1. Arango C. Drug development in ASD, an ISCTM-ECNP joint adventure. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2021; 48: 1-2.

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2. Duncan A, Meinzen-Derr J, Ruble LA, Fassler C, Stark LJ. A Pilot Randomized Controlled Trial of a Daily Living Skills Intervention for Adolescents with Autism. Journal of autism and developmental disorders. 2022; 52(2): 938-49.

Adolescents with autism spectrum disorder (ASD) without an intellectual disability have daily living skills (DLS) impairments. An initial feasibility pilot of Surviving and Thriving in the Real World (STRW), a group intervention that targets DLS, demonstrated significant improvements. A pilot RCT of STRW was conducted to extend these findings. Twelve adolescents with ASD were randomized to the treatment or waitlist groups. The treatment group had significant DLS improvements on the Vineland Adaptive Behavior Scales, 3rd Edition and the DLS goal attainment scale. Four adolescents from the waitlist crossed over and completed STRW. Entire sample analyses with 10 participants demonstrated large DLS gains. Results provide further evidence of the efficacy of STRW for closing the gap between DLS and chronological age.

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3. He W, Tang W, Liao Y, Li W, Gong F, Lu G, Lin G, Du J, Tan Y. [Analysis of FMR1 gene CGG repeats among patients with diminished ovarian reserve]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(4): 343-6.

OBJECTIVE: To explore the correlation between Fragile X mental retardation gene-1 (FMR1) gene CGG repeats with diminished ovarian reserve (DOR). METHODS: For 214 females diagnosed with DOR, DNA was extracted from peripheral blood samples. FMR1 gene CGG repeats were determined by PCR and capillary electrophoresis. RESULTS: Three DOR patients were found to carry FMR1 premutations, and one patient was found to carry gray zone FMR1 repeats. After genetic counseling, one patient and the sister of another patient, both carrying FMR1 permutations, conceived naturally. Prenatal diagnosis showed that both fetuses have carried FMR1 permutations. CONCLUSION: FMR1 gene permutation may be associated with DOR. Determination of FMR1 gene CGG repeats in DOR patients can provide a basis for genetic counseling and guidance for reproduction.

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4. Li J, Brickler T, Banuelos A, Marjon K, Shcherbina A, Banerjee S, Bian J, Narayanan C, Weissman IL, Chetty S. Overexpression of CD47 is associated with brain overgrowth and 16p11.2 deletion syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(15).

Copy number variation (CNV) at the 16p11.2 locus is associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. CNVs of the 16p gene can manifest in opposing head sizes. Carriers of 16p11.2 deletion tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a « don’t eat me » signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Furthermore, 16p11.2 deletion NPCs and OPCs up-regulate cell surface expression of calreticulin (a prophagocytic « eat me » signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. While the CD47 pathway is commonly implicated in cancer progression, we document a role for CD47 in psychiatric disorders associated with brain overgrowth.

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5. Manelis-Baram L, Meiri G, Ilan M, Faroy M, Michaelovski A, Flusser H, Menashe I, Dinstein I. Sleep Disturbances and Sensory Sensitivities Co-Vary in a Longitudinal Manner in Pre-School Children with Autism Spectrum Disorders. Journal of autism and developmental disorders. 2022; 52(2): 923-37.

Previous research has demonstrated that sleep disturbances are positively correlated with sensory sensitivities in children with ASD. Most of these studies, however, were based on cross-sectional analyses, where the relationship across symptom domains was examined at a single time-point. Here, we examined the development of 103 pre-school children with ASD over a 1-3-year period. The results revealed that spontaneous longitudinal changes in sleep disturbances were specifically correlated with changes in sensory sensitivities and not with changes in other sensory processing domains nor with changes in core ASD symptoms. These finding demonstrate a consistent longitudinal relationship between sleep disturbances and sensory sensitivities, which suggests that these symptoms may be generated by common or interacting underlying physiological mechanisms.

