RARE DISEASE
Atypical autism
Atypical autism
Atypical autism
Drug discovery
1
drug
With orphan designation
Overview
Atypical Autism Overview
Atypical autism (PDD-NOS/DSM-IV term, now classified under ASD per DSM-5) presents with social-communication deficits and restricted/repetitive behaviors but does not meet full criteria for classic autism. Symptoms may emerge later or show atypical patterns, such as milder social challenges or isolated sensory sensitivities. Early diagnosis and personalized interventions (e.g., behavioral, speech, and occupational therapies) are critical for improving functional outcomes [1][3][6][11].
Therapies
Behavioral: Applied Behavior Analysis (ABA) for skill development and behavior modification [1][8][13].
Multidisciplinary: Speech therapy (language deficits), occupational therapy (sensory/motor skills), and social skills training [3][6][8].
Adjunctive: Limited pharmacotherapy (e.g., SSRIs for anxiety; risperidone for aggression) [1][3][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
748 drug discovery papers about Atypical autism, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
748 drug discovery papers about Atypical autism, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-12 | Pain Expectation in Individuals With High Autistic Traits: Decision-Evaluation Processes and Oxytocin Modulation.
Pain reflects both sensory input and predictive processes shaped by expectations. Individuals with high autistic traits (HATs) often exhibit atypical pain responses, potentially due to alterations in anticipatory processing. This study investigated pain anticipation in HAT individuals and examined the modulatory effects of oxytocin using behavioral, computational, and pharmacological approaches. In experiment 1, HAT and low autistic trait (LAT) individuals completed a cue-based pain anticipation task. Anticipatory processing was characterized through two components: decision-related processes and evaluative responses. HAT individuals showed altered decision-making, characterized by greater caution under uncertainty and reduced processing efficiency under certain high-pain conditions. They also exhibited more negative evaluative responses, which were associated with poorer psychological health. In experiment 2, HAT participants received intranasal oxytocin or placebo. Oxytocin selectively influenced decision-related processes under uncertainty, increasing evidence accumulation and reducing nondecision time while also increasing the tendency to choose high-pain outcomes under ambiguous conditions. In contrast, oxytocin showed limited effects on evaluative measures. These findings suggest that pain anticipation in HAT individuals involves partially distinct decision-related and evaluative components and that oxytocin exerts process-specific effects on anticipatory processing.
2026-08-11 | Exploring atypical spatial-functional coupling in adolescent autism spectrum disorder: insights from neurodevelopment and transcriptomic architecture.
Autism Spectrum Disorder (ASD) is associated with atypical large-scale brain network organization, yet how spatial-functional dependencies relate to clinical features and molecular reference maps remains incompletely understood. To quantify spatial functional heterogeneity (Sill) and coherence persistence (Range), we analyzed resting-state fMRI data from 162 ASD and 175 TD adolescents, all aged 12-18. Compared with TD, adolescents with ASD exhibited significantly increased Sill within higher-order association networks, including the left Language and right Posterior Multimodal networks, whereas no group differences in Range survived multiple-comparison correction. Within the ASD group, elevated Sill was selectively associated with greater social-affective symptom severity but not restricted and repetitive behaviors. To explore potential biological correlates, we integrated cortical gene expression reference data and identified transcriptomic patterns associated with regional Sill differences. These genes showed enrichment for synaptic signaling, mitochondrial processes, and glial-related functions, highlighting multiscale correspondence between spatial-functional organization and molecular reference maps. Together, these results demonstrate statistical associations among altered spatial-functional properties, clinical severity, and transcriptomic profiles related to synaptic signaling, mitochondrial processes, and glial-related functions in ASD, providing a complementary spatial perspective on large-scale functional organization.
2026-07-23 | CRISPR/Cas9-Engineered HEK293T Cellular Model Harboring the Pathogenic CDKL5 c.172A>T Variant Recapitulates Core Molecular Phenotypes of CDKL5 Deficiency Disorder.
