Introduction

Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) is an ultra-rare genetic disorder caused by heterozygous, often de novo, variants in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene, which encodes the IRF2BPL protein [1, 2]. IRF2BPL is part of the IRF2BP family of transcriptional regulators, which includes IRF2BP1, IRF2BP2, and IRF2BPL. Members of this family are broadly implicated in transcriptional control and neural development [3–5]. NEDAMSS is characterized by progressive neurological decline, with just over 60 cases reported globally to date [6]. The clinical phenotype is heterogeneous and age-dependent. In childhood, common features include developmental delay, intellectual disability, seizures, abnormal movements, neurobehavioral symptoms, and ophthalmologic abnormalities. In adolescence and adulthood, patients are more likely to exhibit progressive cognitive decline, anarthria, psychiatric symptoms, epilepsy, movement disorders, and visual impairment [7, 8]. The disorder was first described in 2018 when several individuals with early-onset neurodevelopmental regression and seizures were identified with truncating mutations in IRF2BPL [1, 8, 9]. Since then, studies have expanded the known mutational spectrum of IRF2BPL and clarified the range of associated phenotypes [1, 2, 9, 10]. Importantly, mutations in IRF2BPL result in reduced production of functional IRF2BPL protein, ultimately leading to loss of its normal role in maintaining neuronal health. While many disease-associated mutations are truncating, producing a shortened, non-functional protein, others may disrupt the localization or stability of the full-length protein. Patient-derived cells often show lower expression levels of full-length IRF2BPL, supporting the hypothesis of a loss-of-function mechanism [1, 2, 11].

The IRF2BPL protein is believed to be critical for neuronal maintenance, and its dysfunction has downstream effects on cellular pathways. Notably, loss of IRF2BPL function has been linked to upregulation of the Wingless-related integration site (WNT/WG) signaling pathway, a crucial regulator of neural development and cellular communication. Dysregulation of this pathway is thought to contribute directly to the neurological manifestations observed in NEDAMSS [12, 13]. Functional similarities between IRF2BPL and its homologs IRF2BP1 and IRF2BP2 may offer further mechanistic insights, though the precise molecular cascades by which IRF2BPL loss leads to progressive neurodegeneration remain poorly understood. Given its severity, early onset, and defined genetic basis, NEDAMSS serves as a valuable model for exploring how single-gene dysfunction can drive complex neurodevelopmental regression.

This review consolidates current molecular and clinical knowledge of NEDAMSS and IRF2BPL, emphasizing key gaps that remain. We examine the function of genes, associated protein biology, clinical features, and emerging insights into disease mechanisms. By integrating genetic, molecular, and clinical perspectives, we aim to elucidate how studies of this ultra-rare disorder can inform broader understanding of neurodevelopmental disease and the consequences of transcriptional dysregulation in the brain.

Role of the IRF2BPL

The IRF2BPL gene, positioned on chromosome 14q24, encodes IRF2BPL, a member of the IRF2BP family of transcriptional regulatory proteins involved in neuronal gene expression [9]. A key feature of IRF2BPL is that it is intron-less, consisting of a single continuous exon. Unlike most multi-exon genes, mutations introducing premature stop codons in IRF2BPL transcripts are not subject to nonsense-mediated decay (NMD). Consequently, truncated and nonfunctional protein fragments accumulate, which can disrupt cellular function and contribute to disease pathogenesis [1, 10, 14]. The IRF2BPL protein is approximately 796 amino acids in length and contains two major structural domains: an N-terminal coiled-coil domain, which facilitates protein-protein interactions, and a C-terminal RING finger domain, characteristic of E3 ubiquitin ligases [2]. The RING finger domain mediates ubiquitin-dependent protein degradation, a critical process for eliminating misfolded proteins and maintaining cellular proteotoxicity [15]. This domain architecture is shared with other family members, IRF2BP1 and IRF2BP2, which are established transcriptional repressors [2, 3, 5].

