IRF2BPL-Related Neurodevelopmental Disorder with Regression

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Mappings

MONDO

MONDO:0060759 neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures

NEDAMSS is catalogued in OMIM as 618088, the number quoted in the neuropathology report that named the syndrome. MONDO:0060759 is the exact anchor for that OMIM concept and is the term this entry curates.

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Definitions

1

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Dominant, and overwhelmingly de novo - roughly 9% of reported individuals have an affected parent. The dominance is not by dose: the truncated product is expressed and interferes with the wild-type protein.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"IRF2BPL-related disorder is inherited in an autosomal dominant manner. The majority of individuals diagnosed with IRF2BPL-related disorder have the disorder as the result of a de novo pathogenic variant; approximately 9% of individuals reported to date have an affected parent."

States both the mode of inheritance and the de novo predominance, with the parental-transmission fraction.

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Discussions and Knowledge Gaps

3

Every in vivo model of this disorder is a loss-of-function model, but the human mechanism is dominant-negative sequestration by an expressed truncated protein. Do the fly and zebrafish results actually speak to the human lesion?

HUMAN MODEL MISMATCH OPEN irf2bpl_lof_models_vs_dominant_negative

Attached to

pathophysiology#Cytoplasmic Sequestration of Wild-Type IRF2BPL pathophysiology#Excess Wnt Signaling

The Wnt arm of this pathograph rests almost entirely on pits knockdown in Drosophila and irf2bpl loss in zebrafish - both of which remove gene function. The human variants do something different: because IRF2BPL is intronless, the mutant transcript escapes NMD, and the resulting truncated protein actively drags wild-type IRF2BPL into cytoplasmic aggregates. A pure loss-of-function model reproduces the *consequence* of nuclear IRF2BPL being absent, but not the sequestration that produces it, and so cannot report on whether aggregate toxicity contributes independently of lost transcriptional repression. Two observations narrow the gap without closing it. Flies co-expressing full-length and truncated IRF2BPL do show cytoplasmic accumulation of the full-length protein, and heterozygous Pits-truncation flies show a progressive motor phenotype - so the allele class has been modelled, even if the Wnt measurements were not made in it. WNT1 is also raised in patient-derived astrocytes, which is human material carrying the real allele. What is missing is the Wnt measurement in a system that has both: the human truncating allele and an intact nervous system.

Proposed experiments

Wnt pathway readout in a knock-in truncating allele model

exp_irf2bpl_knockin_wnt_readout

Measure Wnt ligand and downstream signalling in a vertebrate model carrying a heterozygous knock-in of a human IRF2BPL truncating variant, rather than a null, and test whether Wnt inhibition is neuroprotective in that background.

Would support

pathophysiology#Excess Wnt Signaling

Would refute

pathophysiology#Excess Wnt Signaling

Supporting outcome

Wnt ligand and downstream signalling are elevated in the knock-in heterozygote to a degree comparable with the null, and Wnt inhibition slows the progressive phenotype.

Refuting outcome

Wnt signalling is unchanged in the knock-in heterozygote despite cytoplasmic sequestration and progressive degeneration, which would make the Wnt arm an artifact of complete gene loss and point to aggregate toxicity as the operative mechanism.

Do the polyglutamine inclusions seen at autopsy contribute to neurodegeneration in NEDAMSS, or are they a downstream marker?

KNOWLEDGE GAP OPEN irf2bpl_polyq_inclusion_causality

Attached to

pathophysiology#Intracellular Protein Aggregate Formation

The single detailed neuropathological study of this disorder found polyQ inclusions and a picture consistent with DRPLA, in a patient with no repeat expansion and a variant lying distal to IRF2BPL's own polyQ tract. The authors raise, but explicitly do not establish, the possibility that the unexpanded polyQ tract participates in inclusion formation - which they note would be a novel mechanism for polyQ repeats. This rests on one autopsy. Whether inclusions are present across NEDAMSS generally, whether they precede or follow neuronal loss, and whether they are toxic or protective are all open. The node is curated because the observation is real and mechanistically striking, not because the causal role is settled.

Proposed experiments

Systematic neuropathology across NEDAMSS variant classes

exp_irf2bpl_systematic_neuropathology

Examine additional NEDAMSS brains, spanning proximal and distal truncating variants and missense alleles, for polyQ inclusions and their regional distribution relative to neuronal loss.

Would support

pathophysiology#Intracellular Protein Aggregate Formation

Would refute

pathophysiology#Intracellular Protein Aggregate Formation

Supporting outcome

PolyQ inclusions are found consistently across cases and their regional distribution matches the pattern of neuronal loss.

Refuting outcome

Inclusions are absent in other cases with comparable degeneration, or are confined to regions without neuronal loss, indicating they are incidental rather than on the causal path.

What determines the extraordinary range of onset age, from the first year of life to the sixth decade?

KNOWLEDGE GAP OPEN irf2bpl_onset_age_range

Attached to

pathophysiology#Loss of Previously Acquired Developmental Milestones

Onset spans five decades, and the systematic review found no significant correlation between the number of affected clinical domains and either age at onset or variant type. A separate series found protein-truncating variants clustered around the coiled-coil domain in three adults presenting as progressive myoclonus epilepsy, hinting at a positional effect, but the correlational analysis does not support variant type as the explanation. Modifiers, mosaicism and the degree of NMD escape are all untested candidates, and none can be assigned from the published data.

Proposed experiments

Genotype-onset correlation in an adequately powered cohort

exp_irf2bpl_genotype_onset_cohort

Assemble a cohort large enough to test variant position, predicted escape of nonsense-mediated decay, and measured residual full-length IRF2BPL protein against age at onset and rate of regression.

Would support

pathophysiology#Nonsense-Mediated Decay Escape and Truncated Protein Expression

Would refute

pathophysiology#Nonsense-Mediated Decay Escape and Truncated Protein Expression

Supporting outcome

Residual full-length nuclear IRF2BPL protein predicts age at onset, making the degree of sequestration the dose variable that sets timing.

Refuting outcome

Onset age is unrelated to residual protein or variant position across an adequately powered cohort, pointing to modifiers outside the locus.

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Pathophysiology

11

De Novo Heterozygous IRF2BPL Truncating Variant

A de novo nonsense or frameshift variant in the single-exon IRF2BPL gene, predicted to remove the C-terminal RING-finger domain that carries the protein's transcriptional repressive and transactivating activity.

IRF2BPL hgnc:14282

Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Heterozygous de novo nonsense or frameshift alleles removing the C-terminal RING-finger domain. Classified DOMINANT_NEGATIVE rather than LOSS_OF_FUNCTION because the truncated product is expressed - the intronless transcript escapes nonsense-mediated decay - and sequesters the wild-type protein, rather than the allele simply being absent. Missense alleles are also reported and are milder.

Downstream

Nonsense-Mediated Decay Escape and Truncated Protein Expression

Show evidence (1 reference)

PMID:30166628 SUPPORT Human Clinical

"The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain."

States the predicted protein-level consequence of the disease variants that initiates this chain.

Nonsense-Mediated Decay Escape and Truncated Protein Expression

IRF2BPL is intronless, so a transcript carrying a premature termination codon is not cleared by nonsense-mediated decay. In patient fibroblasts the mutant allele is expressed at a ratio of at least 1:1 with the wild-type allele, so a truncated protein is translated rather than the allele simply being lost.

nonsense-mediated decay of the IRF2BPL premature-stop transcript GO:0000184 ↓ DECREASED

Downstream

Cytoplasmic Sequestration of Wild-Type IRF2BPL

Show evidence (2 references)

PMID:30166628 SUPPORT In Vitro

"in favor of nonsense-mediated decay (NMD) escape because the mutated allele is expressed with a ratio of at least 1:1 with the wild-type (WT) allele, suggesting that the shorter protein might be translated"

Direct measurement in patient-derived fibroblasts showing the mutant transcript is not degraded, which is the observation that makes a truncated product available to act dominant-negatively.

PMID:30166628 SUPPORT Computational

"It belongs to a group of human intronless genes that are known to possibly escape nonsense-mediated decay (NMD), despite presence of a premature stop codon."

Gives the structural reason for NMD escape - the absence of introns - rather than treating it as an unexplained observation. Graded COMPUTATIONAL because this is a statement about gene architecture drawn from genome annotation, not an observation made in a patient.

Cytoplasmic Sequestration of Wild-Type IRF2BPL

Full-length IRF2BPL is normally nuclear. The truncated patient protein instead accumulates in the cytoplasm and pulls wild-type IRF2BPL out of the nucleus with it, forming aggregates. This is the dominant-negative step, and it is why the disorder does not behave as haploinsufficiency.

nuclear import of full-length IRF2BPL GO:0034504 ↓ DECREASED

Experimental models

Patient fibroblast-derived astrocytes and neurons PRIMARY CELL CULTURE The system in which the mislocalisation and aggregation of wild-type IRF2BPL by truncated patient variants was demonstrated.

Downstream

Loss of IRF2BPL Transcriptional Repression

Intracellular Protein Aggregate Formation

Show evidence (2 references)

PMID:36476864 SUPPORT In Vitro

"While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation."

States the sequestration mechanism directly, in patient-derived reprogrammed cells.

PMID:36476864 SUPPORT Model Organism

"co-expression of full-length and truncated IRF2BPL in Drosophila results in cytoplasmic accumulation of full-length IRF2BPL"

In vivo confirmation that the truncated product is sufficient to mislocalise the wild-type protein.

Loss of IRF2BPL Transcriptional Repression

With full-length IRF2BPL depleted from the nucleus, its repressive transcriptional activity is lost. Overexpressing IRF2BPL or its Drosophila ortholog Pits represses Wnt transcription, so removing it releases that repression.

IRF2BPL-mediated transcriptional repression GO:0000122 ↓ DECREASED

Downstream

Excess Wnt Signaling

Show evidence (1 reference)

PMID:35044823 SUPPORT Model Organism

"Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies."

Establishes that IRF2BPL's normal role at this node is repression of Wnt transcription, which is what its loss releases.

Excess Wnt Signaling

Loss of IRF2BPL repression raises Wnt ligand levels and downstream signalling. This is not merely correlative: increasing neuronal wingless in flies is by itself sufficient to cause age-dependent axonal loss, and inhibiting Wnt is neuroprotective. WNT1 is likewise elevated in patient-derived astrocytes.

Wnt signaling pathway GO:0016055 ↑ INCREASED

Animal models

Drosophila pits neuronal RNAi knockdown Drosophila melanogaster recapitulates Depleting pits raises wingless in the brain, and the resulting axonal loss is suppressed by inhibiting Wg - establishing the Wnt step as causal rather than correlative.

Zebrafish irf2bpl loss of function Danio rerio recapitulates Loss of irf2bpl causes neurological defects with increased wnt1 transcription and downstream signalling, reproducing the fly result in a vertebrate.

Downstream

Progressive Neuronal and Axonal Loss

Show evidence (3 references)

PMID:35044823 SUPPORT Model Organism

"In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective."

Links loss of the ortholog to raised Wnt ligand and to axonal loss, and shows the loss is Wnt-dependent because blocking Wnt protects.

PMID:35044823 SUPPORT Model Organism

"Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits."

Sufficiency, and the age dependence that makes this a progressive rather than a developmental lesion.

PMID:35044823 SUPPORT In Vitro

"WNT1 is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes."

Shows the Wnt elevation is present in human patient-derived cells and not only in the invertebrate model.

Astrocyte Mitochondrial Respiratory Dysfunction

Astrocytes reprogrammed from patient fibroblasts carry structurally aberrant mitochondria and measurable respiratory dysfunction. The same direction of change is visible in patient muscle, where biopsies show cytochrome-c-oxidase-negative and ragged-red-like fibres and electron transport chain assay in one patient found generalized deficiencies - so the mitochondrial arm is not an artefact of reprogrammed glia alone.

patient-derived astrocyte CL:0000127

astrocyte mitochondrial respiration GO:0045333 ↓ DECREASED

Experimental models

Patient fibroblast-derived astrocytes and neurons PRIMARY CELL CULTURE Patient astrocytes show structurally aberrant mitochondria and respiratory dysfunction, and CuATSM restores mitochondrial function - the rescue acts on this step specifically.

Downstream

Loss of Astrocytic Trophic Support for Neurons

Show evidence (2 references)

PMID:36476864 SUPPORT In Vitro

"exhibit aberrant mitochondria and respiratory dysfunction"

The mitochondrial half of the astrocyte observation, quoted on its own because it is a separate claim from the coculture survival result.

PMID:30166628 SUPPORT Human Clinical

"Muscle electron transport chain studies performed in patient 1 showed mild generalized deficiencies that could indicate primary or secondary mitochondrial defects."

Patient tissue pointing the same way as the reprogrammed astrocytes. The authors' own hedge - primary or secondary - is why this node is not curated as a primary mitochondrial disease.

Loss of Astrocytic Trophic Support for Neurons

Patient astrocytes fail to keep neurons alive in coculture. Neuronal loss in NEDAMSS is therefore not purely cell-autonomous - a failing glial compartment contributes, downstream of the astrocyte's own metabolic failure.

patient-derived astrocyte CL:0000127

Experimental models

Patient fibroblast-derived astrocytes and neurons PRIMARY CELL CULTURE The coculture in which patient astrocytes were shown to fail to keep neurons alive, and in which CuATSM rescued neuronal survival.

Downstream

Progressive Neuronal and Axonal Loss

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"patient astrocytes fail to support neuronal survival in coculture"

The glial-support half of the astrocyte observation: the measurement is made on the neurons, and it is what makes this a distinct step from the astrocyte's mitochondrial defect.

