IREB2-Related Neurodegeneration

Mendelian MONDO:0032758 Pathograph 23 Show in embeddings browser Inherited neurodegenerative disorder Disorder of iron metabolism Autosomal recessive disease

Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (NDCAMA) is an autosomal recessive disorder caused by bi-allelic variants in IREB2, the gene encoding iron-responsive element-binding protein 2 (IRP2). It is the human counterpart of the long-studied Irp2-null mouse, and it is unusual among neurodegenerative diseases in coupling a severe central nervous system phenotype to a haematological one through a single post-transcriptional regulatory circuit rather than through two separate tissue lesions. IRP2 is a cytosolic RNA-binding protein that reads cellular iron status and rewrites the iron proteome accordingly. When iron is scarce it binds iron-responsive elements (IREs) - conserved stem-loops in the untranslated regions of iron-metabolism transcripts - repressing translation of the ferritin heavy and light chains and of erythroid 5-aminolevulinate synthase (ALAS2) from 5' IREs, while stabilising the transferrin receptor (TFRC) mRNA through 3' IREs. The net effect is more iron imported and less iron stored. When iron and oxygen are plentiful the SCF-FBXL5 ubiquitin ligase binds IRP2, polyubiquitinates it and sends it to the proteasome, releasing the brake. Loss of IRP2 therefore locks the cell into a false "iron-replete" regulatory state: ferritin translation is derepressed and TFRC mRNA is destabilised, so iron is simultaneously under-imported and over-sequestered. Cells become functionally iron-deficient even when systemic iron and transferrin saturation are normal, which is why the anaemia does not behave like ordinary iron-deficiency anaemia and why the brain is affected at all. The published human experience is four patients, all compound heterozygous, reported between 2019 and 2024: a 16-year-old boy of Filipino parentage with two nonsense alleles and complete absence of IRP2, a 10-year-old Australian boy, a 7-year-old boy in the USA with two missense alleles, and a Han Chinese boy with the novel missense pair p.Ile371Val and p.Asp826Val. The shared picture is neonatal feeding difficulty and hypotonia, profound global developmental delay with absent speech and ambulation, a treatment-resistant choreoathetoid and dystonic movement disorder, EEG abnormality with or without clinical seizures, progressive cerebral volume loss with delayed myelination and white matter reduction, and mild microcytic anaemia with serum iron levels in the normal range. In the Chinese proband the anaemia was quantified as a haemoglobin of 114 g/L against a local reference range of 120-140 g/L and a mean corpuscular volume of 79.8 fL against 82-100 fL - mild by haematological standards, and easily overlooked beside the neurological picture. Two mechanistic caveats are load-bearing for this entry. First, the mouse model is more haematologically severe than the human disease: Irp2-null mice develop frank microcytic anaemia with absent marrow iron stores and an erythropoietic protoporphyria driven by ALAS2 derepression, none of which has been documented in a patient. Second, the mouse brain accumulates iron and ferritin in white matter tracts before neurodegeneration begins, so the same lesion presents as cytosolic iron starvation at the level of the labile iron pool and as iron excess at the level of tissue staining. Both points are curated below as explicit knowledge gaps rather than smoothed over.

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Classifications

Harrison's Chapter

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Inheritance

Autosomal recessive inheritance HP:0000007

Two damaged IREB2 alleles are required. All four published probands were compound heterozygous - none was homozygous, and no consanguinity is reported in any family. Both parents in the fourth family were healthy carriers, confirmed by Sanger sequencing of the paternal and maternal alleles, and the proband's younger brother, who carries only the paternal allele, is developing normally. Heterozygous carriers are not described as affected in any report, which is consistent with the Ireb2 heterozygous mouse and with IRP2 abundance being regulated post-translationally rather than by gene dosage. Penetrance is not annotated. With four unrelated probands and no unaffected bi-allelic individual described, there is no basis for calling penetrance either complete or reduced; asserting COMPLETE from four ascertained cases would be an inference from the ascertainment itself.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:30915432 SUPPORT Human Clinical

"Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."

Establishes that the disorder arises from bi-allelic damage to IREB2, the definition of recessive inheritance at this locus.

PMID:39587636 SUPPORT Human Clinical

"Sanger sequencing confirmed the paternal (A2477T) and maternal (A1111G) origins of the"

Demonstrates that the two variants are in trans, inherited one from each unaffected carrier parent, in the fourth reported family.

PMID:39587636 SUPPORT Human Clinical

"This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia."

Records that the parents are healthy and non-consanguineous, so the recessive genotype arose from two independent alleles rather than from identity by descent.

Discussions and Knowledge Gaps

How can the same lesion produce functional cytosolic iron deficiency and tissue iron accumulation in the brain at the same time, and which of the two actually kills neurons?

KNOWLEDGE GAP OPEN ireb2-brain-iron-paradox

Attached to

pathophysiology#Neuronal and Oligodendrocyte Iron Mishandling pathophysiology#Functional Cytosolic Iron Deficiency

This is the central unresolved question of the mechanism. Patient cells show functional iron deficiency - low transferrin receptor, high ferritin, depleted labile ferrous iron - while the Irp2-null mouse brain accumulates ferric iron and ferritin in white matter tracts and in the neuronal populations that subsequently degenerate. The usual reconciliation is that derepressed ferritin sequesters iron into a form the cell cannot mobilise, so the tissue is loaded and the cytosol is starved; but that account is inferred rather than demonstrated, and it has real consequences. If starvation is what kills neurons, therapy should aim to restore iron delivery. If sequestered iron is doing oxidative damage, chelation would be the opposite and could be harmful. No human brain iron measurement - quantitative susceptibility mapping, R2* relaxometry or post-mortem analysis - has been reported in any IREB2 patient, so even the first question, whether human brains accumulate iron at all, is unanswered.

Proposed experiments

Quantitative susceptibility mapping in IREB2 patients

ireb2-qsm-brain-iron

Apply QSM and R2* relaxometry to any living patient to determine whether regional brain iron is increased, normal or reduced, and whether the distribution matches the mouse. This is the single measurement that would settle whether the disorder belongs conceptually with the NBIA disorders or with the iron-deficiency spectrum.

Labile versus total iron in patient iPSC-derived neurons

ireb2-labile-vs-total-iron-neurons

Differentiate patient iPSCs into cortical neurons and oligodendrocytes and measure labile iron pool, total cellular iron and ferritin-bound iron side by side, to test the sequestration model directly in the affected cell types rather than in lymphoblasts.

Why is the haematological phenotype so much milder in patients than in Irp2-null mice, and does the erythropoietic protoporphyria of the mouse occur in humans at all?

HUMAN MODEL MISMATCH OPEN ireb2-mouse-human-haematology-mismatch

Attached to

pathophysiology#Iron-Limited Erythropoiesis

The mouse has frank microcytic anaemia with absent bone marrow iron stores and a florid erythropoietic protoporphyria from ALAS2 derepression, which the authors of that work proposed would identify human patients. The patients found since have mild anaemia - haemoglobin 114 g/L and MCV 79.8 fL in the one case with published values - normal serum iron, and no reported protoporphyrin abnormality whatsoever. Three explanations are live and they are not equivalent: erythrocyte protoporphyrin may simply never have been measured, since no one thought to ask; human erythropoiesis may buffer IRP2 loss better than murine erythropoiesis, for instance through greater IRP1 contribution in the erythron; or the human alleles reported so far may retain more residual function in erythroid cells than a complete gene deletion. The distinction matters diagnostically, because the mouse-derived prediction of a "refractory microcytic anaemia with elevated red cell protoporphyrin" is currently the published screening profile for this disorder and it may be wrong for humans.

Proposed experiments

Erythrocyte free and zinc protoporphyrin in IREB2 patients

ireb2-erythrocyte-protoporphyrin

Measure free and zinc protoporphyrin, reticulocyte haemoglobin content and soluble transferrin receptor in every living patient. The assays are cheap and widely available and would immediately show whether the murine ALAS2 derepression arm operates in humans.

Erythroid differentiation of patient CD34+ cells

ireb2-erythroid-differentiation-assay

Differentiate patient-derived CD34+ progenitors along the erythroid lineage and measure TfR1, ferritin, ALAS2 protein, haem and protoporphyrin output, to establish whether the human erythron reproduces the mouse phenotype under controlled conditions.

Why is the human movement disorder dystonic and choreoathetoid while the mouse is ataxic, bradykinetic and tremulous, and does that reflect different circuits being affected?

HUMAN MODEL MISMATCH OPEN ireb2-movement-phenotype-species-difference

Attached to

pathophysiology#Extrapyramidal Movement Disorder and Neurodevelopmental Arrest pathophysiology#Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss

The convergence between mouse and patient is usually presented as close, and at the level of "neurodegeneration with a movement disorder" it is. But the phenomenology differs systematically: patients have dystonia and choreoathetosis, which point to basal ganglia output, whereas the mouse has ataxia and tremor with Purkinje cell pathology, which points to the cerebellum, and the PT-2385 rescue was scored on Purkinje cell morphology. Human imaging does show basal ganglia and thalamic signal abnormality, so the human lesion may genuinely be striatopallidal while the murine one is cerebellar. If so, a therapy validated on cerebellar endpoints in the mouse may not predict benefit for the disabling human feature. Timing is a confounder that cannot be separated on present evidence: the mouse disease begins in adulthood and the human disease in infancy, so the same lesion is hitting a mature versus a developing circuit.

Proposed experiments

Regional mapping of iron handling and cell loss in knock-in mice

ireb2-regional-vulnerability-mapping

Compare striatum, globus pallidus, cerebellum and cortex in D826V knock-in and null mice for iron content, ferritin, transferrin receptor, neuronal density and microglial activation, to determine whether the regional vulnerability of the mouse genuinely differs from the human pattern or only appears to because cerebellar endpoints have been the ones measured.

Cell-type-conditional Ireb2 deletion

ireb2-conditional-neuronal-knockouts

Delete Ireb2 selectively in medium spiny neurons, in Purkinje cells and in oligodendrocytes to establish which cell type's iron failure is sufficient to produce which movement phenotype.

Does partial loss of IRP2 function cause a milder, currently unrecognised phenotype, and if so what does it look like?

KNOWLEDGE GAP OPEN ireb2-hypomorphic-spectrum

Attached to

pathophysiology#Impaired IRE-Binding Activity of Residual IRP2 genetic#IREB2

All four patients found so far have effectively complete loss of IRP2 function, and the authors of the third report explicitly raised the possibility that individuals with significant but incomplete loss develop less severe disease. The fourth patient's p.Ile371Val allele is the first experimental hint that such alleles exist - assayed alone it produced no measurable change in IRP2 abundance, ferritin, transferrin receptor or labile iron. If a hypomorphic spectrum exists, the phenotype might be an isolated dystonia, a late-onset movement disorder, or an unexplained microcytic anaemia with normal iron studies - all of which would currently be ascertained under different diagnostic labels, if at all. Testing this requires looking outside the severe paediatric neurology population where every case so far has been found.

Proposed experiments

Rare-variant association scan for IREB2 in biobank cohorts

ireb2-biobank-rare-variant-phewas

Test bi-allelic and predicted-hypomorphic IREB2 genotypes in large sequenced biobanks against red cell indices, movement disorder diagnoses and neuroimaging phenotypes. Red cell indices are measured in essentially everyone, so the anaemia arm gives an unusually well-powered quantitative readout for a disorder this rare.

Deep mutational scan of IREB2 IRE-binding activity

ireb2-saturation-allelic-series

Build a saturation mutagenesis library and measure IRE-binding and protein stability for every missense allele, producing a prospective function-severity map that a diagnostic laboratory could use to interpret a novel variant instead of relying on in-silico prediction.

Should the large IREB2 association literature in chronic obstructive pulmonary disease and lung cancer be curated as part of this disease entry?

KNOWLEDGE GAP RESOLVED ireb2-copd-locus-not-causal

Attached to

genetic#IREB2

No, and the question is recorded here because the answer is not obvious from a literature search and because getting it wrong is the most likely way this entry could be corrupted. Most published work naming IREB2 concerns common-variant association with COPD and lung cancer at 15q25.1, where the gene sits immediately adjacent to the nicotinic acetylcholine receptor subunit cluster CHRNA5-CHRNA3-CHRNB4 that carries the smoking-behaviour signal. Those associations describe a different phenotype, a different variant class, a different inheritance model and, most likely, a different causal gene at the same locus. They are not evidence about NDCAMA and none of that literature is cited in this entry. Recorded as RESOLVED because the scoping decision has been made, not because the biology of the 15q25 locus is settled.

A separate and genuinely open question, deliberately not conflated with the one above, is whether IRP2 hypomorphism has any effect on lung biology through the mechanism curated here. Nothing in the four case reports addresses respiratory phenotype, and this entry makes no claim either way.

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Pathophysiology

Bi-allelic Loss-of-Function IREB2 Variants

The primary lesion is bi-allelic damage to IREB2 at 15q25.1, reported against transcript NM_004136. Two allele classes have been seen. The index patient carried two nonsense alleles, and his cells contained no detectable IRP2 at all. The three later patients carried missense alleles - and in one case a three-base in-frame deletion - which do not abolish the protein but either destabilise it or degrade its RNA-binding function. The distinction matters because it predicts the shape of the future phenotypic spectrum: complete loss of function has so far always produced severe disease, and partial loss of function is the untested territory where milder disease should be sought.

IREB2 hgnc:6115

Downstream

Absence or Accelerated Degradation of IRP2 Protein Nonsense alleles remove the protein through transcript decay; the p.Asp826Val allele, which lies near the FBXL5-binding region, leaves the protein constitutively degradable.

Impaired IRE-Binding Activity of Residual IRP2 Missense alleles clustered near the RNA-binding surface leave IRP2 present but functionally weakened, a graded rather than all-or-none lesion.

Show evidence (3 references)

PMID:30915432 SUPPORT Human Clinical

"Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."

Names the causal gene and establishes that bi-allelic loss of function removes the protein product.

PMID:39587636 SUPPORT Human Clinical

"WES identified novel biallelic variants, c.1111 A > G (P.Ile371Val) and c.2477 A > T (P.Asp826Val), in the IREB2 gene, which encodes the iron metabolism-related protein, IRP2."

Provides the second allele class - biallelic missense - and names the gene product whose function the rest of this pathograph concerns.

PMID:39587636 SUPPORT Human Clinical

"The first case exhibited two nonsense mutations"

Records the allele class of the index patient, which is what makes his complete absence of IRP2 interpretable as a null genotype.

Absence or Accelerated Degradation of IRP2 Protein

The abundance arm of the lesion. In the index patient, whose two alleles are nonsense, patient-derived lymphoblasts contained no IRP2, attributed by the authors to nonsense-mediated decay of the transcript. In the fourth patient the mechanism is different and better resolved: the p.Asp826Val allele reduced IRP2 protein by roughly 70% when expressed in SH-SY5Y neuroblastoma cells, and the loss was reversed by the proteasome inhibitor MG-132. That the lesion is post-transcriptional was established in a separate experiment and a separate material - RT-qPCR on the patient's own peripheral blood mononuclear cells showed no appreciable alteration of IREB2 at the mRNA level, which the authors used to exclude the splicing abnormality proposed for earlier patients. Structural modelling places residue 826 close to the surface through which IRP2 is recognised by FBXL5. That is the physiological degradation route being hijacked. In an iron-replete and oxygen-replete cell, the SCF-FBXL5 ubiquitin ligase binds IRP2, polyubiquitinates it and delivers it to the proteasome; FBXL5's substrate-binding domain carries an oxygen-responsive [2Fe2S] cluster that organises the loop which grips IRP2, and the same interaction sterically prises IRP2 off its IRE. A variant that makes IRP2 a better or constitutively available FBXL5 substrate therefore removes the protein by the cell's own quality-control machinery rather than by any defect in folding per se - which is why proteasome inhibition restores it.

patient-derived lymphoblasts CL:0017005

IREB2 hgnc:6115

SCF-FBXL5 ubiquitin ligase complex GO:0019005

proteasomal degradation of IRP2 GO:0043161 ↑ INCREASED polyubiquitination of IRP2 by SCF-FBXL5 GO:0000209 ↑ INCREASED nonsense-mediated decay of nonsense-allele IREB2 transcripts GO:0000184 ↑ INCREASED

Downstream

Loss of IRE-Dependent Post-Transcriptional Control No IRP2 protein means no IRE occupancy, regardless of the cell's actual iron status.

Show evidence (9 references)

PMID:30915432 SUPPORT In Vitro

"Cellular phenotyping at the RNA and protein level was performed using patient and control lymphoblastoid cell lines, and established experimental assays."

Identifies the patient-derived cell system in which the absence of IRP2 and its downstream consequences were demonstrated.

PMID:39587636 SUPPORT In Vitro

"Cellular studies utilizing patient-derived lymphoblasts demonstrated a complete loss of IRP2 expression in the first case"

Confirms in a second publication that the index patient's nonsense genotype produces complete absence of the protein.

PMID:39587636 SUPPORT In Vitro

"Western blot analysis revealed that the A2477T mutation led to an approximate 70% reduction in IRP2 expression,"

Quantifies the abundance defect caused by the p.Asp826Val allele in an isogenic overexpression system, separating it from the second, milder allele.

+ 6 more references

Impaired IRE-Binding Activity of Residual IRP2

The activity arm of the lesion, and the reason the disorder is expected to be a spectrum rather than a binary. IRP2 recognises IREs through a four-domain arrangement homologous to cytosolic aconitase; missense changes on or near that RNA-binding surface can leave the protein present and stable while degrading how well it reads the IRE. In the fourth patient the p.Ile371Val allele behaved exactly this way: expressed alone it left IRP2 abundance, transferrin receptor and labile iron essentially unchanged, with only a slight rise in ferritin heavy chain, and the authors classified it as the mild allele of the pair - not an inert one - sitting close to the IRE-binding domains rather than the FBXL5 interface. The three severely affected patients characterised to date all had effectively complete loss of IRP2 function, which is the explicit basis for the published prediction that partial loss of function should produce milder, currently unrecognised disease.

IREB2 hgnc:6115

iron-responsive element binding GO:0030350 ↓ DECREASED mRNA binding GO:0003729 ↓ DECREASED

Downstream

Loss of IRE-Dependent Post-Transcriptional Control Reduced IRE occupancy produces a partial version of the same regulatory failure.

Show evidence (4 references)

PMID:35602653 SUPPORT Human Clinical

"underscore that IREB2 pathological variants may impact the iron-responsive element-binding activity of IRP2 with varying degrees of severity"

States the mechanism this node models - that pathogenic alleles act by degrading IRE-binding activity to differing extents.

PMID:35602653 SUPPORT Human Clinical

"The three severely affected patients identified so far all suffered from complete loss of function of IRP2, raising the possibility that individuals with significant but incomplete loss of IRP2 function may develop less severe forms of the disease"

Establishes that all severe cases to date are functional nulls and frames partial loss of function as an untested, predicted milder phenotype.

PMID:39587636 SUPPORT Computational

"One mild mutation was located close to functional domains where IRP2 binds to the IRE element of iron metabolism-related"

Locates the milder allele of the fourth patient at the RNA-binding surface rather than at the degradation interface, which is the structural distinction this node captures.

+ 1 more reference

Loss of IRE-Dependent Post-Transcriptional Control

This is the node where a molecular lesion becomes a systems failure. IRPs are the sensor arm of a single feedback loop that operates entirely after transcription: bound to a 5' IRE they block ribosome loading, bound to a 3' IRE they protect the transcript from endonucleolytic decay. The transcripts involved include the ferritin heavy and light chains and erythroid ALAS2 (5' IREs, translationally repressed by IRP binding) and TFRC (3' IREs, stabilised by IRP binding); transcriptome-wide immunoselection has since extended the IRP-bound mRNA set well beyond these canonical members and shown that IRP1 and IRP2 have partly non-overlapping target repertoires. Without IRP2 the loop reads permanently "iron replete" regardless of the truth: ferritin translation is derepressed, so the cell builds storage capacity it does not need and locks iron inside it, while TFRC mRNA loses its stabilising protein and decays, so transferrin-mediated uptake falls. Both changes push iron the same way - out of the metabolically available pool. That is the specific reason the resulting deficiency is a *functional* one that no amount of circulating iron corrects.

cytosolic ferritin GO:0070288

IRE-mediated translational repression of ferritin and ALAS2 GO:0017148 ↓ DECREASED IRP-dependent stabilisation of TFRC mRNA GO:0048255 ↓ DECREASED intracellular iron ion homeostasis GO:0006879 ⚠ ABNORMAL

iron-responsive element binding GO:0030350 ↓ DECREASED

Downstream

Functional Cytosolic Iron Deficiency Derepressed ferritin sequesters iron while reduced transferrin receptor limits its import, emptying the metabolically available pool.

Show evidence (5 references)

PMID:11175792 SUPPORT Other

"Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC)."

States the normal regulatory logic - 5' IRE translational repression and 3' IRE transcript stabilisation - that is lost when IRP2 is absent.

PMID:15831703 SUPPORT Model Organism

"Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues."

Demonstrates the paired direction of the regulatory failure in vivo - ferritin up, transferrin receptor down - across tissues.

PMID:30915432 SUPPORT In Vitro

"Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model."

Confirms in human patient cells that the post-transcriptional regulation of iron metabolism genes is altered and that the consequence is functional iron deficiency.