Mutations in the CDKL5 gene are strongly associated with severe neurodevelopmental disorders, including atypical Rett syndrome and autism spectrum disorder (ASD). This study aimed to establish a cell model carrying a targeted CDKL5 mutation using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and to evaluate the phenotypic and molecular consequences. A single-guide RNA (sgRNA) targeting exon 2 of CDKL5 was designed using in silico tools to minimize off-target activity. The sgRNA and Cas9 nuclease were cloned into the pSpCas9(BB)-2A-green fluorescent protein (GFP) (PX458) vector and transfected into human embryonic kidney 293T (HEK293T) cells. Following fluorescence-activated cell sorting (FACS), genome-editing efficiency was quantified using a T7 endonuclease I (T7E1) assay and Sanger sequencing. Homology-directed repair (HDR) mediated by single-stranded oligodeoxynucleotide (ssODN) templates was used to introduce a specific missense mutation (c.172A>T; p.Lys58Met). Edited clones were evaluated for CDKL5 expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and cell survival and apoptosis were assessed using Annexin V/propidium iodide (PI) staining and caspase-3 activity assays. The CRISPR/Cas9 construct achieved a mean on-target editing efficiency of 41.6 ± 3.2%, as determined by T7E1 digestion, and sequencing confirmed a heterozygous insertion in 28% of sorted clones. HDR-mediated precise editing was detected in 12% of clones. RT-qPCR analysis showed a 55% reduction in CDKL5 mRNA levels (P < 0.01) in edited cells, whereas Western blotting demonstrated a corresponding 48% decrease in protein expression. Functionally, mutant cells exhibited 25% lower viability (P < 0.05) and 2.3-fold higher apoptosis rates (P < 0.01) than wild-type controls. No significant off-target mutations were detected at the top five predicted loci. We successfully generated a human cell line model of CDKL5-related ASD using CRISPR/Cas9 technology. The mutation induced marked reductions in CDKL5 expression and cell survival. Although this HEK293T-based model provides a useful platform for mechanistic and screening studies, its non-neuronal origin limits its ability to fully recapitulate the neuronal context of CDKL5 deficiency disorder (CDD). This study establishes a novel, precisely engineered human cellular model using advanced CRISPR/Cas9 technology to mechanistically dissect the consequences of CDKL5 deficiency. By introducing a defined missense mutation (c.172A>T; p.Lys58Met) into HEK293T cells, this study provides a robust platform for investigating the role of CDKL5 in neurodevelopmental disorders and supports future therapeutic development.
2026-07-17 | Cortical Network Overconnectivity Relates to Sensory, Cognitive, and Social Dimensions in Young Children With Autism Spectrum Disorder.
The heterogeneity in both the neurobiological mechanisms and the phenotypic presentations of autism spectrum disorder (ASD) poses a major challenge to clinical and translational research. Alterations in functional connectivity (FC) have been associated with ASD, yet it remains unclear whether and how divergent brain network properties may account for individual differences across ASD-related symptomatology and behaviors. We applied source-level reconstruction to rest-like non-task-related high-density EEG data in a cohort of 104 young children (38 with ASD) to identify global and local alterations of cortical network connectivity. We subsequently used regularized canonical correlation analysis (rCCA) to characterize specific FC patterns linked to variation in cognitive, social and sensory dimensions derived from standard clinical instruments. We found increased low-frequency FC in frontotemporal cross-hemispheric networks and lateral-occipital regions of young ASD children versus healthy peers. RCCA revealed three distinct FC patterns in recurrent ASD-related networks, each contributing to predict individual differences in cognitive, social and sensory features. These linked FC-behavior dimensions may shed light on atypical brain network topology associated with specific phenotypic manifestations of ASD, which might implicate unique underlying neurobiological mechanisms.
2026-06-15 | Unstable or Stable? Prosodic Features and Voice Quality in Autism Spectrum Disorder: A Systematic Review and Meta-analysis.
Speech prosody is fundamental to human spoken communication, and it is frequently characterized by atypical patterns, alongside voice quality, in individuals with autism spectrum disorder (ASD). However, findings across studies regarding these acoustic features in ASD remain inconsistent. Literature searches across four databases identified eligible studies comparing prosodic or voice quality acoustic parameters between individuals with ASD and matched TD individuals. A total of 40 studies involving 1023 individuals with ASD and 929 TD individuals were included. Subgroup and meta-regression analyses were conducted to assess potential moderators. The meta-analyses revealed a significantly higher mean pitch (Hedges' g = 0.43), broader pitch range (g = 0.29), and higher pitch standard deviation (g = 0.22) in the ASD group. For voice quality, significantly reduced shimmer (g = -0.44) and a trend toward reduced jitter (g = -0.26) indicated heightened stability of vocal fold vibrations in ASD. Our findings reveal a seemingly paradoxical acoustic profile in ASD: while individuals with ASD exhibit suprasegmental instability, they also demonstrate voicing hyper-stability. Moderators identified after subgroup and meta-regression analyses, including language background, IQ status, age span, mean age, and task type, may further moderate the prosodic features.