Intracellular Protein Aggregate Formation

Sequestration of wild-type IRF2BPL by the truncated product produces cytoplasmic aggregates in cells. At autopsy the corresponding human finding is polyglutamine inclusions, in a distribution consistent with DRPLA - despite these patients carrying no repeat expansion, since the variants sit distal to IRF2BPL's own polyQ tract.

inclusion body assembly GO:0070841 ↑ INCREASED

Downstream

Progressive Neuronal and Axonal Loss

Show evidence (3 references)

PMID:39224955 SUPPORT Human Clinical

"Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions."

The only detailed human neuropathology for this disorder, and the direct observation of inclusions in patient brain.

PMID:39224955 SUPPORT Human Clinical

"Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats."

Records the authors' own hedging - that the polyQ involvement is a proposed mechanism, not an established one - so this node is not read as a settled repeat-expansion disease.

PMID:37114479 SUPPORT Human Clinical

"The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders."

A second, independent inclusion finding in patient tissue, from a different group and a different organ than the autopsy polyQ result. It is glycogen rather than protein, so it does not corroborate the polyQ observation directly; what it supports is that intracellular accumulation is a real feature of this disorder outside the brain.

Progressive Neuronal and Axonal Loss

The convergence point of the excess-Wnt, glial-failure and aggregation arms. Partial neuronal knockdown of the IRF2BPL ortholog in flies causes frank neurodegeneration, establishing a requirement for this gene in neuronal maintenance rather than only in neuronal development.

neuron CL:0000540

neuron projection maintenance GO:1990535 ↓ DECREASED

Animal models

Drosophila pits neuronal RNAi knockdown Drosophila melanogaster recapitulates Neuronal knockdown produces frank neurodegeneration, demonstrating that the gene is required for neuronal maintenance and not only for neuronal development.

Drosophila heterozygous Pits truncation with CuATSM rescue Drosophila melanogaster rescues Progressive motor defects in heterozygous-truncation flies are ameliorated by CuATSM, the same compound that restores mitochondrial function and neuronal survival in patient-derived cells.

Downstream

Loss of Previously Acquired Developmental Milestones

Cerebral and Cerebellar Atrophy

Show evidence (2 references)

PMID:30057031 SUPPORT Model Organism

"Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance."

Separates the developmental requirement from the maintenance requirement, which is the distinction that makes this disorder degenerative rather than static.

PMID:35044823 SUPPORT Human Clinical

"De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders."

States plainly that the human disorder is neurodegenerative.

Cerebral and Cerebellar Atrophy

Progressive loss of neurons and their projections is visible on brain MRI as cortical, subcortical, cerebellar (particularly vermian) and brain stem atrophy, together with corpus callosum abnormalities.

Downstream

Progressive cerebellar ataxia

Cerebellar atrophy

Cerebral atrophy

Spasticity

Dysarthria

Nystagmus

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"Brain MRI can show focal or diffuse cortical and/or subcortical atrophy, cerebellar atrophy (particularly of the vermis), brain stem atrophy, and corpus callosum abnormalities including thinning/atrophy or thickening."

The imaging correlate of the tissue-level loss, from the disorder's GeneReviews summary.

Loss of Previously Acquired Developmental Milestones

The clinical signature of the disorder and the reason it is curated as neurodegenerative. Initial psychomotor development is mostly normal and is then followed by severe global neurological regression: acquired skills, including speech, are lost. Onset is highly variable, from the first year of life to the sixth decade.

Downstream

Developmental regression

Loss of speech

Intellectual disability

Seizure

Dysphagia

Show evidence (3 references)

PMID:30166628 SUPPORT Human Clinical

"mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies"

The explicit statement of the acquire-then-lose course, in the cohort that delineated the phenotype.

PMID:30166628 SUPPORT Human Clinical

"These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration"

The authors' own framing of the disorder as neurodegeneration rather than static encephalopathy.

PMID:39571061 SUPPORT Human Clinical

"Onset is highly variable and can be in the first year of life through the sixth decade. In some individuals the course of the disorder is progressive or debilitating."

Records the wide onset range and that the course is progressive in a subset, which qualifies the uniformity of the regression claim.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

24

Digestive 3

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"Feeding issues, gastrointestinal dysmotility, and ophthalmologic manifestations are also reported."

Names feeding issues among the non-neurological manifestations.

Gastrointestinal dysmotility HP:0002579

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"Feeding issues, gastrointestinal dysmotility, and ophthalmologic manifestations are also reported."

Names gastrointestinal dysmotility directly.

Dysphagia OCCASIONAL HP:0002015

Show evidence (2 references)

PMID:30166628 SUPPORT Human Clinical

"Other abnormalities included hypotonia (5/11 cases), dystonia (3/11 cases), dysphagia (3/11 cases)"

The published denominator behind the OCCASIONAL band: 3/11 is 27%.

PMID:37114479 SUPPORT Human Clinical

"IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs."

A second, independent group naming dysphagia among the defining features of IRF2BPL-related disorder.

Endocrine 1

Delayed puberty HP:0000823

Show evidence (2 references)

PMID:39571061 SUPPORT INDIRECT Human Clinical

"assessment of pubertal development at each visit through adolescence"

A surveillance recommendation rather than a reported frequency, so the inference is one step removed: puberty is monitored at every visit because pubertal delay occurs in this disorder often enough to look for.

PMID:39571061 SUPPORT INDIRECT Human Clinical

"treatment of pubertal delay per endocrinologist"

Pubertal delay is a manifestation the disorder's own management guidance expects to have to treat.

Eye 2

Ocular involvement FREQUENT Abnormality of the eye HP:0000478

Show evidence (3 references)

PMID:35525099 SUPPORT Human Clinical

"five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances"

Names ocular disturbance as one of the five recurring domains, at the level of generality the HP binding reflects.

PMID:35525099 SUPPORT Human Clinical

"the relatively high frequency of impairment in at least five main neurological domains"

The authors' own frequency characterization of the domain set that includes ocular disturbance, which is what the FREQUENT band records.

PMID:35525099 SUPPORT Human Clinical

"Ocular disturbances included retinal abnormalities, keratoconus,"

Itemizes what the general binding covers in this cohort, including the keratoconus that is not separately curated.

Nystagmus OCCASIONAL HP:0000639

Show evidence (1 reference)

PMID:30166628 SUPPORT Human Clinical

"dysarthria (2/11 cases), and nystagmus (2/11 cases). Other abnormalities included hypotonia (5/11 cases)"

The published denominator behind the OCCASIONAL band: 2/11 is 18%.

Musculoskeletal 2

Spasticity FREQUENT HP:0001257

Show evidence (3 references)

PMID:35525099 SUPPORT Human Clinical

"spasticity, that was present in 10/14 men and 4/14 women"

The spasticity denominator behind the FREQUENT band: 10 of 14 men plus 4 of 14 women is 14 of the 28 reviewed patients, 50%. This is also the only feature in the series that differed significantly by sex. The body sentence stating "spasticity (14/28 patients)" is interrupted by an inline citation marker and cannot be quoted across.

PMID:35525099 SUPPORT Human Clinical

"five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances"

Names spasticity as one of the five recurring domains.

PMID:39224955 SUPPORT Human Clinical

"we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia"

The spastic-ataxic combination in the autopsy-confirmed case.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:30057031 SUPPORT Human Clinical

"severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination"

Names hypotonia among the features of the nonsense-variant carriers.

Nervous System 15

Developmental regression OBLIGATE HP:0002376

Course: PROGRESSIVE

Show evidence (3 references)

PMID:35525099 SUPPORT Human Clinical

"All patients shared developmental delay/regression."

An explicit "all patients" denominator across the 28-patient systematic review, which is what licenses OBLIGATE here.

PMID:35525099 SUPPORT Human Clinical

"Developmental delay and/or motor/speech regression of variable severity were present in all 28 patients (100%)."

The numeric form of the same denominator - 28/28, stated as 100% - so the OBLIGATE band rests on a counted fraction rather than the phrase "all patients".

PMID:30057031 SUPPORT Human Clinical

"Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination."

The original description of the regressive phenotype in nonsense-allele carriers.

Loss of speech HP:0002371

Show evidence (2 references)

PMID:35525099 SUPPORT Human Clinical

"Developmental delay and/or motor/speech regression of variable severity were present in all 28 patients (100%)."

Speech regression counted across the 28-patient series. This replaces an earlier citation that quoted the syndrome's acronym expansion, which named the feature without observing it in anyone.

PMID:37114479 SUPPORT Human Clinical

"From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome."

Documents speech impairment as progressive rather than a fixed deficit.

Seizure FREQUENT HP:0001250

Show evidence (2 references)

PMID:35525099 SUPPORT Human Clinical

"Demographic and clinical features in patients who did (n. 21) or did not (n.7) had epilepsy."

The 21-of-28 split behind the FREQUENT band, from the table caption that stratifies the reviewed cohort by epilepsy status. The sentence in the body that states "epilepsy (21/28 patients)" directly is interrupted by an inline numeric citation marker, which the snippet validator strips from a quote before matching, so it cannot be quoted across; this caption carries the same two numbers uninterrupted.

PMID:39571061 SUPPORT Human Clinical

"seizures (generalized tonic-clonic, myoclonic, absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures)"

Enumerates the seizure semiologies reported in the disorder.

Myoclonic seizure HP:0032794

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37114479 SUPPORT Human Clinical

"Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel causative gene for PME."

Establishes progressive myoclonus epilepsy as part of the IRF2BPL phenotypic spectrum.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"IRF2BPL-related disorder is characterized by mild-to-profound developmental delay (with regression in many individuals), intellectual disability"

Gives the severity range and states that regression supervenes in many patients.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"IRF2BPL-related disorder is characterized by mild-to-profound developmental delay (with regression in many individuals), intellectual disability"

Names intellectual disability among the core clinical characteristics.

Progressive cerebellar ataxia FREQUENT HP:0002073

Course: PROGRESSIVE

Show evidence (2 references)

PMID:35525099 SUPPORT Human Clinical

"five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances"

Names ataxia as one of the five recurring domains. The review counts it in 10 of 28 patients (36%, the basis for FREQUENT), but the sentence carrying that fraction is interrupted by an inline citation marker and cannot be quoted verbatim.

PMID:30057031 SUPPORT Human Clinical

"severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination"

States the ataxia is progressive, which is the basis for the PROGRESSIVE clinical course and the specific HP term.

Dystonia FREQUENT HP:0001332

Show evidence (2 references)

PMID:35525099 SUPPORT Human Clinical

"segmental/multifocal dystonia in 3/12 cases, whereas no information about dystonia distribution was available in 4/12 patients"

The dystonia denominator behind the FREQUENT band. The distribution sub-counts are all out of 12, which is the number of the 28 reviewed patients who had dystonia - 43%. The body sentence stating "dystonia (12/28 patients)" outright is interrupted by an inline citation marker and so cannot be quoted verbatim.

PMID:35525099 SUPPORT Human Clinical

"Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances."

Names dystonia as one of the five recurring domains across 28 reviewed patients.

Tremor HP:0001337

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"movement disorder (ataxia, dystonia, tremor, and parkinsonism)"

Enumerates tremor within the movement-disorder component of the phenotype.

Parkinsonism HP:0001300

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"movement disorder (ataxia, dystonia, tremor, and parkinsonism)"

Enumerates parkinsonism within the movement-disorder component.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"cerebellar atrophy (particularly of the vermis), brain stem atrophy, and corpus callosum abnormalities including thinning/atrophy or thickening"

The MRI finding, with the vermian predominance.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"Brain MRI can show focal or diffuse cortical and/or subcortical atrophy"

Cortical and subcortical atrophy on imaging.

Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis)"

Names autistic features among the neurobehavioral manifestations.

Psychosis HP:0000709

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis)"

Names psychosis among the psychiatric manifestations.

Dysarthria OCCASIONAL HP:0001260

Show evidence (1 reference)

PMID:30166628 SUPPORT Human Clinical

"dysarthria (2/11 cases), and nystagmus (2/11 cases). Other abnormalities included hypotonia (5/11 cases)"

The published denominator behind the OCCASIONAL band: 2/11 is 18%.

Other 1

Mild dysmorphic features OCCASIONAL

Show evidence (1 reference)

PMID:35525099 SUPPORT Human Clinical

"included mild dysmorphic features (facial weakness, wider inter-nipple distance, joint laxity, etc.) in 5/28 patients (17.9%)"

Both the finding and its denominator, and the enumeration that explains why no single HP term is bound.

🧬

Genetic Associations

1

IRF2BPL

Gene: IRF2BPL hgnc:14282 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Autosomal dominant inheritance

Show evidence (5 references)

PMID:30166628 SUPPORT Human Clinical

"We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL)."

Establishes the gene-disease relationship, the variant class, and that the variants are de novo and heterozygous.

PMID:30166628 SUPPORT Human Clinical

"IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are..."

Identifies the gene product as a transcriptional regulator and names the domain the disease variants delete, which is what links variant class to the transcriptional lesion modelled below.

PMID:30057031 SUPPORT Human Clinical

"Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles."

Supports an allelic series in which missense variants are milder than truncating ones, consistent with the truncated product rather than simple loss of the gene driving severity.

+ 2 more references

💊

Medical Actions

8

Antiseizure Medication

Action: anticonvulsant therapy Ontology label: Anticonvulsant Therapy NCIT:C64172

Platform: Small molecule

Standard management of the epilepsy by an experienced neurologist. No IRF2BPL-specific antiseizure regimen is established; the seizure types are varied and treatment is chosen accordingly.

Mechanism Target:

Seizure — Symptomatic seizure suppression. It does not act on the underlying IRF2BPL lesion or alter the regression.

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"standard treatment of epilepsy and movement disorder by an experienced neurologist"

The management recommendation, and its framing as standard rather than disease-specific.