+ 2 more references

Failure of IRP1 to Compensate

A paralogue exists and does not rescue, and understanding why is what makes a single-gene lesion in a two-gene system disease-causing. IRP1 is bifunctional: with an intact [4Fe-4S] cluster it is cytosolic aconitase, and only in the apo form does it bind IREs. In intact animal tissues most IRP1 is the aconitase form, and - the decisive observation - its RNA-binding activity does not increase on a low-iron diet that is sufficient to activate IRP2. The small RNA-binding fraction of IRP1 is essentially insensitive to cellular iron status. The relationship is asymmetric: IRP2 can compensate for the loss of IRP1 by increasing its binding activity, so Irp1-null mice misregulate iron only in kidney and brown fat, whereas Irp2-null mice misregulate target proteins in every tissue. IRP2 dominates post-transcriptional iron regulation in mammals, and its loss is therefore not buffered. This asymmetry is also the entry point for the only mechanism-directed therapy tested in vivo. Feeding Irp2-null mice the nitroxide Tempol disassembles the IRP1 iron-sulfur cluster, converting latent aconitase into active IRE-binding protein, which restabilises the TfR1 transcript and represses ferritin synthesis - and markedly attenuates the neuromuscular disease. The therapeutic logic is to unmask a redundancy the cell does not normally use.

iron-sulfur cluster assembly in IRP1 GO:0016226

cytosolic aconitase activity of IRP1 GO:0003994 ↑ INCREASED

Downstream

Functional Cytosolic Iron Deficiency Because the paralogue does not step in, the regulatory failure is passed through undamped to the cellular iron pool.

Show evidence (4 references)

PMID:14726953 SUPPORT Model Organism

"IRP1-/- mice misregulate iron metabolism only in the kidney and brown fat, two tissues in which the endogenous expression level of IRP1 greatly exceeds that of IRP2, whereas IRP2-/- mice misregulate the expression of target proteins in all tissues."

Establishes the asymmetry between the two paralogues that makes IRP2 loss, and not IRP1 loss, a systemic disease.

PMID:14726953 SUPPORT Model Organism

"In animal tissues, most of the bifunctional IRP1 is in the form of cytosolic aconitase rather than an RNA-binding protein."

Gives the biochemical reason IRP1 cannot substitute - the majority of it is not in the RNA-binding state.

PMID:14726953 SUPPORT Model Organism

"Thus, IRP2 dominates post-transcriptional regulation of iron metabolism in mammals."

States the conclusion that underwrites treating IREB2 loss as a non-redundant lesion.

+ 1 more reference

Functional Cytosolic Iron Deficiency

The central pathological state of this disease, and the one that unifies the brain and the erythron. Cells lose access to iron even though the organism has enough: transferrin saturation is normal in the Irp2-null mouse and serum iron was within the normal range in the reported patients, yet marrow iron stores are absent in the mouse and patient cells show functional iron deficiency on direct assay. Intracellular ferrous iron fell sharply in cells expressing the severe p.Asp826Val allele and was restored when the protein was restored. Two consequences follow immediately and account for most of the phenotype. Iron is a cofactor for the enzymes of mitochondrial respiration, for iron-sulfur cluster and haem biosynthesis, for myelin lipid synthesis and for monoamine neurotransmitter synthesis; and haemoglobinisation of the developing red cell is quantitatively the largest iron demand in the body. A cell-autonomous iron supply failure therefore strikes hardest at the two tissues with the highest and least interruptible iron requirement - the developing brain and the erythroid marrow.

transferrin-mediated iron import GO:0006826 ↓ DECREASED intracellular iron ion homeostasis GO:0006879 ⚠ ABNORMAL

Downstream

Iron-Limited Erythropoiesis The erythroid arm - the developing red cell cannot obtain the iron it needs for haemoglobinisation.

Mitochondrial Dysfunction from Iron-Sulfur Cluster and Haem Insufficiency The bioenergetic arm, common to all affected tissues but decisive in neurons.

HIF2-alpha Stabilisation and the Glycolytic Shift An iron-sensing consequence layered on top of the direct cofactor shortage, demonstrated in Irp2-null mouse cells and tissue.

Neuronal and Oligodendrocyte Iron Mishandling The central nervous system arm, where the same shortage meets the highest developmental iron demand.

Show evidence (5 references)

PMID:30915432 SUPPORT In Vitro

"Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model."

Direct demonstration of functional iron deficiency in cells from the index patient.

PMID:35602653 SUPPORT In Vitro

"Biochemical characterization of a lymphoblast cell line derived from the patient revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes and mitochondrial dysfunction."

Replicates the same cellular state in an independent patient with a different allele class, which is what makes it a property of the disease rather than of one genotype.

PMID:39587636 SUPPORT In Vitro

"The intracellular Fe 2+ level in the A2477T group was drastically reduced"

Measures the fall in labile ferrous iron attributable specifically to the severe allele.

+ 2 more references

Iron-Limited Erythropoiesis

The erythroid consequence, and the reason the disease name carries the word anaemia. Erythroid precursors depend on transferrin receptor 1 more heavily than any other cell type; when TFRC mRNA loses IRP2-dependent stabilisation, TfR1 falls on the precursor surface and iron delivery to the developing erythroblast fails. In the Irp2-null mouse this produces microcytic anaemia with absent marrow iron stores despite normal transferrin saturation - a genetically distinct paradigm from either classical iron-deficiency anaemia or the thalassaemias. The mouse adds a second, mechanistically instructive lesion. ALAS2, the erythroid-specific first enzyme of haem synthesis, carries a 5' IRE and is normally translationally repressed when iron is scarce - the cell's way of not building porphyrin rings it cannot fill with iron. Losing IRP2 derepresses ALAS2 exactly when iron is unavailable, so protoporphyrin IX is overproduced and accumulates, some of it chelating zinc instead of iron. The result is an erythropoietic protoporphyria on top of the anaemia. In humans the anaemia is present but mild, and the protoporphyrin arm has not been reported at all - see the knowledge gap below.

erythroblast CL:0000765 erythroid lineage cell CL:0000764

erythrocyte differentiation GO:0030218 ⚠ ABNORMAL haem biosynthesis uncoupled from iron availability GO:0006783 ⚠ ABNORMAL

Downstream

Extrapyramidal Movement Disorder and Neurodevelopmental Arrest The haematological arm contributes little to disability directly, but it is the readily measurable systemic signature that points to the diagnosis.

Show evidence (4 references)

PMID:15831703 SUPPORT Model Organism

"Here, we report that ablation of IRP2 results in iron-limited erythropoiesis."

Names the mechanism of the anaemia as iron-limited erythropoiesis rather than a primary erythroid defect.

PMID:15831703 SUPPORT Model Organism

"Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRP-dependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2-/- erythroid cells."

Establishes the ALAS2 derepression arm and its biochemical consequence, the protoporphyrin accumulation.

PMID:15831703 SUPPORT Model Organism

"IRP2-/- mice represent a new paradigm of genetic microcytic anemia."

Positions the anaemia as a distinct genetic entity rather than as ordinary iron deficiency, which is what makes the normal serum iron in patients diagnostically important.

+ 1 more reference

Mitochondrial Dysfunction from Iron-Sulfur Cluster and Haem Insufficiency

Iron reaches the respiratory chain as iron-sulfur clusters and haem prosthetic groups, both assembled in and around the mitochondrion from imported iron. When the cytosolic supply fails, cluster and haem assembly are starved of substrate and respiratory complexes cannot be built. Mitochondrial dysfunction was found in patient-derived cells in both functionally studied patients, alongside the altered iron-gene regulation, and it is the most plausible proximate cause of the vulnerability of neurons - post-mitotic cells with a large and inflexible oxidative demand. The same dependency is why an iron-supply lesion presents as a neurodegenerative rather than a purely haematological disease.

iron-sulfur cluster assembly GO:0016226 ↓ DECREASED oxidative phosphorylation GO:0006119 ↓ DECREASED

mitochondrion GO:0005739

Downstream

Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss Chronic bioenergetic insufficiency in post-mitotic neurons drives progressive attrition.

Show evidence (4 references)

PMID:30915432 SUPPORT In Vitro

"Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model."

Demonstrates mitochondrial dysfunction in cells from the index patient and ties it to the same iron-regulatory lesion.

PMID:35602653 SUPPORT In Vitro

Independent replication of the mitochondrial phenotype in a second patient's cells.

PMID:35602653 SUPPORT Other

"Altered brain iron homeostasis can contribute to neurodegeneration by interfering with the delivery of the iron needed to support key cellular processes, including mitochondrial respiration, synthesis of myelin and essential neurotransmitters."

Names the three iron-dependent neural processes - respiration, myelination and neurotransmitter synthesis - through which a supply failure becomes neurodegeneration.

+ 1 more reference

HIF2-alpha Stabilisation and the Glycolytic Shift

A second, indirect consequence of cellular iron shortage. The prolyl hydroxylases that mark hypoxia-inducible factor subunits for degradation are themselves iron(II)-dependent, so a cell that cannot obtain iron behaves as though it were hypoxic. In globally Irp2-depleted mouse embryonic fibroblasts both Hif1-alpha and Hif2-alpha rose; Hif1-alpha drove glycolytic gene expression while Hif2-alpha suppressed iron-sulfur cluster biogenesis and electron transport chain genes, weakening respiration. In Irp2-null mice the in vivo picture is narrower and more informative - Hif2-alpha, not Hif1-alpha, was elevated in tissues, most markedly in the cerebellum and spinal cord, the regions the disease targets. Inhibiting Hif2-alpha with PT-2385 prevented the neurodegenerative phenotype and restored Purkinje cell architecture, while inhibiting Hif1-alpha did not. This makes the switch from oxidative phosphorylation to aerobic glycolysis a candidate driver rather than a bystander, and it identifies the first druggable node in the pathograph downstream of the untreatable primary lesion.

cellular response to hypoxia GO:0071456 ↑ INCREASED aerobic glycolysis GO:0006096 ↑ INCREASED oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss A sustained shift away from oxidative phosphorylation compounds the direct cofactor shortage in the same cells.

Show evidence (4 references)

PMID:31040213 SUPPORT In Vitro

"we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α."

Establishes that loss of Irp2 stabilises both HIF subunits in cells, the observation on which the whole arm rests.

PMID:31040213 SUPPORT In Vitro

"The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron-sulfur cluster (Fe-S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration."

Separates the two subunits' contributions and links Hif2-alpha specifically to suppression of Fe-S and respiratory chain genes.

PMID:34675764 SUPPORT Model Organism

"we confirmed the upregulation of Hif2α, not Hif1α, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of Irp2 -/- mice."

Shows that in vivo only Hif2-alpha is elevated, and that it is elevated in the CNS regions the disease targets.

+ 1 more reference

Neuronal and Oligodendrocyte Iron Mishandling

The central nervous system is where the regulatory lesion is least tolerable and, confusingly, where it looks most like the opposite of what it is. In Irp2-null mice, ferric iron accumulates in the cytosol of neurons and oligodendrocytes in specific brain regions and in white matter tracts, with ferritin colocalising in the very neuronal populations that later degenerate and ubiquitin-positive inclusions accumulating in iron-laden oligodendrocytes. Those accumulations precede the movement disorder by months. The reconciliation with functional iron deficiency is that derepressed ferritin sequesters iron in a form the cell cannot use: the tissue is iron-loaded and the cytosolic labile pool is empty at the same time. Oligodendrocytes matter disproportionately here because they are the most iron-demanding cells in the brain - myelin lipid synthesis is iron-dependent - and delayed myelination with white matter loss is exactly what the patients' imaging shows.

neuron CL:0000540 oligodendrocyte CL:0000128 cerebellar Purkinje cell CL:0000121

ferritin complex GO:0070288

myelination GO:0042552 ↓ DECREASED

Downstream

Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss Cell-autonomous iron mishandling in neurons and oligodendrocytes precedes and predicts the regions that degenerate.

Synaptic Failure and Microglial Activation Demonstrated in the knock-in model of a patient allele, at an age before overt neuronal loss.

Show evidence (4 references)

PMID:11175792 SUPPORT Model Organism

"Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain."

Identifies the two CNS cell types in which iron is mishandled in the null mouse.

PMID:11175792 SUPPORT Model Organism

"Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions."

Links ferritin-sequestered iron spatially to the neurons that go on to die, which is the basis for treating sequestration rather than simple overload as the pathogenic form.

PMID:11175792 SUPPORT Model Organism

"Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months."

Establishes the temporal order - iron mishandling first, degeneration afterwards - which is what makes this node upstream rather than a consequence of cell death.

+ 1 more reference

Synaptic Failure and Microglial Activation

The newest and most disease-specific piece of the mechanism, and the only in vivo work built on an actual patient allele rather than a null. A CRISPR-Cas9 knock-in mouse homozygous for the p.Asp826Val variant found in the Chinese pedigree shows reduced Ireb2 protein, dysregulated iron metabolism, impaired spatial learning and memory and reduced motor activity, together with increased microglial activation and decreased hippocampal dendritic spine density, impaired long-term potentiation and elevated paired-pulse facilitation. That combination - fewer spines, weaker potentiation, altered presynaptic release probability, activated microglia - describes synaptic failure with neuroinflammation rather than cell loss, and it fits a disorder whose human presentation is developmental as much as degenerative: these children largely never acquired speech or ambulation rather than losing skills they once had.

microglial cell CL:0000129 hippocampal neuron CL:0002608

microglial cell activation GO:0001774 ↑ INCREASED long-term synaptic potentiation GO:0060291 ↓ DECREASED

dendritic spine GO:0043197

Downstream

Extrapyramidal Movement Disorder and Neurodevelopmental Arrest Synaptic dysfunction offers a mechanism for the developmental component of the phenotype that neuronal loss alone does not explain.

Show evidence (3 references)

PMID:41234066 SUPPORT Model Organism

"we establish a CRISPR-Cas9-mediated Ireb2 D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA."

Establishes that this model carries the human patient allele, which is what makes its findings interpretable for this specific disorder rather than for generic Irp2 loss.

PMID:41234066 SUPPORT Model Organism

"Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction."

Provides the synaptic and neuroinflammatory findings that this node asserts.

PMID:41234066 SUPPORT Model Organism

"Mechanistically, Ireb2 D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function."

Confirms that the knock-in reproduces the molecular lesion (reduced protein, disordered iron handling) as well as the behavioural phenotype.

Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss

The tissue-level endpoint. In the Irp2-null mouse the abnormal brain iron metabolism is followed by adult-onset progressive neurodegeneration with widespread axonal degeneration and neuronal loss, and the disease worsens with age. In patients the corresponding observations are radiological rather than histological: progressive cerebral volume loss, delayed myelination and reduced white matter volume across the reported series, with frontal lobe atrophy in the index patient and periventricular, basal ganglia and thalamic signal abnormality in the fourth. The human timescale is compressed relative to the mouse - disease is manifest from infancy rather than from adulthood - which is one of the clearest quantitative mismatches between the model and the disease.

neuron CL:0000540

neuron apoptotic process GO:0051402 ↑ INCREASED

Downstream

Extrapyramidal Movement Disorder and Neurodevelopmental Arrest Loss of striatal, cerebellar and cortical circuitry produces the clinical syndrome.

Show evidence (4 references)

PMID:15831703 SUPPORT Model Organism

"However, in the central nervous system, evidence of abnormal iron metabolism in IRP2-/- mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss."

Gives the neuropathological substrate - axonal degeneration and neuronal loss - and its temporal relationship to the iron abnormality.

PMID:39587636 SUPPORT Human Clinical

"Furthermore, brain imaging studies revealed progressive cerebral volume loss, delayed myelination, and a reduction in white"

The human counterpart, drawn across all four reported patients - progressive volume loss with a myelination deficit.

PMID:39239479 SUPPORT Other

"The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."

Records the structural brain finding in the index patient and the diagnostic label he carried before the genetic cause was known. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.

+ 1 more reference

Extrapyramidal Movement Disorder and Neurodevelopmental Arrest

The clinical endpoint. All four patients converge on the same picture: neonatal feeding difficulty and hypotonia, then profound global developmental delay with no speech and no independent ambulation, severe dystonia and choreoathetoid movements, and epilepsy or EEG abnormality. The movement disorder has been explicitly described as treatment-resistant. The phenotype is developmental and degenerative at once, which is why the first patient carried a diagnosis of dystonic cerebral palsy before exome sequencing reassigned it - a mislabelling that any child with this genotype is likely to receive first.

Show evidence (4 references)

PMID:30915432 SUPPORT Human Clinical

"This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."

Names the defining clinical feature and its refractoriness to treatment.

PMID:35602653 SUPPORT Human Clinical

"Here, we report the case of a 7-year-old male patient with compound heterozygous missense variants in IREB2, whose neurological features resembled those of the two previously reported IRP2-deficient patients, including a profound global neurodevelopmental delay and dystonia."

Confirms the syndrome recurs across patients with different alleles, establishing it as the disease phenotype rather than one family's presentation.

PMID:39587636 SUPPORT Human Clinical

"The patient presented with early global developmental delay, which was characterized by an inability to speak or walk, alongside severe dystonia, choreoathetoid movements, epilepsy, and non-specific facial dysmorphisms such as midface hypoplasia, short philtrum, low-set ears, and thick, wiry hair"

The most detailed single-patient description available, and the source for the dysmorphic features recorded in the phenotype list.

+ 1 more reference

⬡

Pathograph

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

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Phenotypes

Digestive 1

Feeding difficulties Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:39587636 SUPPORT Human Clinical

"All three previously reported cases, along with our patient, exhibited similar clinical features, including neonatal feeding difficulties, hypotonia, choreoathetoid"

Names neonatal feeding difficulties explicitly within the feature list shared by all four genotyped patients.

PMID:39587636 SUPPORT Human Clinical

"His older sister also had developmental delays and feeding difficulties."

Records feeding difficulty additionally in the proband's affected but never-genotyped sister.

Head and Neck 1

Abnormal facial shape Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"impaired ambulation and communication, and non-specific facial dysmorphisms"

Records non-specific facial dysmorphism as a shared feature of the four reported patients.

Musculoskeletal 1

Hypotonia Hypotonia HP:0001252

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"All three previously reported cases, along with our patient, exhibited similar clinical features, including neonatal feeding difficulties, hypotonia, choreoathetoid"

Names hypotonia explicitly within the feature list shared by all four reported patients.

Nervous System 8

Global developmental delay Global developmental delay HP:0001263

Course: PROGRESSIVE

Show evidence (2 references)

PMID:35602653 SUPPORT Human Clinical

Records profound global developmental delay in the third patient and states that it was shared with the two earlier ones.

PMID:39587636 SUPPORT Human Clinical

"impaired ambulation and communication, and non-specific facial dysmorphisms"

Confirms impaired ambulation and communication across all four reported cases.

Choreoathetosis Choreoathetosis HP:0001266

Show evidence (2 references)

PMID:30915432 SUPPORT Human Clinical

"This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."

Documents the choreoathetoid movement disorder and its refractoriness in the index patient.

PMID:39587636 SUPPORT Human Clinical

Records choreoathetoid movements in the fourth patient.

Dystonia Dystonia HP:0001332

Severity: SEVERE

Show evidence (2 references)

PMID:35602653 SUPPORT Human Clinical

Documents dystonia in the third patient and its shared occurrence with earlier cases.

PMID:39587636 SUPPORT Human Clinical

"The patient's clinical presentations, including developmental delay, epilepsy,"

Introduces the fourth patient's feature list, which continues with hypertonia and microcytic anaemia.

Seizure Seizure HP:0001250

Show evidence (2 references)

PMID:39587636 SUPPORT Human Clinical

Records epilepsy in the fourth patient.

PMID:39239479 SUPPORT Other

"The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."

Records epilepsy in the index patient. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.

EEG abnormality EEG abnormality HP:0002353

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"Notably, electroencephalograms (EEG) were abnormal in all three patients, although clinical seizures were not observed in the second patient"

Directly supports both the universality of EEG abnormality in the first three patients and its dissociation from clinical seizures.

Absent speech Absent speech HP:0001344

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

Documents inability to speak in the fourth patient; impaired communication is separately recorded across all four.

Cerebral atrophy Cerebral atrophy HP:0002059

Course: PROGRESSIVE

Show evidence (2 references)

PMID:39587636 SUPPORT Human Clinical

"Furthermore, brain imaging studies revealed progressive cerebral volume loss, delayed myelination, and a reduction in white"

States that progressive cerebral volume loss is a finding of the reported series as a whole.

PMID:39239479 SUPPORT Other

"The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."

Records the regional (frontal) atrophy in the index patient. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.

Delayed myelination Delayed myelination HP:0012448

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"Furthermore, brain imaging studies revealed progressive cerebral volume loss, delayed myelination, and a reduction in white"

Directly reports delayed myelination and white matter reduction across the reported cases.

Other 3

Microcytic anemia Microcytic anemia HP:0001935

Severity: MILD

Reported as microcytic hypochromic anaemia in the index patient. The haemoglobin and MCV figures quoted in this description are the fourth patient's, from the full text of PMID:39587636, together with that laboratory's own reference intervals; they are not population norms and are not a claim about the other three patients, whose values are not available in cached sources.

Show evidence (3 references)

PMID:39239479 SUPPORT Other

"The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."

Records microcytic hypochromic anaemia in the index patient. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.

PMID:39587636 SUPPORT Human Clinical

Records microcytic anaemia in the fourth patient.

PMID:41234066 SUPPORT Other

"Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia."

Confirms that microcytic anaemia is part of the defining triad of the named entity, tied to the same OMIM number as the MONDO term curated here.

Inability to walk Inability to walk HP:0002540

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"impaired ambulation and communication, and non-specific facial dysmorphisms"

Records impaired ambulation as a shared feature of all four reported patients.

Cerebral white matter atrophy Cerebral white matter atrophy HP:0012762

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"A brain MRI at 8 years old revealed abnormal signals around the lateral ventricles, basal ganglia, and thalamus."

Documents the regional distribution of the imaging abnormality in the fourth patient.

🧬

Genetic Associations

IREB2 (Bi-allelic loss-of-function or hypomorphic variants; all four reported probands were compound heterozygous)

Gene: IREB2 hgnc:6115 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:30915432 SUPPORT Human Clinical

"Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."