Clinical features

The earliest and most prominent feature of NEDAMSS is developmental regression, which typically manifests between the ages of 2 and 6 years. Children who had previously achieved developmental milestones begin to lose speech, motor abilities, and cognitive skills. In some cases, regression can begin later, even after the age of 10 [9, 10, 12, 24–26]. The regression process is variable, where some children experience a rapid decline over a few months, while others show a slower, more gradual deterioration. Despite this heterogeneity, the overall path is a similar progressive loss of skills that were once mastered [24, 27–31]. This regression is irreversible, though supportive therapies may help stabilize or modestly slow its progression [1, 2].

Speech is often the first function affected, initially presenting as slurred or unclear speech, followed by gradual language loss [9, 10, 24]. Early presentations of loss of speech typically include slurred speech to significant language and speech decline [24]. Over time, many patients develop severe expressive language decline, progressing in some cases to complete anarthria [24, 31–33]. Alongside speech decline, motor regression is another defining feature. Patients gradually lose coordination, ambulation, and fine motor skills, ultimately increasing dependence on caregivers for daily activities [24, 33]. Severe cases may present early and profound motor impairment. Abnormal movements are frequently observed during or after the regression phase and represent a hallmark of NEDAMSS. These manifestations include dystonia, a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions that produce twisting, repetitive movements or abnormal postures; chorea, which involves rapid, irregular, and unpredictable “dance-like” movements often affecting the hands, feet, and face; ataxia, defined by impaired coordination that leads to unsteady gait, clumsiness, balance difficulties, and sometimes dysarthria; and tremors, involuntary, rhythmic oscillatory movements affecting one or more body parts. The severity of these motor abnormalities can vary widely, ranging from subtle postural changes to profound, disabling movement disorders that substantially impair mobility. Collectively, these abnormal movements, alongside progressive motor decline, significantly compromise independence, posture, and overall quality of life [7, 9, 24–26, 31–33].

Seizures are another major clinical feature and often appear after speech and motor regression have begun. They typically emerge in middle childhood but may also develop during adolescence or, in rare cases, early adulthood. The types of seizures observed include focal, myoclonic, and atonic seizures [7, 25–28, 30]. As with other symptoms, severity varies; some patients develop refractory epilepsy, while others respond relatively well to anti-seizure treatments [24, 29, 33]. The onset of seizures often coincides with or accelerates cognitive and behavioral decline, suggesting shared mechanistic reinforcements between electrogenesis and neurodegeneration in NEDAMSS. In addition to the four cardinal features (e.g., regression, loss of speech, abnormal movements, and seizures), patients exhibit a broader spectrum of neurological and systemic symptoms. Cognitive impairment ranges from mild to severe intellectual disability, and many patients demonstrate behaviors resembling autism spectrum disorder (ASD), including irritability, hyperactivity, and ASD-like social difficulties [24, 33, 34]. Sleep disturbances are common, often linked to painful dystonia and tremors during the night, which lead to insomnia and daytime fatigue [25]. As oral-motor dysfunction progresses, feeding difficulties emerge, sometimes necessitating gastrostomy tube placement. In advanced cases, respiratory complications develop and may become life-threatening [9, 24].

Ophthalmologic manifestations are also documented. Strabismus is relatively common, while cortical visual impairment has been reported in some patients, reflecting deficits in visual processing despite intact ocular structures. More rarely, optic nerve hypoplasia has been observed. These visual problems contribute to learning difficulties, mobility challenges, and increased dependence [9, 24]. Genotype-phenotype correlations are still emerging, but early evidence suggests that truncating variants of IRF2BPL could be associated with earlier onset and more severe disease, whereas some missense variants may lead to later onset or milder progression [9, 10, 24]. Importantly, NEDAMSS is caused by de novo heterozygous variants in IRF2BPL, consistent with an autosomal dominant mechanism. While recurrence risk for siblings is generally low, it cannot be excluded if parental mosaicism is present [9, 10].