Developmental and Educational Support

Action: developmental and educational support Ontology label: Educational Intervention NCIT:C17874

Platform: Behavioral / lifestyle

Developmental and educational support, reassessed at every visit. In a regressive disorder this is directed at maintaining and re-acquiring function as much as at acquiring it. Bound to Educational Intervention rather than a speech- or therapy-specific term deliberately: the source recommends "developmental and educational support" and names physical and occupational therapists under spasticity management, but does not mention speech therapy anywhere. Binding a speech-therapy term here would assert a recommendation the cited source does not make.

Mechanism Target:

Global developmental delay — Educational and developmental support for the delay and its regression. No cited source claims it reverses the regression.

Show evidence (2 references)

PMID:39571061 SUPPORT Human Clinical

"Treatment of manifestations: Developmental and educational support; standard treatment of epilepsy and movement disorder by an experienced neurologist"

The management recommendation, with developmental and educational support listed first among the interventions.

PMID:39571061 SUPPORT Human Clinical

"At each visit, assess developmental progress, educational needs, cognitive function, seizures, movement disorder, spasticity, contractures, behavioral issues, growth, nutritional status, gastrointestinal dysmotility, and family needs"

Establishes that developmental and educational needs are reassessed at every visit, which is what makes this ongoing support rather than a one-off referral.

Spasticity Management and Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Multidisciplinary management of spasticity and contractures across orthopedics, neurology, physical medicine, physiotherapy and occupational therapy.

Mechanism Target:

Spasticity — Symptomatic management of tone and prevention of secondary contractures.

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"standard treatment of spasticity per orthopedist, neurologist, physical medicine and rehabilitation specialist, physical therapist, and occupational therapist"

Names the disciplines involved in spasticity management.

Feeding and Nutritional Support

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Feeding support for poor weight gain and standard treatment for gastric dysmotility.

Mechanism Target:

Feeding difficulties — Symptomatic support for the feeding and gastrointestinal component.

Gastrointestinal dysmotility — Standard treatment of gastric dysmotility. GeneReviews names no IRF2BPL-specific approach, and also asks for nutritional status and dysmotility to be reassessed at every visit.

Dysphagia — Swallowing difficulty is part of what feeding support addresses in a regressive disorder. The cited guidance covers feeding and weight gain rather than dysphagia by name, so this link is the general feeding recommendation applied to the specific phenotype.

Show evidence (2 references)

PMID:39571061 SUPPORT Human Clinical

"feeding support for poor weight gain"

The management recommendation for feeding difficulty.

PMID:39571061 SUPPORT Human Clinical

"standard treatment for gastric dysmotility"

The management recommendation for the gastrointestinal component.

Ophthalmologic Management

Action: ophthalmologic care Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Treatment of vision deficits by the treating ophthalmologist, with more complex findings referred to an ophthalmic subspecialist, plus a dilated eye exam on the ophthalmologist's schedule. Ocular disturbance is one of the five recurring domains in this disorder, so this is a routine rather than exceptional referral.

Mechanism Target:

Ocular involvement — Symptomatic treatment of the ocular component. Nothing in the cited guidance claims it alters the neurodegeneration.

Nystagmus — Nystagmus falls within the ophthalmologic findings this referral covers, though the cited guidance addresses vision deficits generally rather than nystagmus by name.

Show evidence (2 references)

PMID:39571061 SUPPORT Human Clinical

"treatment of vision deficits per ophthalmologist with treatment of more complex findings per ophthalmic subspecialist"

The ophthalmologic management recommendation and its escalation path.

PMID:39571061 SUPPORT Human Clinical

"dilated eye exam per treating ophthalmologist"

The surveillance half of the same recommendation.

Endocrine Management of Pubertal Delay

Action: endocrine management of delayed puberty Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Assessment of pubertal development at every visit through adolescence, with endocrine treatment when puberty is delayed. Worth curating separately from general supportive care because IRF2BPL is EAP1, a hypothalamic regulator of pubertal onset, so the endocrine surveillance is mechanistically motivated rather than generic.

Mechanism Target:

Delayed puberty — Endocrine treatment of the pubertal delay itself. The cited guidance gives no specific regimen, and no cited source connects this to the neurological course.

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"treatment of pubertal delay per endocrinologist"

The management recommendation for pubertal delay.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Autosomal dominant counseling. Most cases are de novo, but about 9% have an affected parent, and each child of an affected individual has a 50% risk.

Show evidence (1 reference)

PMID:39571061 SUPPORT Human Clinical

"Each child of an individual with IRF2BPL-related disorder has a 50% chance of inheriting the IRF2BPL pathogenic variant."

The recurrence risk that the counseling conveys.

📈

Progression

2

Initial acquisition of milestones

Early psychomotor development is mostly normal, or delayed but progressing, before anything is lost. This phase is what makes the disorder regressive rather than a static encephalopathy, and it is why the pathograph terminates in "Loss of Previously Acquired Developmental Milestones" rather than in a failure to acquire them.

Show evidence (1 reference)

PMID:30166628 SUPPORT Human Clinical

"mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies"

States the acquire-then-lose sequence, with the normal phase first.

Regression

Age: First year of life to the sixth decade; most reported onsets before age 10

Onset of regression is spread across the whole of life rather than concentrated in infancy. In the 28-patient review, onset was at one year or less in 6 patients, 1-3 years in 5, 4-5 years in 9, 6-10 years in 3, and 10-23 years in 5; GeneReviews puts the full span from the first year to the sixth decade. Severity does not track onset age - the review found no correlation between the two - which is the observation the `irf2bpl_onset_age_range` discussion is about.

Show evidence (2 references)

PMID:35525099 SUPPORT Human Clinical

"the available information pointed to a disease onset of one year of age or less in 6 cases, between 1 and 3 years of age in 5 cases, between 4 and 5 years of age in 9 cases, between 6 and 10 years of age in 3 cases, and more 10 to 23 years of age (median, 11) in 5 cases."

The full onset distribution across the reviewed cohort.

PMID:39571061 SUPPORT Human Clinical

"Onset is highly variable and can be in the first year of life through the sixth decade. In some individuals the course of the disorder is progressive or debilitating."

The outer bounds of the onset range, and the qualification that the progressive course is not universal.

📊

Prevalence

2

Cases reported in the literature to 2022

Cases In Literature Not yet documented

A published case count, not a population rate. No study has estimated how common NEDAMSS is, so the class is NOT_YET_DOCUMENTED rather than a band back-derived from the count - the reported total measures how many people have been described, which is bounded by ascertainment through exome sequencing, not by how many people have the disorder.

Show evidence (1 reference)

PMID:35525099 SUPPORT Human Clinical

"We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers"

The literature case count assembled by the systematic review.

Cases reported in the literature to 2023

Cases In Literature Not yet documented

A later count from a different group, on a slightly wider inclusion, and the reason the 2022 figure is not treated as the total.

Show evidence (1 reference)

PMID:37114479 SUPPORT Human Clinical

"review the features of the 31 subjects with IRF2BPL-related disorders previously reported"

The count of previously reported subjects at the time of the 2023 series.

🧫

Experimental Models

1

Patient fibroblast-derived astrocytes and neurons PRIMARY_CELL_CULTURE

Skin fibroblasts from NEDAMSS patients reprogrammed directly to astrocytes and neurons. The system that established the sequestration mechanism and the glial contribution, in human cells carrying the actual patient alleles.

Pathograph links

Astrocyte Mitochondrial Respiratory Dysfunction recapitulates fidelity: high Patient astrocytes show structurally aberrant mitochondria and respiratory dysfunction, and CuATSM restores mitochondrial function - the rescue acts on this step specifically.

Limitations: Reprogrammed rather than developmentally derived astrocytes, cultured without microglia, vasculature or myelin, so the metabolic measurements are made outside the tissue context in which the human lesion plays out.

Readouts

Mitochondrial morphology and respiratory function

Direction: DECREASED

Interpretation: The metabolic defect measured in the astrocytes themselves.

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"exhibit aberrant mitochondria and respiratory dysfunction"

Reports the mitochondrial measurement and its direction.

Mitochondrial function after CuATSM

Direction: RESTORED

Interpretation: Pharmacological reversal of the astrocyte metabolic defect. This is the readout that places the mitochondrial step on the causal path rather than treating it as a marker of sick cells, which is why it is attached here rather than to the downstream support failure.

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"Treatment with the small molecule copper ATSM (CuATSM) rescues neuronal survival and restores mitochondrial function."

States the rescue and what was restored. The same sentence also reports the neuronal-survival arm, which is recorded on the trophic-support link below.

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease"

Establishes that the model carries patient alleles in human cells, which is why it is treated as high fidelity for this node.

Loss of Astrocytic Trophic Support for Neurons recapitulates fidelity: high The coculture in which patient astrocytes were shown to fail to keep neurons alive, and in which CuATSM rescued neuronal survival.

Limitations: A two-cell-type coculture without microglia, vasculature or myelin, and reprogrammed rather than developmentally derived - so it cannot report on circuit-level or age-dependent aspects of the human course.

Readouts

Neuronal survival in astrocyte coculture

Direction: DECREASED

Interpretation: The functional consequence of the astrocyte defect, measured on the neurons rather than on the astrocytes.

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"patient astrocytes fail to support neuronal survival in coculture"

Reports the survival readout and its direction.

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"Moreover, patient astrocytes fail to support neuronal survival in coculture and exhibit aberrant mitochondria and respiratory dysfunction."

Supports treating this coculture as informative for the glial support step: it is the system in which the failure was observed.

Cytoplasmic Sequestration of Wild-Type IRF2BPL recapitulates fidelity: high The system in which the mislocalisation and aggregation of wild-type IRF2BPL by truncated patient variants was demonstrated.

Limitations: Localisation and aggregation were assayed in reprogrammed cells; the corresponding human brain finding (polyQ inclusions) comes from a single autopsy in a different patient.

Show evidence (1 reference)

PMID:36476864 SUPPORT In Vitro

"truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation"

The observation itself, in patient-derived human cells.

🐁

Animal Models

3

Drosophila pits neuronal RNAi knockdown

Partial neuronal depletion of the fly ortholog pits. Complete loss is early-lethal, so the partial knockdown is what exposes the maintenance requirement.

Species

Drosophila melanogaster

Genotype

RNAi knockdown of pits (Drosophila IRF2BPL ortholog) in neurons

Publication

PMID:30057031

Pathograph links

Progressive Neuronal and Axonal Loss recapitulates fidelity: moderate Neuronal knockdown produces frank neurodegeneration, demonstrating that the gene is required for neuronal maintenance and not only for neuronal development.

Limitations: An invertebrate nervous system, and a knockdown rather than the human allele - so it models loss of gene function, not the dominant-negative sequestration by a truncated product that the human variants cause.

Show evidence (1 reference)

PMID:30057031 SUPPORT Model Organism

"partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance"

Supports treating the fly knockdown as informative for the human neuronal-maintenance defect.

Excess Wnt Signaling recapitulates fidelity: moderate Depleting pits raises wingless in the brain, and the resulting axonal loss is suppressed by inhibiting Wg - establishing the Wnt step as causal rather than correlative.

Limitations: Wingless is the fly orthologue of a Wnt family that is considerably expanded in vertebrates, so which human WNT ligand matters is not settled by this model.

Readouts

Brain wingless (wg) level

Direction: INCREASED

Interpretation: Elevated Wnt ligand is the measured consequence of losing the IRF2BPL ortholog.

Show evidence (1 reference)

PMID:35044823 SUPPORT Model Organism

"neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss"

Reports the direction of the wingless measurement in the knockdown brain.

Show evidence (1 reference)

PMID:35044823 SUPPORT Model Organism

"whereas inhibition of Wg signaling is neuroprotective"

The rescue arm, which is what makes the Wnt elevation causal for the degeneration rather than a bystander change.

Drosophila heterozygous Pits truncation with CuATSM rescue

A heterozygous truncation matching the human allele class, with progressive motor decline that responds to the copper compound CuATSM.

Species

Drosophila melanogaster

Genotype

heterozygous truncation of Pits (Drosophila IRF2BPL ortholog)

Publication

PMID:36476864

Pathograph links

Progressive Neuronal and Axonal Loss rescues fidelity: moderate Progressive motor defects in heterozygous-truncation flies are ameliorated by CuATSM, the same compound that restores mitochondrial function and neuronal survival in patient-derived cells.

Limitations: A behavioural motor readout in an invertebrate, and a pharmacological rescue only. No human trial of CuATSM in this disorder exists, which is why it is recorded here rather than as a treatment.

Show evidence (1 reference)

PMID:36476864 SUPPORT Model Organism

"flies harboring heterozygous truncations of the IRF2BPL ortholog (Pits) display progressive motor defects that are ameliorated by CuATSM treatment"

Both the progressive phenotype in the matching allele class and the pharmacological rescue.

Zebrafish irf2bpl loss of function

A vertebrate test of the Wnt mechanism, showing the same directional change in wnt1 as the fly model.

Species

Danio rerio

Genotype

loss of irf2bpl

Publication

PMID:35044823

Pathograph links

Excess Wnt Signaling recapitulates fidelity: moderate Loss of irf2bpl causes neurological defects with increased wnt1 transcription and downstream signalling, reproducing the fly result in a vertebrate.

Limitations: Loss of function rather than the human truncating allele, so like the fly knockdown it does not model the dominant-negative sequestration step.

Readouts

wnt1 transcription

Direction: INCREASED

Interpretation: Vertebrate confirmation of the direction of the Wnt change.

Show evidence (1 reference)

PMID:35044823 SUPPORT Model Organism

"Loss of irf2bpl in zebrafish also causes neurological defects with an associated increase in wnt1 transcription and downstream signaling."

Reports the wnt1 measurement and its direction.

Show evidence (1 reference)

PMID:35044823 SUPPORT Model Organism

"Loss of irf2bpl in zebrafish also causes neurological defects"

Supports treating the zebrafish as informative for the human neurological phenotype.