Establishes IREB2 as the causal gene through the index case.

PMID:30915432 SUPPORT In Vitro

"The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression."

The strongest single piece of gene-disease validity evidence available - restoring the gene product in patient cells reverses the cellular phenotype.

PMID:35602653 SUPPORT In Vitro

"The iron metabolism abnormalities of the patient cell line were reversed by lentiviral-mediated restoration of IREB2 expression."

Independent replication of the rescue experiment in a second patient's cells with a different allele class.

+ 2 more references

💊

Medical Actions

Supportive and symptomatic management

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

No disease-modifying therapy exists. Management is supportive: feeding support in infancy, anticonvulsants for epilepsy, physical therapy and posture management for dystonia, and the usual multidisciplinary care of a child with profound developmental impairment. The movement disorder in the index patient was explicitly described as treatment-resistant, so families should not be led to expect a good response to standard antidystonic or antichoreic agents.

Show evidence (1 reference)

PMID:30915432 SUPPORT Human Clinical

"This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."

Documents the refractoriness of the movement disorder, which is the basis for framing management as supportive rather than therapeutic.

Anticonvulsant therapy

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

Seizures occur in most patients and are managed with standard antiseizure medication. No agent has been reported as preferred or as contraindicated in this disorder, and no seizure-outcome data exist; the recommendation is therefore generic epilepsy care rather than anything IREB2-specific.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:39239479 SUPPORT Other

"The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."

Establishes that epilepsy is part of the phenotype requiring management. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.

Genetic counselling for an autosomal recessive disorder

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

Both parents of an affected child are obligate carriers and the recurrence risk in each pregnancy is one in four. All four reported families were non-consanguineous and each child was compound heterozygous, so carrier testing must cover both parental alleles rather than assume a single familial variant. Carrier siblings, such as the fourth proband's younger brother, are healthy.

Show evidence (1 reference)

PMID:39587636 SUPPORT Human Clinical

"Sanger sequencing confirmed the paternal (A2477T) and maternal (A1111G) origins of the"

Demonstrates the biparental origin of the two alleles that underlies the recurrence risk and the need to test both parents.

Physical therapy and rehabilitation

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

Physiotherapy, positioning and contracture prevention are the mainstay of motor management in a child with severe dystonia who does not ambulate. No trial data exist in this disorder; the rationale is extrapolated from care of other severe early-onset dystonic syndromes.

Investigational - HIF2-alpha inhibition

Category: Therapeutic

The most developed mechanism-directed lead, and preclinical only. In Irp2-null mice the selective HIF2-alpha inhibitor PT-2385 prevented neurodegenerative symptoms and restored Purkinje cell architecture, while inhibiting HIF1-alpha with PX-478 did not; PT-2385 also improved mitochondrial morphology and suppressed the glycolytic shift. PT-2385 is a small-molecule HIF2-alpha inhibitor of the same pharmacological class as belzutifan, the first-in-class HIF-2alpha inhibitor developed for clear cell renal carcinoma, so the chemistry is tractable in principle. That class comparison also carries a warning specific to this disorder: anaemia is a recognised on-target toxicity of belzutifan, and NDCAMA patients are already anaemic. Nothing has been tested in a patient and the murine treatment was given to adult animals with a slowly progressive disease, which is a poor match for an infant with established developmental arrest.

Mechanism Target:

INHIBITS HIF2-alpha Stabilisation and the Glycolytic Shift — PT-2385 blocks HIF2-alpha directly, which in the null mouse was sufficient to prevent the neurodegenerative phenotype.

Show evidence (4 references)

PMID:34675764 SUPPORT Model Organism

"Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array."

The primary preclinical result behind this lead, including the negative control arm that makes it specific to HIF2-alpha.

PMID:34675764 SUPPORT Model Organism

"PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo but also suppressed glycolysis."

Shows the treatment acts on the proposed mechanism and not only on the behavioural readout.

PMID:39670660 SUPPORT Other

"Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor."

Sources the class comparison drawn in the description; this reference is about oncology, not IREB2, and is cited only to establish that HIF2-alpha inhibition is a clinically developed pharmacology.

+ 1 more reference

Investigational - recruiting latent IRP1 activity

Category: Therapeutic

A conceptually distinct preclinical strategy: rather than replacing IRP2, convert the abundant but latent aconitase pool of IRP1 into IRE-binding protein. Dietary Tempol, a stable nitroxide, did exactly this in Irp2-null mice - disassembling the IRP1 iron-sulfur cluster, restabilising the TfR1 transcript, repressing ferritin synthesis and markedly attenuating the progression of neuromuscular impairment. It is the only intervention shown to modify the neurological phenotype of an Irp2-null animal from the upstream regulatory node rather than from a downstream consequence, and it has never been tried in a patient.

Mechanism Target:

MODULATES Failure of IRP1 to Compensate — Tempol acts on the compensation failure itself, converting latent IRP1 aconitase into IRE-binding protein so that the paralogue substitutes for the missing IRP2.

Show evidence (2 references)

PMID:18685102 SUPPORT Model Organism

"In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated."

The efficacy result in the null mouse.

PMID:18685102 SUPPORT Model Organism

"We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain."

Gives the proposed mechanism, which is what makes this strategy allele-agnostic and applicable even to nonsense genotypes.

Investigational - stabilising a degradation-prone IRP2

Category: Therapeutic

An allele-specific idea rather than a therapy. Because the p.Asp826Val protein is lost to the proteasome rather than mis-folded into uselessness, blocking its degradation restores both the protein and its regulatory output in cells. The authors of the fourth case report frame proteasome inhibition as a potential therapeutic direction. The caveats are severe: MG-132 is a research tool with no clinical use, clinically approved proteasome inhibitors are systemically toxic and poorly CNS-penetrant, and the strategy could only ever help the subset of patients whose alleles are degradation-prone. Restoration of IREB2 expression itself - achieved lentivirally in two independent patient cell lines - is the corresponding gene-directed proof of principle.

Mechanism Target:

INHIBITS Absence or Accelerated Degradation of IRP2 Protein — Blocking proteasomal turnover restores a degradation-prone IRP2 and with it the downstream iron-regulatory output; applicable only to alleles that act by destabilising the protein.

Show evidence (2 references)

PMID:39587636 SUPPORT In Vitro

"Moreover, the use of proteasome inhibitors can potentially restore the expression of IRP2, highlighting a promising therapeutic target"

The authors' own statement of the therapeutic hypothesis, made on the basis of the MG-132 rescue in their cell model.

PMID:30915432 SUPPORT In Vitro

"The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression."

Establishes that restoring the gene product is sufficient to reverse the cellular disease phenotype, the premise of any gene-directed therapy.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from IREB2-Related Neurodegeneration:

Aceruloplasminemia MONDO:0011426

Overlapping Features The closest conceptual mimic: a recessive disorder of iron handling that couples anaemia to neurodegeneration. Loss of ceruloplasmin ferroxidase activity blocks iron export from cells, so iron is trapped in brain and other tissues while the erythron goes short. Both disorders therefore present as anaemia plus movement disorder from a lesion in cellular iron trafficking rather than in iron supply.

Distinguishing Features

Caused by bi-allelic CP variants (HGNC:2295), not IREB2; verified with OAK as MONDO:0011426, OMIM:604290.
Onset is typically in adulthood, most often the fourth to sixth decade, whereas NDCAMA presents in infancy.
Serum ceruloplasmin is absent or near-absent and serum ferritin is markedly elevated, neither of which is a feature of NDCAMA.
Brain MRI shows striking iron deposition with hypointensity in basal ganglia, thalamus and dentate nucleus; NDCAMA imaging shows volume loss and delayed myelination without documented iron deposition.
Diabetes mellitus and retinal degeneration are characteristic of aceruloplasminemia and have not been reported in NDCAMA.

Neuroferritinopathy MONDO:0011638

Overlapping Features The instructive contrast within the IRE/IRP system itself. Neuroferritinopathy is caused by variants in FTL, the ferritin light chain - one of the very transcripts whose translation IRP2 represses. Both disorders produce a chorea-dominant extrapyramidal syndrome through disordered ferritin biology, but from opposite directions: NDCAMA loses the repressor, so ferritin is derepressed and iron is sequestered away from use, whereas neuroferritinopathy alters the ferritin polypeptide itself so that the assembled shell handles iron abnormally.

Distinguishing Features

Caused by FTL variants (HGNC:3999) and inherited dominantly; NDCAMA is recessive at IREB2. Verified with OAK as MONDO:0011638, OMIM:606159.
Adult onset, typically in the fourth or fifth decade, versus infantile onset in NDCAMA.
Serum ferritin is characteristically low in neuroferritinopathy; ferritin has been within the reference range in the reported NDCAMA patients.
MRI shows cavitation and iron deposition in the basal ganglia, which has not been described in NDCAMA.
Anaemia is not a feature of neuroferritinopathy.

Neurodegeneration with brain iron accumulation MONDO:0018307

Overlapping Features The category NDCAMA superficially resembles and deliberately is not assigned to. The NBIA disorders are defined by radiologically demonstrable iron accumulation in the basal ganglia together with an extrapyramidal movement disorder, and pantothenate kinase-associated neurodegeneration is their prototype. NDCAMA shares the movement disorder and the involvement of iron biology but has never been shown to accumulate brain iron in a human, and its cellular lesion is functional iron deficiency rather than overload. The Irp2-null mouse does accumulate brain iron, which is precisely why the distinction has to be made explicitly rather than assumed.

Distinguishing Features

NBIA is defined by demonstrable brain iron accumulation on MRI; no patient with IREB2 variants has been shown to have brain iron accumulation.
The NBIA prototype PKAN shows the eye-of-the-tiger sign in the globus pallidus, which has not been reported in NDCAMA.
NBIA disorders are genetically heterogeneous (PANK2, PLA2G6, C19orf12 and others) and do not include IREB2; MONDO:0018307 carries the OMIM phenotypic series OMIMPS:234200, verified with OAK.
Microcytic anaemia is not a feature of the NBIA disorders and is part of the defining triad of NDCAMA.
The cellular lesion in NDCAMA is functional cytosolic iron deficiency, the opposite of overload, even where tissue iron staining is increased in the mouse.

X-linked sideroblastic anemia with ataxia Not Yet Curated MONDO:0010524

Overlapping Features The other Mendelian disorder that pairs a microcytic anaemia with a movement disorder through a lesion in iron biology. ABCB7 exports a mitochondrial iron-sulfur cluster intermediate to the cytosol, so its loss impairs cytosolic Fe-S assembly and erythroid iron utilisation simultaneously - structurally the same kind of coupling as NDCAMA, at a different step.

Distinguishing Features

Caused by ABCB7 variants (HGNC:48) and X-linked recessive; NDCAMA is autosomal recessive at IREB2. Verified with OAK as MONDO:0010524, OMIM:301310.
The anaemia is sideroblastic with ring sideroblasts on marrow examination; the NDCAMA anaemia is iron-limited without reported ring sideroblasts.
The neurological phenotype is non-progressive or slowly progressive cerebellar ataxia from early childhood, not a choreoathetoid and dystonic syndrome with developmental arrest.
Affected individuals are male, with carrier females typically unaffected or mildly affected.

IRIDA syndrome Not Yet Curated MONDO:0008788

Overlapping Features The haematological differential for the anaemia considered in isolation. Iron-refractory iron deficiency anaemia is a recessive microcytic anaemia caused by TMPRSS6 variants that fails to respond to oral iron - a phenotype that can superficially resemble the treatment-unresponsive microcytosis of NDCAMA. The mechanisms are unrelated: IRIDA is a disorder of systemic hepcidin regulation limiting iron absorption and release, whereas NDCAMA is a cell-autonomous failure to use iron that is already present.

Distinguishing Features

Caused by bi-allelic TMPRSS6 variants (HGNC:16517); verified with OAK as MONDO:0008788, OMIM:206200.
There is no neurological phenotype in IRIDA; NDCAMA is dominated by neurological disease.
IRIDA shows low transferrin saturation and inappropriately high hepcidin; serum iron has been normal in the reported NDCAMA patients.
IRIDA anaemia is typically more marked and is the presenting problem, whereas the NDCAMA anaemia is mild and incidental to the presentation.

Erythropoietic protoporphyria MONDO:0001676

Overlapping Features Included because the Irp2-null mouse has erythropoietic protoporphyria as part of its phenotype, generated by ALAS2 derepression rather than by a ferrochelatase defect. If protoporphyrin accumulation is ever demonstrated in an IREB2 patient, the biochemical picture could be mistaken for classical EPP, and the distinction would rest on the absence of photosensitivity and on the accompanying neurological disease.

Distinguishing Features

Classical EPP arises from reduced ferrochelatase activity, most often bi-allelic FECH hypomorphism, not from IRP2 loss.
Photosensitivity with painful non-blistering phototoxicity is the cardinal feature of EPP and has not been reported in any IREB2 patient.
The protoporphyria of IRP2 deficiency is so far a murine finding only; no patient has had erythrocyte protoporphyrin reported.
EPP has no neurodegenerative component.

{ }

Source YAML

click to show

name: IREB2-Related Neurodegeneration
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
  term:
    id: MONDO:0032758
    label: neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
description: >-
  Neurodegeneration, early-onset, with choreoathetoid movements and microcytic
  anemia (NDCAMA) is an autosomal recessive disorder caused by bi-allelic
  variants in IREB2, the gene encoding iron-responsive element-binding protein 2
  (IRP2). It is the human counterpart of the long-studied Irp2-null mouse, and
  it is unusual among neurodegenerative diseases in coupling a severe central
  nervous system phenotype to a haematological one through a single
  post-transcriptional regulatory circuit rather than through two separate
  tissue lesions.

  IRP2 is a cytosolic RNA-binding protein that reads cellular iron status and
  rewrites the iron proteome accordingly. When iron is scarce it binds
  iron-responsive elements (IREs) - conserved stem-loops in the untranslated
  regions of iron-metabolism transcripts - repressing translation of the
  ferritin heavy and light chains and of erythroid 5-aminolevulinate synthase
  (ALAS2) from 5' IREs, while stabilising the transferrin receptor (TFRC) mRNA
  through 3' IREs. The net effect is more iron imported and less iron stored.
  When iron and oxygen are plentiful the SCF-FBXL5 ubiquitin ligase binds IRP2,
  polyubiquitinates it and sends it to the proteasome, releasing the brake. Loss
  of IRP2 therefore locks the cell into a false "iron-replete" regulatory state:
  ferritin translation is derepressed and TFRC mRNA is destabilised, so iron is
  simultaneously under-imported and over-sequestered. Cells become functionally
  iron-deficient even when systemic iron and transferrin saturation are normal,
  which is why the anaemia does not behave like ordinary iron-deficiency anaemia
  and why the brain is affected at all.

  The published human experience is four patients, all compound heterozygous,
  reported between 2019 and 2024: a 16-year-old boy of Filipino parentage with
  two nonsense alleles and complete absence of IRP2, a 10-year-old Australian
  boy, a 7-year-old boy in the USA with two missense alleles, and a Han Chinese
  boy with the novel missense pair p.Ile371Val and p.Asp826Val. The
  shared picture is neonatal feeding difficulty and hypotonia, profound global
  developmental delay with absent speech and ambulation, a treatment-resistant
  choreoathetoid and dystonic movement disorder, EEG abnormality with or without
  clinical seizures, progressive cerebral volume loss with delayed myelination
  and white matter reduction, and mild microcytic anaemia with serum iron levels
  in the normal range. In the Chinese proband the anaemia was quantified as a
  haemoglobin of 114 g/L against a local reference range of 120-140 g/L and a
  mean corpuscular volume of 79.8 fL against 82-100 fL - mild by haematological
  standards, and easily overlooked beside the neurological picture.

  Two mechanistic caveats are load-bearing for this entry. First, the mouse
  model is more haematologically severe than the human disease: Irp2-null mice
  develop frank microcytic anaemia with absent marrow iron stores and an
  erythropoietic protoporphyria driven by ALAS2 derepression, none of which has
  been documented in a patient. Second, the mouse brain accumulates iron and
  ferritin in white matter tracts before neurodegeneration begins, so the same
  lesion presents as cytosolic iron starvation at the level of the labile iron
  pool and as iron excess at the level of tissue staining. Both points are
  curated below as explicit knowledge gaps rather than smoothed over.
parents:
- Inherited neurodegenerative disorder
- Disorder of iron metabolism
- Autosomal recessive disease
synonyms:
- NDCAMA
- neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
- IRP2 deficiency
- IREB2-associated neurodegeneration
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The dominant and disabling morbidity is neurological: profound global
      developmental delay, a choreoathetoid and dystonic movement disorder that
      has not responded to treatment, epilepsy or EEG abnormality, and
      progressive loss of cerebral volume. The haematological component is real
      and mechanistically inseparable from the neurological one, but in every
      reported patient the anaemia has been mild and was not the presenting
      problem, so a single-chapter assignment to NEUROLOGIC is correct. The
      disorder would be missed entirely by a haematology-first workup.
    evidence:
    - reference: PMID:30915432
      reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."
      explanation: The founding report frames the phenotype as neurological with an accompanying haematological component, which is the basis for the NEUROLOGIC chapter assignment.
notes: >-
  Entity verification, done with OAK before any content was written.
  `runoak -i sqlite:obo:mondo info MONDO:0032758 -O obo` returns the label
  "neurodegeneration, early-onset, with choreoathetoid movements and microcytic
  anemia", the exact synonym NDCAMA, xrefs OMIM:618451, MEDGEN:1676579,
  GARD:0027271 and UMLS:C5193104, and `is_a MONDO:0024237` (inherited
  neurodegenerative disorder).
  `runoak -i sqlite:obo:mondo relationships -p RO:0004003 MONDO:0032758`
  returns exactly one gene, `HGNC:6115 ! IREB2`. Both anchors - gene and OMIM
  number - agree with the disease-causing gene named in every clinical report
  cited here.

  Named Entity Confusion gate, and the specific trap for this gene. A PubMed
  search performed on 2026-08-01 for IREB2 combined with clinical terms returned
  a record set dominated by two bodies of work unrelated to this MONDO entity:
  genome-wide association and expression studies of chronic obstructive
  pulmonary disease and lung cancer, and a large ferroptosis/oncology literature
  that uses IREB2 as an iron metabolism marker. That is a search result observed
  on one date, not an established fact about the literature, and no artifact of
  it is cached here. None of it was used. The COPD/lung-cancer signals are
  common-variant susceptibility associations at a locus shared with neighbouring
  genes and concern a different phenotype entirely; importing them as causal for
  this Mendelian disorder would be a textbook locus-adjacency NEC error. They
  are deliberately not curated here, not even as risk factors. (The cytogenetic
  location of IREB2 and the identity of its neighbouring genes are not asserted
  in this entry: no COPD or 15q25 reference was fetched, so there is nothing
  cached to support such a statement.)
  The four human reports that ARE about this MONDO entity were each read and
  confirmed to name IREB2/IRP2 as the causal gene: PMID:30915432 (Costain 2019,
  case 1), PMID:31243445 (Cooper 2019, case 2), PMID:35602653 (Maio 2022, case
  3) and PMID:39587636 (Guo 2024, case 4).

  Evidence base and its limits. Only four patients have been published, and no
  deep-research provider report was used for this entry - it was built directly
  from primary literature fetched into `references_cache/`. Of the four case
  reports, three are cached as abstracts only; PMID:39587636 is cached as full
  text and is therefore the only source from which per-patient clinical detail
  can be quoted. PMID:31243445 (Cooper et al., Brain 2019;142(8):e40) is a
  correspondence letter with no abstract in PubMed, so its cache file contains
  metadata only and NOTHING is quoted from it anywhere in this entry; what is
  known of that patient is quoted instead from Guo et al.'s summary of the
  published series. The paired reply (PMID:31243430) is likewise unquotable.

  Two discrepancies in the source literature, recorded rather than propagated.
  (i) PMID:39587636 describes its proband as "an 8-month-old male patient from
  China" in the abstract methods and as "an 8-year-old boy" in the results; the
  results text is internally consistent with a brain MRI performed "at 8 years
  old" and with a younger brother born in 2023, so the age is left unstated in
  this entry rather than asserted from the conflicting abstract. (ii) The same
  paper's introduction calls the 2019 index case "adult-onset", which
  contradicts PMID:30915432 itself - that patient was 16 years old at report,
  with disease from infancy - and contradicts the MONDO/OMIM label
  "early-onset". The "adult-onset" wording belongs to the Irp2-null mouse, whose
  movement disorder begins in adulthood, and it is not repeated here.

  Case count arithmetic. PMID:35602653 (2022) states that two patients were
  "first identified and clinically characterized in 2019"; PMID:30915432 (2019)
  reports one patient and describes him as the first human. Both are correct:
  the second 2019 patient is the one in the Cooper correspondence, published
  later the same year. PMID:39587636 (2024) reconciles them, counting four
  reported cases including its own. Four is the number used throughout this
  entry.

  Structured-source evidence was unavailable. `data/orphadata/` and
  `data/clingen/` in this checkout contain only `MANIFEST.yaml` with no
  downloaded payload, so no Orphanet prevalence class and no ClinGen
  gene-disease validity classification could be consulted or cited. This is
  recorded as a gap, not as an assertion that no such classification exists. Per
  the scope rules those manifests were not touched.

  Ontology bindings. Every HP, GO, CL, CHEBI, NCIT, MONDO and HGNC identifier in
  this file was resolved with OAK on 2026-08-01 rather than recalled. Two
  lookups changed what was written: GO:0070997 ("neuron death") is obsolete, so
  the neurodegeneration node uses GO:0051402 (neuron apoptotic process) and
  HP-level phenotype terms instead; and the intracellular iron homeostasis term
  is GO:0006879 "intracellular iron ion homeostasis", not the "cellular iron ion
  homeostasis" label it is often cited under.