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6. Marbach F, Stoyanov G, Erger F, Stratakis CA, Settas N, London E, Rosenfeld JA, Torti E, Haldeman-Englert C, Sklirou E, Kessler E, Ceulemans S, Nelson SF, Martinez-Agosto JA, Palmer CGS, Signer RH, Andrews MV, Grange DK, Willaert R, Person R, Telegrafi A, Sievers A, Laugsch M, Theiß S, Cheng Y, Lichtarge O, Katsonis P, Stocco A, Schaaf CP. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain. Genetics in medicine : official journal of the American College of Medical Genetics. 2021; 23(8): 1465-73.

PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

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7. Nardello R, Antona V, Mangano GD, Salpietro V, Mangano S, Fontana A. A paradigmatic autistic phenotype associated with loss of PCDH11Y and NLGN4Y genes. BMC medical genomics. 2021; 14(1): 98.

BACKGROUND: Most studies relative to Y chromosome abnormalities are focused on the sexual developmental disorders. Recently, a few studies suggest that some genes located on Y chromosome may be related to different neurodevelopment disorders. CASE PRESENTATION: We report a child with sexual developmental disorder associated with a peculiar phenotype characterized by severe language impairment and autistic behaviour associated with a mosaicism [45,X(11)/46,XY(89)] and a partial deletion of the short and long arm of Y chromosome (del Yp11.31q11.23) that also involves the loss of both PCDH11Y and NLGN4Y genes. To our knowledge no study has ever reported the occurrence of the lack of both PCDH11Y and NLGN4Y located in the Y chromosome in the same patient. CONCLUSIONS: We hypothesized a functional complementary role of PCDH11Y and NLGN4Y within formation/maturation of the cerebral cortex. The impairment of early language development may be mainly related to the lack of PCDH11Y that underlies the early language network development and the later appearance of the autistic behaviour may be mainly related to deficit of inhibitory glicinergic neurotransmission NLGN4Y-linked.

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8. Smith EG, Pedapati EV, Liu R, Schmitt LM, Dominick KC, Shaffer RC, Sweeney JA, Erickson CA. Sex differences in resting EEG power in Fragile X Syndrome. Journal of psychiatric research. 2021; 138: 89-95.

Electrophysiological alterations may represent a neural substrate of impaired neurocognitive processes and other phenotypic features in Fragile X Syndrome (FXS). However, the role of biological sex in electroencephalography (EEG) patterns that differentiate FXS from typical development has not been determined. This limits use of EEG in both the search for biomarkers of impairment in FXS as well as application of those markers to enhance our understanding of underlying neural mechanisms to speed treatment discovery. We investigated topographical relative EEG power in participants at rest in a sample of males and females with FXS and in age- and sex-matched typically developing controls (TDC) using a cluster-based analysis. While alterations in theta and low beta power were similar across males and females in FXS, relative power varied by sex in the alpha, upper beta, gamma, and epsilon frequency bands. Follow up analyses showed that Individual Alpha Peak Frequency (IAPF), a continuous variable that may capture atypicalities across the theta and alpha ranges in neurodevelopmental disorders, also varied by sex. Finally, performance on an auditory filtering task correlated with theta power in males, but not females with FXS. The impact of biological sex on resting state EEG power differences in FXS is discussed as it relates to potential GABAergic and glutamatergic etiologies of neurocognitive deficits in FXS.

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9. Tebartz van Elst L, Fangmeier T, Schaller UM, Hennig O, Kieser M, Koelkebeck K, Kuepper C, Roessner V, Wildgruber D, Dziobek I. FASTER and SCOTT&EVA trainings for adults with high-functioning autism spectrum disorder (ASD): study protocol for a randomized controlled trial. Trials. 2021; 22(1): 261.