Because NEDAMSS was first described in 2018, its rarity and phenotypic overlap with other disorders make diagnosis challenging [9, 10]. Its core features can be mistaken for Rett syndrome, ASD, cerebral palsy, or mitochondrial and metabolic diseases [9, 31]. However, certain distinguishing features can help differentiate NEDAMSS, which is the later age of onset compared to Rett syndrome or cerebral palsy; the lack of dysmorphic features, which are common in mitochondrial disorders; and the absence of progressive vision loss, which is often seen in neuronal ceroid lipofuscinoses [9, 24, 31–33].

Laboratory evaluations for metabolic disorders are typically unremarkable, providing limited diagnostic direction in most individuals. Neuroimaging is similarly nonspecific in the early stages, as MRI scans may appear normal before gradually evolving to show mild cerebral or cerebellar atrophy over time [35]. Electroencephalography tends to offer more consistent evidence of neurological dysfunction, frequently demonstrating background slowing and epileptiform discharges [36]. Because these routine clinical assessments often yield nondiagnostic or only subtly abnormal findings, genetic testing becomes essential for identifying rare neurodevelopmental conditions [37]. In this context, whole-exome sequencing remains the most reliable and informative approach, enabling definitive confirmation of pathogenic IRF2BPL variants that underlie the disorder [10, 26, 27, 30, 32].

Despite increasing recognition, NEDAMSS remains substantially underdiagnosed. At the time of its initial description, only about 34 cases had been reported, and although the number has since grown to more than 60 confirmed individuals worldwide, the true prevalence is almost certainly higher [9, 24, 31, 33]. The marked phenotypic variability, ranging from early developmental delay to later-onset regression, movement disorders, and epilepsy, further complicates clinical recognition. In regions with limited access to genomic testing, these challenges are amplified, increasing the likelihood that additional individuals remain undiagnosed or misdiagnosed.

Currently, there are no disease-modifying therapies for NEDAMSS, and treatment is primarily supportive, requiring a multidisciplinary approach [2]. Seizure management is central, with anti-seizure medications such as levetiracetam or valproate commonly prescribed, though drug resistance is frequent [30, 33]. Movement disorders may be treated with medications such as baclofen or botulinum toxin, and physical therapy is often employed to preserve mobility as long as possible. Speech therapy and augmentative communication devices help maintain communication, while feeding support, including swallow assessments and gastrostomy feeding, becomes necessary as oral-motor skills decline [24]. Behavioral and cognitive challenges are managed with occupational therapy, behavioral interventions, and, when appropriate, medications to address irritability or sleep disturbances [34]. In advanced disease stages, proactive respiratory support is critical, including vigilant monitoring for aspiration and implementation of respiratory therapy when clinically indicated [9].

Supportive care remains a central component of management for patients with NEDAMSS, extending not only to patients but also to their families. Multidisciplinary coordination across neurology, physical and occupational therapy, nutrition, and, when appropriate, palliative care services is essential for optimizing day-to-day functioning and long-term well-being [1, 12]. Because NEDAMSS is a progressive neurodevelopmental disorder, families often experience substantial emotional, logistical, and caregiving burdens, drawing attention to the importance of ongoing counseling and psychosocial support.

Alongside supportive care, active research efforts are advancing potential therapeutic strategies. Preclinical studies in animal and cellular models have evaluated WNT-signaling inhibitors and autophagy-enhancing agents as approaches to mitigate the downstream molecular consequences of IRF2BPL dysfunction [1, 2, 12]. Early exploratory work in gene-directed therapies, including antisense oligonucleotides and adeno-associated virus (AAV) mediated gene delivery, is also underway [2, 23]. Although these approaches remain experimental, they represent promising steps toward future disease-modifying interventions. Until such therapies mature, clinical management continues to focus on maximizing quality of life through comprehensive, anticipatory, and family-centered supportive care.