  Not curated, deliberately. No `histopathology:` section: the only
  neuropathology in this literature is murine (axonal degeneration, neuronal
  loss, ferritin-positive and iron-laden inclusions in Irp2-null mice), and
  attaching it to the human MONDO term would overstate what has been observed in
  patients. No gnomAD constraint metrics, no ClinVar counts and no allele
  frequencies are asserted anywhere: they were not retrieved from an
  authoritative source during this curation and are not written from memory.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Two damaged IREB2 alleles are required. All four published probands were
    compound heterozygous - none was homozygous, and no consanguinity is
    reported in any family. Both parents in the fourth family were healthy
    carriers, confirmed by Sanger sequencing of the paternal and maternal
    alleles, and the proband's younger brother, who carries only the paternal
    allele, is developing normally. Heterozygous carriers are not described as
    affected in any report, which is consistent with the Ireb2 heterozygous
    mouse and with IRP2 abundance being regulated post-translationally rather
    than by gene dosage.

    Penetrance is not annotated. With four unrelated probands and no unaffected
    bi-allelic individual described, there is no basis for calling penetrance
    either complete or reduced; asserting COMPLETE from four ascertained cases
    would be an inference from the ascertainment itself.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."
    explanation: Establishes that the disorder arises from bi-allelic damage to IREB2, the definition of recessive inheritance at this locus.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed the paternal (A2477T) and maternal (A1111G) origins of the"
    explanation: Demonstrates that the two variants are in trans, inherited one from each unaffected carrier parent, in the fourth reported family.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia."
    explanation: Records that the parents are healthy and non-consanguineous, so the recessive genotype arose from two independent alleles rather than from identity by descent.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Four patients have been reported in total, in four publications between 2019
    and 2024. The parental origins recorded in the published series are Filipino
    (case 1, reported from Toronto), Australian (case 2), Sephardic and
    Sephardic/Irish in the USA (case 3), and Han Chinese (case 4).
    `rate_per_100000` is
    deliberately empty: no incidence or prevalence estimate of any kind has been
    published, no ORPHA code was retrievable in this checkout, and a
    denominator-free case count cannot be converted into a rate. The
    geographical spread of four unrelated families on three continents argues
    against a founder effect and suggests the disorder is under-ascertained
    rather than population-restricted - a child with developmental delay,
    dystonia and a mildly low MCV would not usually prompt IREB2 testing outside
    of exome-first practice.
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A literature review has identified four reported cases of IREB2-associated NDCAMA"
    explanation: Establishes the total published case count at the time of curation.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 2019, three cases of a genetic neurodegenerative syndrome resulting from compound heterozygous mutations in IREB2 have been documented"
    explanation: Independently confirms the three prior cases to which the fourth was added, fixing the denominator used throughout this entry.
pathophysiology:
- name: Bi-allelic Loss-of-Function IREB2 Variants
  biological_scale: MOLECULAR
  description: >-
    The primary lesion is bi-allelic damage to IREB2 at 15q25.1, reported
    against transcript NM_004136. Two allele classes have been seen. The index
    patient carried two nonsense alleles, and his cells contained no detectable
    IRP2 at all. The three later patients carried missense alleles - and in one
    case a three-base in-frame deletion - which do not abolish the protein but
    either destabilise it or degrade its RNA-binding function. The distinction
    matters because it predicts the shape of the future phenotypic spectrum:
    complete loss of function has so far always produced severe disease, and
    partial loss of function is the untested territory where milder disease
    should be sought.
  genes:
  - preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."
    explanation: Names the causal gene and establishes that bi-allelic loss of function removes the protein product.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified novel biallelic variants, c.1111 A > G (P.Ile371Val) and c.2477 A > T (P.Asp826Val), in the IREB2 gene, which encodes the iron metabolism-related protein, IRP2."
    explanation: Provides the second allele class - biallelic missense - and names the gene product whose function the rest of this pathograph concerns.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first case exhibited two nonsense mutations"
    explanation: Records the allele class of the index patient, which is what makes his complete absence of IRP2 interpretable as a null genotype.
  downstream:
  - target: Absence or Accelerated Degradation of IRP2 Protein
    description: >-
      Nonsense alleles remove the protein through transcript decay; the
      p.Asp826Val allele, which lies near the FBXL5-binding region, leaves the
      protein constitutively degradable.
  - target: Impaired IRE-Binding Activity of Residual IRP2
    description: >-
      Missense alleles clustered near the RNA-binding surface leave IRP2 present
      but functionally weakened, a graded rather than all-or-none lesion.
- name: Absence or Accelerated Degradation of IRP2 Protein
  biological_scale: MOLECULAR
  description: >-
    The abundance arm of the lesion. In the index patient, whose two alleles are
    nonsense, patient-derived lymphoblasts contained no IRP2, attributed by the
    authors to nonsense-mediated decay of the transcript. In the fourth patient
    the mechanism is different and better resolved: the p.Asp826Val allele
    reduced IRP2 protein by roughly 70% when expressed in SH-SY5Y neuroblastoma
    cells, and the loss was reversed by the proteasome inhibitor MG-132. That
    the lesion is post-transcriptional was established in a separate experiment
    and a separate material - RT-qPCR on the patient's own peripheral blood
    mononuclear cells showed no appreciable alteration of IREB2 at the mRNA
    level, which the authors used to exclude the splicing abnormality proposed
    for earlier patients. Structural modelling places residue 826 close to the
    surface through which IRP2 is recognised by FBXL5.

    That is the physiological degradation route being hijacked. In an
    iron-replete and oxygen-replete cell, the SCF-FBXL5 ubiquitin ligase binds
    IRP2, polyubiquitinates it and delivers it to the proteasome; FBXL5's
    substrate-binding domain carries an oxygen-responsive [2Fe2S] cluster that
    organises the loop which grips IRP2, and the same interaction sterically
    prises IRP2 off its IRE. A variant that makes IRP2 a better or
    constitutively available FBXL5 substrate therefore removes the protein by
    the cell's own quality-control machinery rather than by any defect in
    folding per se - which is why proteasome inhibition restores it.
  genes:
  - preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  biological_processes:
  - preferred_term: proteasomal degradation of IRP2
    modifier: INCREASED
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  - preferred_term: polyubiquitination of IRP2 by SCF-FBXL5
    modifier: INCREASED
    term:
      id: GO:0000209
      label: protein polyubiquitination
  - preferred_term: nonsense-mediated decay of nonsense-allele IREB2 transcripts
    modifier: INCREASED
    term:
      id: GO:0000184
      label: "nuclear-transcribed mRNA catabolic process, nonsense-mediated decay"
  protein_complexes:
  - preferred_term: SCF-FBXL5 ubiquitin ligase complex
    term:
      id: GO:0019005
      label: SCF ubiquitin ligase complex
  cell_types:
  - preferred_term: patient-derived lymphoblasts
    term:
      id: CL:0017005
      label: lymphoblast
  notes: >-
    The two routes to absent protein are not equivalent for therapy. A
    nonsense-mediated decay genotype leaves nothing to stabilise, whereas a
    degradation-prone missense genotype leaves a protein that pharmacological
    stabilisation could in principle rescue - the MG-132 experiment is a
    proof of principle for that idea and nothing more, since MG-132 is a
    research tool compound with no therapeutic application. The 70% figure and
    the MG-132 rescue are properties of an overexpression system in a
    neuroblastoma line, not measurements in patient neurons.
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cellular phenotyping at the RNA and protein level was performed using patient and control lymphoblastoid cell lines, and established experimental assays."
    explanation: Identifies the patient-derived cell system in which the absence of IRP2 and its downstream consequences were demonstrated.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cellular studies utilizing patient-derived lymphoblasts demonstrated a complete loss of IRP2 expression in the first case"
    explanation: Confirms in a second publication that the index patient's nonsense genotype produces complete absence of the protein.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blot analysis revealed that the A2477T mutation led to an approximate 70% reduction in IRP2 expression,"
    explanation: Quantifies the abundance defect caused by the p.Asp826Val allele in an isogenic overexpression system, separating it from the second, milder allele.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IREB2 and iron metabolism-related genes in patient-derived PBMCs. The results aligned with the A2477T mutation, showing indistinctive alteration in IREB2 at the mRNA level"
    explanation: The transcript-level result, recorded here with its own material - patient PBMCs, not the SH-SY5Y overexpression system in which the 70% protein loss was measured - because the two experiments are separate and only together establish that the lesion is post-transcriptional.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "led to IRP2 restoration and iron metabolism-related proteins' expression"
    explanation: Shows the loss is proteasome-dependent, since blocking the proteasome restores both IRP2 and its regulatory output.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "while the severe one was near the region where IRP2 binds to FBXL5"
    explanation: Places the severe allele structurally at the FBXL5 interface, which is the proposed reason it is degraded.
  - reference: PMID:19762597
    reference_title: "An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation."
    explanation: Establishes the physiological ligase that normally sets IRP2 abundance, the machinery the p.Asp826Val allele is proposed to over-engage.
  - reference: PMID:32126207
    reference_title: "FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A cryoelectron microscopy (cryo-EM) structure of the IRP2-FBXL5-SKP1 complex reveals that the cluster organizes the FBXL5 C-terminal loop responsible for recruiting IRP2."
    explanation: Provides the structural basis of the IRP2-FBXL5 interface against which the position of p.Asp826Val is interpreted.
  - reference: PMID:32126207
    reference_title: "FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Steric incompatibility also allows FBXL5 to physically dislodge IRP2 from iron-responsive element RNA to facilitate its turnover."
    explanation: Shows that FBXL5 engagement and IRE binding are mutually exclusive, so a variant that favours FBXL5 binding removes IRP2 from its regulatory targets as well as from the cell.
  downstream:
  - target: Loss of IRE-Dependent Post-Transcriptional Control
    description: No IRP2 protein means no IRE occupancy, regardless of the cell's actual iron status.
- name: Impaired IRE-Binding Activity of Residual IRP2
  biological_scale: MOLECULAR
  description: >-
    The activity arm of the lesion, and the reason the disorder is expected to
    be a spectrum rather than a binary. IRP2 recognises IREs through a
    four-domain arrangement homologous to cytosolic aconitase; missense changes
    on or near that RNA-binding surface can leave the protein present and
    stable while degrading how well it reads the IRE. In the fourth patient the
    p.Ile371Val allele behaved exactly this way: expressed alone it left IRP2
    abundance, transferrin receptor and labile iron essentially unchanged, with
    only a slight rise in ferritin heavy chain, and the authors classified it as
    the mild allele of the pair - not an inert one - sitting
    close to the IRE-binding domains rather than the FBXL5 interface. The three
    severely affected patients characterised to date all had effectively
    complete loss of IRP2 function, which is the explicit basis for the
    published prediction that partial loss of function should produce milder,
    currently unrecognised disease.
  genes:
  - preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  molecular_functions:
  - preferred_term: iron-responsive element binding
    modifier: DECREASED
    term:
      id: GO:0030350
      label: iron-responsive element binding
  - preferred_term: mRNA binding
    modifier: DECREASED
    term:
      id: GO:0003729
      label: mRNA binding
  mechanism_confidence: PROVISIONAL
  notes: >-
    Marked PROVISIONAL because the allele-resolved functional data are thin. Only
    the fourth patient's two alleles have been assayed separately from one
    another; for the second patient no cellular study was performed at all, and
    for the third the interpretation rests on the observed fall in IRP2 protein
    plus the authors' proposals about mis-splicing and IRE-binding activity. The
    prediction that hypomorphic genotypes cause milder disease is a stated
    hypothesis in PMID:35602653, not an observation - no such patient has been
    reported.
  evidence:
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "underscore that IREB2 pathological variants may impact the iron-responsive element-binding activity of IRP2 with varying degrees of severity"
    explanation: States the mechanism this node models - that pathogenic alleles act by degrading IRE-binding activity to differing extents.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three severely affected patients identified so far all suffered from complete loss of function of IRP2, raising the possibility that individuals with significant but incomplete loss of IRP2 function may develop less severe forms of the disease"
    explanation: Establishes that all severe cases to date are functional nulls and frames partial loss of function as an untested, predicted milder phenotype.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "One mild mutation was located close to functional domains where IRP2 binds to the IRE element of iron metabolism-related"
    explanation: Locates the milder allele of the fourth patient at the RNA-binding surface rather than at the degradation interface, which is the structural distinction this node captures.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the A1111G mutation did not impact the expression of iron metabolism proteins, although there was a slight increase in FTH expression"
    explanation: The measured effect of the milder allele in isolation, quoted with the authors' own qualifier so the entry does not read as a flat negative result.
  downstream:
  - target: Loss of IRE-Dependent Post-Transcriptional Control
    description: Reduced IRE occupancy produces a partial version of the same regulatory failure.
- name: Loss of IRE-Dependent Post-Transcriptional Control
  biological_scale: MOLECULAR
  description: >-
    This is the node where a molecular lesion becomes a systems failure. IRPs
    are the sensor arm of a single feedback loop that operates entirely after
    transcription: bound to a 5' IRE they block ribosome loading, bound to a 3'
    IRE they protect the transcript from endonucleolytic decay. The transcripts
    involved include the ferritin heavy and light chains and erythroid ALAS2
    (5' IREs, translationally repressed by IRP binding) and TFRC (3' IREs,
    stabilised by IRP binding); transcriptome-wide immunoselection has since
    extended the IRP-bound mRNA set well beyond these canonical members and
    shown that IRP1 and IRP2 have partly non-overlapping target repertoires.

    Without IRP2 the loop reads permanently "iron replete" regardless of the
    truth: ferritin translation is derepressed, so the cell builds storage
    capacity it does not need and locks iron inside it, while TFRC mRNA loses
    its stabilising protein and decays, so transferrin-mediated uptake falls.
    Both changes push iron the same way - out of the metabolically available
    pool. That is the specific reason the resulting deficiency is a *functional*
    one that no amount of circulating iron corrects.
  molecular_functions:
  - preferred_term: iron-responsive element binding
    modifier: DECREASED
    term:
      id: GO:0030350
      label: iron-responsive element binding
  biological_processes:
  - preferred_term: IRE-mediated translational repression of ferritin and ALAS2
    modifier: DECREASED
    term:
      id: GO:0017148
      label: negative regulation of translation
  - preferred_term: IRP-dependent stabilisation of TFRC mRNA
    modifier: DECREASED
    term:
      id: GO:0048255
      label: mRNA stabilization
  - preferred_term: intracellular iron ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
  protein_complexes:
  - preferred_term: cytosolic ferritin
    modifier: INCREASED
    term:
      id: GO:0070288
      label: ferritin complex
  evidence:
  - reference: PMID:11175792
    reference_title: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC)."
    explanation: States the normal regulatory logic - 5' IRE translational repression and 3' IRE transcript stabilisation - that is lost when IRP2 is absent.
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues."
    explanation: Demonstrates the paired direction of the regulatory failure in vivo - ferritin up, transferrin receptor down - across tissues.
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model."
    explanation: Confirms in human patient cells that the post-transcriptional regulation of iron metabolism genes is altered and that the consequence is functional iron deficiency.
  - reference: PMID:21940823
    reference_title: "Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identify 35 novel mRNAs that bind both IRP1 and IRP2, and we also report for the first time cellular mRNAs with exclusive specificity for IRP1 or IRP2."
    explanation: Shows the IRE/IRP regulon is broader than the canonical ferritin/TFRC pair and that some transcripts depend on IRP2 specifically, so IRP1 cannot cover the whole target set.
  - reference: PMID:21940823
    reference_title: "Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Iron regulatory proteins (IRPs) 1 and 2 are RNA-binding proteins that control cellular iron metabolism by binding to conserved RNA motifs called iron-responsive elements (IREs)."
    explanation: Defines the molecular activity - sequence-specific IRE binding - that this node reports as lost.
  downstream:
  - target: Functional Cytosolic Iron Deficiency
    description: >-
      Derepressed ferritin sequesters iron while reduced transferrin receptor
      limits its import, emptying the metabolically available pool.
- name: Failure of IRP1 to Compensate
  biological_scale: MOLECULAR
  description: >-
    A paralogue exists and does not rescue, and understanding why is what makes
    a single-gene lesion in a two-gene system disease-causing. IRP1 is
    bifunctional: with an intact [4Fe-4S] cluster it is cytosolic aconitase, and
    only in the apo form does it bind IREs. In intact animal tissues most IRP1 is
    the aconitase form, and - the decisive observation - its RNA-binding
    activity does not increase on a low-iron diet that is sufficient to activate
    IRP2. The small RNA-binding fraction of IRP1 is essentially insensitive to
    cellular iron status. The relationship is asymmetric: IRP2 can compensate for
    the loss of IRP1 by increasing its binding activity, so Irp1-null mice
    misregulate iron only in kidney and brown fat, whereas Irp2-null mice
    misregulate target proteins in every tissue. IRP2 dominates
    post-transcriptional iron regulation in mammals, and its loss is therefore
    not buffered.

    This asymmetry is also the entry point for the only mechanism-directed
    therapy tested in vivo. Feeding Irp2-null mice the nitroxide Tempol
    disassembles the IRP1 iron-sulfur cluster, converting latent aconitase into
    active IRE-binding protein, which restabilises the TfR1 transcript and
    represses ferritin synthesis - and markedly attenuates the neuromuscular
    disease. The therapeutic logic is to unmask a redundancy the cell does not
    normally use.
  biological_processes:
  - preferred_term: iron-sulfur cluster assembly in IRP1
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
  molecular_functions:
  - preferred_term: cytosolic aconitase activity of IRP1
    modifier: INCREASED
    term:
      id: GO:0003994
      label: aconitate hydratase activity
  evidence:
  - reference: PMID:14726953
    reference_title: "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IRP1-/- mice misregulate iron metabolism only in the kidney and brown fat, two tissues in which the endogenous expression level of IRP1 greatly exceeds that of IRP2, whereas IRP2-/- mice misregulate the expression of target proteins in all tissues."
    explanation: Establishes the asymmetry between the two paralogues that makes IRP2 loss, and not IRP1 loss, a systemic disease.
  - reference: PMID:14726953
    reference_title: "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In animal tissues, most of the bifunctional IRP1 is in the form of cytosolic aconitase rather than an RNA-binding protein."
    explanation: Gives the biochemical reason IRP1 cannot substitute - the majority of it is not in the RNA-binding state.
  - reference: PMID:14726953
    reference_title: "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, IRP2 dominates post-transcriptional regulation of iron metabolism in mammals."
    explanation: States the conclusion that underwrites treating IREB2 loss as a non-redundant lesion.
  - reference: PMID:18685102
    reference_title: "Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain."
    explanation: Demonstrates that the latent IRP1 reserve can be recruited pharmacologically, which both confirms the compensation failure and defines a therapeutic strategy.
  downstream:
  - target: Functional Cytosolic Iron Deficiency
    description: >-
      Because the paralogue does not step in, the regulatory failure is passed
      through undamped to the cellular iron pool.
- name: Functional Cytosolic Iron Deficiency
  biological_scale: CELLULAR
  description: >-
    The central pathological state of this disease, and the one that unifies the
    brain and the erythron. Cells lose access to iron even though the organism
    has enough: transferrin saturation is normal in the Irp2-null mouse and
    serum iron was within the normal range in the reported patients, yet marrow
    iron stores are absent in the mouse and patient cells show functional iron
    deficiency on direct assay. Intracellular ferrous iron fell sharply in cells
    expressing the severe p.Asp826Val allele and was restored when the protein
    was restored.

    Two consequences follow immediately and account for most of the phenotype.
    Iron is a cofactor for the enzymes of mitochondrial respiration, for
    iron-sulfur cluster and haem biosynthesis, for myelin lipid synthesis and for
    monoamine neurotransmitter synthesis; and haemoglobinisation of the
    developing red cell is quantitatively the largest iron demand in the body.
    A cell-autonomous iron supply failure therefore strikes hardest at the two
    tissues with the highest and least interruptible iron requirement - the
    developing brain and the erythroid marrow.
  chemical_entities:
  - preferred_term: labile cytosolic iron(2+)
    modifier: DECREASED
    term:
      id: CHEBI:29033
      label: iron(2+)
  biological_processes:
  - preferred_term: transferrin-mediated iron import
    modifier: DECREASED
    term:
      id: GO:0006826
      label: iron ion transport
  - preferred_term: intracellular iron ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model."
    explanation: Direct demonstration of functional iron deficiency in cells from the index patient.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical characterization of a lymphoblast cell line derived from the patient revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes and mitochondrial dysfunction."
    explanation: Replicates the same cellular state in an independent patient with a different allele class, which is what makes it a property of the disease rather than of one genotype.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The intracellular Fe 2+ level in the A2477T group was drastically reduced"
    explanation: Measures the fall in labile ferrous iron attributable specifically to the severe allele.
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TfR expression in erythroid precursors of IRP2-/- mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal."
    explanation: The clearest statement of the paradox that defines this node - empty tissue iron in the presence of normal systemic iron delivery.
  - reference: PMID:18685102
    reference_title: "Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice that lack IRP2 develop microcytic anemia and neurodegeneration associated with functional cellular iron depletion caused by low TfR1 and high ferritin expression."
    explanation: Names functional cellular iron depletion, caused by the low-TfR1/high-ferritin combination, as the shared cause of both the anaemia and the neurodegeneration.
  downstream:
  - target: Iron-Limited Erythropoiesis
    description: The erythroid arm - the developing red cell cannot obtain the iron it needs for haemoglobinisation.
  - target: Mitochondrial Dysfunction from Iron-Sulfur Cluster and Haem Insufficiency
    description: The bioenergetic arm, common to all affected tissues but decisive in neurons.
  - target: HIF2-alpha Stabilisation and the Glycolytic Shift
    description: >-
      An iron-sensing consequence layered on top of the direct cofactor
      shortage, demonstrated in Irp2-null mouse cells and tissue.
  - target: Neuronal and Oligodendrocyte Iron Mishandling
    description: The central nervous system arm, where the same shortage meets the highest developmental iron demand.
- name: Iron-Limited Erythropoiesis
  biological_scale: CELLULAR
  description: >-
    The erythroid consequence, and the reason the disease name carries the word
    anaemia. Erythroid precursors depend on transferrin receptor 1 more heavily
    than any other cell type; when TFRC mRNA loses IRP2-dependent stabilisation,
    TfR1 falls on the precursor surface and iron delivery to the developing
    erythroblast fails. In the Irp2-null mouse this produces microcytic anaemia
    with absent marrow iron stores despite normal transferrin saturation - a
    genetically distinct paradigm from either classical iron-deficiency anaemia
    or the thalassaemias.

