Characterizing Sensory Phenotypes of Subgroups with a Known Genetic Etiology Pertaining to Diagnoses of Autism Spectrum Disorder and Intellectual Disability

Hudac, Caitlin M.; Friedman, Nicole R; Ward, Victoria R; Estreicher, Rachel E; Dorsey, Grace C; Bernier, Raphael; Kurtz-Nelson, Evangeline; Earl, Rachel K.; Eichler, Evan E.; Neuhaus, Emily

doi:10.1007/s10803-023-05897-9

Cited by 8 publications

(3 citation statements)

References 102 publications

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“…Individuals were recruited as part of two genetics-first research projects at the University of Washington (UW). The study included two groups of participants: (1) individuals with a disruptive mutation that is associated with ASD and NDDs via the TIGER study (Beighley et al, 2020) and (2) a comparison group of individuals with idiopathic ASD via the ZEBRA study (Hudac et al, 2023). The TIGER and ZEBRA studies are both focused on comprehensive genotypic and phenotypic characterization of individuals with ASD and/or ASDassociated genetic disorders, with participants receiving genetic testing and an aligned battery of clinical measures as described further below.…”

Section: Methods Participantsmentioning

confidence: 99%

Characterizing the autism spectrum phenotype in DYRK1A‐related syndrome

et al. 2023

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Likely gene‐disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS‐2, ADI‐R, SRS‐2, SCQ, and RBS‐R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below‐average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory‐seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co‐occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.

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Section: Methods Participantsmentioning

confidence: 99%

Characterizing the autism spectrum phenotype in DYRK1A‐related syndrome

et al. 2023

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“…Sensory seeking is thought to reflect underlying hyposensitivity to sensory stimuli, while sensory avoidance may be driven by hypersensitivity. Individual syndromic forms of autism also exhibit a mixture of these sensory phenotypes across different sensory modalities, depending on the type of stimulus and its social relevance ( 10 , 11 ). Cluster analyses of sensory profiles of individuals with autism tend to reveal two main behavioral subgroups: one that is impaired relative to typically developing individuals across all four sensory domains (poor registration, sensitivity, sensory seeking, and sensory avoiding), and one that shows no impairment across any of the four ( 12 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

Monday,

Wang,

Feldman

2023

Front. Neurol.

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Individuals with autism spectrum disorder (ASD) exhibit a diverse range of behavioral features and genetic backgrounds, but whether different genetic forms of autism involve convergent pathophysiology of brain function is unknown. Here, we analyze evidence for convergent deficits in neural circuit function across multiple transgenic mouse models of ASD. We focus on sensory areas of neocortex, where circuit differences may underlie atypical sensory processing, a central feature of autism. Many distinct circuit-level theories for ASD have been proposed, including increased excitation–inhibition (E–I) ratio and hyperexcitability, hypofunction of parvalbumin (PV) interneuron circuits, impaired homeostatic plasticity, degraded sensory coding, and others. We review these theories and assess the degree of convergence across ASD mouse models for each. Behaviorally, our analysis reveals that innate sensory detection behavior is heightened and sensory discrimination behavior is impaired across many ASD models. Neurophysiologically, PV hypofunction and increased E–I ratio are prevalent but only rarely generate hyperexcitability and excess spiking. Instead, sensory tuning and other aspects of neural coding are commonly degraded and may explain impaired discrimination behavior. Two distinct phenotypic clusters with opposing neural circuit signatures are evident across mouse models. Such clustering could suggest physiological subtypes of autism, which may facilitate the development of tailored therapeutic approaches.

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“…ADNP syndrome (also known as Helsmoortel-Van Der Aa syndrome) is a rare condition characterized by autistic/intellectual disabilities, such as memory and communication problems and prominent sensory seeking and muscle weakness, accompanied by brain pathology and tauopathy [ 12 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. The syndrome occurs when one allele of the ADNP gene undergoes a de novo mutation, resulting in the loss of normal functions [ 10 ] and expressing distinct mutation-specific epigenetic signatures [ 29 , 30 ], which may also be linked with differential phenotypic outcomes [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms

Ganaiem,

Gildor,

Shazman

et al. 2023

Cells

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(1) Background: Recently, we showed aberrant nuclear/cytoplasmic boundaries/activity-dependent neuroprotective protein (ADNP) distribution in ADNP-mutated cells. This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide). Here, we investigated the mechanism of NAP nuclear protection. (2) Methods: CRISPR/Cas9 DNA-editing established N1E-115 neuroblastoma cell lines that express two different green fluorescent proteins (GFPs)—labeled mutated ADNP variants (p.Tyr718* and p.Ser403*). Cells were exposed to NAP conjugated to Cy5, followed by live imaging. Cells were further characterized using quantitative morphology/immunocytochemistry/RNA and protein quantifications. (3) Results: NAP rapidly distributed in the cytoplasm and was also seen in the nucleus. Furthermore, reduced microtubule content was observed in the ADNP-mutated cell lines. In parallel, disrupting microtubules by zinc or nocodazole intoxication mimicked ADNP mutation phenotypes and resulted in aberrant nuclear–cytoplasmic boundaries, which were rapidly corrected by NAP treatment. No NAP effects were noted on ADNP levels. Ketamine, used as a control, was ineffective, but both NAP and ketamine exhibited direct interactions with ADNP, as observed via in silico docking. (4) Conclusions: Through a microtubule-linked mechanism, NAP rapidly localized to the cytoplasmic and nuclear compartments, ameliorating mutated ADNP-related deficiencies. These novel findings explain previously published gene expression results and broaden NAP (davunetide) utilization in research and clinical development.

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Characterizing Sensory Phenotypes of Subgroups with a Known Genetic Etiology Pertaining to Diagnoses of Autism Spectrum Disorder and Intellectual Disability

Cited by 8 publications

References 102 publications

Characterizing the autism spectrum phenotype in DYRK1A‐related syndrome

Characterizing the autism spectrum phenotype in DYRK1A‐related syndrome

Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms

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