pathophysiological features associated with ASD. However, if the GM truly plays a causative role in ASD, then the manipulation of the GM could potentially be leveraged as a therapeutic approach to improve ASD symptoms and/or comorbidities, including gastrointestinal symptoms. One approach to investigating this possibility in greater detail includes a highly controlled clinical trial in which the GM is systematically manipulated to determine its significance in individuals with ASD. To outline the important issues that would be required to design such a study, a group of clinicians, research scientists, and parents of children with ASD participated in an interdisciplinary daylong workshop as an extension of the 1st International Symposium on the Microbiome in Health and Disease with a Special Focus on Autism (www.microbiome-autism.com). The group considered several aspects of designing clinical studies, including clinical trial design, treatments that could potentially be used in a clinical trial, appropriate ASD participants for the clinical trial, behavioral and cognitive assessments, important biomarkers, safety concerns, and ethical considerations. Overall, the group not only felt that this was a promising area of research for the ASD population and a promising avenue for potential treatment but also felt that further basic and translational research was needed to clarify the clinical utility of such treatments and to elucidate possible mechanisms responsible for a clinical response, so that new treatments and approaches may be discovered and/or fostered in the future.
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7. Gdalyahu A, Lazaro M, Penagarikano O, Golshani P, Trachtenberg JT, Gescwind DH. {{The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study}}. {PloS one}. 2015;10(5):e0125633.
The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.
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8. Oh SY, He F, Krans A, Frazer M, Taylor JP, Paulson HL, Todd PK. {{RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome}}. {Human molecular genetics}. 2015 May 7.
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5’UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via Repeat-Associated Non-AUG (RAN) initiated translation. Pathologically, FXTAS is characterized by ubiquitin positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila and cell based models of CGG-repeat associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat induced degeneration whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG-repeat expression triggered accumulation of a GFP-UPS reporter in a length-dependent fashion. To delineate the contributions from CGG repeats as RNA from RAN translation associated toxicity, we enhanced or impaired the production of FMRpolyG in these models. Driving expression of FMRpolyG enhanced induction of UPS impairment in cell models while prevention of RAN translation attenuated UPS impairment in cells and suppressed the genetic interaction with UPS manipulation in Drosophila. Taken together, these findings suggest that CGG repeats induce ubiquitin proteasome system impairment at least in part through activation of RAN translation.
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9. Ring M, Gaigg SB, Bowler DM. {{Relational Memory Processes in Adults with Autism Spectrum Disorder}}. {Autism research : official journal of the International Society for Autism Research}. 2015 May 7.
Research into memory in Autism Spectrum Disorder (ASD) suggests intact item memory but difficulties in forming relations between items (Bowler, Gaigg, & Lind, 2011). In this study, we tested memory for items as well as for sequential, spatial, and associative relations between items with the same paradigm using abstract shapes in ASD and typically developing (TD) individuals. Participants studied shape triplets on a computer screen and memory was subsequently tested either for the individual items making up the triplets, the screen-locations, the order or the combinations of items presented at study. Contrary to our predictions, performance was significantly lower in the ASD group on all four tasks. The result raises questions about how intact item memory is in ASD, which role task complexity plays, and how item-specific versus relational processing affect task performance. One possibility is that TD individuals relied more on relational processing in the current study and might have therefore had an advantage over ASD individuals. This idea is supported by the result of a preliminary analysis of age-related differences in memory across the midadult lifespan in both groups. Age seems to affect order memory less in ASD compared with TD individuals where it leads to a significant decrease in performance. This might indicate a decrease in relational processing in TD but not ASD individuals with increasing age. More research is needed to answer questions about the change in cognition in ASD individuals across the lifespan. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Saigal R, Clark AJ, Scheer JK, Smith JS, Bess S, Mummaneni PV, McCarthy IM, Hart RA, Kebaish KM, Klineberg EO, Deviren V, Schwab F, Shaffrey CI, Ames CP. {{Adult Deformity Surgery (ASD) Patients Recall Fewer than 50% of the Risks Discussed in the Informed Consent Process Preoperatively and the Recall Rate Worsens Significantly in the Postoperative Period}}. {Spine}. 2015 May 5.
STRUCTURED ABSTRACT: Study Design. Recall of the informed consent process in patients undergoing adult spinal deformity surgery and their family members was investigated prospectively. OBJECTIVE: To quantify the percentage recall of the most common complications discussed during the informed consent process in adult spinal deformity (ASD) surgery, assess for differences between patients and family members, and correlate with mental status. SUMMARY OF BACKGROUND DATA: Given high rates of complications in ASD surgery, it is critical to shared decision making that patients are adequately informed about risks and are able to recall pre-operative discussion of possible complications to mitigate medical legal risk. METHODS: Patients undergoing ASD surgery underwent an augmented informed consent process involving both verbal and video explanations. Recall of the 11 most common complications was scored. Mental status was assessed with the mini-mental status examination (MMSE-BV). Patients subjectively scored the informed consent process and video. After surgery, the recall test and MMSE-BV were re-administered at 5 additional time points: hospital discharge, six-eight weeks, three months, six months, and one year post-operatively. Family members were assessed at the first three time points for comparison. RESULTS: 56 patients enrolled. Despite ranking the consent process as important (median overall score 10/10; video score 9/10), median patient recall was only 45% immediately after discussion and video re-enforcement, and subsequently declined to 18% at 6-8 weeks and 1 year post-operatively. Median family recall trended higher, at 55% immediately and 36% at 6-8 weeks post-op. The perception of the severity of complications significantly differs between patient and surgeon. Mental status scores showed a transient, significant decrease from pre-op to discharge, but were significantly higher at one year. CONCLUSIONS: Despite being well-informed in an optimized informed consent process, patients cannot recall most surgical risks discussed and recall declines over time. Significant progress remains to improve informed consent retention.