    The mouse adds a second, mechanistically instructive lesion. ALAS2, the
    erythroid-specific first enzyme of haem synthesis, carries a 5' IRE and is
    normally translationally repressed when iron is scarce - the cell's way of
    not building porphyrin rings it cannot fill with iron. Losing IRP2
    derepresses ALAS2 exactly when iron is unavailable, so protoporphyrin IX is
    overproduced and accumulates, some of it chelating zinc instead of iron. The
    result is an erythropoietic protoporphyria on top of the anaemia. In humans
    the anaemia is present but mild, and the protoporphyrin arm has not been
    reported at all - see the knowledge gap below.
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  - preferred_term: erythroid lineage cell
    term:
      id: CL:0000764
      label: erythroid lineage cell
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  - preferred_term: haem biosynthesis uncoupled from iron availability
    modifier: ABNORMAL
    term:
      id: GO:0006783
      label: heme biosynthetic process
  chemical_entities:
  - preferred_term: protoporphyrin IX
    modifier: INCREASED
    term:
      id: CHEBI:15430
      label: protoporphyrin
  - preferred_term: zinc protoporphyrin
    modifier: INCREASED
    term:
      id: CHEBI:28783
      label: zinc protoporphyrin
  notes: >-
    Species scope. The protoporphyrin findings and the absent marrow iron stores
    are murine. The human evidence for this node is the observation of mild
    microcytic anaemia with normal serum iron in the reported patients, plus the
    shared upstream mechanism. Free and zinc protoporphyrin have not, to this
    curation's knowledge, been measured in an IREB2 patient; if they were, the
    mouse predicts they would be raised, and this is the single cheapest test
    that could confirm or refute the model in a human.
  evidence:
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that ablation of IRP2 results in iron-limited erythropoiesis."
    explanation: Names the mechanism of the anaemia as iron-limited erythropoiesis rather than a primary erythroid defect.
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRP-dependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2-/- erythroid cells."
    explanation: Establishes the ALAS2 derepression arm and its biochemical consequence, the protoporphyrin accumulation.
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IRP2-/- mice represent a new paradigm of genetic microcytic anemia."
    explanation: Positions the anaemia as a distinct genetic entity rather than as ordinary iron deficiency, which is what makes the normal serum iron in patients diagnostically important.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia."
    explanation: Confirms that microcytic anaemia is part of the human presentation and not only a mouse phenomenon.
  downstream:
  - target: Extrapyramidal Movement Disorder and Neurodevelopmental Arrest
    description: >-
      The haematological arm contributes little to disability directly, but it
      is the readily measurable systemic signature that points to the diagnosis.
- name: Mitochondrial Dysfunction from Iron-Sulfur Cluster and Haem Insufficiency
  biological_scale: CELLULAR
  description: >-
    Iron reaches the respiratory chain as iron-sulfur clusters and haem
    prosthetic groups, both assembled in and around the mitochondrion from
    imported iron. When the cytosolic supply fails, cluster and haem assembly
    are starved of substrate and respiratory complexes cannot be built.
    Mitochondrial dysfunction was found in patient-derived cells in both
    functionally studied patients, alongside the altered iron-gene regulation,
    and it is the most plausible proximate cause of the vulnerability of
    neurons - post-mitotic cells with a large and inflexible oxidative demand.
    The same dependency is why an iron-supply lesion presents as a
    neurodegenerative rather than a purely haematological disease.
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: iron-sulfur cluster assembly
    modifier: DECREASED
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  chemical_entities:
  - preferred_term: haem
    modifier: DECREASED
    term:
      id: CHEBI:30413
      label: heme
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model."
    explanation: Demonstrates mitochondrial dysfunction in cells from the index patient and ties it to the same iron-regulatory lesion.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical characterization of a lymphoblast cell line derived from the patient revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes and mitochondrial dysfunction."
    explanation: Independent replication of the mitochondrial phenotype in a second patient's cells.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Altered brain iron homeostasis can contribute to neurodegeneration by interfering with the delivery of the iron needed to support key cellular processes, including mitochondrial respiration, synthesis of myelin and essential neurotransmitters."
    explanation: Names the three iron-dependent neural processes - respiration, myelination and neurotransmitter synthesis - through which a supply failure becomes neurodegeneration.
  - reference: PMID:22003390
    reference_title: "Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology"
    explanation: >-
      The only in vivo measurement of respiratory-complex activity supporting
      this node. The other three items are patient-derived cell studies that
      establish mitochondrial dysfunction as a cellular phenotype without
      resolving which complexes are affected in nervous tissue; this measures
      Complex I and II activity directly in Irp2-null lumbar spinal cord, which
      is the assay the cell work cannot supply. Complex I and II are the two
      respiratory complexes most dependent on iron-sulfur clusters, so the
      result is specific to the substrate-starvation mechanism this node
      proposes rather than to generic mitochondrial failure. Mouse, not human.
  downstream:
  - target: Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss
    description: Chronic bioenergetic insufficiency in post-mitotic neurons drives progressive attrition.
- name: HIF2-alpha Stabilisation and the Glycolytic Shift
  biological_scale: CELLULAR
  description: >-
    A second, indirect consequence of cellular iron shortage. The prolyl
    hydroxylases that mark hypoxia-inducible factor subunits for degradation are
    themselves iron(II)-dependent, so a cell that cannot obtain iron behaves as
    though it were hypoxic. In globally Irp2-depleted mouse embryonic
    fibroblasts both Hif1-alpha and Hif2-alpha rose; Hif1-alpha drove glycolytic
    gene expression while Hif2-alpha suppressed iron-sulfur cluster biogenesis
    and electron transport chain genes, weakening respiration. In Irp2-null mice
    the in vivo picture is narrower and more informative - Hif2-alpha, not
    Hif1-alpha, was elevated in tissues, most markedly in the cerebellum and
    spinal cord, the regions the disease targets. Inhibiting Hif2-alpha with
    PT-2385 prevented the neurodegenerative phenotype and restored Purkinje cell
    architecture, while inhibiting Hif1-alpha did not.

    This makes the switch from oxidative phosphorylation to aerobic glycolysis a
    candidate driver rather than a bystander, and it identifies the first
    druggable node in the pathograph downstream of the untreatable primary
    lesion.
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  - preferred_term: aerobic glycolysis
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  mechanism_confidence: PROVISIONAL
  notes: >-
    Marked PROVISIONAL because every observation in this node is murine - MEFs
    and Irp2-null mice. No HIF pathway measurement has been reported in a
    patient or in patient-derived cells, so the arm is a strong mechanistic
    hypothesis for the human disease rather than an established part of it. The
    discrepancy between the cell-culture result (both subunits up) and the in
    vivo result (Hif2-alpha only) is itself unexplained and is a reason to treat
    the cell-culture version with caution.
  evidence:
  - reference: PMID:31040213
    reference_title: "Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α."
    explanation: Establishes that loss of Irp2 stabilises both HIF subunits in cells, the observation on which the whole arm rests.
  - reference: PMID:31040213
    reference_title: "Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron-sulfur cluster (Fe-S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration."
    explanation: Separates the two subunits' contributions and links Hif2-alpha specifically to suppression of Fe-S and respiratory chain genes.
  - reference: PMID:34675764
    reference_title: "Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we confirmed the upregulation of Hif2α, not Hif1α, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of Irp2 -/- mice."
    explanation: Shows that in vivo only Hif2-alpha is elevated, and that it is elevated in the CNS regions the disease targets.
  - reference: PMID:34675764
    reference_title: "Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array."
    explanation: Provides the causal test - blocking Hif2-alpha prevents the neurodegenerative phenotype, which is what elevates this arm from correlation to candidate driver.
  downstream:
  - target: Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss
    description: >-
      A sustained shift away from oxidative phosphorylation compounds the direct
      cofactor shortage in the same cells.
- name: Neuronal and Oligodendrocyte Iron Mishandling
  biological_scale: CELLULAR
  description: >-
    The central nervous system is where the regulatory lesion is least tolerable
    and, confusingly, where it looks most like the opposite of what it is. In
    Irp2-null mice, ferric iron accumulates in the cytosol of neurons and
    oligodendrocytes in specific brain regions and in white matter tracts, with
    ferritin colocalising in the very neuronal populations that later degenerate
    and ubiquitin-positive inclusions accumulating in iron-laden
    oligodendrocytes. Those accumulations precede the movement disorder by
    months. The reconciliation with functional iron deficiency is that
    derepressed ferritin sequesters iron in a form the cell cannot use: the
    tissue is iron-loaded and the cytosolic labile pool is empty at the same
    time. Oligodendrocytes matter disproportionately here because they are the
    most iron-demanding cells in the brain - myelin lipid synthesis is
    iron-dependent - and delayed myelination with white matter loss is exactly
    what the patients' imaging shows.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  chemical_entities:
  - preferred_term: ferritin-sequestered iron(3+)
    modifier: INCREASED
    term:
      id: CHEBI:29034
      label: iron(3+)
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  protein_complexes:
  - preferred_term: ferritin complex
    modifier: INCREASED
    term:
      id: GO:0070288
      label: ferritin complex
  notes: >-
    The strongest evidence in this node is murine. Human brain iron content has
    not been quantified in any reported patient; the imaging descriptions are of
    volume loss, delayed myelination, white matter reduction and abnormal signal
    around the lateral ventricles, basal ganglia and thalamus, and abnormal
    signal on conventional sequences is not a measurement of iron. This entry
    therefore does NOT assert brain iron accumulation in humans, and NDCAMA is
    deliberately not curated as a neurodegeneration with brain iron accumulation
    (NBIA) disorder - see the differential and the knowledge gap on this point.
  evidence:
  - reference: PMID:11175792
    reference_title: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain."
    explanation: Identifies the two CNS cell types in which iron is mishandled in the null mouse.
  - reference: PMID:11175792
    reference_title: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions."
    explanation: Links ferritin-sequestered iron spatially to the neurons that go on to die, which is the basis for treating sequestration rather than simple overload as the pathogenic form.
  - reference: PMID:11175792
    reference_title: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months."
    explanation: Establishes the temporal order - iron mishandling first, degeneration afterwards - which is what makes this node upstream rather than a consequence of cell death.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Altered brain iron homeostasis can contribute to neurodegeneration by interfering with the delivery of the iron needed to support key cellular processes, including mitochondrial respiration, synthesis of myelin and essential neurotransmitters."
    explanation: Supports the specific claim that myelin synthesis is one of the iron-dependent processes compromised, which connects this node to the delayed myelination seen on patient imaging.
  downstream:
  - target: Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss
    description: Cell-autonomous iron mishandling in neurons and oligodendrocytes precedes and predicts the regions that degenerate.
  - target: Synaptic Failure and Microglial Activation
    description: >-
      Demonstrated in the knock-in model of a patient allele, at an age before
      overt neuronal loss.
- name: Synaptic Failure and Microglial Activation
  biological_scale: CELLULAR
  description: >-
    The newest and most disease-specific piece of the mechanism, and the only
    in vivo work built on an actual patient allele rather than a null. A
    CRISPR-Cas9 knock-in mouse homozygous for the p.Asp826Val variant found in
    the Chinese pedigree shows reduced Ireb2 protein, dysregulated iron
    metabolism, impaired spatial learning and memory and reduced motor activity,
    together with increased microglial activation and decreased hippocampal
    dendritic spine density, impaired long-term potentiation and elevated
    paired-pulse facilitation. That combination - fewer spines, weaker
    potentiation, altered presynaptic release probability, activated microglia -
    describes synaptic failure with neuroinflammation rather than cell loss, and
    it fits a disorder whose human presentation is developmental as much as
    degenerative: these children largely never acquired speech or ambulation
    rather than losing skills they once had.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  biological_processes:
  - preferred_term: microglial cell activation
    modifier: INCREASED
    term:
      id: GO:0001774
      label: microglial cell activation
  - preferred_term: long-term synaptic potentiation
    modifier: DECREASED
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
  cellular_components:
  - preferred_term: dendritic spine
    term:
      id: GO:0043197
      label: dendritic spine
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we establish a CRISPR-Cas9-mediated Ireb2 D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA."
    explanation: Establishes that this model carries the human patient allele, which is what makes its findings interpretable for this specific disorder rather than for generic Irp2 loss.
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction."
    explanation: Provides the synaptic and neuroinflammatory findings that this node asserts.
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistically, Ireb2 D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function."
    explanation: Confirms that the knock-in reproduces the molecular lesion (reduced protein, disordered iron handling) as well as the behavioural phenotype.
  downstream:
  - target: Extrapyramidal Movement Disorder and Neurodevelopmental Arrest
    description: >-
      Synaptic dysfunction offers a mechanism for the developmental component of
      the phenotype that neuronal loss alone does not explain.
- name: Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss
  biological_scale: TISSUE
  description: >-
    The tissue-level endpoint. In the Irp2-null mouse the abnormal brain iron
    metabolism is followed by adult-onset progressive neurodegeneration with
    widespread axonal degeneration and neuronal loss, and the disease worsens
    with age. In patients the corresponding observations are radiological rather
    than histological: progressive cerebral volume loss, delayed myelination and
    reduced white matter volume across the reported series, with frontal lobe
    atrophy in the index patient and periventricular, basal ganglia and thalamic
    signal abnormality in the fourth. The human timescale is compressed relative
    to the mouse - disease is manifest from infancy rather than from adulthood -
    which is one of the clearest quantitative mismatches between the model and
    the disease.
  biological_processes:
  - preferred_term: neuron apoptotic process
    modifier: INCREASED
    term:
      id: GO:0051402
      label: neuron apoptotic process
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, in the central nervous system, evidence of abnormal iron metabolism in IRP2-/- mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss."
    explanation: Gives the neuropathological substrate - axonal degeneration and neuronal loss - and its temporal relationship to the iron abnormality.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, brain imaging studies revealed progressive cerebral volume loss, delayed myelination, and a reduction in white"
    explanation: The human counterpart, drawn across all four reported patients - progressive volume loss with a myelination deficit.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."
    explanation: Records the structural brain finding in the index patient and the diagnostic label he carried before the genetic cause was known. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.
  - reference: PMID:18685102
    reference_title: "Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The neurodegenerative disease of IRP2(-/-) animals progresses slowly as the animals age."
    explanation: Establishes the progressive, age-dependent character of the model's disease, against which the much earlier human onset is judged.
  downstream:
  - target: Extrapyramidal Movement Disorder and Neurodevelopmental Arrest
    description: Loss of striatal, cerebellar and cortical circuitry produces the clinical syndrome.
- name: Extrapyramidal Movement Disorder and Neurodevelopmental Arrest
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint. All four patients converge on the same picture:
    neonatal feeding difficulty and hypotonia, then profound global
    developmental delay with no speech and no independent ambulation, severe
    dystonia and choreoathetoid movements, and epilepsy or EEG abnormality. The
    movement disorder has been explicitly described as treatment-resistant. The
    phenotype is developmental and degenerative at once, which is why the first
    patient carried a diagnosis of dystonic cerebral palsy before exome
    sequencing reassigned it - a mislabelling that any child with this genotype
    is likely to receive first.
  notes: >-
    The Irp2-null mouse produces a strikingly parallel behavioural syndrome -
    motor deficits on rotarod and hanging wire, somatosensory impairment on hot
    and cold plate, impaired spatial search and impaired reversal learning, the
    last a prefrontal-dependent task. It is a genuine convergence rather than a
    superficial one, but the movement phenotypes are not the same: the mouse has
    ataxia, bradykinesia and tremor, whereas the human disorder is dominated by
    dystonia and choreoathetosis. That difference is not explained.
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."
    explanation: Names the defining clinical feature and its refractoriness to treatment.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the case of a 7-year-old male patient with compound heterozygous missense variants in IREB2, whose neurological features resembled those of the two previously reported IRP2-deficient patients, including a profound global neurodevelopmental delay and dystonia."
    explanation: Confirms the syndrome recurs across patients with different alleles, establishing it as the disease phenotype rather than one family's presentation.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with early global developmental delay, which was characterized by an inability to speak or walk, alongside severe dystonia, choreoathetoid movements, epilepsy, and non-specific facial dysmorphisms such as midface hypoplasia, short philtrum, low-set ears, and thick, wiry hair"
    explanation: The most detailed single-patient description available, and the source for the dysmorphic features recorded in the phenotype list.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results suggest that loss of Irp2 in mice causes motor and behavioral deficits that faithfully reflect the IREB2 patient's neurodegenerative disorder."
    explanation: The model-organism claim of clinical convergence, recorded here with the species caveat in this node's notes.
genetic:
- name: IREB2
  association: Bi-allelic loss-of-function or hypomorphic variants; all four reported probands were compound heterozygous
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  notes: >-
    Gene identity. HGNC:6115 is the single gene returned by
    `runoak -i sqlite:obo:mondo relationships -p RO:0004003 MONDO:0032758`,
    with symbol IREB2. The protein is universally called IRP2 in the literature,
    and older papers use the symbol IRP2 or Ireb2 interchangeably; every source
    cited here was checked to be about that protein.

    Allelic series across the four published patients, as summarised in
    PMID:39587636. Patient 1: two nonsense alleles, c.1069G>T (p.Gly357*) and
    c.1255C>T (p.Arg419*). Patient 2: a missense allele c.2353G>A (p.Gly785Arg)
    with a three-base in-frame deletion c.1329_1331del (p.Ser444del). Patient 3:
    two missense alleles, c.656A>C (p.Glu219Ala) and c.2240G>A (p.Gly747Glu).
    Patient 4: two missense alleles, c.1111A>G (p.Ile371Val) and c.2477A>T
    (p.Asp826Val), reported against GenBank NM_004136.2 and located in exons 9
    and 20. The per-variant cDNA and protein designations for patients 1 to 3
    appear in the full text of PMID:39587636 in text that is broken by PDF
    line-wrap hyphenation and so cannot be quoted verbatim; they are recorded
    here as notes, with the quotable allele-class statements attached as
    evidence.

    Genotype-function correlation, which is the useful part. Complete absence of
    protein (patient 1, nonsense alleles, attributed to nonsense-mediated decay)
    and near-complete functional loss (patients 2 and 3) have both produced
    severe disease. In patient 4 the two alleles were assayed separately - the
    only such experiment in this literature - and behaved very differently:
    c.2477A>T destabilised IRP2 and disturbed iron handling, while c.1111A>G
    did neither on its own. This is the first functional evidence that IREB2
    alleles form a graded series, and it is the basis for expecting milder,
    still-unascertained phenotypes at the hypomorphic end.