{ }

Source YAML

click to show

name: IRF2BPL-Related Neurodevelopmental Disorder with Regression
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
description: >-
  NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss
  of speech, and seizures) is an autosomal dominant, almost always de novo
  disorder caused by heterozygous truncating variants in IRF2BPL, a single-exon
  gene encoding a nuclear transcriptional regulator also known as EAP1 (enhanced
  at puberty protein 1).

  The feature that defines the entry, and that the pathophysiology below is built
  around, is that the disorder is *regressive*. Affected children reach their
  early psychomotor milestones - often normally - and then lose them, together
  with speech, alongside emerging epilepsy, dystonia, ataxia and spasticity. That
  makes NEDAMSS a genuine childhood neurodegenerative disease rather than the
  static encephalopathy its MONDO placement under "Mendelian neurodevelopmental
  disorder" would suggest, and postmortem neuropathology bears this out: the one
  detailed autopsy reported shows polyglutamine inclusions and a picture
  consistent with DRPLA.

  The molecular route to that progression is unusual and is not simple
  haploinsufficiency. IRF2BPL is intronless, so a transcript carrying a premature
  stop codon escapes nonsense-mediated decay and is expressed at roughly the same
  level as the wild-type allele - meaning a truncated protein is actually made.
  That truncated product mislocalises to the cytoplasm and drags full-length
  IRF2BPL out of the nucleus with it, forming aggregates. The result is a
  dominant-negative loss of nuclear IRF2BPL transcriptional repression, which
  releases Wnt signalling; excess Wnt is by itself sufficient to cause
  age-dependent axonal loss in flies, and inhibiting Wnt is neuroprotective.
  Patient-derived astrocytes carry the same lesion, show abnormal mitochondria
  and respiratory dysfunction, and fail to support neuronal survival in coculture
  - so neuronal loss is driven both cell-autonomously and through failing glial
  support.
parents:
  - Neurodevelopmental Disorder
synonyms:
  - NEDAMSS
  - IRF2BPL-related disorder
  - IRF2BPL mutation syndrome
  - neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures
disease_term:
  preferred_term: neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures
  term:
    id: MONDO:0060759
    label: neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures
mappings:
  mondo_mappings:
    - term:
        id: MONDO:0060759
        label: neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures
      mapping_predicate: skos:exactMatch
      mapping_source: OMIM:618088
      mapping_justification: >-
        NEDAMSS is catalogued in OMIM as 618088, the number quoted in the
        neuropathology report that named the syndrome. MONDO:0060759 is the
        exact anchor for that OMIM concept and is the term this entry curates.
references:
  - reference: PMID:39571061
    title: IRF2BPL-Related Disorder.
    tags:
      - GeneReviews
  - reference: PMID:30057031
    title: IRF2BPL Is Associated with Neurological Phenotypes.
  - reference: PMID:30166628
    title: De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.
  - reference: PMID:35044823
    title: Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling.
  - reference: PMID:35525099
    title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
  - reference: PMID:36476864
    title: Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy.
  - reference: PMID:37114479
    title: IRF2BPL as a novel causative gene for progressive myoclonus epilepsy.
  - reference: PMID:39224955
    title: "IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA."
notes: >-
  Lump/split. Curated as a standalone DISEASE. Its two MONDO parents
  (MONDO:0002254 syndromic disease, MONDO:0100500 Mendelian neurodevelopmental
  disorder) are broad groupings with no corresponding curated dismech entry, so
  there is no parent disease for this to be a has_subtypes entry on. It has one
  causal gene, one reasonably conserved pathograph, and a mechanism
  (NMD-escaping truncation acting dominant-negatively through cytoplasmic
  sequestration of the wild-type protein) that is specific to it rather than
  shared with the encephalopathies it is grouped with.

  No deep-research provider report backs this entry. `just research-disorder
  falcon` returned HTTP 402 (provider account out of credits) and two attempts at
  the documented `claude_code` fallback - one plain, one with `--fallback` -
  failed identically with `agentapi not found in PATH` and `exited with code 1`.
  The entry was therefore curated from literature retrieved directly from PubMed,
  with every reference fetched through `just fetch-reference`. No file was left
  under `research/`, because no report was produced.

  Phenotype frequencies come from the two cohort papers whose full text is
  cached, and every band below is a denominator someone published rather than a
  reading of a qualitative phrase. The 28-patient systematic review gives
  developmental delay/regression in all 28 (OBLIGATE), then epilepsy 21/28,
  spasticity 14/28, dystonia 12/28, ocular disturbances 12/28 and ataxia 10/28 -
  36% to 75%, so FREQUENT for all five - plus dysmorphic features in 5/28
  (17.9%, OCCASIONAL). The earlier 11-patient cohort adds dysphagia 3/11 and
  dysarthria and nystagmus at 2/11 each, all OCCASIONAL.

  Where a feature is named only in a GeneReviews list or a narrative sentence -
  tremor, parkinsonism, psychosis, autistic behaviour, the psychiatric and
  gastrointestinal manifestations, delayed puberty - no `frequency` is recorded
  at all. Those sources do give the feature, but not a denominator, and a band
  read off "many individuals" or "are also reported" would be invented rather
  than cited. The two denominators are also not interchangeable: the 11-patient
  series is a developmental-epileptic-encephalopathy ascertainment and the
  28-patient review is a literature aggregate, so a feature counted in one is
  not silently rescaled to the other.

  Two of those denominators are stated in the review's descriptive prose rather
  than quoted below, and the reason is mechanical, not evidential. The sentence
  that lists them runs the fractions together with inline numeric citation
  markers, which the snippet validator strips out of a quote before matching, so
  no verbatim span can cross one; and the ocular fraction sits inside a word the
  PDF extraction wrapped across a hyphen. Where a second, uninterrupted sentence
  carries the same numbers - the epilepsy table caption, the sex breakdown of
  spasticity, the dystonia distribution sub-counts - that sentence is cited
  instead. Where none does, as for ocular disturbance, the band rests on the
  authors' own "relatively high frequency" characterization of the domain set,
  and the fraction is recorded in the phenotype description with this caveat
  attached rather than being quoted in a form that no longer reads as the
  source.

  Keratoconus is not curated as a phenotype. It is reported in the IRF2BPL
  literature and there is a specific paper on the question, but PMID:32291157
  returned no retrievable content through the reference fetcher, so no exact
  snippet can be quoted for it. The systematic review's more general "ocular
  disturbances" is curated instead, bound to a correspondingly general HP term.

  CuATSM is not curated as a treatment. It rescues neuronal survival and
  mitochondrial function in patient-derived cells and ameliorates motor defects
  in flies, but there is no human trial in this disease. It is recorded where the
  evidence actually sits - as a RESCUES link on the model systems that
  demonstrated it - rather than in `treatments`, which would imply a clinical
  option that does not exist.
inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Dominant, and overwhelmingly de novo - roughly 9% of reported individuals
      have an affected parent. The dominance is not by dose: the truncated
      product is expressed and interferes with the wild-type protein.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          IRF2BPL-related disorder is inherited in an autosomal dominant manner.
          The majority of individuals diagnosed with IRF2BPL-related disorder
          have the disorder as the result of a de novo pathogenic variant;
          approximately 9% of individuals reported to date have an affected
          parent.
        explanation: >-
          States both the mode of inheritance and the de novo predominance, with
          the parental-transmission fraction.
genetic:
  - name: IRF2BPL
    relationship_type: CAUSATIVE
    variant_origin: DE_NOVO
    gene_term:
      preferred_term: IRF2BPL
      term:
        id: hgnc:14282
        label: IRF2BPL
    notes: >-
      Nonsense and frameshift variants predominate and remove the C-terminal
      RING-finger domain required for IRF2BPL's transcriptional repressive and
      transactivating properties. Missense variants are reported and give a
      milder phenotype than nonsense alleles.

      The `genetic_context.functional_impact_category: DOMINANT_NEGATIVE` on the
      initiating pathophysiology node, rather than LOSS_OF_FUNCTION, is a
      deliberate call, and it is the point of the entry.
      The gene is intronless, the premature-stop transcript escapes
      nonsense-mediated decay and is expressed roughly 1:1 with the wild-type
      allele, and the resulting truncated protein sequesters full-length IRF2BPL
      into cytoplasmic aggregates. That is interference with the remaining
      wild-type product, which is what DOMINANT_NEGATIVE means here, not a
      halved dose.

