1. 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.
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2. 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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3. Roberts AL, Koenen KC, Lyall K, Robinson EB, Weisskopf MG. {{Association of autistic traits in adulthood with childhood abuse, interpersonal victimization, and posttraumatic stress}}. {Child abuse & neglect}. 2015 May 5.
Persons with autistic traits may be at elevated risk for interpersonal victimization across the life course. Children with high levels of autistic traits may be targeted for abuse, and deficits in social awareness may increase risk of interpersonal victimization. Additionally, persons with autistic traits may be at elevated risk of posttraumatic stress disorder (PTSD) symptoms subsequent to trauma. We examined retrospectively reported prevalence of childhood abuse, trauma victimization and PTSD symptoms by autistic traits among adult women in a population-based longitudinal cohort, the Nurses’ Health Study II (N=1,077). Autistic traits were measured by the 65-item Social Responsiveness Scale. We estimated odds ratios (OR) for childhood sexual and physical/emotional abuse and PTSD symptoms by quintiles of autistic traits. We examined possible mediation of PTSD risk by abuse and trauma type. Women in the highest versus lowest quintile of autistic traits were more likely to have been sexually abused (40.1% versus 26.7%), physically/emotionally abused (23.9% versus 14.3%), mugged (17.1% versus 10.1%), pressured into sexual contact (25.4% versus 15.6%) and have high PTSD symptoms (10.7% versus 4.5%). Odds of PTSD were elevated in women in the top three quintiles of autistic traits compared with the reference group (OR range=1.4 to 1.9). Childhood abuse exposure partly accounted for elevated risk of PTSD in women with autistic traits. We identify for the first time an association between autistic traits, childhood abuse, trauma victimization, and PTSD. Levels of autistic traits that are highly prevalent in the general population are associated with abuse, trauma and PTSD.
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4. Penner M, Rayar M, Bashir N, Roberts SW, Hancock-Howard RL, Coyte PC. {{Cost-Effectiveness Analysis Comparing Pre-diagnosis Autism Spectrum Disorder (ASD)-Targeted Intervention with Ontario’s Autism Intervention Program}}. {J Autism Dev Disord}. 2015 May 5.
Novel management strategies for autism spectrum disorder (ASD) propose providing interventions before diagnosis. We performed a cost-effectiveness analysis comparing the costs and dependency-free life years (DFLYs) generated by pre-diagnosis intensive Early Start Denver Model (ESDM-I); pre-diagnosis parent-delivered ESDM (ESDM-PD); and the Ontario Status Quo (SQ). The analyses took government and societal perspectives to age 65. We assigned probabilities of Independent, Semi-dependent or Dependent living based on projected IQ. Costs per person (in Canadian dollars) were ascribed to each living setting. From a government perspective, the ESDM-PD produced an additional 0.17 DFLYs for $8600 less than SQ. From a societal perspective, the ESDM-I produced an additional 0.53 DFLYs for $45,000 less than SQ. Pre-diagnosis interventions targeting ASD symptoms warrant further investigation.
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5. Gross C, Raj N, Molinaro G, Allen AG, Whyte AJ, Gibson JR, Huber KM, Gourley SL, Bassell GJ. {{Selective Role of the Catalytic PI3K Subunit p110beta in Impaired Higher Order Cognition in Fragile X Syndrome}}. {Cell reports}. 2015 May 5(5):681-8.
Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110beta plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110beta, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110beta in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110beta knockdown. Our results suggest that FMRP-mediated control of p110beta is crucial for neuronal protein synthesis and cognition.
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6. Gross C, Chang CW, Kelly SM, Bhattacharya A, McBride SM, Danielson SW, Jiang MQ, Chan CB, Ye K, Gibson JR, Klann E, Jongens TA, Moberg KH, Huber KM, Bassell GJ. {{Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome}}. {Cell reports}. 2015 May 5(5):727-36.
The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.
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7. Chisholm K, Lin A, Abu-Akel A, Wood SJ. {{The association between autism and schizophrenia spectrum disorders: A review of eight alternate models of co-occurrence}}. {Neuroscience and biobehavioral reviews}. 2015 May 5.
Although now believed to be two distinct disorders, autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD) share multiple phenotypic similarities and risk factors, and have been reported to co-occur at elevated rates. In this narrative review, we give a brief overview of the phenomenological, genetic, environmental, and imaging evidence for the overlap between ASD and SSD, highlighting similarities and areas of distinction. We examine eight possible alternate models of explanation for the association and comorbidity between the disorders, and set out a research agenda to test these models. Understanding how and why these disorders co-occur has important implications for diagnosis, treatment, and prognosis, as well as for developing fundamental aetiological models of the disorders.
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8. 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.