    Not asserted. No population allele frequency, gnomAD constraint metric or
    ClinVar classification is recorded anywhere in this entry - none was
    retrieved from an authoritative source during this curation. The fourth
    patient's variants were reported as absent from HGMD and ClinVar at the time
    of that publication, which is a statement about those databases in 2024 and
    is not restated here as a current fact.
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."
    explanation: Establishes IREB2 as the causal gene through the index case.
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression."
    explanation: The strongest single piece of gene-disease validity evidence available - restoring the gene product in patient cells reverses the cellular phenotype.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The iron metabolism abnormalities of the patient cell line were reversed by lentiviral-mediated restoration of IREB2 expression."
    explanation: Independent replication of the rescue experiment in a second patient's cells with a different allele class.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The third case, along with our patient, displayed two missense mutations"
    explanation: Records the allele class of patients 3 and 4, which is what distinguishes them from the nonsense genotype of patient 1.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations were classified as likely pathogenic according to American College of Medical Genetics and Genom"
    explanation: Records the ACMG classification assigned to the fourth patient's variants by the reporting laboratory.
variants:
- name: p.Gly357*
  description: >-
    Nonsense allele c.1069G>T carried by the index patient in trans with
    p.Arg419*. Together the two nonsense alleles produced complete absence of
    IRP2 in patient lymphoblasts, attributed to nonsense-mediated decay of the
    transcript. This genotype defines the null end of the allelic series.
  gene:
    preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  type: single_nucleotide_variant
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first case exhibited two nonsense mutations"
    explanation: Records the allele class; the specific cDNA and protein designations are in the same paragraph but are broken by PDF hyphenation and so are recorded in the genetic notes rather than quoted.
- name: p.Arg419*
  description: >-
    The second nonsense allele of the index patient, c.1255C>T, in trans with
    p.Gly357*.
  gene:
    preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  type: single_nucleotide_variant
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cellular studies utilizing patient-derived lymphoblasts demonstrated a complete loss of IRP2 expression in the first case"
    explanation: Documents the functional consequence of this genotype - no detectable protein.
- name: p.Ile371Val
  description: >-
    Missense allele c.1111A>G, maternally inherited in the fourth patient and
    classified by the reporting authors as the milder of his two alleles.
    Expressed alone in SH-SY5Y cells it did not measurably reduce IRP2, alter
    transferrin receptor or lower labile iron, and the only change recorded was
    a slight increase in ferritin heavy chain; structural modelling
    places residue 371 near the surface through which IRP2 engages the IRE. Its
    pathogenic contribution is therefore inferred from position and conservation
    rather than demonstrated functionally, which is the main uncertainty in the
    fourth patient's genotype.
  gene:
    preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  type: single_nucleotide_variant
  clinical_significance: LIKELY_PATHOGENIC
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified novel biallelic variants, c.1111 A > G (P.Ile371Val) and c.2477 A > T (P.Asp826Val), in the IREB2 gene, which encodes the iron metabolism-related protein, IRP2."
    explanation: Reports the variant and its pairing.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Both mutations, at positions Ile371 and Asp826, resulted in valine substitutions, which in silico analysis suggests deleterious effects"
    explanation: Records that the evidence for this allele's pathogenicity is in-silico rather than experimental.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the A1111G mutation did not impact the expression of iron metabolism proteins, although there was a slight increase in FTH expression"
    explanation: The isolated in-vitro result for this allele, including the one positive change the authors record.
- name: p.Asp826Val
  description: >-
    Missense allele c.2477A>T, paternally inherited in the fourth patient and the
    only IREB2 allele with both an isolated in-vitro characterisation and a
    knock-in mouse. Expressed in SH-SY5Y cells it reduces IRP2 protein by around
    70%, raises ferritin heavy chain, lowers transferrin receptor and depletes
    labile ferrous iron; IREB2 transcript levels were separately shown to be
    essentially unaltered in the patient's own PBMCs, so the defect is
    post-transcriptional. The protein is recovered by proteasome inhibition, and
    residue 826 lies near the FBXL5 interaction region. Homozygous D826V
    knock-in mice reproduce neurobehavioural deficits, microglial activation,
    dendritic spine loss and impaired long-term potentiation. This is the
    best-characterised pathogenic allele in the disorder.
  gene:
    preferred_term: IREB2
    term:
      id: hgnc:6115
      label: IREB2
  type: single_nucleotide_variant
  clinical_significance: LIKELY_PATHOGENIC
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies revealed that c.2477 A > T resulted in a significant degradation of IRP2, which led to the misregulation of intracellular ferric iron."
    explanation: States the functional consequence that makes this the severe allele of the pair.
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we establish a CRISPR-Cas9-mediated Ireb2 D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA."
    explanation: Confirms the allele was modelled in vivo, providing organism-level evidence of its pathogenicity.
phenotypes:
- name: Global developmental delay
  category: Neurologic
  diagnostic: true
  description: >-
    Profound global developmental delay is the constant feature. Affected
    children do not acquire speech or independent ambulation; the impairment of
    ambulation and communication is shared by all four reported patients. The
    delay is present from infancy rather than following a period of normal
    development, which is why the disorder reads as neurodevelopmental as well
    as neurodegenerative.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the case of a 7-year-old male patient with compound heterozygous missense variants in IREB2, whose neurological features resembled those of the two previously reported IRP2-deficient patients, including a profound global neurodevelopmental delay and dystonia."
    explanation: Records profound global developmental delay in the third patient and states that it was shared with the two earlier ones.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired ambulation and communication, and non-specific facial dysmorphisms"
    explanation: Confirms impaired ambulation and communication across all four reported cases.
- name: Choreoathetosis
  category: Neurologic
  diagnostic: true
  description: >-
    Choreoathetoid movements are named in the disease term itself and are the
    single most distinctive clinical feature. In the index patient the movement
    disorder was explicitly treatment-resistant. Choreoathetosis with dystonia
    in a child who also has a mildly low mean corpuscular volume is the
    combination that should prompt consideration of this diagnosis.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."
    explanation: Documents the choreoathetoid movement disorder and its refractoriness in the index patient.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with early global developmental delay, which was characterized by an inability to speak or walk, alongside severe dystonia, choreoathetoid movements, epilepsy, and non-specific facial dysmorphisms such as midface hypoplasia, short philtrum, low-set ears, and thick, wiry hair"
    explanation: Records choreoathetoid movements in the fourth patient.
- name: Dystonia
  category: Neurologic
  diagnostic: true
  description: >-
    Severe dystonia accompanies the choreoathetosis and in some patients
    dominates it; the third patient's presentation was characterised as
    neurodevelopmental delay with dystonia and seizures, and the fourth had
    severe dystonia with hypertonia. The index patient was diagnosed with
    dystonic cerebral palsy before the genetic cause was identified.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
    severity: SEVERE
  evidence:
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the case of a 7-year-old male patient with compound heterozygous missense variants in IREB2, whose neurological features resembled those of the two previously reported IRP2-deficient patients, including a profound global neurodevelopmental delay and dystonia."
    explanation: Documents dystonia in the third patient and its shared occurrence with earlier cases.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's clinical presentations, including developmental delay, epilepsy,"
    explanation: Introduces the fourth patient's feature list, which continues with hypertonia and microcytic anaemia.
- name: Microcytic anemia
  category: Hematologic
  diagnostic: true
  description: >-
    Mild microcytic anaemia is the haematological signature and the second half
    of the disease name. It is mild in every reported patient and would not by
    itself prompt investigation: in the fourth patient the haemoglobin was
    114 g/L against a stated reference range of 120-140 g/L, with a mean
    corpuscular volume of 79.8 fL against 82-100 fL. Crucially, serum iron
    remained within the normal range, so the anaemia does not look like
    nutritional iron deficiency on standard iron studies. The Irp2-null mouse
    shows the same disconnect in a more extreme form - absent marrow iron stores
    with normal transferrin saturation.
  phenotype_term:
    preferred_term: Microcytic anemia
    term:
      id: HP:0001935
      label: Microcytic anemia
    severity: MILD
  notes: >-
    Reported as microcytic hypochromic anaemia in the index patient. The
    haemoglobin and MCV figures quoted in this description are the fourth
    patient's, from the full text of PMID:39587636, together with that
    laboratory's own reference intervals; they are not population norms and are
    not a claim about the other three patients, whose values are not available
    in cached sources.
  evidence:
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."
    explanation: Records microcytic hypochromic anaemia in the index patient. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia."
    explanation: Records microcytic anaemia in the fourth patient.
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia."
    explanation: Confirms that microcytic anaemia is part of the defining triad of the named entity, tied to the same OMIM number as the MONDO term curated here.
- name: Seizure
  category: Neurologic
  description: >-
    Epilepsy is present in most but not all patients, and the distinction
    matters for diagnosis. Electroencephalography was abnormal in all three of
    the earlier patients, but clinical seizures were not observed in the second;
    the fourth patient had epilepsy diagnosed in the neonatal period. A normal
    seizure history therefore does not exclude the diagnosis, whereas a normal
    EEG would be unusual.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with early global developmental delay, which was characterized by an inability to speak or walk, alongside severe dystonia, choreoathetoid movements, epilepsy, and non-specific facial dysmorphisms such as midface hypoplasia, short philtrum, low-set ears, and thick, wiry hair"
    explanation: Records epilepsy in the fourth patient.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."
    explanation: Records epilepsy in the index patient. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.
- name: EEG abnormality
  category: Neurologic
  description: >-
    Abnormal EEG was recorded in all three of the patients reported up to 2022,
    including the one who never had a clinical seizure. This dissociation makes
    EEG a more sensitive marker of cortical involvement than seizure history in
    this disorder.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, electroencephalograms (EEG) were abnormal in all three patients, although clinical seizures were not observed in the second patient"
    explanation: Directly supports both the universality of EEG abnormality in the first three patients and its dissociation from clinical seizures.
- name: Hypotonia
  category: Neurologic
  description: >-
    Neonatal and early hypotonia is one of the shared features of the published
    series, typically presenting together with feeding difficulty in the newborn
    period. Hypertonia and dystonia supervene later, so tone findings depend on
    the age at examination.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three previously reported cases, along with our patient, exhibited similar clinical features, including neonatal feeding difficulties, hypotonia, choreoathetoid"
    explanation: Names hypotonia explicitly within the feature list shared by all four reported patients.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Neonatal feeding difficulty is part of the shared presentation across the
    four reported patients and is often the first abnormality noticed. The
    proband's sister in the fourth family, who was never genotyped, also had
    developmental delay and feeding difficulties.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three previously reported cases, along with our patient, exhibited similar clinical features, including neonatal feeding difficulties, hypotonia, choreoathetoid"
    explanation: Names neonatal feeding difficulties explicitly within the feature list shared by all four genotyped patients.
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His older sister also had developmental delays and feeding difficulties."
    explanation: Records feeding difficulty additionally in the proband's affected but never-genotyped sister.
- name: Absent speech
  category: Neurologic
  description: >-
    None of the reported patients acquired speech. Communication impairment is
    listed among the features shared by all four.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with early global developmental delay, which was characterized by an inability to speak or walk, alongside severe dystonia, choreoathetoid movements, epilepsy, and non-specific facial dysmorphisms such as midface hypoplasia, short philtrum, low-set ears, and thick, wiry hair"
    explanation: Documents inability to speak in the fourth patient; impaired communication is separately recorded across all four.
- name: Inability to walk
  category: Neurologic
  description: >-
    Independent ambulation is not achieved. Impaired ambulation is one of the
    features listed as common to the whole reported series.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired ambulation and communication, and non-specific facial dysmorphisms"
    explanation: Records impaired ambulation as a shared feature of all four reported patients.
- name: Cerebral atrophy
  category: Neurologic
  description: >-
    Progressive cerebral volume loss is reported across the series; the index
    patient had frontal lobe atrophy, and the fourth had deepened sulci with
    widened frontotemporal subarachnoid spaces. HPO has no specific term for
    frontal lobe atrophy, so the finding is bound to the general cerebral
    atrophy term.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, brain imaging studies revealed progressive cerebral volume loss, delayed myelination, and a reduction in white"
    explanation: States that progressive cerebral volume loss is a finding of the reported series as a whole.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."
    explanation: Records the regional (frontal) atrophy in the index patient. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.
- name: Delayed myelination
  category: Neurologic
  description: >-
    Delayed myelination with reduced white matter volume is part of the imaging
    phenotype and is mechanistically the most interpretable of the radiological
    findings, since oligodendrocytes have the highest iron requirement of any
    brain cell type and myelin lipid synthesis is iron-dependent.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, brain imaging studies revealed progressive cerebral volume loss, delayed myelination, and a reduction in white"
    explanation: Directly reports delayed myelination and white matter reduction across the reported cases.
- name: Cerebral white matter atrophy
  category: Neurologic
  description: >-
    White matter volume is reduced. In the fourth patient the MRI at eight years
    showed abnormal signal around the lateral ventricles, basal ganglia and
    thalamus together with a small, thickened corpus callosum. Conventional
    signal abnormality is not a measurement of tissue iron and is not curated as
    such here.
  phenotype_term:
    preferred_term: Cerebral white matter atrophy
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A brain MRI at 8 years old revealed abnormal signals around the lateral ventricles, basal ganglia, and thalamus."
    explanation: Documents the regional distribution of the imaging abnormality in the fourth patient.
- name: Abnormal facial shape
  category: Craniofacial
  description: >-
    Non-specific facial dysmorphism is reported in all four patients; in the
    fourth it comprised midface hypoplasia, a short philtrum, low-set ears and
    thick, wiry hair. The features are not distinctive enough to be recognisable
    and are recorded here only so that their presence does not argue against the
    diagnosis.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired ambulation and communication, and non-specific facial dysmorphisms"
    explanation: Records non-specific facial dysmorphism as a shared feature of the four reported patients.
diagnosis:
- name: Trio exome or genome sequencing
  description: >-
    Molecular diagnosis rests on identifying bi-allelic IREB2 variants by exome
    or genome sequencing, ideally as a trio so that the two alleles can be shown
    to be in trans - every reported patient has been compound heterozygous, and
    both parents were unaffected carriers. Every published patient reached
    diagnosis through broad sequencing rather than through a targeted clinical
    suspicion: exome sequencing in the index case, and whole-exome or parallel
    gene sequencing across the reported series. The most likely
    pre-genetic label is dystonic cerebral palsy, which the index patient
    carried, so reanalysis of undiagnosed cerebral-palsy-like exomes is a
    reasonable route to further cases.
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2."
    explanation: Establishes exome sequencing as the diagnostic modality that identified the disorder.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."
    explanation: Documents the clinical label carried before the molecular diagnosis, which is the population in which further cases are most likely to be found. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.
- name: Full blood count with red cell indices and iron studies
  description: >-
    A complete blood count showing mild microcytic, hypochromic anaemia, with
    serum iron and transferrin saturation in the normal range, is the
    inexpensive finding that distinguishes this disorder from an isolated
    neurological syndrome. The combination of microcytosis with normal iron
    studies is the diagnostic signature: it is what would be expected if the
    problem were cellular iron handling rather than iron supply, and it means
    that a normal ferritin or serum iron does not argue against the diagnosis.
  notes: >-
    The mouse predicts two further laboratory findings that have not been
    reported in patients and are worth measuring: absent bone marrow iron stores
    despite normal transferrin saturation, and raised free and zinc
    protoporphyrin from ALAS2 derepression. Erythrocyte protoporphyrin is a
    cheap, widely available test and is the most direct available probe of the
    mechanism in a living patient.
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum ferritin was measured at 24.34 ng/mL"
    explanation: Illustrates that ferritin in the reported patient was within the quoted reference interval, so normal iron studies do not exclude the diagnosis.
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We postulate that IRP2 mutations or deletions may be a cause of refractory microcytic anemia and bone marrow iron depletion in patients with normal transferrin saturations, elevated serum ferritins, elevated red cell protoporphyrin IX levels, and adult-onset neurodegeneration."
    explanation: The authors' own prospective description of the laboratory profile that should prompt IREB2 testing, written fourteen years before the first patient was found.
- name: Brain MRI
  description: >-
    Imaging documents the structural correlates - progressive cerebral volume
    loss, delayed myelination, reduced white matter volume, and signal
    abnormality around the lateral ventricles, basal ganglia and thalamus - and
    excludes the main radiological differentials. It is specifically worth
    noting what is NOT reported: no patient has been described with the
    "eye-of-the-tiger" pallidal appearance of pantothenate kinase-associated
    neurodegeneration or with the marked pallidal and dentate hypointensity of
    the NBIA disorders and aceruloplasminemia.
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A brain MRI at 8 years old revealed abnormal signals around the lateral ventricles, basal ganglia, and thalamus."
    explanation: Gives the reported MRI findings in the most fully described patient.
- name: Functional confirmation in patient-derived cells
  description: >-
    Where a variant of uncertain significance is found, the published approach
    is to derive lymphoblastoid cells and measure IRP2 protein, ferritin and
    transferrin receptor levels, labile iron and mitochondrial function, then
    show that lentiviral restoration of IREB2 reverses the abnormalities. This
    assay set has now been applied in two independent patients and is the
    reference method for demonstrating that a novel IREB2 allele is pathogenic.
    For alleles suspected of destabilising the protein, adding a proteasome
    inhibitor arm distinguishes accelerated degradation from impaired
    IRE-binding.
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression."
    explanation: Defines the rescue experiment that converts a cellular phenotype into evidence of causality.
  - reference: PMID:35602653
    reference_title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The iron metabolism abnormalities of the patient cell line were reversed by lentiviral-mediated restoration of IREB2 expression."
    explanation: Shows the same assay applied independently to a missense genotype.
differential_diagnoses:
- name: Aceruloplasminemia
  disease_term:
    preferred_term: aceruloplasminemia
    term:
      id: MONDO:0011426
      label: aceruloplasminemia
  description: >-
    The closest conceptual mimic: a recessive disorder of iron handling that
    couples anaemia to neurodegeneration. Loss of ceruloplasmin ferroxidase
    activity blocks iron export from cells, so iron is trapped in brain and
    other tissues while the erythron goes short. Both disorders therefore
    present as anaemia plus movement disorder from a lesion in cellular iron
    trafficking rather than in iron supply.
  distinguishing_features:
  - Caused by bi-allelic CP variants (HGNC:2295), not IREB2; verified with OAK as MONDO:0011426, OMIM:604290.
  - Onset is typically in adulthood, most often the fourth to sixth decade, whereas NDCAMA presents in infancy.
  - Serum ceruloplasmin is absent or near-absent and serum ferritin is markedly elevated, neither of which is a feature of NDCAMA.
  - Brain MRI shows striking iron deposition with hypointensity in basal ganglia, thalamus and dentate nucleus; NDCAMA imaging shows volume loss and delayed myelination without documented iron deposition.
  - Diabetes mellitus and retinal degeneration are characteristic of aceruloplasminemia and have not been reported in NDCAMA.
  notes: >-
    MONDO:0011426 and its causal gene were verified with OAK
    (`runoak -i sqlite:obo:mondo info MONDO:0011426 -O obo`), which returns
    `RO:0004003 HGNC:2295 ! CP` and xref OMIM:604290. The clinical distinguishing
    features above are general knowledge of aceruloplasminemia and are recorded
    as notes rather than as evidence-backed claims, because no aceruloplasminemia
    reference was fetched for this curation.
- name: Neuroferritinopathy
  disease_term:
    preferred_term: neuroferritinopathy
    term:
      id: MONDO:0011638
      label: neuroferritinopathy
  description: >-
    The instructive contrast within the IRE/IRP system itself. Neuroferritinopathy
    is caused by variants in FTL, the ferritin light chain - one of the very
    transcripts whose translation IRP2 represses. Both disorders produce a
    chorea-dominant extrapyramidal syndrome through disordered ferritin biology,
    but from opposite directions: NDCAMA loses the repressor, so ferritin is
    derepressed and iron is sequestered away from use, whereas
    neuroferritinopathy alters the ferritin polypeptide itself so that the
    assembled shell handles iron abnormally.
  distinguishing_features:
  - Caused by FTL variants (HGNC:3999) and inherited dominantly; NDCAMA is recessive at IREB2. Verified with OAK as MONDO:0011638, OMIM:606159.
  - Adult onset, typically in the fourth or fifth decade, versus infantile onset in NDCAMA.
  - Serum ferritin is characteristically low in neuroferritinopathy; ferritin has been within the reference range in the reported NDCAMA patients.
  - MRI shows cavitation and iron deposition in the basal ganglia, which has not been described in NDCAMA.
  - Anaemia is not a feature of neuroferritinopathy.
  notes: >-
    MONDO:0011638 was verified with OAK and returns `RO:0004003 HGNC:3999 ! FTL`
    with xref OMIM:606159. The KB already contains an entry for this disorder
    (`kb/disorders/neuroferritinopathy.yaml`); it is cited here only as a
    mechanistic contrast and no content was copied from it. As for
    aceruloplasminemia above, the clinical distinguishing features (adult onset,
    characteristically low serum ferritin, basal ganglia cavitation) are general
    knowledge of neuroferritinopathy recorded as orientation for a differential,
    not evidence-backed claims: no neuroferritinopathy reference was fetched for
    this curation.
- name: Neurodegeneration with brain iron accumulation
  disease_term:
    preferred_term: neurodegeneration with brain iron accumulation
    term:
      id: MONDO:0018307
      label: neurodegeneration with brain iron accumulation
  description: >-
    The category NDCAMA superficially resembles and deliberately is not assigned
    to. The NBIA disorders are defined by radiologically demonstrable iron
    accumulation in the basal ganglia together with an extrapyramidal movement
    disorder, and pantothenate kinase-associated neurodegeneration is their
    prototype. NDCAMA shares the movement disorder and the involvement of iron
    biology but has never been shown to accumulate brain iron in a human, and
    its cellular lesion is functional iron deficiency rather than overload. The
    Irp2-null mouse does accumulate brain iron, which is precisely why the
    distinction has to be made explicitly rather than assumed.
  distinguishing_features:
  - NBIA is defined by demonstrable brain iron accumulation on MRI; no patient with IREB2 variants has been shown to have brain iron accumulation.
  - The NBIA prototype PKAN shows the eye-of-the-tiger sign in the globus pallidus, which has not been reported in NDCAMA.
  - NBIA disorders are genetically heterogeneous (PANK2, PLA2G6, C19orf12 and others) and do not include IREB2; MONDO:0018307 carries the OMIM phenotypic series OMIMPS:234200, verified with OAK.
  - Microcytic anaemia is not a feature of the NBIA disorders and is part of the defining triad of NDCAMA.
  - The cellular lesion in NDCAMA is functional cytosolic iron deficiency, the opposite of overload, even where tissue iron staining is increased in the mouse.
  notes: >-
    MONDO:0018307 was verified with OAK
    (`runoak -i sqlite:obo:mondo info MONDO:0018307 -O obo`), which returns the
    grouping definition sourced to Orphanet:385 and xref OMIMPS:234200; the term
    is a `disease_grouping` with no single causal gene, which is why no
    `RO:0004003` gene relation is quoted here as it is for the monogenic
    differentials above. As for aceruloplasminemia and neuroferritinopathy, the
    clinical distinguishing features (the eye-of-the-tiger sign in PKAN, the
    PANK2/PLA2G6/C19orf12 gene list, absence of anaemia) are general knowledge
    of the NBIA disorders recorded as orientation for a differential, not
    evidence-backed claims: no NBIA reference was fetched for this curation. The
    NDCAMA-side statements (no documented brain iron accumulation in a patient,
    microcytic anaemia in the defining triad, functional cytosolic iron
    deficiency) are evidenced elsewhere in this entry.
- name: X-linked sideroblastic anemia with ataxia
  disease_term:
    preferred_term: X-linked sideroblastic anemia with ataxia
    term:
      id: MONDO:0010524
      label: X-linked sideroblastic anemia with ataxia
  description: >-
    The other Mendelian disorder that pairs a microcytic anaemia with a movement
    disorder through a lesion in iron biology. ABCB7 exports a mitochondrial
    iron-sulfur cluster intermediate to the cytosol, so its loss impairs
    cytosolic Fe-S assembly and erythroid iron utilisation simultaneously -
    structurally the same kind of coupling as NDCAMA, at a different step.
  distinguishing_features:
  - Caused by ABCB7 variants (HGNC:48) and X-linked recessive; NDCAMA is autosomal recessive at IREB2. Verified with OAK as MONDO:0010524, OMIM:301310.
  - The anaemia is sideroblastic with ring sideroblasts on marrow examination; the NDCAMA anaemia is iron-limited without reported ring sideroblasts.
  - The neurological phenotype is non-progressive or slowly progressive cerebellar ataxia from early childhood, not a choreoathetoid and dystonic syndrome with developmental arrest.
  - Affected individuals are male, with carrier females typically unaffected or mildly affected.
  notes: >-
    MONDO:0010524 and its causal gene were verified with OAK. The clinical
    features attributed to XLSA-A here (ring sideroblasts on marrow examination,
    the ataxia phenotype, the X-linked sex distribution) are general knowledge of
    that disorder, recorded as orientation for a differential rather than as
    evidence-backed claims, because no XLSA-A reference was fetched for this
    curation.
- name: IRIDA syndrome
  disease_term:
    preferred_term: IRIDA syndrome
    term:
      id: MONDO:0008788
      label: IRIDA syndrome
  description: >-
    The haematological differential for the anaemia considered in isolation.
    Iron-refractory iron deficiency anaemia is a recessive microcytic anaemia
    caused by TMPRSS6 variants that fails to respond to oral iron - a phenotype
    that can superficially resemble the treatment-unresponsive microcytosis of
    NDCAMA. The mechanisms are unrelated: IRIDA is a disorder of systemic
    hepcidin regulation limiting iron absorption and release, whereas NDCAMA is
    a cell-autonomous failure to use iron that is already present.
  distinguishing_features:
  - Caused by bi-allelic TMPRSS6 variants (HGNC:16517); verified with OAK as MONDO:0008788, OMIM:206200.
  - There is no neurological phenotype in IRIDA; NDCAMA is dominated by neurological disease.
  - IRIDA shows low transferrin saturation and inappropriately high hepcidin; serum iron has been normal in the reported NDCAMA patients.
  - IRIDA anaemia is typically more marked and is the presenting problem, whereas the NDCAMA anaemia is mild and incidental to the presentation.
  notes: >-
    MONDO:0008788 and its causal gene were verified with OAK. The IRIDA
    laboratory profile quoted here (low transferrin saturation, inappropriately
    high hepcidin, oral-iron refractoriness) is general knowledge of that
    disorder, recorded as orientation for a differential rather than as an
    evidence-backed claim, because no IRIDA reference was fetched for this
    curation.
- name: Erythropoietic protoporphyria
  disease_term:
    preferred_term: erythropoietic protoporphyria
    term:
      id: MONDO:0001676
      label: erythropoietic protoporphyria
  description: >-
    Included because the Irp2-null mouse has erythropoietic protoporphyria as
    part of its phenotype, generated by ALAS2 derepression rather than by a
    ferrochelatase defect. If protoporphyrin accumulation is ever demonstrated
    in an IREB2 patient, the biochemical picture could be mistaken for classical
    EPP, and the distinction would rest on the absence of photosensitivity and
    on the accompanying neurological disease.
  distinguishing_features:
  - Classical EPP arises from reduced ferrochelatase activity, most often bi-allelic FECH hypomorphism, not from IRP2 loss.
  - Photosensitivity with painful non-blistering phototoxicity is the cardinal feature of EPP and has not been reported in any IREB2 patient.
  - The protoporphyria of IRP2 deficiency is so far a murine finding only; no patient has had erythrocyte protoporphyrin reported.
  - EPP has no neurodegenerative component.
  notes: >-
    MONDO:0001676 was verified with OAK. The description of classical EPP here
    (FECH hypomorphism, painful non-blistering photosensitivity) is general
    knowledge of that disorder, recorded as orientation for a differential
    rather than as an evidence-backed claim, because no EPP reference was
    fetched for this curation.
treatments:
- name: Supportive and symptomatic management
  description: >-
    No disease-modifying therapy exists. Management is supportive: feeding
    support in infancy, anticonvulsants for epilepsy, physical therapy and
    posture management for dystonia, and the usual multidisciplinary care of a
    child with profound developmental impairment. The movement disorder in the
    index patient was explicitly described as treatment-resistant, so families
    should not be led to expect a good response to standard antidystonic or
    antichoreic agents.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder."
    explanation: Documents the refractoriness of the movement disorder, which is the basis for framing management as supportive rather than therapeutic.
- name: Anticonvulsant therapy
  description: >-
    Seizures occur in most patients and are managed with standard antiseizure
    medication. No agent has been reported as preferred or as contraindicated in
    this disorder, and no seizure-outcome data exist; the recommendation is
    therefore generic epilepsy care rather than anything IREB2-specific.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy."
    explanation: Establishes that epilepsy is part of the phenotype requiring management. Tagged OTHER rather than HUMAN_CLINICAL because this sentence is the Irp2-null mouse paper's secondhand restatement of the human index patient first reported by Costain et al. (PMID:30915432), not primary human data from this publication.
- name: Genetic counselling for an autosomal recessive disorder
  description: >-
    Both parents of an affected child are obligate carriers and the recurrence
    risk in each pregnancy is one in four. All four reported families were
    non-consanguineous and each child was compound heterozygous, so carrier
    testing must cover both parental alleles rather than assume a single
    familial variant. Carrier siblings, such as the fourth proband's younger
    brother, are healthy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed the paternal (A2477T) and maternal (A1111G) origins of the"
    explanation: Demonstrates the biparental origin of the two alleles that underlies the recurrence risk and the need to test both parents.
- name: Physical therapy and rehabilitation
  description: >-
    Physiotherapy, positioning and contracture prevention are the mainstay of
    motor management in a child with severe dystonia who does not ambulate. No
    trial data exist in this disorder; the rationale is extrapolated from care
    of other severe early-onset dystonic syndromes.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  notes: >-
    No evidence item is attached. There is no publication reporting
    rehabilitation outcomes in an IREB2 patient, and attaching a snippet from
    one of the case reports would misrepresent what those papers show.
- name: Investigational - HIF2-alpha inhibition
  description: >-
    The most developed mechanism-directed lead, and preclinical only. In
    Irp2-null mice the selective HIF2-alpha inhibitor PT-2385 prevented
    neurodegenerative symptoms and restored Purkinje cell architecture, while
    inhibiting HIF1-alpha with PX-478 did not; PT-2385 also improved
    mitochondrial morphology and suppressed the glycolytic shift. PT-2385 is a
    small-molecule HIF2-alpha inhibitor of the same pharmacological class as
    belzutifan, the first-in-class HIF-2alpha inhibitor developed for clear cell
    renal carcinoma, so the chemistry is tractable in principle. That class
    comparison also carries a warning specific to this disorder: anaemia is a
    recognised on-target toxicity of belzutifan, and NDCAMA patients are already
    anaemic. Nothing has been tested in a patient and the murine treatment was
    given to adult animals with a slowly progressive disease, which is a poor
    match for an infant with established developmental arrest.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: HIF2-alpha inhibitor (investigational)
  target_mechanisms:
  - target: HIF2-alpha Stabilisation and the Glycolytic Shift
    treatment_effect: INHIBITS
    description: >-
      PT-2385 blocks HIF2-alpha directly, which in the null mouse was sufficient
      to prevent the neurodegenerative phenotype.
  evidence:
  - reference: PMID:34675764
    reference_title: "Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array."
    explanation: The primary preclinical result behind this lead, including the negative control arm that makes it specific to HIF2-alpha.
  - reference: PMID:34675764
    reference_title: "Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo but also suppressed glycolysis."
    explanation: Shows the treatment acts on the proposed mechanism and not only on the behavioural readout.
  - reference: PMID:39670660
    reference_title: "Targeting HIF-2α: the role of belzutifan in clear cell renal carcinoma management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor."
    explanation: Sources the class comparison drawn in the description; this reference is about oncology, not IREB2, and is cited only to establish that HIF2-alpha inhibition is a clinically developed pharmacology.
  - reference: PMID:39670660
    reference_title: "Targeting HIF-2α: the role of belzutifan in clear cell renal carcinoma management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Belzutifan is a relatively safe drug, with manageable adverse events, including anemia and hypoxia as on-target toxicity."
    explanation: Records the class liability that matters most here - on-target anaemia in a disorder whose phenotype already includes microcytic anaemia.
- name: Investigational - recruiting latent IRP1 activity
  description: >-
    A conceptually distinct preclinical strategy: rather than replacing IRP2,
    convert the abundant but latent aconitase pool of IRP1 into IRE-binding
    protein. Dietary Tempol, a stable nitroxide, did exactly this in Irp2-null
    mice - disassembling the IRP1 iron-sulfur cluster, restabilising the TfR1
    transcript, repressing ferritin synthesis and markedly attenuating the
    progression of neuromuscular impairment. It is the only intervention shown
    to modify the neurological phenotype of an Irp2-null animal from the
    upstream regulatory node rather than from a downstream consequence, and it
    has never been tried in a patient.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Tempol (investigational nitroxide)
  target_mechanisms:
  - target: Failure of IRP1 to Compensate
    treatment_effect: MODULATES
    description: >-
      Tempol acts on the compensation failure itself, converting latent IRP1
      aconitase into IRE-binding protein so that the paralogue substitutes for
      the missing IRP2.
  evidence:
  - reference: PMID:18685102
    reference_title: "Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated."
    explanation: The efficacy result in the null mouse.
  - reference: PMID:18685102
    reference_title: "Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain."
    explanation: Gives the proposed mechanism, which is what makes this strategy allele-agnostic and applicable even to nonsense genotypes.
- name: Investigational - stabilising a degradation-prone IRP2
  description: >-
    An allele-specific idea rather than a therapy. Because the p.Asp826Val
    protein is lost to the proteasome rather than mis-folded into uselessness,
    blocking its degradation restores both the protein and its regulatory
    output in cells. The authors of the fourth case report frame proteasome
    inhibition as a potential therapeutic direction. The caveats are severe:
    MG-132 is a research tool with no clinical use, clinically approved
    proteasome inhibitors are systemically toxic and poorly CNS-penetrant, and
    the strategy could only ever help the subset of patients whose alleles are
    degradation-prone. Restoration of IREB2 expression itself - achieved
    lentivirally in two independent patient cell lines - is the corresponding
    gene-directed proof of principle.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: proteasome inhibition or IRP2 stabilisation (investigational)
  target_mechanisms:
  - target: Absence or Accelerated Degradation of IRP2 Protein
    treatment_effect: INHIBITS
    description: >-
      Blocking proteasomal turnover restores a degradation-prone IRP2 and with
      it the downstream iron-regulatory output; applicable only to alleles that
      act by destabilising the protein.
  evidence:
  - reference: PMID:39587636
    reference_title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, the use of proteasome inhibitors can potentially restore the expression of IRP2, highlighting a promising therapeutic target"
    explanation: The authors' own statement of the therapeutic hypothesis, made on the basis of the MG-132 rescue in their cell model.
  - reference: PMID:30915432
    reference_title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression."
    explanation: Establishes that restoring the gene product is sufficient to reverse the cellular disease phenotype, the premise of any gene-directed therapy.
animal_models:
- species: Mus musculus
  genotype: Ireb2 (Irp2) targeted null, homozygous
  category: Knockout
  description: >-
    The founding model, and the reason the human disorder was recognisable when
    the first patient appeared. Irp2-null mice misregulate iron metabolism in
    the intestinal mucosa and the central nervous system, overexpress ferritin
    and express abnormally low transferrin receptor in multiple tissues, and
    develop in adulthood a movement disorder of ataxia, bradykinesia and tremor
    on a background of progressive neurodegeneration with widespread axonal
    degeneration and neuronal loss. Iron and ferritin accumulate in white matter
    tracts and in the neurons that later die, months before symptoms. In the
    erythron the same lesion produces iron-limited erythropoiesis with absent
    marrow iron stores, microcytic anaemia and, through ALAS2 derepression, an
    erythropoietic protoporphyria.

