RARE DISEASE
Phelan-McDermid syndrome
Phelan-McDermid syndrome
Phelan-McDermid syndrome
Drug discovery
5
drugs
With orphan designations
Overview
Phelan-McDermid syndrome (PMS) is a rare neurogenetic disorder caused by 22q13.3 deletions or pathogenic SHANK3 variants, disrupting synaptic function. Core features include global developmental delay, severe speech impairment, hypotonia, and autism spectrum disorder (ASD) in ~75% of cases. Associated manifestations encompass seizures, gastrointestinal dysfunction, sleep disturbances, and dysmorphic traits (e.g., dolichocephaly, large ears). Lifelong multidisciplinary care addresses developmental, behavioral, and systemic comorbidities [1][6][14][19].
Categories: rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare skin diseases
Research Papers
163 drug discovery papers about Phelan-McDermid syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
163 drug discovery papers about Phelan-McDermid syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-22 | Data from: Developmental CA2 perineuronal net reduction restores social memory in Shank3 mutant mice
Individuals with Autism Spectrum Disorder (ASD) and related neurodevelopmental conditions, like Phelan-McDermid syndrome (PMDS), exhibit social recognition deficits. Shank3B knockout (KO) mice, a genetic model with relevance to ASD and PMDS, have deficits in social memory in adulthood, but the developmental mechanisms underlying this dysfunction remain unknown. We found that Shank3B KOs have deficits in short-term social recognition during development that persist into adulthood, along with CA2 network aberrations. In CA2, perineuronal nets (PNNs), extracellular matrix structures, support social memory in adult mice. In developing CA2, we found excessive PNNs in KOs, greater sequestration of the guidance cue semaphorin-3A, and overgrowth of afferents. Reduction of PNN levels restored semaphorin-3A, afferent input to CA2, and social recognition, which persisted into adulthood and partially normalized CA2 network activity. These findings suggest that excess CA2 PNN formation impairs social recognition by disrupting afferent input, effects that are reversible by early life intervention.
2026-02-22 | Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models.
Extracellular vesicles (EVs) are lipid bilayer-enclosed structures that mediate intercellular communication by transferring diverse cargoes, including RNA and proteins. SHANK3, a synaptic scaffolding protein critical for synapse structure and function, is implicated in autism spectrum disorder (ASD) and Phelan-McDermid Syndrome (PMS). Early hyperexcitability in cortical neurons is a characterized endophenotype in ASD. Here, we investigated EV-mediated effects in the context of SHANK3 deficiency using human iPSC-derived cortical neurons and Shank3B-/- mice. Switching EVs between SHANK3 mutant and control neurons revealed that SHANK3 mutant-derived EVs transferred the hyperexcitability and accelerated maturation phenotypes to control neurons. Proteomic analysis revealed enrichment of synaptic structural regulators (e.g., ACTB, CFL1, AGRN, and CLSTN1) in SHANK3 mutant neuron-derived EVs. This is consistent with known actin cytoskeletal dysregulation driven by SHANK3 deficiency. However, control neuron-derived EVs failed to rescue mutant phenotypes, likely due to their decreased enrichment of synaptic proteins and related pathways. Further, EVs from mesenchymal stem cells (MSCs) and healthy donor iPSCs, containing synaptic modulators such as complement proteins (C1R, C1S), plasticity-associated proteins (MDK, IGFBP3), and homeostatic regulators (FGF2, SFRP1), rescued the hyperexcitability and normalized the maturation in SHANK3 mutant neurons. In addition, intranasal administration of iPSC-derived EVs in Shank3B-/- mice significantly rescued ASD-like behavioral deficits, emphasizing their therapeutic potential. Together, these findings reveal a novel EV-mediated mechanism for modulating dysregulated excitability and synaptic maturation, addressing a critical unmet need in ASD and associated neurodevelopmental disorders.
2026-02-04 | Abnormal neuronal excitability and reduced parvalbumin expression in Shank3-deficient parvalbumin neurons of the thalamic reticular nucleus.
