RARE DISEASE
ADNP syndrome
ADNP syndrome
ADNP syndrome
Synonyms: ADNP-related syndromic intellectual disability-autism spectrum disorder, HVDAS, Helsmoortel-Van Der Aa Syndrome
Synonyms: ADNP-related syndromic intellectual disability-autism spectrum disorder, HVDAS, Helsmoortel-Van Der Aa Syndrome
Synonyms: ADNP-related syndromic intellectual disability-autism spectrum disorder, HVDAS, Helsmoortel-Van Der Aa Syndrome
Drug discovery
2
drugs
With orphan designations
Overview
ADNP syndrome (Helsmoortel-VanDerAa syndrome) is a rare neurodevelopmental disorder caused by de novo mutations in the ADNP gene, affecting chromatin remodeling and neurodevelopment. Core features include global developmental delay, intellectual disability (ranging from mild to profound), autism spectrum disorder (67% of cases), and speech apraxia. Multisystem involvement often includes hypotonia (75%), seizures (16-40%), congenital heart defects (38%), gastrointestinal dysfunction, vision abnormalities (74%), and early tooth eruption. Prevalence is estimated at 1-2/100,000, representing ~0.17% of ASD cases [1][7][11][17].
Burden
Clinical: 65% require lifelong care for severe ID; 40% have life-threatening comorbidities (sepsis, liver failure, cardiomyopathy) [2][4][6]
Functional: 52% never achieve independent speech; median walking age 3.5 years [1][14]
Economic: High healthcare utilization (83% require frequent specialist visits); 20% mortality <10 years from organ failure [2][4][6]
Therapies
Symptomatic care: Multidisciplinary therapy (speech/OT/PT), behavioral interventions (ABA), PROMPT method for apraxia [3][14]
Investigational: Low-dose ketamine (improves social/behavioral symptoms in trials) [8][12], CP201 peptide therapy (targets tauopathy) [2], CRISPR/gene therapy research [6]
Management: Seizure control, cardiac surveillance, nutritional support [7][9]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
55 drug discovery papers about ADNP syndrome, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
55 drug discovery papers about ADNP syndrome, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
2026-07-07 | ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome
The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer’s disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.
2026-06-27 | Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity.
Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp+/- mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp+/- mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.
2026-04-07 | ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is a critical regulator of neurodevelopment, and most pathogenic variants reported in Helsmoortel–Van der Aa syndrome (HVDAS) are truncating variants. In contrast, the functional consequences of ADNP missense variants remain largely unclear. We integrated an ADNP variant cohort in China with variants recorded in the NCBI ClinVar database, revealing a major gap in the interpretation of ADNP missense variants. METHODS: We investigated a rare de novo ADNP missense variant, p.C687R, predicted to disrupt the ninth zinc finger domain. In vitro, p.C687R was overexpressed in HEK293T cells to assess subnuclear localization by immunofluorescence and chromatin binding patterns using CUT&Tag, with chromatin interactions inferred from published Hi-C datasets. CRISPR/Cas9-mediated ADNP knockout was performed for comparison. In vivo, wild-type ADNP or p.C687R was introduced into the embryonic mouse cortex at E14.5 via in utero electroporation (IUE) and neuronal development was evaluated at E18.5 and P14. Patient-derived induced pluripotent stem cells (iPSCs) from a de novo p.C687R carrier were differentiated into neural progenitor cells (NPCs) and analyzed by multi-omic profiling (RNA-seq, ChIP-seq, ATAC-seq), with lineage-specific markers examined by immunofluorescence. RESULTS: p.C687R displays altered subnuclear localization and redistributes wild-type ADNP when overexpressed in HEK293T. IUE in the mouse cortical plate revealed impaired neuronal migration and abnormal cortical arborization. Genome-wide profiling in HEK293T demonstrated a p.C687R-specific chromatin occupancy pattern, preferentially targeting histone modification-related genes. Knockout of ADNP led to upregulation of neuronal genes, including GABAergic lineage-associated genes. In patient-derived iPSCs, a distinct set of neurodevelopmental genes, including key regulators of GABAergic differentiation, showed increased bivalent histone marks (H3K4me3/H3K27me3). Although their promoters remained in an open chromatin state, these genes were transcriptionally silent in pluripotent cells but became more activated upon GABAergic differentiation. LIMITATIONS: This study is based on a single patient-derived line in combination with complementary experimental models. In the heterozygous endogenous context, distinguishing increased functional activity from dosage-related effects requires further investigation. Replication in additional patient-derived or engineered lines is required to determine the generalizability. CONCLUSIONS: Our results suggest that p.C687R may exert gain-of-function-like effects in experimental systems and underscore chromatin-mediated regulation of GABAergic lineage genes in HVDAS.
2026-01-28 | A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.