BACKGROUND: Autism spectrum disorder (ASD) is a chronic neurodevelopmental condition with a prevalence rate above 1%, characterized by deficits in social communication and interaction; restrictive, repetitive patterns of behavior, interests, or activities; and a preference for sameness and routines. The majority of adult ASD patients suffer from comorbid conditions such as depression and anxiety. Therapy options for adult ASD patients are lacking, with presently no available evidence-based interventions in Germany. Recently, two interventions to improve social responsiveness have been published. FASTER (« Freiburger Asperger-Spezifische Therapie für ERwachsene » = Freiburg Asperger-specific therapy for adults) is a manualized group psychotherapy program including three modules on psychoeducation, stress regulation management, and non-verbal and verbal social communication training with videotaped tasks. SCOTT&EVA (« Social Cognition Training Tool », and its enhancement « Emotionen Verstehen und Ausdruecken » = understanding and expressing emotions) is a computer-based training program to enhance social cognition including video and audio material of emotional expressions and complex real-life social situations. Initial studies for both programs have shown good feasibility and efficacy. METHODS: Three hundred sixty adult participants with an autism spectrum disorder (ASD) will take part in a randomized controlled three-armed multi-center trial to prove the efficacy of manualized group psychotherapy and a manualized computer-based training program. Both interventions will be compared with a treatment as usual (TAU) group, aiming to establish evidence-based psychotherapy approaches for adult individuals with ASD. The primary outcome is evaluated by parents, spouses, or others who have sufficient insight into the respective participant’s social communication and interaction, and will be measured with the Social Responsiveness Scale. First, each of both interventions will be compared to TAU. If at least one of the differences is significant, both interventions will be compared against each other. The primary outcome will be measured at baseline (T0) and 4 months after baseline (T1). DISCUSSION: The trial is the first to validate psychiatric therapeutic and training interventions for adult ASD patients in Germany. A trial is needed because the prevalence of ASD in adulthood without intellectual disability is high, and no evidence-based intervention can be offered in Germany. TRIAL REGISTRATION: German Clinical Trial Register DRKS00017817 . Registered on 20 April 2020.

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10. Uusitalo K, Haataja L, Nyman A, Lehtonen T, Setänen S. Hammersmith Infant Neurological Examination and long-term cognitive outcome in children born very preterm. Developmental medicine and child neurology. 2021; 63(8): 947-53.

AIM: To study the association between the Hammersmith Infant Neurological Examination (HINE) at age 2 years and neurocognition at age 11 years in children born very preterm. We hypothesized that the HINE at 2 years would be associated with neurocognition, that is, neurological, motor, and cognitive outcomes at 11 years. METHOD: A total of 174 children (mean gestational age 29.0wks, SD 2.7; minimum 23.0, maximum 35.9; 95 [55%] males, 79 [45%] females) born very preterm (birthweight ≤1500g/gestational age <32wks), were included in a prospective cohort recruited from 2001 to 2006 in Turku, Finland. The HINE was performed at 2 years' corrected age. Neurocognition at 11 years was assessed with the Touwen neurological examination, Movement Assessment Battery for Children, Second Edition (MABC-2), and full-scale IQ (Wechsler Intelligence Scale for Children, Fourth Edition). RESULTS: The HINE global score was associated with the results of the Touwen neurological examination (odds ratio [OR]=0.9, 95% confidence interval [CI] 0.8-0.9, p=0.001), MABC-2 (β=1.4, 95% CI 0.7-2.2, p<0.001), and full-scale IQ (β=1.2, 95% CI 0.8-1.7, p<0.001), even when adjusted. When children with cerebral palsy (CP) were excluded, the HINE was still associated with full-scale IQ (unadjusted β=1.2, 95% CI 0.3-2.1, p=0.01). INTERPRETATION: A higher HINE global score at 2 years was associated with better general intelligence at 11 years even in children without CP. The HINE may be a useful tool to detect children at risk for later cognitive impairment. What this paper adds A Hammersmith Infant Neurological Examination (HINE) global score at 2 years was associated with long-term neurocognitive function. Severe cognitive impairment was significantly more common in 11-year-old children with complex minor neurological dysfunction compared to typically developing children. The HINE performed at 2 years detects risks of cognitive impairment at 11 years in children born very preterm. A higher HINE score at 2 years was associated with better general intelligence at 11 years.

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