      Variant position may matter, though it is not established. The three
      adults who presented as progressive myoclonus epilepsy all carried
      protein-truncating variants clustered in a proximal, highly conserved
      region around the coiled-coil domain, which hints at a positional effect
      on presentation and onset age. Set against that, the 28-patient
      systematic review found no significant correlation between the number of
      affected clinical domains and variant type, so the clustering is a lead
      rather than a genotype-phenotype rule. See the `irf2bpl_onset_age_range`
      discussion.
    inheritance:
      - name: Autosomal dominant inheritance
        inheritance_term:
          preferred_term: Autosomal dominant inheritance
          term:
            id: HP:0000006
            label: Autosomal dominant inheritance
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We identified 11 unrelated individuals with DEE and de novo
          heterozygous truncating variants in the interferon regulatory factor
          2-binding protein-like gene (IRF2BPL).
        explanation: >-
          Establishes the gene-disease relationship, the variant class, and that
          the variants are de novo and heterozygous.
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a
          transcriptional regulator containing a C-terminal RING-finger domain
          common to E3 ubiquitin ligases. This domain is required for its
          repressive and transactivating transcriptional properties. The
          variants identified are expected to encode a protein lacking the
          C-terminal RING-finger domain.
        explanation: >-
          Identifies the gene product as a transcriptional regulator and names
          the domain the disease variants delete, which is what links variant
          class to the transcriptional lesion modelled below.
      - reference: PMID:30057031
        reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Two additional individuals, both with missense variants, display
          global developmental delay and seizures and a relatively milder
          phenotype than those with nonsense alleles.
        explanation: >-
          Supports an allelic series in which missense variants are milder than
          truncating ones, consistent with the truncated product rather than
          simple loss of the gene driving severity.
      - reference: PMID:30057031
        reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          The IRF2BPL bioinformatics signature based on population genomics is
          consistent with a gene that is intolerant to variation.
        explanation: >-
          Population-genomic constraint supporting pathogenicity of the observed
          variants. Graded COMPUTATIONAL because the claim is a bioinformatic
          signature, not a patient observation.
      - reference: PMID:37114479
        reference_title: "IRF2BPL as a novel causative gene for progressive myoclonus epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          all three patients harbored protein-truncating variants clustered in
          a proximal, highly conserved gene region around the "coiled-coil"
          domain
        explanation: >-
          The positional clustering behind the note above. Three patients with a
          shared presentation is a lead about variant position, not an
          established genotype-phenotype correlation.
pathophysiology:
  - name: De Novo Heterozygous IRF2BPL Truncating Variant
    biological_scale: MOLECULAR
    description: >-
      A de novo nonsense or frameshift variant in the single-exon IRF2BPL gene,
      predicted to remove the C-terminal RING-finger domain that carries the
      protein's transcriptional repressive and transactivating activity.
    genes:
      - preferred_term: IRF2BPL
        term:
          id: hgnc:14282
          label: IRF2BPL
    genetic_context:
      variant_origin: DE_NOVO
      zygosity: HETEROZYGOUS
      functional_impact_category: DOMINANT_NEGATIVE
      description: >-
        Heterozygous de novo nonsense or frameshift alleles removing the
        C-terminal RING-finger domain. Classified DOMINANT_NEGATIVE rather than
        LOSS_OF_FUNCTION because the truncated product is expressed - the
        intronless transcript escapes nonsense-mediated decay - and sequesters
        the wild-type protein, rather than the allele simply being absent.
        Missense alleles are also reported and are milder.
    downstream:
      - target: Nonsense-Mediated Decay Escape and Truncated Protein Expression
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The variants identified are expected to encode a protein lacking the
          C-terminal RING-finger domain.
        explanation: >-
          States the predicted protein-level consequence of the disease variants
          that initiates this chain.
  - name: Nonsense-Mediated Decay Escape and Truncated Protein Expression
    biological_scale: MOLECULAR
    description: >-
      IRF2BPL is intronless, so a transcript carrying a premature termination
      codon is not cleared by nonsense-mediated decay. In patient fibroblasts the
      mutant allele is expressed at a ratio of at least 1:1 with the wild-type
      allele, so a truncated protein is translated rather than the allele simply
      being lost.
    biological_processes:
      - preferred_term: nonsense-mediated decay of the IRF2BPL premature-stop transcript
        term:
          id: GO:0000184
          label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
        modifier: DECREASED
    downstream:
      - target: Cytoplasmic Sequestration of Wild-Type IRF2BPL
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          in favor of nonsense-mediated decay (NMD) escape because the mutated
          allele is expressed with a ratio of at least 1:1 with the wild-type
          (WT) allele, suggesting that the shorter protein might be translated
        explanation: >-
          Direct measurement in patient-derived fibroblasts showing the mutant
          transcript is not degraded, which is the observation that makes a
          truncated product available to act dominant-negatively.
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          It belongs to a group of human intronless genes that are known to
          possibly escape nonsense-mediated decay (NMD), despite presence of a
          premature stop codon.
        explanation: >-
          Gives the structural reason for NMD escape - the absence of introns -
          rather than treating it as an unexplained observation. Graded
          COMPUTATIONAL because this is a statement about gene architecture
          drawn from genome annotation, not an observation made in a patient.
  - name: Cytoplasmic Sequestration of Wild-Type IRF2BPL
    biological_scale: MOLECULAR
    description: >-
      Full-length IRF2BPL is normally nuclear. The truncated patient protein
      instead accumulates in the cytoplasm and pulls wild-type IRF2BPL out of the
      nucleus with it, forming aggregates. This is the dominant-negative step,
      and it is why the disorder does not behave as haploinsufficiency.
    biological_processes:
      - preferred_term: nuclear import of full-length IRF2BPL
        term:
          id: GO:0034504
          label: protein localization to nucleus
        modifier: DECREASED
    downstream:
      - target: Loss of IRF2BPL Transcriptional Repression
      - target: Intracellular Protein Aggregate Formation
    evidence:
      - reference: PMID:36476864
        reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          While full-length IRF2BPL primarily localizes to the nucleus,
          truncated patient variants sequester the wild-type protein to the
          cytoplasm and cause aggregation.
        explanation: >-
          States the sequestration mechanism directly, in patient-derived
          reprogrammed cells.
      - reference: PMID:36476864
        reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          co-expression of full-length and truncated IRF2BPL in Drosophila
          results in cytoplasmic accumulation of full-length IRF2BPL
        explanation: >-
          In vivo confirmation that the truncated product is sufficient to
          mislocalise the wild-type protein.
  - name: Loss of IRF2BPL Transcriptional Repression
    biological_scale: MOLECULAR
    description: >-
      With full-length IRF2BPL depleted from the nucleus, its repressive
      transcriptional activity is lost. Overexpressing IRF2BPL or its Drosophila
      ortholog Pits represses Wnt transcription, so removing it releases that
      repression.
    biological_processes:
      - preferred_term: IRF2BPL-mediated transcriptional repression
        term:
          id: GO:0000122
          label: negative regulation of transcription by RNA polymerase II
        modifier: DECREASED
    downstream:
      - target: Excess Wnt Signaling
    evidence:
      - reference: PMID:35044823
        reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Overexpression of either IRF2BPL or Pits, the Drosophila ortholog,
          represses Wnt transcription in flies.
        explanation: >-
          Establishes that IRF2BPL's normal role at this node is repression of
          Wnt transcription, which is what its loss releases.
  - name: Excess Wnt Signaling
    biological_scale: CELLULAR
    description: >-
      Loss of IRF2BPL repression raises Wnt ligand levels and downstream
      signalling. This is not merely correlative: increasing neuronal wingless in
      flies is by itself sufficient to cause age-dependent axonal loss, and
      inhibiting Wnt is neuroprotective. WNT1 is likewise elevated in
      patient-derived astrocytes.
    biological_processes:
      - preferred_term: Wnt signaling pathway
        term:
          id: GO:0016055
          label: Wnt signaling pathway
        modifier: INCREASED
    downstream:
      - target: Progressive Neuronal and Axonal Loss
    evidence:
      - reference: PMID:35044823
        reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In contrast, neuronal depletion of Pits leads to increased wingless
          (wg) levels in the brain and is associated with axonal loss, whereas
          inhibition of Wg signaling is neuroprotective.
        explanation: >-
          Links loss of the ortholog to raised Wnt ligand and to axonal loss, and
          shows the loss is Wnt-dependent because blocking Wnt protects.
      - reference: PMID:35044823
        reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Moreover, increased neuronal expression of wg in flies is sufficient
          to cause age-dependent axonal loss, similar to reduction of Pits.
        explanation: >-
          Sufficiency, and the age dependence that makes this a progressive
          rather than a developmental lesion.
      - reference: PMID:35044823
        reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          WNT1 is also increased in patient-derived astrocytes, and
          pharmacological inhibition of Wnt suppresses the neurological
          phenotypes.
        explanation: >-
          Shows the Wnt elevation is present in human patient-derived cells and
          not only in the invertebrate model.
  - name: Astrocyte Mitochondrial Respiratory Dysfunction
    biological_scale: CELLULAR
    description: >-
      Astrocytes reprogrammed from patient fibroblasts carry structurally
      aberrant mitochondria and measurable respiratory dysfunction. The same
      direction of change is visible in patient muscle, where biopsies show
      cytochrome-c-oxidase-negative and ragged-red-like fibres and electron
      transport chain assay in one patient found generalized deficiencies - so
      the mitochondrial arm is not an artefact of reprogrammed glia alone.
    cell_types:
      - preferred_term: patient-derived astrocyte
        term:
          id: CL:0000127
          label: astrocyte
    biological_processes:
      - preferred_term: astrocyte mitochondrial respiration
        term:
          id: GO:0045333
          label: cellular respiration
        modifier: DECREASED
    downstream:
      - target: Loss of Astrocytic Trophic Support for Neurons
    evidence:
      - reference: PMID:36476864
        reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          exhibit aberrant mitochondria and respiratory dysfunction
        explanation: >-
          The mitochondrial half of the astrocyte observation, quoted on its own
          because it is a separate claim from the coculture survival result.
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Muscle electron transport chain studies performed in patient 1 showed
          mild generalized deficiencies that could indicate primary or secondary
          mitochondrial defects.
        explanation: >-
          Patient tissue pointing the same way as the reprogrammed astrocytes.
          The authors' own hedge - primary or secondary - is why this node is
          not curated as a primary mitochondrial disease.
  - name: Loss of Astrocytic Trophic Support for Neurons
    biological_scale: CELLULAR
    description: >-
      Patient astrocytes fail to keep neurons alive in coculture. Neuronal loss
      in NEDAMSS is therefore not purely cell-autonomous - a failing glial
      compartment contributes, downstream of the astrocyte's own metabolic
      failure.
    cell_types:
      - preferred_term: patient-derived astrocyte
        term:
          id: CL:0000127
          label: astrocyte
    downstream:
      - target: Progressive Neuronal and Axonal Loss
    evidence:
      - reference: PMID:36476864
        reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          patient astrocytes fail to support neuronal survival in coculture
        explanation: >-
          The glial-support half of the astrocyte observation: the measurement
          is made on the neurons, and it is what makes this a distinct step from
          the astrocyte's mitochondrial defect.
  - name: Intracellular Protein Aggregate Formation
    biological_scale: CELLULAR
    description: >-
      Sequestration of wild-type IRF2BPL by the truncated product produces
      cytoplasmic aggregates in cells. At autopsy the corresponding human finding
      is polyglutamine inclusions, in a distribution consistent with DRPLA -
      despite these patients carrying no repeat expansion, since the variants sit
      distal to IRF2BPL's own polyQ tract.
    biological_processes:
      - preferred_term: inclusion body assembly
        term:
          id: GO:0070841
          label: inclusion body assembly
        modifier: INCREASED
    downstream:
      - target: Progressive Neuronal and Axonal Loss
    evidence:
      - reference: PMID:39224955
        reference_title: "IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Detailed postmortem gross and histological examination was conducted,
          and findings consistent with dentatorubral-pallidoluysian atrophy
          (DRPLA) and included polyglutamine (polyQ) inclusions.
        explanation: >-
          The only detailed human neuropathology for this disorder, and the
          direct observation of inclusions in patient brain.
      - reference: PMID:39224955
        reference_title: "IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Although the individuals with NEDAMSS do not carry an expansion, the
          polyQ repeat tract may play a role in the pathological inclusions that
          would represent a novel disease mechanism for polyQ repeats.
        explanation: >-
          Records the authors' own hedging - that the polyQ involvement is a
          proposed mechanism, not an established one - so this node is not read
          as a settled repeat-expansion disease.
      - reference: PMID:37114479
        reference_title: "IRF2BPL as a novel causative gene for progressive myoclonus epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The skin biopsy revealed massive intracellular glycogen inclusions in
          one proband, suggesting a similar pathogenic pathway to other storage
          disorders.
        explanation: >-
          A second, independent inclusion finding in patient tissue, from a
          different group and a different organ than the autopsy polyQ result.
          It is glycogen rather than protein, so it does not corroborate the
          polyQ observation directly; what it supports is that intracellular
          accumulation is a real feature of this disorder outside the brain.
  - name: Progressive Neuronal and Axonal Loss
    biological_scale: TISSUE
    description: >-
      The convergence point of the excess-Wnt, glial-failure and aggregation
      arms. Partial neuronal knockdown of the IRF2BPL ortholog in flies causes
      frank neurodegeneration, establishing a requirement for this gene in
      neuronal maintenance rather than only in neuronal development.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: neuron projection maintenance
        term:
          id: GO:1990535
          label: neuron projection maintenance
        modifier: DECREASED
    downstream:
      - target: Loss of Previously Acquired Developmental Milestones
      - target: Cerebral and Cerebellar Atrophy
    evidence:
      - reference: PMID:30057031
        reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Complete loss of pits is lethal early in development, whereas partial
          knockdown with RNA interference in neurons leads to neurodegeneration,
          revealing a requirement for this gene in proper neuronal function and
          maintenance.
        explanation: >-
          Separates the developmental requirement from the maintenance
          requirement, which is the distinction that makes this disorder
          degenerative rather than static.
      - reference: PMID:35044823
        reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          De novo truncations in Interferon Regulatory Factor 2 Binding Protein
          Like (IRF2BPL) lead to severe childhood-onset neurodegenerative
          disorders.
        explanation: >-
          States plainly that the human disorder is neurodegenerative.
  - name: Cerebral and Cerebellar Atrophy
    biological_scale: TISSUE
    description: >-
      Progressive loss of neurons and their projections is visible on brain MRI
      as cortical, subcortical, cerebellar (particularly vermian) and brain stem
      atrophy, together with corpus callosum abnormalities.
    downstream:
      - target: Progressive cerebellar ataxia
      - target: Cerebellar atrophy
      - target: Cerebral atrophy
      - target: Spasticity
      - target: Dysarthria
      - target: Nystagmus
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Brain MRI can show focal or diffuse cortical and/or subcortical
          atrophy, cerebellar atrophy (particularly of the vermis), brain stem
          atrophy, and corpus callosum abnormalities including thinning/atrophy
          or thickening.
        explanation: >-
          The imaging correlate of the tissue-level loss, from the disorder's
          GeneReviews summary.
  - name: Loss of Previously Acquired Developmental Milestones
    biological_scale: ORGANISM
    description: >-
      The clinical signature of the disorder and the reason it is curated as
      neurodegenerative. Initial psychomotor development is mostly normal and is
      then followed by severe global neurological regression: acquired skills,
      including speech, are lost. Onset is highly variable, from the first year of
      life to the sixth decade.
    downstream:
      - target: Developmental regression
      - target: Loss of speech
      - target: Intellectual disability
      - target: Seizure
      - target: Dysphagia
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          mostly normal initial psychomotor development followed by severe
          global neurological regression and epilepsy with nonspecific
          electroencephalogram (EEG) abnormalities and variable central nervous
          system (CNS) anomalies
        explanation: >-
          The explicit statement of the acquire-then-lose course, in the cohort
          that delineated the phenotype.
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          These data support the causative role of truncating IRF2BPL variants
          in pediatric neurodegeneration
        explanation: >-
          The authors' own framing of the disorder as neurodegeneration rather
          than static encephalopathy.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Onset is highly variable and can be in the first year of life through
          the sixth decade. In some individuals the course of the disorder is
          progressive or debilitating.
        explanation: >-
          Records the wide onset range and that the course is progressive in a
          subset, which qualifies the uniformity of the regression claim.
phenotypes:
  - name: Developmental regression
    category: Neurologic
    frequency: OBLIGATE
    description: >-
      Loss of previously acquired developmental skills. The one feature shared by
      every patient in the largest published series.
    phenotype_term:
      preferred_term: Developmental regression
      term:
        id: HP:0002376
        label: Developmental regression
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          All patients shared developmental delay/regression.
        explanation: >-
          An explicit "all patients" denominator across the 28-patient
          systematic review, which is what licenses OBLIGATE here.
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Developmental delay and/or motor/speech regression of variable
          severity were present in all 28 patients (100%).
        explanation: >-
          The numeric form of the same denominator - 28/28, stated as 100% - so
          the OBLIGATE band rests on a counted fraction rather than the phrase
          "all patients".
      - reference: PMID:30057031
        reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Five individuals who carry IRF2BPL nonsense variants resulting in a
          premature stop codon display severe neurodevelopmental regression,
          hypotonia, progressive ataxia, seizures, and a lack of coordination.
        explanation: >-
          The original description of the regressive phenotype in nonsense-allele
          carriers.
  - name: Loss of speech
    category: Neurologic
    description: >-
      Loss of previously acquired speech - one of the four features named in the
      disorder's own MONDO label.
    phenotype_term:
      preferred_term: Loss of speech
      term:
        id: HP:0002371
        label: Loss of speech
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Developmental delay and/or motor/speech regression of variable
          severity were present in all 28 patients (100%).
        explanation: >-
          Speech regression counted across the 28-patient series. This replaces
          an earlier citation that quoted the syndrome's acronym expansion,
          which named the feature without observing it in anyone.
      - reference: PMID:37114479
        reference_title: "IRF2BPL as a novel causative gene for progressive myoclonus epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          From late childhood/adolescence, they presented with severe myoclonus
          epilepsy, stimulus-sensitive myoclonus, and progressive cognitive,
          speech, and cerebellar impairment, consistent with a typical PME
          syndrome.
        explanation: >-
          Documents speech impairment as progressive rather than a fixed deficit.
  - name: Seizure
    category: Neurologic
    frequency: FREQUENT
    description: >-
      Epilepsy affected 21 of the 28 patients in the systematic review (75%) and
      is of many types - generalized tonic-clonic, myoclonic, absence, focal
      tonic-clonic, complex partial, infantile spasms and atonic.
    phenotype_term:
      preferred_term: Seizure
      term:
        id: HP:0001250
        label: Seizure
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Demographic and clinical features in patients who did (n. 21) or did
          not (n.7) had epilepsy.
        explanation: >-
          The 21-of-28 split behind the FREQUENT band, from the table caption
          that stratifies the reviewed cohort by epilepsy status. The sentence
          in the body that states "epilepsy (21/28 patients)" directly is
          interrupted by an inline numeric citation marker, which the snippet
          validator strips from a quote before matching, so it cannot be quoted
          across; this caption carries the same two numbers uninterrupted.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          seizures (generalized tonic-clonic, myoclonic, absence, focal
          tonic-clonic, complex partial, infantile spasms, and/or atonic
          seizures)
        explanation: >-
          Enumerates the seizure semiologies reported in the disorder.
  - name: Myoclonic seizure
    category: Neurologic
    description: >-
      A subset of patients meet criteria for a progressive myoclonus epilepsy
      syndrome, with stimulus-sensitive myoclonus from late childhood or
      adolescence.
    phenotype_term:
      preferred_term: Myoclonic seizure
      term:
        id: HP:0032794
        label: Myoclonic seizure
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:37114479
        reference_title: "IRF2BPL as a novel causative gene for progressive myoclonus epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Our data show that PME can be an additional phenotype within the
          spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel
          causative gene for PME.
        explanation: >-
          Establishes progressive myoclonus epilepsy as part of the IRF2BPL
          phenotypic spectrum.
  - name: Global developmental delay
    category: Neurologic
    description: >-
      Developmental delay ranges from mild to profound, and in many individuals
      is followed by regression.
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          IRF2BPL-related disorder is characterized by mild-to-profound
          developmental delay (with regression in many individuals),
          intellectual disability
        explanation: >-
          Gives the severity range and states that regression supervenes in many
          patients.
  - name: Intellectual disability
    category: Neurologic
    phenotype_term:
      preferred_term: Intellectual disability
      term:
        id: HP:0001249
        label: Intellectual disability
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          IRF2BPL-related disorder is characterized by mild-to-profound
          developmental delay (with regression in many individuals),
          intellectual disability
        explanation: >-
          Names intellectual disability among the core clinical characteristics.
  - name: Progressive cerebellar ataxia
    category: Neurologic
    frequency: FREQUENT
    description: >-
      Ataxia is one of the five main neurological domains involved, present in
      10 of 28 reviewed patients (36%), and is described as progressive from the
      original cohort onward.
    phenotype_term:
      preferred_term: Progressive cerebellar ataxia
      term:
        id: HP:0002073
        label: Progressive cerebellar ataxia
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          five main neurological domains, i.e. epilepsy, dystonia, ataxia,
          spasticity, and ocular disturbances
        explanation: >-
          Names ataxia as one of the five recurring domains. The review counts
          it in 10 of 28 patients (36%, the basis for FREQUENT), but the
          sentence carrying that fraction is interrupted by an inline citation
          marker and cannot be quoted verbatim.
      - reference: PMID:30057031
        reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          severe neurodevelopmental regression, hypotonia, progressive ataxia,
          seizures, and a lack of coordination
        explanation: >-
          States the ataxia is progressive, which is the basis for the
          PROGRESSIVE clinical course and the specific HP term.
  - name: Dystonia
    category: Neurologic
    frequency: FREQUENT
    description: >-
      Dystonia is one of the five recurring neurological domains and part of the
      "abnormal movements" in the syndrome name, present in 12 of 28 reviewed
      patients (43%).
    phenotype_term:
      preferred_term: Dystonia
      term:
        id: HP:0001332
        label: Dystonia
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          segmental/multifocal dystonia in 3/12 cases, whereas no information
          about dystonia distribution was available in 4/12 patients
        explanation: >-
          The dystonia denominator behind the FREQUENT band. The distribution
          sub-counts are all out of 12, which is the number of the 28 reviewed
          patients who had dystonia - 43%. The body sentence stating "dystonia
          (12/28 patients)" outright is interrupted by an inline citation
          marker and so cannot be quoted verbatim.
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Additional neurological symptoms were present in a large proportion of
          patients and reflected the involvement of five main neurological
          domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular
          disturbances.
        explanation: >-
          Names dystonia as one of the five recurring domains across 28 reviewed
          patients.
  - name: Spasticity
    category: Neurologic
    frequency: FREQUENT
    description: >-
      Present in 14 of 28 reviewed patients (50%), and the one feature in the
      series that differed significantly by sex.
    phenotype_term:
      preferred_term: Spasticity
      term:
        id: HP:0001257
        label: Spasticity
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          spasticity, that was present in 10/14 men and 4/14 women
        explanation: >-
          The spasticity denominator behind the FREQUENT band: 10 of 14 men
          plus 4 of 14 women is 14 of the 28 reviewed patients, 50%. This is
          also the only feature in the series that differed significantly by
          sex. The body sentence stating "spasticity (14/28 patients)" is
          interrupted by an inline citation marker and cannot be quoted across.
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          five main neurological domains, i.e. epilepsy, dystonia, ataxia,
          spasticity, and ocular disturbances
        explanation: >-
          Names spasticity as one of the five recurring domains.
      - reference: PMID:39224955
        reference_title: "IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          we present a child with progressive neurodegeneration consisting of
          spasticity, dystonia, and ataxia
        explanation: >-
          The spastic-ataxic combination in the autopsy-confirmed case.
  - name: Hypotonia
    category: Neurologic
    phenotype_term:
      preferred_term: Hypotonia
      term:
        id: HP:0001252
        label: Hypotonia
    evidence:
      - reference: PMID:30057031
        reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          severe neurodevelopmental regression, hypotonia, progressive ataxia,
          seizures, and a lack of coordination
        explanation: >-
          Names hypotonia among the features of the nonsense-variant carriers.
  - name: Tremor
    category: Neurologic
    phenotype_term:
      preferred_term: Tremor
      term:
        id: HP:0001337
        label: Tremor
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          movement disorder (ataxia, dystonia, tremor, and parkinsonism)
        explanation: >-
          Enumerates tremor within the movement-disorder component of the
          phenotype.
  - name: Parkinsonism
    category: Neurologic
    phenotype_term:
      preferred_term: Parkinsonism
      term:
        id: HP:0001300
        label: Parkinsonism
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          movement disorder (ataxia, dystonia, tremor, and parkinsonism)
        explanation: >-
          Enumerates parkinsonism within the movement-disorder component.
  - name: Cerebellar atrophy
    category: Neurologic
    description: >-
      Cerebellar atrophy, particularly of the vermis, on brain MRI.
    phenotype_term:
      preferred_term: Cerebellar atrophy
      term:
        id: HP:0001272
        label: Cerebellar atrophy
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          cerebellar atrophy (particularly of the vermis), brain stem atrophy,
          and corpus callosum abnormalities including thinning/atrophy or
          thickening
        explanation: >-
          The MRI finding, with the vermian predominance.
  - name: Cerebral atrophy
    category: Neurologic
    phenotype_term:
      preferred_term: Cerebral atrophy
      term:
        id: HP:0002059
        label: Cerebral atrophy
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Brain MRI can show focal or diffuse cortical and/or subcortical
          atrophy
        explanation: >-
          Cortical and subcortical atrophy on imaging.
  - name: Autistic behavior
    category: Behavioral
    phenotype_term:
      preferred_term: Autistic behavior
      term:
        id: HP:0000729
        label: Autistic behavior
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          neurobehavioral/psychiatric manifestations (autism spectrum disorder,
          autistic features, anxiety, depression, and psychosis)
        explanation: >-
          Names autistic features among the neurobehavioral manifestations.
  - name: Psychosis
    category: Behavioral
    phenotype_term:
      preferred_term: Psychosis
      term:
        id: HP:0000709
        label: Psychosis
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          neurobehavioral/psychiatric manifestations (autism spectrum disorder,
          autistic features, anxiety, depression, and psychosis)
        explanation: >-
          Names psychosis among the psychiatric manifestations.
  - name: Feeding difficulties
    category: Gastrointestinal
    phenotype_term:
      preferred_term: Feeding difficulties
      term:
        id: HP:0011968
        label: Feeding difficulties
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Feeding issues, gastrointestinal dysmotility, and ophthalmologic
          manifestations are also reported.
        explanation: >-
          Names feeding issues among the non-neurological manifestations.
  - name: Gastrointestinal dysmotility
    category: Gastrointestinal
    phenotype_term:
      preferred_term: Gastrointestinal dysmotility
      term:
        id: HP:0002579
        label: Gastrointestinal dysmotility
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Feeding issues, gastrointestinal dysmotility, and ophthalmologic
          manifestations are also reported.
        explanation: >-
          Names gastrointestinal dysmotility directly.
  - name: Ocular involvement
    category: Ophthalmologic
    frequency: FREQUENT
    description: >-
      Ocular disturbance is one of the five recurring neurological domains in the
      systematic review, reported in 12 of 28 patients (43%) - retinal
      abnormalities, keratoconus, ophthalmoplegia, nystagmus, and slow or
      dysmetric saccades. Bound to a general HP term because the sources
      describe the domain only as "ocular disturbances" or "ophthalmologic
      manifestations" - a more specific binding would assert more than they
      carry. Keratoconus is reported in this gene's literature but is not
      curated as its own phenotype, because the paper devoted to it returned no
      retrievable text to quote.