Background: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare multisystemic neurodevelopmental disorder caused by pathogenic variants in the Activity-Dependent Neuroprotective Homeobox Protein (ADNP) gene. Since the extensive clinical description of a cohort of 78 affected individuals in 2019, numerous reports described additional cases affected by the condition. However, no systematic synthesis of the clinical and molecular spectrum of these additional individuals has been conducted to date. Methods: In accordance with the PRISMA 2020 guidelines, we performed a systematic review of all publications describing individuals with genetically confirmed HVDAS. Clinical characteristics, comorbidities, and developmental milestones were systematically extracted to illustrate novel or underrecognized manifestations. Results: A total of 105 individuals reported across 34 publications were included. Of these, 66 were clinically and genetically evaluated, and 39 were analyzed only at the genetic level. Our analysis refines the phenotypic spectrum of HVDAS, including developmental delay, visual anomalies, and congenital heart defects. The additional literature also allows us to characterize in more detail the ophthalmological abnormalities, gait disturbances, and the cognitive profile of HVDAS. Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome. Conclusions: This systematic review provides a comprehensive synthesis of the clinical, genetic, and epigenetic landscape of HVDAS. It underscores the multisystemic nature of the disorder and the need for multidisciplinary management. The expanding phenotypic heterogeneity likely reflects both improved clinical recognition of the more subtle features and the tendency to prioritize publication of more complex or severely affected cases.
2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
2026-07-07 | ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome
The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer’s disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.
2026-06-27 | Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity.
Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp+/- mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp+/- mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.
2026-04-07 | ADNP missense variant p.C687R disrupts chromatin regulation and GABAergic differentiation in Helsmoortel-Van der Aa syndrome.
BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is a critical regulator of neurodevelopment, and most pathogenic variants reported in Helsmoortel–Van der Aa syndrome (HVDAS) are truncating variants. In contrast, the functional consequences of ADNP missense variants remain largely unclear. We integrated an ADNP variant cohort in China with variants recorded in the NCBI ClinVar database, revealing a major gap in the interpretation of ADNP missense variants. METHODS: We investigated a rare de novo ADNP missense variant, p.C687R, predicted to disrupt the ninth zinc finger domain. In vitro, p.C687R was overexpressed in HEK293T cells to assess subnuclear localization by immunofluorescence and chromatin binding patterns using CUT&Tag, with chromatin interactions inferred from published Hi-C datasets. CRISPR/Cas9-mediated ADNP knockout was performed for comparison. In vivo, wild-type ADNP or p.C687R was introduced into the embryonic mouse cortex at E14.5 via in utero electroporation (IUE) and neuronal development was evaluated at E18.5 and P14. Patient-derived induced pluripotent stem cells (iPSCs) from a de novo p.C687R carrier were differentiated into neural progenitor cells (NPCs) and analyzed by multi-omic profiling (RNA-seq, ChIP-seq, ATAC-seq), with lineage-specific markers examined by immunofluorescence. RESULTS: p.C687R displays altered subnuclear localization and redistributes wild-type ADNP when overexpressed in HEK293T. IUE in the mouse cortical plate revealed impaired neuronal migration and abnormal cortical arborization. Genome-wide profiling in HEK293T demonstrated a p.C687R-specific chromatin occupancy pattern, preferentially targeting histone modification-related genes. Knockout of ADNP led to upregulation of neuronal genes, including GABAergic lineage-associated genes. In patient-derived iPSCs, a distinct set of neurodevelopmental genes, including key regulators of GABAergic differentiation, showed increased bivalent histone marks (H3K4me3/H3K27me3). Although their promoters remained in an open chromatin state, these genes were transcriptionally silent in pluripotent cells but became more activated upon GABAergic differentiation. LIMITATIONS: This study is based on a single patient-derived line in combination with complementary experimental models. In the heterozygous endogenous context, distinguishing increased functional activity from dosage-related effects requires further investigation. Replication in additional patient-derived or engineered lines is required to determine the generalizability. CONCLUSIONS: Our results suggest that p.C687R may exert gain-of-function-like effects in experimental systems and underscore chromatin-mediated regulation of GABAergic lineage genes in HVDAS.
2026-01-28 | A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.
Background: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare multisystemic neurodevelopmental disorder caused by pathogenic variants in the Activity-Dependent Neuroprotective Homeobox Protein (ADNP) gene. Since the extensive clinical description of a cohort of 78 affected individuals in 2019, numerous reports described additional cases affected by the condition. However, no systematic synthesis of the clinical and molecular spectrum of these additional individuals has been conducted to date. Methods: In accordance with the PRISMA 2020 guidelines, we performed a systematic review of all publications describing individuals with genetically confirmed HVDAS. Clinical characteristics, comorbidities, and developmental milestones were systematically extracted to illustrate novel or underrecognized manifestations. Results: A total of 105 individuals reported across 34 publications were included. Of these, 66 were clinically and genetically evaluated, and 39 were analyzed only at the genetic level. Our analysis refines the phenotypic spectrum of HVDAS, including developmental delay, visual anomalies, and congenital heart defects. The additional literature also allows us to characterize in more detail the ophthalmological abnormalities, gait disturbances, and the cognitive profile of HVDAS. Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome. Conclusions: This systematic review provides a comprehensive synthesis of the clinical, genetic, and epigenetic landscape of HVDAS. It underscores the multisystemic nature of the disorder and the need for multidisciplinary management. The expanding phenotypic heterogeneity likely reflects both improved clinical recognition of the more subtle features and the tendency to prioritize publication of more complex or severely affected cases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for ADNP syndrome.
2 orphan drug designations for ADNP syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Davunetide | peptides | EMA | 2024-12-13 | — | AdRes EU B.V. |
davunetide | peptides | FDA | 2018-02-22 | — | Exonavis Therapeutics Ltd. |
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