Fast-spiking, non-adaptive inhibitory neurons in the thalamic reticular nucleus (TRN) critically gate the reciprocal communication between the thalamus and the cortex. Parvalbumin (PV) neurons express high levels of PV, the sole role of which appears to be calcium buffering. The significance of the PV protein - and its related high calcium-buffering capacity - under pathological conditions, especially in various neuropsychiatric disorders, is underappreciated. Deficiency of SHANK3, an important neuronal protein containing ankyrin, SH3, and PDZ, three canonical domains for protein recognition, causes behavioral changes relevant to autism spectrum disorders (ASD). Here we report TRN PV neurons of Shank3-/- (exon 4-22 deletion) mice of either sex exhibit pronounced increases in burst firing occurrence, decreased tonic firing frequency, and faster dendritic calcium transient decay. We pinpointed reduced PV expression as the culprit and used the added-buffer approach to confirm the decrease in calcium-buffering capacity in mutant neurons. Conversely, supplementing Shank3-/- PV neurons with extra EGTA reversed the abnormal action potential (AP) firing. In addition, the PV neurons from HCN2-/- mice exhibit consistent changes in neuronal excitability, PV expression, and calcium signaling. Together with the study of dopaminergic (DA) neurons in the ventral tegmental area (VTA), these results uncover reduced PV expression, calcium-buffering capacity, and altered neuronal excitability in Shank3-/- and HCN2-/- mice. This pathway, downstream of Shank3 deficiency and HCN channelopathy, may form an important pathological basis not only for ASD but also other neuropsychiatric disorders.Significance Statement SHANK3 is a scaffolding protein that is highly enriched in the postsynaptic density (PSD) of synapses. Mutations and deletions of the SHANK3 gene are directly connected to Phelan-McDermid syndrome (PMS) and autism spectrum disorders (ASD). However, the links between genetic alterations and abnormalities at the cellular, network, and behavioral levels remain unclear. This study uncovered abnormal physiological changes in inhibitory neurons in the thalamus. A definitive link at the cellular level is established between the Shank3 protein deficiency and the pathological basis of related neuropsychiatric disorders.
2026-01-01 | P377: Response to intravenous immunoglobulin in a patient with Phelan McDermid syndrome and subacute regression
IVIG was initiated at 2 g/kg divided over 2 days (1g/kg per day over 2 days) for presumed autoimmune encephalitis. A gastric tube was also placed during admission to optimize nutrition. The patient was discharged with outpatient follow up to evaluate response to IVIG.
2025-12-26 | NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results.
Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder with no currently approved treatments. NNZ-2591, a synthetic analog of the insulin-like growth factor 1 metabolite cyclic glycine-proline, was evaluated in children and adolescents with PMS in a phase 2, multisite, open-label clinical trial. Participants aged 3-12 years at screening received twice-daily oral NNZ-2591 for 13 weeks; doses were uptitrated from 4 mg/kg to 12 mg/kg over 6 weeks (NCT05025241). Safety and pharmacokinetic profiles were primary end points; 14 efficacy assessments were secondary end points, which included global and symptom-specific PMS assessments, quality of life, communication, behavior, adaptive behavior/self-care, gastrointestinal health, and sleep assessments. Wilcoxon signed-rank tests evaluated change from or observed change relative to baseline vs the null median, with p < 0.05 indicating significance. Eighteen participants received NNZ-2591 (mean [SD] age 8.6 years, mean [SD] weight: 30.4 [10.8] kg). NNZ-2591 was well tolerated; most treatment-emergent adverse events were mild to moderate. Significant improvements from baseline were observed in 10 of 14 efficacy assessments at week 13, including global and symptom-specific PMS assessments, quality of life, behavior, gastrointestinal symptoms, and sleep. At week 13, the PMS-specific Clinical Global Impression (CGI) of Improvement mean (SD) score was 2.4 (0.9) and the median (range) score was 2.0 (1.0, 4.0) (p < 0.0001), with 16 of 18 participants showing improvement; the PMS-specific Caregiver Impression of Change mean (SD) score was 2.7 (1.0) and the median (range) score was 3.0 (1.0, 5.0) (p = 0.0003), with 15 of 18 participants showing improvement. PMS-specific assessment subdomains of communication, cognition/learning, and socialization showed consistent improvements. A 24-hour steady-state area under the curve (AUC24,ss) was estimated for each participant using a one-compartment, linear, population pharmacokinetic model where clearance and volume of distribution parameters were scaled by body weight. Participants with an NNZ-2591 AUC24,ss > 300 μg ⋅ h/mL experienced improvements in the PMS-specific CGI of Improvement scores. For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefit-risk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS. ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022.