      The 12/28 count is not quoted below. The only sentence carrying it wraps
      "disturbances" across a hyphenated line break in the extracted full text
      ("ocular distur-" / "bances (12/28)"), so no verbatim substring states the
      fraction, and reproducing the extraction artefact as a snippet would put a
      broken word on the page. The FREQUENT band is instead cited to the two
      clean sentences below, which place this domain in the same
      "relatively high frequency" group as the four features whose fractions are
      quotable and which run 36% to 75%.
    phenotype_term:
      preferred_term: Ocular disturbance
      term:
        id: HP:0000478
        label: Abnormality of the eye
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          five main neurological domains, i.e. epilepsy, dystonia, ataxia,
          spasticity, and ocular disturbances
        explanation: >-
          Names ocular disturbance as one of the five recurring domains, at the
          level of generality the HP binding reflects.
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          the relatively high frequency of impairment in at least five main
          neurological domains
        explanation: >-
          The authors' own frequency characterization of the domain set that
          includes ocular disturbance, which is what the FREQUENT band records.
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Ocular disturbances included retinal abnormalities, keratoconus,
        explanation: >-
          Itemizes what the general binding covers in this cohort, including the
          keratoconus that is not separately curated.
  - name: Dysphagia
    category: Gastrointestinal
    frequency: OCCASIONAL
    description: >-
      Swallowing difficulty in 3 of the 11 patients in the original cohort
      (27%), and named again in the progressive-myoclonus-epilepsy series as
      part of the IRF2BPL phenotype. It matters clinically out of proportion to
      that fraction in a regressive disorder where feeding support is already
      part of management.
    phenotype_term:
      preferred_term: Dysphagia
      term:
        id: HP:0002015
        label: Dysphagia
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Other abnormalities included hypotonia (5/11 cases), dystonia (3/11
          cases), dysphagia (3/11 cases)
        explanation: >-
          The published denominator behind the OCCASIONAL band: 3/11 is 27%.
      - reference: PMID:37114479
        reference_title: "IRF2BPL as a novel causative gene for progressive myoclonus epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          IRF2BPL has recently been described as a novel cause of
          neurodevelopmental disorders with multisystemic regression, epilepsy,
          cerebellar symptoms, dysphagia, dystonia, and pyramidal signs.
        explanation: >-
          A second, independent group naming dysphagia among the defining
          features of IRF2BPL-related disorder.
  - name: Dysarthria
    category: Neurologic
    frequency: OCCASIONAL
    description: >-
      Present in 2 of 11 patients in the original cohort (18%), within the
      cerebellar syndrome rather than as an isolated speech finding.
    phenotype_term:
      preferred_term: Dysarthria
      term:
        id: HP:0001260
        label: Dysarthria
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          dysarthria (2/11 cases), and nystagmus (2/11 cases). Other
          abnormalities included hypotonia (5/11 cases)
        explanation: >-
          The published denominator behind the OCCASIONAL band: 2/11 is 18%.
  - name: Nystagmus
    category: Ophthalmologic
    frequency: OCCASIONAL
    description: >-
      Present in 2 of 11 patients in the original cohort (18%). Curated
      separately from the general "ocular involvement" node because it has a
      specific HP term and a denominator of its own, and because the systematic
      review lists nystagmus among the ocular disturbances it counts.
    phenotype_term:
      preferred_term: Nystagmus
      term:
        id: HP:0000639
        label: Nystagmus
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          dysarthria (2/11 cases), and nystagmus (2/11 cases). Other
          abnormalities included hypotonia (5/11 cases)
        explanation: >-
          The published denominator behind the OCCASIONAL band: 2/11 is 18%.
  - name: Mild dysmorphic features
    category: Other
    frequency: OCCASIONAL
    description: >-
      Non-neurological findings were uncommon, but 5 of 28 reviewed patients
      (17.9%) had mild dysmorphic features - facial weakness, a wider
      inter-nipple distance, joint laxity. Left without an ontology binding on
      purpose: the reported findings span the face, the chest wall and the
      joints, so no single HP term covers what the source counted, and the
      obvious candidates (facial dysmorphism terms) would assert a facial-only
      finding the source does not.
    phenotype_term:
      preferred_term: Mild dysmorphic features
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          included mild dysmorphic features (facial weakness, wider inter-nipple
          distance, joint laxity, etc.) in 5/28 patients (17.9%)
        explanation: >-
          Both the finding and its denominator, and the enumeration that
          explains why no single HP term is bound.
  - name: Delayed puberty
    category: Endocrine
    description: >-
      Pubertal delay is tracked and treated in this disorder, which is notable
      because IRF2BPL is EAP1 - enhanced at puberty protein 1 - a
      hypothalamic transcriptional regulator of the onset of puberty. No
      denominator is published, so no frequency band is recorded; what is
      published is that GeneReviews directs assessment of pubertal development
      at every visit through adolescence and endocrine treatment when it is
      delayed.
    phenotype_term:
      preferred_term: Delayed puberty
      term:
        id: HP:0000823
        label: Delayed puberty
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          assessment of pubertal development at each visit through adolescence
        explanation: >-
          A surveillance recommendation rather than a reported frequency, so
          the inference is one step removed: puberty is monitored at every visit
          because pubertal delay occurs in this disorder often enough to look
          for.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          treatment of pubertal delay per endocrinologist
        explanation: >-
          Pubertal delay is a manifestation the disorder's own management
          guidance expects to have to treat.
prevalence:
  - population: Cases reported in the literature to 2022
    measure_type: CASES_IN_LITERATURE
    prevalence_class: NOT_YET_DOCUMENTED
    notes: >-
      A published case count, not a population rate. No study has estimated how
      common NEDAMSS is, so the class is NOT_YET_DOCUMENTED rather than a band
      back-derived from the count - the reported total measures how many people
      have been described, which is bounded by ascertainment through exome
      sequencing, not by how many people have the disorder.
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We reported on 28 patients carrying the IRF2BPL mutation who were
          identified in 10 papers
        explanation: >-
          The literature case count assembled by the systematic review.
  - population: Cases reported in the literature to 2023
    measure_type: CASES_IN_LITERATURE
    prevalence_class: NOT_YET_DOCUMENTED
    notes: >-
      A later count from a different group, on a slightly wider inclusion, and
      the reason the 2022 figure is not treated as the total.
    evidence:
      - reference: PMID:37114479
        reference_title: "IRF2BPL as a novel causative gene for progressive myoclonus epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          review the features of the 31 subjects with IRF2BPL-related disorders
          previously reported
        explanation: >-
          The count of previously reported subjects at the time of the 2023
          series.
progression:
  - phase: Initial acquisition of milestones
    notes: >-
      Early psychomotor development is mostly normal, or delayed but
      progressing, before anything is lost. This phase is what makes the
      disorder regressive rather than a static encephalopathy, and it is why the
      pathograph terminates in "Loss of Previously Acquired Developmental
      Milestones" rather than in a failure to acquire them.
    evidence:
      - reference: PMID:30166628
        reference_title: "De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          mostly normal initial psychomotor development followed by severe
          global neurological regression and epilepsy with nonspecific
          electroencephalogram (EEG) abnormalities and variable central nervous
          system (CNS) anomalies
        explanation: >-
          States the acquire-then-lose sequence, with the normal phase first.
  - phase: Regression
    age_range: First year of life to the sixth decade; most reported onsets before age 10
    notes: >-
      Onset of regression is spread across the whole of life rather than
      concentrated in infancy. In the 28-patient review, onset was at one year
      or less in 6 patients, 1-3 years in 5, 4-5 years in 9, 6-10 years in 3,
      and 10-23 years in 5; GeneReviews puts the full span from the first year
      to the sixth decade. Severity does not track onset age - the review found
      no correlation between the two - which is the observation the
      `irf2bpl_onset_age_range` discussion is about.
    evidence:
      - reference: PMID:35525099
        reference_title: "Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          the available information pointed to a disease onset of one year of
          age or less in 6 cases, between 1 and 3 years of age in 5 cases,
          between 4 and 5 years of age in 9 cases, between 6 and 10 years of age
          in 3 cases, and more 10 to 23 years of age (median, 11) in 5 cases.
        explanation: >-
          The full onset distribution across the reviewed cohort.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Onset is highly variable and can be in the first year of life through
          the sixth decade. In some individuals the course of the disorder is
          progressive or debilitating.
        explanation: >-
          The outer bounds of the onset range, and the qualification that the
          progressive course is not universal.
animal_models:
  - name: Drosophila pits neuronal RNAi knockdown
    species: Drosophila melanogaster
    genotype: RNAi knockdown of pits (Drosophila IRF2BPL ortholog) in neurons
    publication: PMID:30057031
    description: >-
      Partial neuronal depletion of the fly ortholog pits. Complete loss is
      early-lethal, so the partial knockdown is what exposes the maintenance
      requirement.
    modeled_mechanisms:
      - target: Progressive Neuronal and Axonal Loss
        relationship: RECAPITULATES
        fidelity: MODERATE
        description: >-
          Neuronal knockdown produces frank neurodegeneration, demonstrating
          that the gene is required for neuronal maintenance and not only for
          neuronal development.
        limitations: >-
          An invertebrate nervous system, and a knockdown rather than the human
          allele - so it models loss of gene function, not the dominant-negative
          sequestration by a truncated product that the human variants cause.
        evidence:
          - reference: PMID:30057031
            reference_title: "IRF2BPL Is Associated with Neurological Phenotypes."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              partial knockdown with RNA interference in neurons leads to
              neurodegeneration, revealing a requirement for this gene in proper
              neuronal function and maintenance
            explanation: >-
              Supports treating the fly knockdown as informative for the human
              neuronal-maintenance defect.
      - target: Excess Wnt Signaling
        relationship: RECAPITULATES
        fidelity: MODERATE
        description: >-
          Depleting pits raises wingless in the brain, and the resulting axonal
          loss is suppressed by inhibiting Wg - establishing the Wnt step as
          causal rather than correlative.
        limitations: >-
          Wingless is the fly orthologue of a Wnt family that is considerably
          expanded in vertebrates, so which human WNT ligand matters is not
          settled by this model.
        readouts:
          - name: Brain wingless (wg) level
            target: Excess Wnt Signaling
            direction: INCREASED
            interpretation: >-
              Elevated Wnt ligand is the measured consequence of losing the
              IRF2BPL ortholog.
            evidence:
              - reference: PMID:35044823
                reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  neuronal depletion of Pits leads to increased wingless (wg)
                  levels in the brain and is associated with axonal loss
                explanation: >-
                  Reports the direction of the wingless measurement in the
                  knockdown brain.
        evidence:
          - reference: PMID:35044823
            reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              whereas inhibition of Wg signaling is neuroprotective
            explanation: >-
              The rescue arm, which is what makes the Wnt elevation causal for
              the degeneration rather than a bystander change.
  - name: Drosophila heterozygous Pits truncation with CuATSM rescue
    species: Drosophila melanogaster
    genotype: heterozygous truncation of Pits (Drosophila IRF2BPL ortholog)
    publication: PMID:36476864
    description: >-
      A heterozygous truncation matching the human allele class, with progressive
      motor decline that responds to the copper compound CuATSM.
    modeled_mechanisms:
      - target: Progressive Neuronal and Axonal Loss
        relationship: RESCUES
        fidelity: MODERATE
        description: >-
          Progressive motor defects in heterozygous-truncation flies are
          ameliorated by CuATSM, the same compound that restores mitochondrial
          function and neuronal survival in patient-derived cells.
        limitations: >-
          A behavioural motor readout in an invertebrate, and a pharmacological
          rescue only. No human trial of CuATSM in this disorder exists, which is
          why it is recorded here rather than as a treatment.
        evidence:
          - reference: PMID:36476864
            reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              flies harboring heterozygous truncations of the IRF2BPL ortholog
              (Pits) display progressive motor defects that are ameliorated by
              CuATSM treatment
            explanation: >-
              Both the progressive phenotype in the matching allele class and
              the pharmacological rescue.
  - name: Zebrafish irf2bpl loss of function
    species: Danio rerio
    genotype: loss of irf2bpl
    publication: PMID:35044823
    description: >-
      A vertebrate test of the Wnt mechanism, showing the same directional change
      in wnt1 as the fly model.
    modeled_mechanisms:
      - target: Excess Wnt Signaling
        relationship: RECAPITULATES
        fidelity: MODERATE
        description: >-
          Loss of irf2bpl causes neurological defects with increased wnt1
          transcription and downstream signalling, reproducing the fly result in
          a vertebrate.
        limitations: >-
          Loss of function rather than the human truncating allele, so like the
          fly knockdown it does not model the dominant-negative sequestration
          step.
        readouts:
          - name: wnt1 transcription
            target: Excess Wnt Signaling
            direction: INCREASED
            interpretation: >-
              Vertebrate confirmation of the direction of the Wnt change.
            evidence:
              - reference: PMID:35044823
                reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  Loss of irf2bpl in zebrafish also causes neurological defects
                  with an associated increase in wnt1 transcription and
                  downstream signaling.
                explanation: >-
                  Reports the wnt1 measurement and its direction.
        evidence:
          - reference: PMID:35044823
            reference_title: "Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              Loss of irf2bpl in zebrafish also causes neurological defects
            explanation: >-
              Supports treating the zebrafish as informative for the human
              neurological phenotype.
experimental_models:
  - name: Patient fibroblast-derived astrocytes and neurons
    experimental_model_type: PRIMARY_CELL_CULTURE
    description: >-
      Skin fibroblasts from NEDAMSS patients reprogrammed directly to astrocytes
      and neurons. The system that established the sequestration mechanism and
      the glial contribution, in human cells carrying the actual patient alleles.
    modeled_mechanisms:
      - target: Astrocyte Mitochondrial Respiratory Dysfunction
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          Patient astrocytes show structurally aberrant mitochondria and
          respiratory dysfunction, and CuATSM restores mitochondrial function -
          the rescue acts on this step specifically.
        limitations: >-
          Reprogrammed rather than developmentally derived astrocytes, cultured
          without microglia, vasculature or myelin, so the metabolic
          measurements are made outside the tissue context in which the human
          lesion plays out.
        readouts:
          - name: Mitochondrial morphology and respiratory function
            target: Astrocyte Mitochondrial Respiratory Dysfunction
            direction: DECREASED
            interpretation: >-
              The metabolic defect measured in the astrocytes themselves.
            evidence:
              - reference: PMID:36476864
                reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
                supports: SUPPORT
                evidence_source: IN_VITRO
                snippet: >-
                  exhibit aberrant mitochondria and respiratory dysfunction
                explanation: >-
                  Reports the mitochondrial measurement and its direction.
          - name: Mitochondrial function after CuATSM
            target: Astrocyte Mitochondrial Respiratory Dysfunction
            direction: RESTORED
            interpretation: >-
              Pharmacological reversal of the astrocyte metabolic defect. This
              is the readout that places the mitochondrial step on the causal
              path rather than treating it as a marker of sick cells, which is
              why it is attached here rather than to the downstream support
              failure.
            evidence:
              - reference: PMID:36476864
                reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
                supports: SUPPORT
                evidence_source: IN_VITRO
                snippet: >-
                  Treatment with the small molecule copper ATSM (CuATSM) rescues
                  neuronal survival and restores mitochondrial function.
                explanation: >-
                  States the rescue and what was restored. The same sentence
                  also reports the neuronal-survival arm, which is recorded on
                  the trophic-support link below.
        evidence:
          - reference: PMID:36476864
            reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: >-
              we reprogram patient skin fibroblasts to astrocytes and neurons to
              study mechanisms of this newly described disease
            explanation: >-
              Establishes that the model carries patient alleles in human cells,
              which is why it is treated as high fidelity for this node.
      - target: Loss of Astrocytic Trophic Support for Neurons
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          The coculture in which patient astrocytes were shown to fail to keep
          neurons alive, and in which CuATSM rescued neuronal survival.
        limitations: >-
          A two-cell-type coculture without microglia, vasculature or myelin,
          and reprogrammed rather than developmentally derived - so it cannot
          report on circuit-level or age-dependent aspects of the human course.
        readouts:
          - name: Neuronal survival in astrocyte coculture
            target: Loss of Astrocytic Trophic Support for Neurons
            direction: DECREASED
            interpretation: >-
              The functional consequence of the astrocyte defect, measured on
              the neurons rather than on the astrocytes.
            evidence:
              - reference: PMID:36476864
                reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
                supports: SUPPORT
                evidence_source: IN_VITRO
                snippet: >-
                  patient astrocytes fail to support neuronal survival in
                  coculture
                explanation: >-
                  Reports the survival readout and its direction.
        evidence:
          - reference: PMID:36476864
            reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: >-
              Moreover, patient astrocytes fail to support neuronal survival in
              coculture and exhibit aberrant mitochondria and respiratory
              dysfunction.
            explanation: >-
              Supports treating this coculture as informative for the glial
              support step: it is the system in which the failure was observed.
      - target: Cytoplasmic Sequestration of Wild-Type IRF2BPL
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          The system in which the mislocalisation and aggregation of wild-type
          IRF2BPL by truncated patient variants was demonstrated.
        limitations: >-
          Localisation and aggregation were assayed in reprogrammed cells; the
          corresponding human brain finding (polyQ inclusions) comes from a
          single autopsy in a different patient.
        evidence:
          - reference: PMID:36476864
            reference_title: "Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: >-
              truncated patient variants sequester the wild-type protein to the
              cytoplasm and cause aggregation
            explanation: >-
              The observation itself, in patient-derived human cells.
treatments:
  - name: Antiseizure Medication
    description: >-
      Standard management of the epilepsy by an experienced neurologist. No
      IRF2BPL-specific antiseizure regimen is established; the seizure types are
      varied and treatment is chosen accordingly.
    treatment_term:
      preferred_term: anticonvulsant therapy
      term:
        id: NCIT:C64172
        label: Anticonvulsant Therapy
    therapeutic_modality: SMALL_MOLECULE
    target_mechanisms:
      - target: Seizure
        description: >-
          Symptomatic seizure suppression. It does not act on the underlying
          IRF2BPL lesion or alter the regression.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          standard treatment of epilepsy and movement disorder by an experienced
          neurologist
        explanation: >-
          The management recommendation, and its framing as standard rather than
          disease-specific.
  - name: Developmental and Educational Support
    description: >-
      Developmental and educational support, reassessed at every visit. In a
      regressive disorder this is directed at maintaining and re-acquiring
      function as much as at acquiring it.