2026-08-12 | Pain Expectation in Individuals With High Autistic Traits: Decision-Evaluation Processes and Oxytocin Modulation.
Pain reflects both sensory input and predictive processes shaped by expectations. Individuals with high autistic traits (HATs) often exhibit atypical pain responses, potentially due to alterations in anticipatory processing. This study investigated pain anticipation in HAT individuals and examined the modulatory effects of oxytocin using behavioral, computational, and pharmacological approaches. In experiment 1, HAT and low autistic trait (LAT) individuals completed a cue-based pain anticipation task. Anticipatory processing was characterized through two components: decision-related processes and evaluative responses. HAT individuals showed altered decision-making, characterized by greater caution under uncertainty and reduced processing efficiency under certain high-pain conditions. They also exhibited more negative evaluative responses, which were associated with poorer psychological health. In experiment 2, HAT participants received intranasal oxytocin or placebo. Oxytocin selectively influenced decision-related processes under uncertainty, increasing evidence accumulation and reducing nondecision time while also increasing the tendency to choose high-pain outcomes under ambiguous conditions. In contrast, oxytocin showed limited effects on evaluative measures. These findings suggest that pain anticipation in HAT individuals involves partially distinct decision-related and evaluative components and that oxytocin exerts process-specific effects on anticipatory processing.
2026-08-11 | Exploring atypical spatial-functional coupling in adolescent autism spectrum disorder: insights from neurodevelopment and transcriptomic architecture.
Autism Spectrum Disorder (ASD) is associated with atypical large-scale brain network organization, yet how spatial-functional dependencies relate to clinical features and molecular reference maps remains incompletely understood. To quantify spatial functional heterogeneity (Sill) and coherence persistence (Range), we analyzed resting-state fMRI data from 162 ASD and 175 TD adolescents, all aged 12-18. Compared with TD, adolescents with ASD exhibited significantly increased Sill within higher-order association networks, including the left Language and right Posterior Multimodal networks, whereas no group differences in Range survived multiple-comparison correction. Within the ASD group, elevated Sill was selectively associated with greater social-affective symptom severity but not restricted and repetitive behaviors. To explore potential biological correlates, we integrated cortical gene expression reference data and identified transcriptomic patterns associated with regional Sill differences. These genes showed enrichment for synaptic signaling, mitochondrial processes, and glial-related functions, highlighting multiscale correspondence between spatial-functional organization and molecular reference maps. Together, these results demonstrate statistical associations among altered spatial-functional properties, clinical severity, and transcriptomic profiles related to synaptic signaling, mitochondrial processes, and glial-related functions in ASD, providing a complementary spatial perspective on large-scale functional organization.
2026-07-23 | CRISPR/Cas9-Engineered HEK293T Cellular Model Harboring the Pathogenic CDKL5 c.172A>T Variant Recapitulates Core Molecular Phenotypes of CDKL5 Deficiency Disorder.