    Extensive behavioural phenotyping has since shown motor deficits on rotarod
    and hanging wire, somatosensory impairment on hot and cold plate testing,
    impaired spatial search in the Barnes maze and impaired reversal learning on
    an operant touchscreen task - a prefrontal-dependent measure. The authors
    read this as faithfully reflecting the patient's disorder.

    The mismatches are as informative as the matches, and are curated as a
    discussion below: the mouse's disease is adult-onset and slowly progressive
    where the human disease is manifest from infancy, its anaemia and
    protoporphyria are more severe than anything reported in a patient, its
    movement disorder is ataxic and hypokinetic rather than dystonic and
    choreoathetoid, and it accumulates brain iron in a way no patient has been
    shown to do.
  associated_phenotypes:
  - Ataxia, bradykinesia and tremor in adulthood
  - Progressive neurodegeneration with axonal degeneration and neuronal loss
  - Brain iron and ferritin accumulation preceding symptoms
  - Microcytic anaemia with absent bone marrow iron stores
  - Erythropoietic protoporphyria with raised free and zinc protoporphyrin
  - Motor, somatosensory and executive deficits on behavioural testing
  evidence:
  - reference: PMID:11175792
    reference_title: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor."
    explanation: Defines the model's neurological phenotype and its adult onset.
  - reference: PMID:15831703
    reference_title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IRP2-/- mice represent a new paradigm of genetic microcytic anemia."
    explanation: Establishes the haematological arm of the model, which is what made the human anaemia interpretable.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Irp2-null mice had a significant motor deficit demonstrated by reduced performance on rotarod and hanging wire tests."
    explanation: Reports the motor phenotype on standardised testing.
  - reference: PMID:39239479
    reference_title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Their spatial search strategy was impaired in the Barnes maze and they exhibited a difficulty in flexibly adapting their response in the operant touchscreen reversal learning task."
    explanation: Extends the model phenotype into the cognitive domain, matching the profound developmental impairment of the patients.
- species: Mus musculus
  genotype: Ireb2 D826V/D826V knock-in (CRISPR-Cas9)
  category: Knock-in of a patient allele
  description: >-
    The first model of an actual patient variant rather than of gene ablation,
    generated from the p.Asp826Val allele of the Chinese proband. Homozygotes
    show reduced Ireb2 protein, dysregulated iron metabolism, impaired spatial
    learning and memory, reduced motor activity, increased microglial
    activation, decreased hippocampal dendritic spine density, impaired
    long-term potentiation and elevated paired-pulse facilitation. It moves the
    mechanism from iron chemistry into synaptic biology and neuroinflammation,
    and it is the model in which allele-specific therapeutic ideas such as
    IRP2 stabilisation could be tested.

    Its limitations are the obvious ones. It is homozygous for an allele that
    occurs in patients only in the compound heterozygous state, it has been
    reported once, and its behavioural readouts (Morris water maze, open field,
    Y-maze) address learning and activity rather than the dystonia and
    choreoathetosis that dominate the human phenotype. No haematological
    phenotype is reported in the cached abstract.
  associated_phenotypes:
  - Impaired spatial learning and memory
  - Reduced motor activity
  - Increased microglial activation in the hippocampus
  - Decreased dendritic spine density
  - Impaired long-term potentiation with elevated paired-pulse facilitation
  - Reduced Ireb2 protein with dysregulated iron metabolism
  evidence:
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Behavioral studies, including the Morris water maze (MWM), open field test (OFT), and Y-maze, reveal significant neurobehavioral deficits, such as impaired spatial learning and memory and reduced motor activity, in Ireb2 D826V/D826V mice."
    explanation: Reports the behavioural phenotype of the knock-in.
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This finding links the instability of IREB2 to synaptic failure and neuroinflammation"
    explanation: States the mechanistic contribution of this model - connecting protein instability to synaptic and inflammatory endpoints.
  - reference: PMID:41234066
    reference_title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood."
    explanation: The authors' statement of the gap this model fills, which is also the reason the older null mouse cannot answer allele-specific questions.
discussions:
- discussion_id: ireb2-brain-iron-paradox
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How can the same lesion produce functional cytosolic iron deficiency and
    tissue iron accumulation in the brain at the same time, and which of the two
    actually kills neurons?
  rationale: >-
    This is the central unresolved question of the mechanism. Patient cells show
    functional iron deficiency - low transferrin receptor, high ferritin,
    depleted labile ferrous iron - while the Irp2-null mouse brain accumulates
    ferric iron and ferritin in white matter tracts and in the neuronal
    populations that subsequently degenerate. The usual reconciliation is that
    derepressed ferritin sequesters iron into a form the cell cannot mobilise,
    so the tissue is loaded and the cytosol is starved; but that account is
    inferred rather than demonstrated, and it has real consequences. If
    starvation is what kills neurons, therapy should aim to restore iron
    delivery. If sequestered iron is doing oxidative damage, chelation would be
    the opposite and could be harmful. No human brain iron measurement -
    quantitative susceptibility mapping, R2* relaxometry or post-mortem
    analysis - has been reported in any IREB2 patient, so even the first
    question, whether human brains accumulate iron at all, is unanswered.
  attaches_to:
  - "pathophysiology#Neuronal and Oligodendrocyte Iron Mishandling"
  - "pathophysiology#Functional Cytosolic Iron Deficiency"
  proposed_experiments:
  - experiment_id: ireb2-qsm-brain-iron
    name: Quantitative susceptibility mapping in IREB2 patients
    description: >-
      Apply QSM and R2* relaxometry to any living patient to determine whether
      regional brain iron is increased, normal or reduced, and whether the
      distribution matches the mouse. This is the single measurement that would
      settle whether the disorder belongs conceptually with the NBIA disorders
      or with the iron-deficiency spectrum.
  - experiment_id: ireb2-labile-vs-total-iron-neurons
    name: Labile versus total iron in patient iPSC-derived neurons
    description: >-
      Differentiate patient iPSCs into cortical neurons and oligodendrocytes and
      measure labile iron pool, total cellular iron and ferritin-bound iron
      side by side, to test the sequestration model directly in the affected
      cell types rather than in lymphoblasts.
- discussion_id: ireb2-mouse-human-haematology-mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is the haematological phenotype so much milder in patients than in
    Irp2-null mice, and does the erythropoietic protoporphyria of the mouse
    occur in humans at all?
  rationale: >-
    The mouse has frank microcytic anaemia with absent bone marrow iron stores
    and a florid erythropoietic protoporphyria from ALAS2 derepression, which
    the authors of that work proposed would identify human patients. The
    patients found since have mild anaemia - haemoglobin 114 g/L and MCV 79.8 fL
    in the one case with published values - normal serum iron, and no reported
    protoporphyrin abnormality whatsoever. Three explanations are live and they
    are not equivalent: erythrocyte protoporphyrin may simply never have been
    measured, since no one thought to ask; human erythropoiesis may buffer IRP2
    loss better than murine erythropoiesis, for instance through greater IRP1
    contribution in the erythron; or the human alleles reported so far may
    retain more residual function in erythroid cells than a complete gene
    deletion. The distinction matters diagnostically, because the mouse-derived
    prediction of a "refractory microcytic anaemia with elevated red cell
    protoporphyrin" is currently the published screening profile for this
    disorder and it may be wrong for humans.
  attaches_to:
  - "pathophysiology#Iron-Limited Erythropoiesis"
  proposed_experiments:
  - experiment_id: ireb2-erythrocyte-protoporphyrin
    name: Erythrocyte free and zinc protoporphyrin in IREB2 patients
    description: >-
      Measure free and zinc protoporphyrin, reticulocyte haemoglobin content and
      soluble transferrin receptor in every living patient. The assays are cheap
      and widely available and would immediately show whether the murine ALAS2
      derepression arm operates in humans.
  - experiment_id: ireb2-erythroid-differentiation-assay
    name: Erythroid differentiation of patient CD34+ cells
    description: >-
      Differentiate patient-derived CD34+ progenitors along the erythroid
      lineage and measure TfR1, ferritin, ALAS2 protein, haem and protoporphyrin
      output, to establish whether the human erythron reproduces the mouse
      phenotype under controlled conditions.
- discussion_id: ireb2-movement-phenotype-species-difference
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is the human movement disorder dystonic and choreoathetoid while the
    mouse is ataxic, bradykinetic and tremulous, and does that reflect different
    circuits being affected?
  rationale: >-
    The convergence between mouse and patient is usually presented as close, and
    at the level of "neurodegeneration with a movement disorder" it is. But the
    phenomenology differs systematically: patients have dystonia and
    choreoathetosis, which point to basal ganglia output, whereas the mouse has
    ataxia and tremor with Purkinje cell pathology, which points to the
    cerebellum, and the PT-2385 rescue was scored on Purkinje cell morphology.
    Human imaging does show basal ganglia and thalamic signal abnormality, so
    the human lesion may genuinely be striatopallidal while the murine one is
    cerebellar. If so, a therapy validated on cerebellar endpoints in the mouse
    may not predict benefit for the disabling human feature. Timing is a
    confounder that cannot be separated on present evidence: the mouse disease
    begins in adulthood and the human disease in infancy, so the same lesion is
    hitting a mature versus a developing circuit.
  attaches_to:
  - "pathophysiology#Extrapyramidal Movement Disorder and Neurodevelopmental Arrest"
  - "pathophysiology#Progressive Neurodegeneration with Axonal Degeneration and Neuronal Loss"
  proposed_experiments:
  - experiment_id: ireb2-regional-vulnerability-mapping
    name: Regional mapping of iron handling and cell loss in knock-in mice
    description: >-
      Compare striatum, globus pallidus, cerebellum and cortex in D826V knock-in
      and null mice for iron content, ferritin, transferrin receptor, neuronal
      density and microglial activation, to determine whether the regional
      vulnerability of the mouse genuinely differs from the human pattern or
      only appears to because cerebellar endpoints have been the ones measured.
  - experiment_id: ireb2-conditional-neuronal-knockouts
    name: Cell-type-conditional Ireb2 deletion
    description: >-
      Delete Ireb2 selectively in medium spiny neurons, in Purkinje cells and in
      oligodendrocytes to establish which cell type's iron failure is sufficient
      to produce which movement phenotype.
- discussion_id: ireb2-hypomorphic-spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does partial loss of IRP2 function cause a milder, currently unrecognised
    phenotype, and if so what does it look like?
  rationale: >-
    All four patients found so far have effectively complete loss of IRP2
    function, and the authors of the third report explicitly raised the
    possibility that individuals with significant but incomplete loss develop
    less severe disease. The fourth patient's p.Ile371Val allele is the first
    experimental hint that such alleles exist - assayed alone it produced no
    measurable change in IRP2 abundance, ferritin, transferrin receptor or
    labile iron. If a hypomorphic spectrum exists, the phenotype might be an
    isolated dystonia, a late-onset movement disorder, or an unexplained
    microcytic anaemia with normal iron studies - all of which would currently be
    ascertained under different diagnostic labels, if at all. Testing this
    requires looking outside the severe paediatric neurology population where
    every case so far has been found.
  attaches_to:
  - "pathophysiology#Impaired IRE-Binding Activity of Residual IRP2"
  - "genetic#IREB2"
  proposed_experiments:
  - experiment_id: ireb2-biobank-rare-variant-phewas
    name: Rare-variant association scan for IREB2 in biobank cohorts
    description: >-
      Test bi-allelic and predicted-hypomorphic IREB2 genotypes in large
      sequenced biobanks against red cell indices, movement disorder diagnoses
      and neuroimaging phenotypes. Red cell indices are measured in essentially
      everyone, so the anaemia arm gives an unusually well-powered quantitative
      readout for a disorder this rare.
  - experiment_id: ireb2-saturation-allelic-series
    name: Deep mutational scan of IREB2 IRE-binding activity
    description: >-
      Build a saturation mutagenesis library and measure IRE-binding and protein
      stability for every missense allele, producing a prospective
      function-severity map that a diagnostic laboratory could use to interpret
      a novel variant instead of relying on in-silico prediction.
- discussion_id: ireb2-copd-locus-not-causal
  kind: KNOWLEDGE_GAP
  status: RESOLVED
  prompt: >-
    Should the large IREB2 association literature in chronic obstructive
    pulmonary disease and lung cancer be curated as part of this disease entry?
  rationale: >-
    No, and the question is recorded here because the answer is not obvious from
    a literature search and because getting it wrong is the most likely way this
    entry could be corrupted. Most published work naming IREB2 concerns
    common-variant association with COPD and lung cancer at 15q25.1, where the
    gene sits immediately adjacent to the nicotinic acetylcholine receptor
    subunit cluster CHRNA5-CHRNA3-CHRNB4 that carries the smoking-behaviour
    signal. Those associations describe a different phenotype, a different
    variant class, a different inheritance model and, most likely, a different
    causal gene at the same locus. They are not evidence about NDCAMA and none of
    that literature is cited in this entry. Recorded as RESOLVED because the
    scoping decision has been made, not because the biology of the 15q25 locus
    is settled.
  attaches_to:
  - "genetic#IREB2"
  notes: >-
    A separate and genuinely open question, deliberately not conflated with the
    one above, is whether IRP2 hypomorphism has any effect on lung biology
    through the mechanism curated here. Nothing in the four case reports
    addresses respiratory phenotype, and this entry makes no claim either way.
references:
- reference: PMID:30915432
  title: "Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome."
- reference: PMID:31243445
  title: "IREB2-associated neurodegeneration."
- reference: PMID:31243430
  title: "Reply: IREB2-associated neurodegeneration."
- reference: PMID:35602653
  title: "Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures."
- reference: PMID:39587636
  title: "Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree."
- reference: PMID:11175792
  title: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice."
- reference: PMID:15831703
  title: "Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2."
- reference: PMID:14726953
  title: "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis."
- reference: PMID:18685102
  title: "Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice."
- reference: PMID:39239479
  title: "Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice."
- reference: PMID:41234066
  title: "The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice."
- reference: PMID:19762597
  title: "An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis."
- reference: PMID:32126207
  title: "FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster."
- reference: PMID:21940823
  title: "Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins."
- reference: PMID:22003390
  title: "Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice."
- reference: PMID:31040213
  title: "Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts."
- reference: PMID:34675764
  title: "Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2."
- reference: PMID:39670660
  title: "Targeting HIF-2α: the role of belzutifan in clear cell renal carcinoma management."