      Bound to Educational Intervention rather than a speech- or
      therapy-specific term deliberately: the source recommends "developmental
      and educational support" and names physical and occupational therapists
      under spasticity management, but does not mention speech therapy anywhere.
      Binding a speech-therapy term here would assert a recommendation the
      cited source does not make.
    treatment_term:
      preferred_term: developmental and educational support
      term:
        id: NCIT:C17874
        label: Educational Intervention
    therapeutic_modality: BEHAVIORAL
    target_mechanisms:
      - target: Global developmental delay
        description: >-
          Educational and developmental support for the delay and its
          regression. No cited source claims it reverses the regression.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Treatment of manifestations: Developmental and educational support;
          standard treatment of epilepsy and movement disorder by an experienced
          neurologist
        explanation: >-
          The management recommendation, with developmental and educational
          support listed first among the interventions.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          At each visit, assess developmental progress, educational needs,
          cognitive function, seizures, movement disorder, spasticity,
          contractures, behavioral issues, growth, nutritional status,
          gastrointestinal dysmotility, and family needs
        explanation: >-
          Establishes that developmental and educational needs are reassessed at
          every visit, which is what makes this ongoing support rather than a
          one-off referral.
  - name: Spasticity Management and Rehabilitation
    description: >-
      Multidisciplinary management of spasticity and contractures across
      orthopedics, neurology, physical medicine, physiotherapy and occupational
      therapy.
    treatment_term:
      preferred_term: physical therapy
      term:
        id: NCIT:C15302
        label: Physical Therapy
    therapeutic_modality: BEHAVIORAL
    target_mechanisms:
      - target: Spasticity
        description: >-
          Symptomatic management of tone and prevention of secondary
          contractures.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          standard treatment of spasticity per orthopedist, neurologist,
          physical medicine and rehabilitation specialist, physical therapist,
          and occupational therapist
        explanation: >-
          Names the disciplines involved in spasticity management.
  - name: Feeding and Nutritional Support
    description: >-
      Feeding support for poor weight gain and standard treatment for gastric
      dysmotility.
    treatment_term:
      preferred_term: supportive care
      term:
        id: NCIT:C15747
        label: Supportive Care
    therapeutic_modality: OTHER
    target_mechanisms:
      - target: Feeding difficulties
        description: >-
          Symptomatic support for the feeding and gastrointestinal component.
      - target: Gastrointestinal dysmotility
        description: >-
          Standard treatment of gastric dysmotility. GeneReviews names no
          IRF2BPL-specific approach, and also asks for nutritional status and
          dysmotility to be reassessed at every visit.
      - target: Dysphagia
        description: >-
          Swallowing difficulty is part of what feeding support addresses in a
          regressive disorder. The cited guidance covers feeding and weight gain
          rather than dysphagia by name, so this link is the general feeding
          recommendation applied to the specific phenotype.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          feeding support for poor weight gain
        explanation: >-
          The management recommendation for feeding difficulty.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          standard treatment for gastric dysmotility
        explanation: >-
          The management recommendation for the gastrointestinal component.
  - name: Ophthalmologic Management
    description: >-
      Treatment of vision deficits by the treating ophthalmologist, with more
      complex findings referred to an ophthalmic subspecialist, plus a dilated
      eye exam on the ophthalmologist's schedule. Ocular disturbance is one of
      the five recurring domains in this disorder, so this is a routine rather
      than exceptional referral.
    treatment_term:
      preferred_term: ophthalmologic care
      term:
        id: NCIT:C49236
        label: Therapeutic Procedure
    therapeutic_modality: OTHER
    target_mechanisms:
      - target: Ocular involvement
        description: >-
          Symptomatic treatment of the ocular component. Nothing in the cited
          guidance claims it alters the neurodegeneration.
      - target: Nystagmus
        description: >-
          Nystagmus falls within the ophthalmologic findings this referral
          covers, though the cited guidance addresses vision deficits generally
          rather than nystagmus by name.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          treatment of vision deficits per ophthalmologist with treatment of
          more complex findings per ophthalmic subspecialist
        explanation: >-
          The ophthalmologic management recommendation and its escalation path.
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          dilated eye exam per treating ophthalmologist
        explanation: >-
          The surveillance half of the same recommendation.
  - name: Endocrine Management of Pubertal Delay
    description: >-
      Assessment of pubertal development at every visit through adolescence,
      with endocrine treatment when puberty is delayed. Worth curating
      separately from general supportive care because IRF2BPL is EAP1, a
      hypothalamic regulator of pubertal onset, so the endocrine surveillance is
      mechanistically motivated rather than generic.
    treatment_term:
      preferred_term: endocrine management of delayed puberty
      term:
        id: NCIT:C49236
        label: Therapeutic Procedure
    therapeutic_modality: OTHER
    target_mechanisms:
      - target: Delayed puberty
        description: >-
          Endocrine treatment of the pubertal delay itself. The cited guidance
          gives no specific regimen, and no cited source connects this to the
          neurological course.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          treatment of pubertal delay per endocrinologist
        explanation: >-
          The management recommendation for pubertal delay.
  - name: Family and Social Work Support
    description: >-
      Family and social work support, with family needs reassessed at each
      visit. In a disorder where children lose skills they had already acquired,
      this is a named part of management rather than an afterthought.
    treatment_term:
      preferred_term: family and social work support
      term:
        id: NCIT:C15747
        label: Supportive Care
    therapeutic_modality: OTHER
    target_mechanisms:
      - target: Loss of Previously Acquired Developmental Milestones
        description: >-
          Support directed at the family carrying the consequences of the
          regression, not at the mechanism itself.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          family and social work support
        explanation: >-
          Names family and social work support among the treatments of
          manifestations.
  - name: Genetic Counseling
    description: >-
      Autosomal dominant counseling. Most cases are de novo, but about 9% have an
      affected parent, and each child of an affected individual has a 50% risk.
    treatment_term:
      preferred_term: genetic counseling
      term:
        id: NCIT:C15240
        label: Genetic Counseling
    therapeutic_modality: OTHER
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Each child of an individual with IRF2BPL-related disorder has a 50%
          chance of inheriting the IRF2BPL pathogenic variant.
        explanation: >-
          The recurrence risk that the counseling conveys.
definitions:
  - name: Molecular diagnosis of IRF2BPL-related disorder
    definition_type: DIAGNOSTIC_CRITERIA
    derivation_basis: ESTABLISHED_CRITERIA
    description: >-
      Diagnosis rests on characteristic clinical findings together with a
      heterozygous pathogenic IRF2BPL variant on molecular genetic testing. There
      is no biochemical or imaging finding specific enough to stand in for the
      genetic result.
    evidence:
      - reference: PMID:39571061
        reference_title: "IRF2BPL-Related Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The diagnosis of IRF2BPL-related disorder is established in a proband
          with characteristic clinical findings and a heterozygous pathogenic
          variant in IRF2BPL identified by molecular genetic testing.
        explanation: >-
          States the diagnostic requirement directly.
discussions:
  - discussion_id: irf2bpl_lof_models_vs_dominant_negative
    kind: HUMAN_MODEL_MISMATCH
    status: OPEN
    prompt: >-
      Every in vivo model of this disorder is a loss-of-function model, but the
      human mechanism is dominant-negative sequestration by an expressed
      truncated protein. Do the fly and zebrafish results actually speak to the
      human lesion?
    attaches_to:
      - pathophysiology#Cytoplasmic Sequestration of Wild-Type IRF2BPL
      - pathophysiology#Excess Wnt Signaling
    rationale: >-
      The Wnt arm of this pathograph rests almost entirely on pits knockdown in
      Drosophila and irf2bpl loss in zebrafish - both of which remove gene
      function. The human variants do something different: because IRF2BPL is
      intronless, the mutant transcript escapes NMD, and the resulting truncated
      protein actively drags wild-type IRF2BPL into cytoplasmic aggregates. A
      pure loss-of-function model reproduces the *consequence* of nuclear IRF2BPL
      being absent, but not the sequestration that produces it, and so cannot
      report on whether aggregate toxicity contributes independently of lost
      transcriptional repression.