Pathogenic mechanisms driving NEDAMSS

Although the pathogenic mechanism underlying NEDAMSS is not yet fully resolved, multiple converging lines of evidence indicate that IRF2BPL loss-of-function represents the primary driver of disease. Developing observations further suggest that mislocalized or truncated IRF2BPL species may impose an additional gain-of-burden effect through aberrant protein interactions, impaired proteostasis, or cytoplasmic aggregation, but these secondary processes appear to amplify, rather than replace, the core loss-of-function mechanism. Collectively, these insights provide a mechanistic bridge between the period of early normal development in affected children and the subsequent onset of progressive neurological decline. Central to this line is a de novo pathogenic IRF2BPL variant that yields truncated or dysfunctional protein fragments, which compromise neuronal cell maintenance, destabilize proteostasis networks, and ultimately promote neurodegeneration [1, 9, 10, 12, 24].

Under physiological conditions, IRF2BPL functions as an E3 ubiquitin ligase, a role essential for maintaining neuronal proteostasis given the high metabolic demands and vulnerability of neurons to protein misfolding [1, 15]. By ubiquitinating damaged or misfolded proteins, IRF2BPL facilitates their proteasomal degradation. Pathogenic variants impair this function, reducing ubiquitination efficiency and leading to the accumulation of misfolded and polyubiquitinated proteins within neurons. The resulting proteostatic burden disrupts axonal transport, perturbs lysosomal function, and imposes chronic cellular stress [1, 12]. IRF2BPL deficiency disrupts multiple cellular processes, contributing to the progressive neurodegeneration characteristic of NEDAMSS [1, 2, 12].

IRF2BPL functions as a critical regulator of WNT/WG signaling, a pathway essential for neuronal differentiation, synaptic development, and circuit maturation [1, 12, 38]. WNT/WG pathway dysregulation is a shared pathogenic feature across Alzheimer’s disease, ASD, Parkinson’s disease, and major neuropsychiatric disorders, where it contributes to synaptic failure, neurodevelopmental disruption, dopaminergic neuron vulnerability, and impairments in higher-order cognitive function (Table 1). Mechanistically, IRF2BPL normally represses WNT target gene expression and promotes β-catenin ubiquitination, thereby constraining pathway activity [1, 12]. When IRF2BPL is defective, β-catenin escapes ubiquitination and accumulates, leading to pathological overactivation of WNT signaling. This dysregulated signaling environment drives aberrant synaptic growth, heightened neuronal excitability, and progressive cellular dysfunction and degeneration [1, 12]. Together, these findings support a model in which excessive WNT/β-catenin signaling represents a central driver of NEDAMSS-associated brain pathology.

IRF2BPL also exerts key nuclear functions, acting as a transcriptional co-repressor through its N-terminal coiled-coil and C-terminal RING finger domains [1]. It regulates genes involved in neuroendocrine signaling and neuronal cell activity. For example, IRF2BPL normally represses GnRH, and loss-of-function may impair this regulatory axis in NEDAMSS [18]. In addition, IRF2BPL represses IEGs, which are critical for neuronal cell plasticity, learning, and memory [5, 25]. Loss of IRF2BPL-mediated repression leads to IEG overexpression, excessive synaptic activity, heightened excitability, and dysregulated calcium dynamics [5, 25]. This hyperexcitability lowers the seizure threshold, predisposing patients to epilepsy, a clinical hallmark of NEDAMSS [1, 25]. Seizures, in turn, exacerbate neuronal stress by amplifying excitotoxic glutamate release and calcium influx, creating a self-reinforcing cycle of oxidative stress, metabolic strain, and neuronal injury [1, 2, 14]. This impaired metabolic resilience likely accelerates neuronal cell vulnerability and degeneration [1, 2, 12].

Taken together, the emerging pathogenic architecture of NEDAMSS reflects a multilayered convergence of nuclear, cytoplasmic, and neuroimmune dysfunction, with dysregulated WNT/β-catenin signaling increasingly recognized as a central mechanistic hub. Loss of IRF2BPL function disrupts transcriptional repression and proteostatic surveillance, promoting cytoplasmic mislocalization and aggregation of IRF2BPL and related neuronal proteins, aberrant activation of WNT/β-catenin dependent transcription, and secondary mitochondrial and metabolic impairment [1, 9, 12]. These primary defects destabilize neuronal cell maintenance programs, lower the threshold for progressive neurodegeneration, and prime the CNS for maladaptive inflammatory responses.