2026-04-22 | Data from: Developmental CA2 perineuronal net reduction restores social memory in Shank3 mutant mice
Individuals with Autism Spectrum Disorder (ASD) and related neurodevelopmental conditions, like Phelan-McDermid syndrome (PMDS), exhibit social recognition deficits. Shank3B knockout (KO) mice, a genetic model with relevance to ASD and PMDS, have deficits in social memory in adulthood, but the developmental mechanisms underlying this dysfunction remain unknown. We found that Shank3B KOs have deficits in short-term social recognition during development that persist into adulthood, along with CA2 network aberrations. In CA2, perineuronal nets (PNNs), extracellular matrix structures, support social memory in adult mice. In developing CA2, we found excessive PNNs in KOs, greater sequestration of the guidance cue semaphorin-3A, and overgrowth of afferents. Reduction of PNN levels restored semaphorin-3A, afferent input to CA2, and social recognition, which persisted into adulthood and partially normalized CA2 network activity. These findings suggest that excess CA2 PNN formation impairs social recognition by disrupting afferent input, effects that are reversible by early life intervention.
2026-02-22 | Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models.
Extracellular vesicles (EVs) are lipid bilayer-enclosed structures that mediate intercellular communication by transferring diverse cargoes, including RNA and proteins. SHANK3, a synaptic scaffolding protein critical for synapse structure and function, is implicated in autism spectrum disorder (ASD) and Phelan-McDermid Syndrome (PMS). Early hyperexcitability in cortical neurons is a characterized endophenotype in ASD. Here, we investigated EV-mediated effects in the context of SHANK3 deficiency using human iPSC-derived cortical neurons and Shank3B-/- mice. Switching EVs between SHANK3 mutant and control neurons revealed that SHANK3 mutant-derived EVs transferred the hyperexcitability and accelerated maturation phenotypes to control neurons. Proteomic analysis revealed enrichment of synaptic structural regulators (e.g., ACTB, CFL1, AGRN, and CLSTN1) in SHANK3 mutant neuron-derived EVs. This is consistent with known actin cytoskeletal dysregulation driven by SHANK3 deficiency. However, control neuron-derived EVs failed to rescue mutant phenotypes, likely due to their decreased enrichment of synaptic proteins and related pathways. Further, EVs from mesenchymal stem cells (MSCs) and healthy donor iPSCs, containing synaptic modulators such as complement proteins (C1R, C1S), plasticity-associated proteins (MDK, IGFBP3), and homeostatic regulators (FGF2, SFRP1), rescued the hyperexcitability and normalized the maturation in SHANK3 mutant neurons. In addition, intranasal administration of iPSC-derived EVs in Shank3B-/- mice significantly rescued ASD-like behavioral deficits, emphasizing their therapeutic potential. Together, these findings reveal a novel EV-mediated mechanism for modulating dysregulated excitability and synaptic maturation, addressing a critical unmet need in ASD and associated neurodevelopmental disorders.
2026-02-04 | Abnormal neuronal excitability and reduced parvalbumin expression in Shank3-deficient parvalbumin neurons of the thalamic reticular nucleus.
Fast-spiking, non-adaptive inhibitory neurons in the thalamic reticular nucleus (TRN) critically gate the reciprocal communication between the thalamus and the cortex. Parvalbumin (PV) neurons express high levels of PV, the sole role of which appears to be calcium buffering. The significance of the PV protein - and its related high calcium-buffering capacity - under pathological conditions, especially in various neuropsychiatric disorders, is underappreciated. Deficiency of SHANK3, an important neuronal protein containing ankyrin, SH3, and PDZ, three canonical domains for protein recognition, causes behavioral changes relevant to autism spectrum disorders (ASD). Here we report TRN PV neurons of Shank3-/- (exon 4-22 deletion) mice of either sex exhibit pronounced increases in burst firing occurrence, decreased tonic firing frequency, and faster dendritic calcium transient decay. We pinpointed reduced PV expression as the culprit and used the added-buffer approach to confirm the decrease in calcium-buffering capacity in mutant neurons. Conversely, supplementing Shank3-/- PV neurons with extra EGTA reversed the abnormal action potential (AP) firing. In addition, the PV neurons from HCN2-/- mice exhibit consistent changes in neuronal excitability, PV expression, and calcium signaling. Together with the study of dopaminergic (DA) neurons in the ventral tegmental area (VTA), these results uncover reduced PV expression, calcium-buffering capacity, and altered neuronal excitability in Shank3-/- and HCN2-/- mice. This pathway, downstream of Shank3 deficiency and HCN channelopathy, may form an important pathological basis not only for ASD but also other neuropsychiatric disorders.Significance Statement SHANK3 is a scaffolding protein that is highly enriched in the postsynaptic density (PSD) of synapses. Mutations and deletions of the SHANK3 gene are directly connected to Phelan-McDermid syndrome (PMS) and autism spectrum disorders (ASD). However, the links between genetic alterations and abnormalities at the cellular, network, and behavioral levels remain unclear. This study uncovered abnormal physiological changes in inhibitory neurons in the thalamus. A definitive link at the cellular level is established between the Shank3 protein deficiency and the pathological basis of related neuropsychiatric disorders.