Mutations in the CDKL5 gene are strongly associated with severe neurodevelopmental disorders, including atypical Rett syndrome and autism spectrum disorder (ASD). This study aimed to establish a cell model carrying a targeted CDKL5 mutation using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and to evaluate the phenotypic and molecular consequences. A single-guide RNA (sgRNA) targeting exon 2 of CDKL5 was designed using in silico tools to minimize off-target activity. The sgRNA and Cas9 nuclease were cloned into the pSpCas9(BB)-2A-green fluorescent protein (GFP) (PX458) vector and transfected into human embryonic kidney 293T (HEK293T) cells. Following fluorescence-activated cell sorting (FACS), genome-editing efficiency was quantified using a T7 endonuclease I (T7E1) assay and Sanger sequencing. Homology-directed repair (HDR) mediated by single-stranded oligodeoxynucleotide (ssODN) templates was used to introduce a specific missense mutation (c.172A>T; p.Lys58Met). Edited clones were evaluated for CDKL5 expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and cell survival and apoptosis were assessed using Annexin V/propidium iodide (PI) staining and caspase-3 activity assays. The CRISPR/Cas9 construct achieved a mean on-target editing efficiency of 41.6 ± 3.2%, as determined by T7E1 digestion, and sequencing confirmed a heterozygous insertion in 28% of sorted clones. HDR-mediated precise editing was detected in 12% of clones. RT-qPCR analysis showed a 55% reduction in CDKL5 mRNA levels (P < 0.01) in edited cells, whereas Western blotting demonstrated a corresponding 48% decrease in protein expression. Functionally, mutant cells exhibited 25% lower viability (P < 0.05) and 2.3-fold higher apoptosis rates (P < 0.01) than wild-type controls. No significant off-target mutations were detected at the top five predicted loci. We successfully generated a human cell line model of CDKL5-related ASD using CRISPR/Cas9 technology. The mutation induced marked reductions in CDKL5 expression and cell survival. Although this HEK293T-based model provides a useful platform for mechanistic and screening studies, its non-neuronal origin limits its ability to fully recapitulate the neuronal context of CDKL5 deficiency disorder (CDD). This study establishes a novel, precisely engineered human cellular model using advanced CRISPR/Cas9 technology to mechanistically dissect the consequences of CDKL5 deficiency. By introducing a defined missense mutation (c.172A>T; p.Lys58Met) into HEK293T cells, this study provides a robust platform for investigating the role of CDKL5 in neurodevelopmental disorders and supports future therapeutic development.
2026-07-17 | Cortical Network Overconnectivity Relates to Sensory, Cognitive, and Social Dimensions in Young Children With Autism Spectrum Disorder.
The heterogeneity in both the neurobiological mechanisms and the phenotypic presentations of autism spectrum disorder (ASD) poses a major challenge to clinical and translational research. Alterations in functional connectivity (FC) have been associated with ASD, yet it remains unclear whether and how divergent brain network properties may account for individual differences across ASD-related symptomatology and behaviors. We applied source-level reconstruction to rest-like non-task-related high-density EEG data in a cohort of 104 young children (38 with ASD) to identify global and local alterations of cortical network connectivity. We subsequently used regularized canonical correlation analysis (rCCA) to characterize specific FC patterns linked to variation in cognitive, social and sensory dimensions derived from standard clinical instruments. We found increased low-frequency FC in frontotemporal cross-hemispheric networks and lateral-occipital regions of young ASD children versus healthy peers. RCCA revealed three distinct FC patterns in recurrent ASD-related networks, each contributing to predict individual differences in cognitive, social and sensory features. These linked FC-behavior dimensions may shed light on atypical brain network topology associated with specific phenotypic manifestations of ASD, which might implicate unique underlying neurobiological mechanisms.
2026-06-15 | Unstable or Stable? Prosodic Features and Voice Quality in Autism Spectrum Disorder: A Systematic Review and Meta-analysis.
Speech prosody is fundamental to human spoken communication, and it is frequently characterized by atypical patterns, alongside voice quality, in individuals with autism spectrum disorder (ASD). However, findings across studies regarding these acoustic features in ASD remain inconsistent. Literature searches across four databases identified eligible studies comparing prosodic or voice quality acoustic parameters between individuals with ASD and matched TD individuals. A total of 40 studies involving 1023 individuals with ASD and 929 TD individuals were included. Subgroup and meta-regression analyses were conducted to assess potential moderators. The meta-analyses revealed a significantly higher mean pitch (Hedges' g = 0.43), broader pitch range (g = 0.29), and higher pitch standard deviation (g = 0.22) in the ASD group. For voice quality, significantly reduced shimmer (g = -0.44) and a trend toward reduced jitter (g = -0.26) indicated heightened stability of vocal fold vibrations in ASD. Our findings reveal a seemingly paradoxical acoustic profile in ASD: while individuals with ASD exhibit suprasegmental instability, they also demonstrate voicing hyper-stability. Moderators identified after subgroup and meta-regression analyses, including language background, IQ status, age span, mean age, and task type, may further moderate the prosodic features.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Atypical autism.
1 orphan drug designation for Atypical autism.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Fluoxetine | small molecules | FDA | 1999-04-30 | — | Neuropharm, Ltd. |
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