Viewed within this broader mechanistic architecture, the cascade observed in NEDAMSS aligns with a well-recognized paradigm across other CNS diseases, in which abnormal accumulation of neuronal proteins and glycolipids triggers protein misfolding and is tightly interconnected with disease progression [54–64]. In neurodegenerative disorders defined by pathogenic protein aggregation, including α-synuclein in Parkinson’s disease, amyloid-β and tau in Alzheimer’s disease, and combined α-synuclein/tau pathologies in dementia with Lewy bodies and multiple system atrophy, misfolded protein species act as potent activators of neuronal and glial cell sensing pathways [65–74]. Their accumulation and aberrant conformations trigger innate immune receptors, amplify neuroinflammatory cascades, and accelerate the progression of neurodegeneration [55, 56, 65–75]. These parallels focus on a unifying principle that the biochemical identity, conformational state, and cellular handling of aggregated or misfolded IRF2BPL proteins likely determine how neural cells detect, interpret, and respond to injury-associated signals. This background suggests that similar protein-aggregation-driven mechanisms may be operative in NEDAMSS, shaping both the inflammatory milieu and the trajectory of neurodegeneration.

If this happens as predicted here, immunotherapy development against such abnormal neuronal protein could be a direct potential treatment for NEDAMSS patients, as such therapies, like anti-alpha synuclein and anti-amyloid β therapy, are currently in place for the treatment of patients with Parkinson’s and Alzheimer’s diseases [76–82]. Active and passive α-synuclein immunotherapies are already being explored as disease-modifying approaches in Parkinson’s disease [76, 77, 83–88]. Similarly, substantial progress has been achieved in Aβ-directed therapies, with agents such as aducanumab, lecanemab, and donanemab demonstrating robust amyloid plaque clearance and potential clinical benefit in Alzheimer’s disease [78–82, 89]. These advances suggest the feasibility of designing targeted immunotherapies against disease-defining protein species and provide a compelling conceptual foundation for future therapeutic development in NEDAMSS.

Perspectives and future challenges

Despite meaningful progress in defining IRF2BPL-related neurodevelopmental disorders, substantial challenges remain in timely diagnosis, mechanistic resolution, and therapeutic development for NEDAMSS. Clinical overlap with other early-onset regression syndromes continues to delay recognition, reinforcing the need for heightened clinical awareness and early genomic evaluation. Ensuring equitable access to sequencing technologies and coordinated multidisciplinary care will be essential for improving diagnostic yield and long-term outcomes. The absence of validated biomarkers, quantitative functional readouts, and standardized outcome measures continues to limit clinical monitoring and impede trial readiness. Coordinated efforts, including multicenter natural history studies, harmonized phenotyping principles, and prospective patient registries, will be critical for defining disease paths, refining genotype-phenotype correlations, and supporting the development of mechanism-based interventions.

Mechanistic gaps also persist. Current evidence indicates that IRF2BPL dysfunction primarily reflects loss of nuclear function and dysregulated WNT signaling, while the cytoplasmic puncta observed in some model systems likely represent mislocalized, unstable, or truncated IRF2BPL protein species [1, 2, 10–12]. An important emerging concept is that, under conditions of chronic stress or impaired proteostasis, these species may interact, coalesce, and potentially evolve into higher-order aggregated structures, thereby adding a second layer of toxicity beyond simple loss of function. Future studies should define the biochemical composition, aggregation propensity, and cellular handling of these cytoplasmic species and determine whether they act as seeds for broader disturbances in protein homeostasis or neuroinflammatory mechanism activation. Parallel efforts should clarify how IRF2BPL loss alters neuronal signaling, synaptic maintenance, and vulnerability to injury, and how downstream consequences, such as WNT pathway overactivation, impaired transcriptional repression, and secondary neuroinflammatory responses, shape disease progression. Additional priorities include identifying selectively vulnerable neuronal cell populations, mapping disruptions in cellular signaling and protein homeostasis, and integrating these insights with rational therapeutic strategies. By linking mechanistic understanding with early diagnosis, structured natural history data, and coordinated clinical care, the field is increasingly well-positioned to accelerate the development of precision-based therapies for NEDAMSS.