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11. Salmasi A, Harrison R, Brondani MA. {{They stole her teeth! An exploration of adults with developmental disability experiences with dental care}}. {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}. 2015 May 7.
PURPOSE: The aim of this paper was to explore the experiences of adults with developmental disabilities (AWDD) in accessing and utilizing dental services in Vancouver, BC. METHODS: Participants were either self-advocates or parents/caregivers who discussed their experiences in five focus group discussions with 20 participants in total (age range 17-60 years, 2 males). Each focus group lasted on average 40 minutes. Transcripts were coded for thematic analysis; the codes were organized into themes and finally into domains. RESULTS: Seven domains relating to the participants’ experiences with dental care were identified, and included communication, trust, and respect as provided-based domains to the quality of the dental experience for AWDD and their parents, while financial issues, transitional services, and waiting times were system-based barriers to access to dental care for theses AWDD. Finally, what makes for a positive dental experience was shared in terms of acknowledging parent’s role as advocates and making simple accommodations to see AWDD by the dental office. CONCLUSIONS: Access to a care provider did not necessarily equate to satisfaction with quality of experience. Efforts have to focus on establishing communication and trust with AWDD patients as key to a positive dental experience. We encourage a global discussion on the need to better incorporate dental care for special needs individuals within dental school curricula.
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12. Serret S, Thummler S, Dor E, Vesperini S, Santos A, Askenazy F. {{Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports}}. {BMC psychiatry}. 2015 May 7;15(1):107.
BACKGROUND: Phelan-Mc Dermid syndrome is a contiguous disorder resulting from 22q13.3 deletion implicating the SHANK3 gene. The typical phenotype includes neonatal hypotonia, moderate to severe intellectual disability, absent or delayed speech, minor dysmorphic features and autism or autistic-like behaviour. Recently, point mutations or micro-deletions of the SHANK3 gene have been identified, accompanied by a phenotype different from the initial clinically description in Phelan McDermid syndrome. CASE PRESENTATION: Here we present two case studies with similar psychiatric and genetic diagnosis as well as similar clinical history and evolution. The two patients were diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence. Interestingly, both patients presented mutation/microdeletion of the SHANK3 gene, inducing a premature stop codon in exon 21. Different pharmacological treatments (antipsychotics, benzodiazepines, mood stabilizer drugs, antidepressants, and methylphenidate) failed to improve clinical symptoms and lead to multiple adverse events. In contrast, lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects. CONCLUSION: These cases support the hypothesis of a specific SHANK3 phenotype. This phenotype might be linked to catatonia-like deterioration for which lithium use could be an efficient treatment. Therefore, these cases provide an important contribution to the field of autism research, clinical genetics and possible pharmacological answers.
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13. Verdyck P, Berckmoes V, De Vos A, Verpoest W, Liebaers I, Bonduelle M, De Rycke M. {{Chromosome fragility at FRAXA in human cleavage stage embryos at risk for fragile X syndrome}}. {American journal of medical genetics Part A}. 2015 May 7.
Fragile X syndrome (FXS), the most common inherited intellectual disability syndrome, is caused by expansion and hypermethylation of the CGG repeat in the 5′ UTR of the FMR1 gene. This expanded repeat, also known as the rare fragile site FRAXA, causes X chromosome fragility in cultured cells from patients but only when induced by perturbing pyrimidine synthesis. We performed preimplantation genetic diagnosis (PGD) on 595 blastomeres biopsied from 442 cleavage stage embryos at risk for FXS using short tandem repeat (STR) markers. In six blastomeres, from five embryos an incomplete haplotype was observed with loss of all alleles telomeric to the CGG repeat. In all five embryos, the incomplete haplotype corresponded to the haplotype carrying the CGG repeat expansion. Subsequent analysis of additional blastomeres from three embryos by array comparative genomic hybridization (aCGH) confirmed the presence of a terminal deletion with a breakpoint close to the CGG repeat in two blastomeres from one embryo. A blastomere from another embryo showed the complementary duplication. We conclude that a CGG repeat expansion at FRAXA causes X chromosome fragility in early human IVF embryos at risk for FXS. (c) 2015 Wiley Periodicals, Inc.
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14. Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP. {{Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation}}. {American journal of medical genetics Part A}. 2015 May 5.
Disorders of carnitine biosynthesis have recently been associated with neurodevelopmental syndromes such as autism spectrum disorder (ASD). A 4-year-old male with autism and two episodes of neurodevelopmental regression was identified to have a mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency. Following carnitine supplementation, the patient’s regression ended, and the boy started gaining developmental milestones. This case report suggests that deficits in carnitine biosynthesis may be responsible for some cases of regression in individuals with ASD, and that testing for the respective biochemical pathway should be considered. Furthermore, this case suggests that carnitine supplementation may be useful in treating (and potentially preventing) regressive episodes in patients with carnitine deficiency. Further work to better define the role of disorders of carnitine biosynthesis in autism spectrum disorder is warranted. (c) 2015 Wiley Periodicals, Inc.