2026-01-01 | P377: Response to intravenous immunoglobulin in a patient with Phelan McDermid syndrome and subacute regression
IVIG was initiated at 2 g/kg divided over 2 days (1g/kg per day over 2 days) for presumed autoimmune encephalitis. A gastric tube was also placed during admission to optimize nutrition. The patient was discharged with outpatient follow up to evaluate response to IVIG.
2025-12-26 | NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results.
Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder with no currently approved treatments. NNZ-2591, a synthetic analog of the insulin-like growth factor 1 metabolite cyclic glycine-proline, was evaluated in children and adolescents with PMS in a phase 2, multisite, open-label clinical trial. Participants aged 3-12 years at screening received twice-daily oral NNZ-2591 for 13 weeks; doses were uptitrated from 4 mg/kg to 12 mg/kg over 6 weeks (NCT05025241). Safety and pharmacokinetic profiles were primary end points; 14 efficacy assessments were secondary end points, which included global and symptom-specific PMS assessments, quality of life, communication, behavior, adaptive behavior/self-care, gastrointestinal health, and sleep assessments. Wilcoxon signed-rank tests evaluated change from or observed change relative to baseline vs the null median, with p < 0.05 indicating significance. Eighteen participants received NNZ-2591 (mean [SD] age 8.6 years, mean [SD] weight: 30.4 [10.8] kg). NNZ-2591 was well tolerated; most treatment-emergent adverse events were mild to moderate. Significant improvements from baseline were observed in 10 of 14 efficacy assessments at week 13, including global and symptom-specific PMS assessments, quality of life, behavior, gastrointestinal symptoms, and sleep. At week 13, the PMS-specific Clinical Global Impression (CGI) of Improvement mean (SD) score was 2.4 (0.9) and the median (range) score was 2.0 (1.0, 4.0) (p < 0.0001), with 16 of 18 participants showing improvement; the PMS-specific Caregiver Impression of Change mean (SD) score was 2.7 (1.0) and the median (range) score was 3.0 (1.0, 5.0) (p = 0.0003), with 15 of 18 participants showing improvement. PMS-specific assessment subdomains of communication, cognition/learning, and socialization showed consistent improvements. A 24-hour steady-state area under the curve (AUC24,ss) was estimated for each participant using a one-compartment, linear, population pharmacokinetic model where clearance and volume of distribution parameters were scaled by body weight. Participants with an NNZ-2591 AUC24,ss > 300 μg ⋅ h/mL experienced improvements in the PMS-specific CGI of Improvement scores. For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefit-risk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS. ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022.
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
5 orphan drug designations for Phelan-McDermid syndrome.
5 orphan drug designations for Phelan-McDermid syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
N-omega-propyl-l-arginine phosphate salt | small molecules | FDA | 2025-04-14 | — | nNOS U.S., Inc. |
insulin-like growth factor-1(IGF-1) | proteins | FDA | 2024-07-18 | — | Sarcomed AB |
adeno-associated virus 2/9 expressing a miniature version of the human SHANK3 gene (AAV2/9-miniSHANK3) | gene therapies | FDA | 2024-07-16 | — | Jaguar Gene Therapy, LLC |
Cyclo-L-glycyl-L-2-allylproline | small molecules | EMA | 2021-01-06 | — | Orphix Consulting GmbH |
Cyclo(-L-Glycyl-L-2-Allylproline) | small molecules | FDA | 2019-10-15 | — | Neuren Pharmaceuticals, Ltd. |
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