      Two observations narrow the gap without closing it. Flies co-expressing
      full-length and truncated IRF2BPL do show cytoplasmic accumulation of the
      full-length protein, and heterozygous Pits-truncation flies show a
      progressive motor phenotype - so the allele class has been modelled, even
      if the Wnt measurements were not made in it. WNT1 is also raised in
      patient-derived astrocytes, which is human material carrying the real
      allele.

      What is missing is the Wnt measurement in a system that has both: the human
      truncating allele and an intact nervous system.
    proposed_experiments:
      - experiment_id: exp_irf2bpl_knockin_wnt_readout
        name: Wnt pathway readout in a knock-in truncating allele model
        description: >-
          Measure Wnt ligand and downstream signalling in a vertebrate model
          carrying a heterozygous knock-in of a human IRF2BPL truncating variant,
          rather than a null, and test whether Wnt inhibition is neuroprotective
          in that background.
        would_support:
          - pathophysiology#Excess Wnt Signaling
        supporting_outcome:
        - >-
          Wnt ligand and downstream signalling are elevated in the knock-in
          heterozygote to a degree comparable with the null, and Wnt inhibition
          slows the progressive phenotype.
        would_refute:
          - pathophysiology#Excess Wnt Signaling
        refuting_outcome:
        - >-
          Wnt signalling is unchanged in the knock-in heterozygote despite
          cytoplasmic sequestration and progressive degeneration, which would
          make the Wnt arm an artifact of complete gene loss and point to
          aggregate toxicity as the operative mechanism.
  - discussion_id: irf2bpl_polyq_inclusion_causality
    kind: KNOWLEDGE_GAP
    status: OPEN
    prompt: >-
      Do the polyglutamine inclusions seen at autopsy contribute to
      neurodegeneration in NEDAMSS, or are they a downstream marker?
    attaches_to:
      - pathophysiology#Intracellular Protein Aggregate Formation
    rationale: >-
      The single detailed neuropathological study of this disorder found polyQ
      inclusions and a picture consistent with DRPLA, in a patient with no repeat
      expansion and a variant lying distal to IRF2BPL's own polyQ tract. The
      authors raise, but explicitly do not establish, the possibility that the
      unexpanded polyQ tract participates in inclusion formation - which they
      note would be a novel mechanism for polyQ repeats.

      This rests on one autopsy. Whether inclusions are present across NEDAMSS
      generally, whether they precede or follow neuronal loss, and whether they
      are toxic or protective are all open. The node is curated because the
      observation is real and mechanistically striking, not because the causal
      role is settled.
    proposed_experiments:
      - experiment_id: exp_irf2bpl_systematic_neuropathology
        name: Systematic neuropathology across NEDAMSS variant classes
        description: >-
          Examine additional NEDAMSS brains, spanning proximal and distal
          truncating variants and missense alleles, for polyQ inclusions and
          their regional distribution relative to neuronal loss.
        would_support:
          - pathophysiology#Intracellular Protein Aggregate Formation
        supporting_outcome:
        - >-
          PolyQ inclusions are found consistently across cases and their regional
          distribution matches the pattern of neuronal loss.
        would_refute:
          - pathophysiology#Intracellular Protein Aggregate Formation
        refuting_outcome:
        - >-
          Inclusions are absent in other cases with comparable degeneration, or
          are confined to regions without neuronal loss, indicating they are
          incidental rather than on the causal path.
  - discussion_id: irf2bpl_onset_age_range
    kind: KNOWLEDGE_GAP
    status: OPEN
    prompt: >-
      What determines the extraordinary range of onset age, from the first year
      of life to the sixth decade?
    attaches_to:
      - pathophysiology#Loss of Previously Acquired Developmental Milestones
    rationale: >-
      Onset spans five decades, and the systematic review found no significant
      correlation between the number of affected clinical domains and either age
      at onset or variant type. A separate series found protein-truncating
      variants clustered around the coiled-coil domain in three adults presenting
      as progressive myoclonus epilepsy, hinting at a positional effect, but the
      correlational analysis does not support variant type as the explanation.
      Modifiers, mosaicism and the degree of NMD escape are all untested
      candidates, and none can be assigned from the published data.
    proposed_experiments:
      - experiment_id: exp_irf2bpl_genotype_onset_cohort
        name: Genotype-onset correlation in an adequately powered cohort
        description: >-
          Assemble a cohort large enough to test variant position, predicted
          escape of nonsense-mediated decay, and measured residual full-length
          IRF2BPL protein against age at onset and rate of regression.
        would_support:
          - pathophysiology#Nonsense-Mediated Decay Escape and Truncated Protein Expression
        supporting_outcome:
        - >-
          Residual full-length nuclear IRF2BPL protein predicts age at onset,
          making the degree of sequestration the dose variable that sets timing.
        would_refute:
          - pathophysiology#Nonsense-Mediated Decay Escape and Truncated Protein Expression
        refuting_outcome:
        - >-
          Onset age is unrelated to residual protein or variant position across
          an adequately powered cohort, pointing to modifiers outside the locus.

📚

References & Deep Research

References

8

PMID:39571061

IRF2BPL-Related Disorder.

No top-level findings curated for this source.

PMID:30057031

IRF2BPL Is Associated with Neurological Phenotypes.

No top-level findings curated for this source.

PMID:30166628

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

No top-level findings curated for this source.

PMID:35044823

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling.

No top-level findings curated for this source.

PMID:35525099

Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature.

No top-level findings curated for this source.

PMID:36476864

Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy.

No top-level findings curated for this source.

PMID:37114479

IRF2BPL as a novel causative gene for progressive myoclonus epilepsy.

No top-level findings curated for this source.

PMID:39224955

IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA.

No top-level findings curated for this source.

IRF2BPL-Related Neurodevelopmental Disorder with Regression

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References & Deep Research

References