Conclusion

NEDAMSS is an ultra-rare neurological disorder marked by substantial clinical heterogeneity, contributing to delayed diagnosis and persistent under-recognition [9, 24, 33]. Variation in age of onset, disease severity, and rate of progression is likely shaped by mutation type, residual IRF2BPL activity, and additional genetic modifiers; however, clear genotype-phenotype correlations remain elusive [9, 10, 24]. This uncertainty continues to impede accurate prognostication and the rational design of targeted therapeutic strategies [2, 31]. Converging evidence supports loss of IRF2BPL function as the central pathogenic mechanism in NEDAMSS. IRF2BPL is essential for maintaining neuronal homeostasis, and disruption of its transcriptional and regulatory roles [1, 2, 38, 90] precipitates neurodevelopmental regression, progressive neurodegeneration, and frequently refractory seizures [24, 31].

Although the precise molecular intermediates linking IRF2BPL dysfunction to WNT hyperactivation, emerging protein aggregation, and neuroimmune engagement remain incompletely defined, the integrated model illustrated in Figure 1 provides a coherent systems-level explanation for how a single-gene defect can drive developmental regression, seizures, and progressive neurodegeneration. In this operational model, loss of IRF2BPL function initiates a cascade in which nuclear depletion and cytoplasmic mislocalization of mutant IRF2BPL promote aggregate formation that aberrantly activates WNT/β-catenin signaling, leading to dysregulated gene expression and neuronal cell vulnerability. Within this model, WNT/β-catenin signaling and its downstream inflammatory mediators emerge as central, pathway-targeted points of intervention. Therapeutic strategies that restore proteostasis, recalibrate aberrant WNT activity, or attenuate chronic neuroinflammation may therefore hold promise for modifying the disease pathway in NEDAMSS, rather than merely mitigating downstream manifestations.

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Figure 1. Proposed mechanistic model linking IRF2BPL loss of function to NEDAMSS pathophysiology. This figure was conceptualized and produced by M.K.P. using original artistic expertise, integrating mechanistic insights derived from the literature. Interferon Regulatory Factor 2 Binding Protein-Like (IRF2BPL) gene defects and the resulting translocation of mutant IRF2BPL protein from the nucleus to the cytoplasm trigger the formation of protein aggregates that aberrantly activate WNT/β-catenin signaling. This cascade leads to dysregulated gene expression, neuronal dysfunction, and the characteristic features of Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS).

As depicted in Figure 1, pathogenic IRF2BPL variants disrupt transcriptional repression and proteostatic surveillance, enabling truncated or mislocalized IRF2BPL species normally unstable and rapidly degraded to accumulate under conditions of cellular stress. These species may aberrantly interact and assemble into higher-order aggregated structures that impose a secondary gain-of-burden effect, amplifying stress-response pathways, perturbing protein homeostasis, and further sensitizing neurons to injury. In this view, aggregation-linked toxicity operates in parallel with the primary loss of nuclear IRF2BPL function, together creating a multilayered vulnerability across neuronal compartments that ultimately converges on WNT dysregulation and neuroimmune activation.

Despite several such advances, major challenges remain, including delayed diagnosis, limited access to comprehensive genomic testing, and the absence of validated biomarkers for disease monitoring or therapeutic response [1, 2, 26–28, 30, 31, 33, 91]. Addressing these gaps while deepening mechanistic understanding of IRF2BPL dysfunction, WNT pathway dysregulation, proteostasis failure, and neuroimmune activation will be essential for translating emerging biological insights into effective therapies. Continued progress in defining NEDAMSS pathogenesis and natural history provides a critical foundation for therapeutic development and integrating these clinical and mechanistic insights to advance rational, pathway-directed interventions. As the field moves toward targeted strategies that restore proteostasis, modulate WNT signaling, or temper chronic neuroinflammation, a more complete understanding of disease biology will be indispensable for shaping the next generation of treatments for this disturbing disorder.