1. Andrade C. Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Offspring. J Clin Psychiatry;2023 (Mar 27);84(2)

Two recent cohort studies, one from Norway and the other from Taiwan, examined for perhaps the first time whether gestational exposure to benzodiazepines and to z-hypnotics was associated with a clinical diagnosis of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring. The studies had important methodological strengths that are not often seen; these included actual assessment during pregnancy of whether drugs prescribed were used, and, if so, when; adjustment of analyses for postbaseline time-varying covariates; inclusion of discordant sibling pair and paternal exposure analyses; inclusion of pre-pregnancy vs intrapregnancy analyses; and others. The studies also had important limitations; these included inadequate statistical power resulting in a failure to identify potential associations in even unadjusted analyses; lack of information on intermittent use vs daily dosing; and others. The strengths and limitations are identified and explained to empower readers to identify similar issues in other studies. Important findings apparent in these studies are that benzodiazepine exposure may be associated with an increased risk of both ASD and ADHD, regardless of the trimester of exposure. The magnitude of increased risk is small and diminishes to statistical nonsignificance in adjusted analyses. The risks appear elevated in association with paternal exposure. In discordant sibling pair analyses, risks do not appear to be significantly higher in the exposed sib relative to the unexposed sib. These findings imply that observed associations, if any, between gestational exposure to benzodiazepines and ASD or ADHD in offspring may be due to maternal and paternal genetic factors, to family environmental variables, and to confounding by indication, rather than to benzodiazepine exposure itself. Nevertheless, decision-making should be tailored to individual context and shared between prescriber and patient. Finally, no conclusions can be drawn regarding the neurodevelopmental safety of z-drug exposure during pregnancy.

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2. Bouzy J, Brunelle J, Cohen D, Condat A. Transidentities and autism spectrum disorder: A systematic review. Psychiatry Res;2023 (Mar 27);323:115176.

Transidentity and autism frequently co-occur. Previous reviews have focused mainly on frequencies. Here, we conducted a systematic review to condense all the studies and themes on this co-occurrence and to offer a global view. We followed the PRISMA method and selected 77 articles (including 59 clinical studies) in April 2022. We found 5 main themes (sex ratio, theories, sexual orientation, clinical and social consequences, and care implications) in addition to frequencies. Many theories have been proposed to explain the co-occurrence. One posits that social difficulties related to autism would lead to less identification with gender norms and less pressure to conform to these norms, allowing for greater gender diversity in people with autism. Given their difficulties with social interactions and communication, the announcement of one’s transidentity to one’s social group is often discredited, increasing the risk of suffering and delayed care. Many reports reaffirm the importance of providing specialised care for transgender people with autism. Autism is not a contraindication for gender-affirming treatment. However, some cognitive specificities can affect the planning of care, and transgender people with autism are at high risk of discrimination and harassment. We conclude that there is a need to raise awareness about gender and autism.

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3. Bruce MR, Couch ACM, Grant S, McLellan J, Ku K, Chang C, Bachman A, Matson M, Berman RF, Maddock RJ, Rowland D, Kim E, Ponzini MD, Harvey D, Taylor SL, Vernon AC, Bauman MD, Van de Water J. Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure. Mol Psychiatry;2023 (Mar 27)

Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant connection exists between inflammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following confirmation of aAb production in rat dams and antigen-specific immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deficit in social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-specific differences in total and regional brain volume. Treatment-specific effects by region appeared to converge on midbrain and cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo (1)H magnetic resonance spectroscopy ((1)H-MRS) data were collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and neurometabolites; reminiscent of findings observed in clinical ASD.

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4. Kabil SE, Abdelshafy R, Ahmed AIA, Zahran AM, Attalah M, Sallam Y, El Lateef AGA. Mismatch Negativity and Auditory Brain Stem Response in Children with Autism Spectrum Disorders and Language Disorders. J Multidiscip Healthc;2023;16:811-817.

OBJECTIVE: Language disorders (LD) in autism spectrum disorders (ASD) are highly variable and has a severe impact on the level of functioning in autistic children. Early diagnosis of these language disorders is essential for early interventions for children at risk. The electrophysiological measurements are considered valuable tools for determining language disabilities in children with ASD. This study aimed to study and compare ABR and MMN in autistic children with language disorders. METHODS: This study included a group of typically developing children and a group of children diagnosed with autistic spectrum disorders and language disorders. Both groups were matching according to age and gender. After confirming bilateral normal peripheral hearing sensitivity, ABR was done and both absolute and interpeak wave latencies were correlated. MMN using frequency oddball paradigms were also obtained and correlated. RESULTS: More abnormalities were reported in ABR test results in the form of delayed absolute latencies and prolonged interpeak intervals. Also, we reported prolonged latencies of MMN. Consequently, both ABR and MMN are complementary test in evaluating autistic children with language disorders. CONCLUSION: Our results support the hypothesis of remarkable dysfunction in basic auditory sound processing that may impact the linguistic development of autistic children.

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5. Miyake N, Tsurusaki Y, Fukai R, Kushima I, Okamoto N, Ohashi K, Nakamura K, Hashimoto R, Hiraki Y, Son S, Kato M, Sakai Y, Osaka H, Deguchi K, Matsuishi T, Takeshita S, Fattal-Valevski A, Ekhilevitch N, Tohyama J, Yap P, Keng WT, Kobayashi H, Takubo K, Okada T, Saitoh S, Yasuda Y, Murai T, Ohga S, Matsumoto A, Inoue K, Saikusa T, Hershkovitz T, Kobayashi Y, Morikawa M, Ito A, Hara T, Uno Y, Seiwa C, Ishizuka K, Shirahata E, Fujita A, Koshimizu E, Miyatake S, Takata A, Mizuguchi T, Ozaki N, Matsumoto N. Molecular diagnosis of 405 individuals with autism spectrum disorder. Eur J Hum Genet;2023 (Mar 27)

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

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6. Suresh A, Dunaevsky A. Impaired AMPARs Translocation into Dendritic Spines with Motor Skill Learning in the Fragile X Mouse Model. eNeuro;2023 (Mar);10(3)

Motor skill learning induces changes in synaptic structure and function in the primary motor cortex (M1). In the fragile X syndrome (FXS) mouse model an impairment in motor skill learning and associated formation of new dendritic spines was previously reported. However, whether modulation of synaptic strength through trafficking of AMPA receptors (AMPARs) with motor skill training is impaired in FXS is not known. Here, we performed in vivo imaging of a tagged AMPA receptor subunit, GluA2, in layer (L)2/3 neurons in the primary motor cortex of wild-type (WT) and Fmr1 knock-out (KO) male mice at different stages of learning a single forelimb-reaching task. Surprisingly, in the Fmr1 KO mice, despite impairments in learning there was no deficit in motor skill training-induced spine formation. However, the gradual accumulation of GluA2 in WT stable spines, which persists after training is completed and past the phase of spine number normalization, is absent in the Fmr1 KO mouse. These results demonstrate that motor skill learning not only reorganizes circuits through formation of new synapses, but also strengthens existing synapses through accumulation of AMPA receptors and GluA2 changes are better associated with learning than new spine formation.

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