📚

References & Deep Research

References

PMID:30915432

Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome.

No top-level findings curated for this source.

PMID:31243445

IREB2-associated neurodegeneration.

No top-level findings curated for this source.

PMID:31243430

Reply: IREB2-associated neurodegeneration.

No top-level findings curated for this source.

PMID:35602653

Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures.

No top-level findings curated for this source.

PMID:39587636

Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree.

No top-level findings curated for this source.

PMID:11175792

Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice.

No top-level findings curated for this source.

PMID:15831703

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2.

No top-level findings curated for this source.

PMID:14726953

Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis.

No top-level findings curated for this source.

PMID:18685102

Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice.

No top-level findings curated for this source.

PMID:39239479

Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice.

No top-level findings curated for this source.

PMID:41234066

The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice.

No top-level findings curated for this source.

PMID:19762597

An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis.

No top-level findings curated for this source.

PMID:32126207

FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.

No top-level findings curated for this source.

PMID:21940823

Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins.

No top-level findings curated for this source.

PMID:22003390

Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice.

No top-level findings curated for this source.

PMID:31040213

Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts.

No top-level findings curated for this source.

PMID:34675764

Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2.

No top-level findings curated for this source.

PMID:39670660

Targeting HIF-2α: the role of belzutifan in clear cell renal carcinoma management.

No top-level findings curated for this source.

Deep Research

Claude Code ▸

IREB2-Related Neurodegeneration (Neurodegeneration, Early-Onset, with Choreoathetoid Movements and Microcytic Anemia — NDCAMA): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-08-03T01:12:10.959031

IREB2-Related Neurodegeneration (Neurodegeneration, Early-Onset, with Choreoathetoid Movements and Microcytic Anemia — NDCAMA): Comprehensive Research Report

1. Disease Information

Overview. IREB2-related neurodegeneration — formally designated NDCAMA (Neurodegeneration, Early-onset, with Choreoathetoid Movements and Microcytic Anemia) — is an ultra-rare, autosomal recessive, early-onset neurodevelopmental/neurodegenerative disorder caused by biallelic loss-of-function or hypomorphic variants in IREB2, the gene encoding Iron Regulatory Protein 2 (IRP2). IRP2 is a cytosolic RNA-binding protein that post-transcriptionally controls cellular iron homeostasis by binding iron-responsive elements (IREs) in the untranslated regions of mRNAs encoding ferritin (FTH1/FTL), transferrin receptor (TFRC), ferroportin, and other iron-metabolism proteins. Loss of IRP2 produces a state of functional/cytosolic iron deficiency despite normal or elevated body iron stores, with downstream mitochondrial dysfunction (particularly loss of iron-sulfur-cluster-containing respiratory chain subunits) that is thought to drive progressive neurodegeneration, severe developmental impairment, extrapyramidal movement disorder, and a distinctive microcytic, iron-refractory anemia.

The disorder was first described in humans in 2019 (Costain et al., Brain) and remains exceedingly rare — as of the most recent literature (2024–2025) only ~5 patients from ~4 unrelated families worldwide have been reported (Filipino, Australian, US, and two Chinese kindreds).

Key identifiers: - OMIM phenotype: #618451 — "NEURODEGENERATION, EARLY-ONSET, WITH CHOREOATHETOID MOVEMENTS AND MICROCYTIC ANEMIA; NDCAMA" (OMIM 618451) - OMIM gene: 147582 — IRON-RESPONSIVE ELEMENT-BINDING PROTEIN 2; IREB2 (OMIM 147582) - MONDO: MONDO:0032871 (NDCAMA) — recommend independent verification against the live MONDO API before curation - MedGen Concept ID: C5193104 (MedGen) - Gene: IREB2, HGNC:6115, NCBI Gene ID: 3658, chromosome 15q25.1 (GRCh38: chr15:78,437,431–78,501,453) - Inheritance: Autosomal recessive - Orphanet: No dedicated ORPHA number was confidently identified in this search sweep given the disease's very recent (2019+) description; this should be checked directly against the live Orphanet API before curation, as Orphanet coverage of ultra-recently-described Mendelian disorders often lags OMIM by 1–3 years. - Synonyms:* NDCAMA; IRP2 deficiency; IREB2-associated neurodegeneration; IRP2-related neurodevelopmental disorder

Distinction from a common naming trap: IREB2 is separately and much more prominently known in the literature as a COPD/lung-cancer GWAS susceptibility locus at chromosome 15q25 (in linkage disequilibrium with the CHRNA3/CHRNA5/CHRNB4 nicotinic receptor cluster) — see Section 5. This GWAS association is a distinct line of evidence (common noncoding variants, complex/polygenic trait) from the Mendelian neurodegenerative syndrome described here (rare biallelic coding variants causing complete or partial IRP2 loss of function). Curators should keep these evidence streams clearly separated in any pathophysiology model — they converge on the same gene but are mechanistically and clinically distinct entities.

Evidence basis: All disease-level clinical information is derived from individual patient case reports/series (5 published patients across 4 families) plus supporting mouse and cellular model organism data — this is not yet an aggregated disease-level resource (no large natural-history cohort exists given the rarity).

2. Etiology

Disease Causal Factors: Purely genetic/monogenic. Biallelic (homozygous or compound heterozygous) pathogenic variants in IREB2 causing loss or severe reduction of IRP2 protein/function are necessary and sufficient to cause the disease. There is no known environmental, infectious, or purely mechanistic (non-genetic) causal contributor to the Mendelian syndrome itself.

Genetic risk factors: - Biallelic IREB2 variants (nonsense, missense, in-frame deletion) — see Section 4 for the full variant catalog. - All reported cases are compound heterozygous except where consanguinity/founder effects might predispose to homozygosity (not explicitly reported in the literature reviewed). - No modifier genes have yet been identified, though IRP1 (ACO1) functions as a partial, incomplete compensatory paralog — patients and Ireb2−/− mice show ~2-fold upregulation of IRP1 IRE-binding activity that is insufficient to normalize iron metabolism (Costain et al. 2019, PMID:30915432; Maio et al. 2022, PMID:35602653).

Environmental risk factors: None established for the Mendelian disorder. (By contrast, for the unrelated IREB2 COPD-susceptibility locus, cigarette smoking is a major environmental modifier/gene-environment interaction — see Section 5.)

Protective factors: None specific to the Mendelian syndrome are established in humans. In the Ireb2−/− mouse model, dietary TEMPOL (a stable nitroxide) activates latent IRE-binding activity of the paralog IRP1, converting it from its aconitase form to an IRE-binding form, and this "rescues" the neurodegenerative/neuromuscular phenotype (though not the anemia) — this is a pharmacological/experimental protective intervention, not a naturally occurring protective genetic or environmental factor (Ghosh et al. 2008, PNAS, PMID:18685102).

Gene-environment interactions: Not established for the Mendelian NDCAMA phenotype. For the distinct IREB2 COPD locus, gene-environment interaction with smoking is well documented (see Section 5), and this is a useful point of contrast for dismech curation — the same gene/locus name, entirely different disease and etiologic model.

3. Phenotypes

Phenotype data below is synthesized across the 5 published human cases (Costain 2019, PMID:30915432; Cooper 2019, Brain 142:e40, DOI 10.1093/brain/awz183 — PMID not independently confirmed in this search sweep, please verify; Maio 2022, PMID:35602653; and the 2024 Chinese-pedigree report, DOI 10.1186/s13023-024-03465-7, PMID not independently confirmed — verify directly).

Core/most-consistent phenotypes (reported in ≥4/5 patients)

Phenotype	HPO suggestion	Notes
Global developmental delay / regression	HP:0001263 (Global developmental delay)	Onset in infancy in all reported cases
Choreoathetoid movement disorder	HP:0001266 (Choreoathetosis)	Defining/eponymous feature of NDCAMA
Dystonia	HP:0001332 (Dystonia)	Present in all reported cases; often progressive
Microcytic anemia, iron-refractory	HP:0001935 (Microcytic anemia); consider HP:0004840 (Refractory anemia) qualifier	Unresponsive to iron supplementation — a key diagnostic clue distinguishing this from true iron-deficiency anemia
Cerebral/cortical atrophy	HP:0002500 (Cerebral atrophy) or HP:0002120 (Cerebral cortical atrophy)	Progressive on serial MRI in Costain and Cooper cases
Spasticity	HP:0001257 (Spasticity)
Seizures	HP:0001250 (Seizure)	Includes infantile spasms/hypsarrhythmia in the Maio 2022 patient (HP:0011097, Epileptic spasm)
Absent or minimal speech	HP:0001344 (Absent speech) or HP:0001348 (Poor speech)
Non-ambulatory / impaired ambulation	HP:0002540 (Inability to walk)

Additional reported features

Microcephaly (HP:0000252) — OFC −2.6 SD in the Maio 2022 patient
Peripheral neuropathy (HP:0009830)
Pes cavus, bilateral (HP:0001761)
Stereotypies (HP:0000733)
Dysautonomia (HP:0002960)
Optic nerve hypoplasia (HP:0000609) and cortical visual impairment (HP:0100704)
Sensorineural and conductive hearing loss (HP:0000407, HP:0000405) — Cooper 2019 patient
Recurrent infections / neutropenia episodes, oral ulcers, cyclic vomiting, feeding intolerance — Cooper 2019 patient (may represent a broader phenotypic spectrum or additional comorbidity — treat cautiously as n=1 findings)
Thick corpus callosum with progressive cerebral atrophy (imaging finding) — Cooper 2019
Non-specific facial dysmorphism — Cooper 2019
Elevated zinc protoporphyrin IX — a laboratory marker of functional iron deficiency in erythroid precursors, reported in the Costain and Maio patients
Elevated serum ferritin (paradoxically, despite functional iron deficiency) in the Cooper 2019 and 2024 Chinese-pedigree patients, versus low-normal ferritin in the Maio 2022 patient — ferritin direction appears variant/patient-dependent and should not be treated as a uniform diagnostic marker across all IREB2 genotypes.

Onset: All reported cases are infantile-onset (symptom onset from ~5 months to ~16 months of age), consistent with a severe, early pediatric neurodegenerative/neurodevelopmental disorder rather than an adult-onset process.

Progression: Progressive in all reported cases — cerebral atrophy worsens on serial imaging; one patient (Cooper 2019) died at age 10 of progressive neurological disease. The disorder should be modeled as progressive (clinical_course: PROGRESSIVE) rather than static, distinguishing it from cerebral palsy phenocopies despite the "dystonic cerebral palsy" label sometimes applied clinically before genetic diagnosis.

Severity/frequency: Given n=5 patients total, only qualitative frequency descriptors are appropriate (e.g., "reported in all/most published cases") rather than population percentages — standard FrequencyEnum quantitative bands are not well supported by the evidence base and should be used cautiously or omitted per dismech's frequency-evidence guidelines.

Quality of life impact: Severe — profound impairment of ambulation, communication, and functional independence reported in all surviving patients; no formal EQ-5D/SF-36 data exists given the pediatric, severely affected population and disease rarity.

4. Genetic/Molecular Information

Causal gene: IREB2 (HGNC:6115; NCBI Gene 3658; *147582; chr15q25.1). Encodes IRP2 (Iron Regulatory Protein 2), a 963-amino-acid, ~105 kDa cytosolic aconitase-family RNA-binding protein.

Reported pathogenic variants (all biallelic, autosomal recessive):

Patient / Source	Allele 1	Allele 2	Zygosity	Consequence
Costain 2019 (Filipino, 16y)	c.1255C>T, p.Arg419Ter (R419X)	c.1069G>T, p.Gly357Ter (G357X)	Compound het	Complete IRP2 loss (protein undetectable by Western blot)
Cooper 2019 (Australian, died age 10)	p.Gly785Arg (maternal)	p.Ser444del (in-frame 3-nt deletion, paternal)	Compound het	Missense/in-frame deletion; Gly785Arg predicted to disrupt a major IRE–IRP contact point
Maio 2022 (7yo, US)	c.2240G>A, p.Gly747Glu (paternal)	c.656A>C, p.Glu219Ala (maternal)	Compound het	Missense; predicted mis-splicing/increased protein turnover; IRP2 mRNA and protein effectively undetectable
Chinese pedigree 2024 (8mo, China)	c.1111A>G, p.Ile371Val	c.2477A>T, p.Asp826Val	Compound het	Missense; p.Asp826Val causes marked proteasomal degradation of IRP2

Classification (ACMG/AMP): All reported variants have been treated as pathogenic/likely pathogenic based on segregation, absence/near-absence in population databases (gnomAD), functional evidence of loss of protein/function, and phenotype match — but formal ClinVar submission status should be checked directly (not confirmed in this search sweep).

Variant type spectrum: Nonsense (complete loss of function), in-frame deletion, and missense (destabilizing/mis-splicing) — i.e., the disease spectrum spans complete null alleles through severe hypomorphs, consistent with a loss-of-function mechanism of varying severity, which may partly explain phenotypic variability (e.g., complete-null Costain patient vs. hypomorphic missense patients).

Population frequency: Given only 4 known families, these variants are expected to be absent or singleton in gnomAD; no established carrier frequency or founder-population enrichment has been reported. gnomAD constraint metrics (pLI/LOEUF) for IREB2 itself were not independently confirmed in this search sweep — recommend a direct gnomAD browser query before citing a specific value.

Functional consequences (mechanistically established across studies): - Loss/near-loss of IRP2 protein and complete loss of IRE-binding activity in patient-derived lymphoblasts - Compensatory ~2-fold increase in IRP1 protein/IRE-binding activity — insufficient to normalize iron handling - Downregulation of TFRC (reduced iron import) and upregulation of ferritin (FTH1/FTL) (increased iron sequestration) — the opposite of the expected response to cellular iron deficiency, i.e., a "misread" iron status - Reduced labile (usable) cytosolic iron pool — a state of functional iron deficiency at the cellular level despite whole-body iron sufficiency/excess - Reduced ferrochelatase levels - Mitochondrial dysfunction: decreased Complex I (~28% of normal) and Complex II (~52% of normal) respiratory chain activity in patient fibroblasts, with reduced levels of Fe-S-cluster-containing subunits (NDUFS1, NDUFS8 in Complex I; SDHB in Complex II; UQCRFS1 in Complex III) and reduced assembly of Complexes I–V (Maio et al. 2022, PMID:35602653) - Functional rescue: lentiviral re-expression of wild-type IREB2 in patient lymphoblasts normalizes TFRC/ferritin levels, IRE-binding activity, labile iron pool, and Complex I/II activity — strong causal confirmation (Costain 2019; Maio 2022)

Modifier genes: IRP1/ACO1 is the closest functional paralog and partial compensator, though not curated as a formal disease modifier gene in any published report. OTUD3 (a deubiquitylase that stabilizes IRP2 in an iron-independent manner) is mechanistically relevant — Otud3-knockout mice show nigral iron accumulation and nigrostriatal dopaminergic degeneration resembling Parkinson's disease (Jia et al. 2022, Cell Death Dis 13:418, DOI 10.1038/s41419-022-04704-0; PMID not independently confirmed in this sweep) — relevant as a candidate genetic modulator of IRP2 abundance/stability but not itself an established modifier in human NDCAMA patients.

Epigenetic information: None specifically reported for this disorder.

Chromosomal abnormalities: Not applicable — this is a single-gene coding-variant disorder, not a copy-number/structural disorder.

5. Environmental Information

No environmental, lifestyle, or infectious causal factors are established for the Mendelian NDCAMA phenotype itself.

Important gene-level context (distinct entity): IREB2 is one of the most replicated genes at the chromosome 15q25 locus in COPD and lung cancer genome-wide association studies, in strong linkage disequilibrium with the CHRNA3/CHRNA5/CHRNB4 nicotinic acetylcholine receptor gene cluster (DeMeo et al. 2009, Am J Hum Genet 85:493–502, PMID:19800047; Pillai et al. 2009, PLoS Genet, GWAS identifying two major COPD susceptibility loci). Key mechanistic point for curators: "the effect of variants in CHRNA3/5 appeared to largely be mediated by smoking, while a variant at IREB2 was associated with COPD independent of smoking" — i.e., the IREB2 COPD association operates through a smoking-independent mechanism (plausibly related to iron-driven oxidative injury in airway epithelium — see Nature Medicine 2016, "Mitochondrial iron chelation ameliorates cigarette smoke–induced bronchitis and emphysema in mice"), distinguishing it from the nicotine-dependence-mediated CHRNA3/5 signal. This is a separate disease entity (COPD, a common complex trait driven by common noncoding variants) from the Mendelian NDCAMA syndrome (driven by rare biallelic coding variants) and should not be conflated in the KB pathophysiology model, though both converge on IRP2/iron-metabolism dysregulation as a shared mechanistic thread worth noting as a cross-reference.

Infectious agents: None implicated.

6. Mechanism / Pathophysiology

Causal chain (established, human + mouse + cellular evidence):

Trigger: Biallelic loss-of-function or hypomorphic IREB2 variant → absent/reduced IRP2 protein and loss of IRE-binding activity
Post-transcriptional iron-gene misregulation: Failure to stabilize TFRC mRNA and failure to repress ferritin (FTH1/FTL) mRNA translation → paradoxical downregulation of iron import (TFRC↓) and upregulation of iron sequestration (ferritin↑), despite the cell being in a state of cytosolic iron deficiency
Functional/cytosolic iron deficiency: Reduced labile iron pool available for iron-dependent enzymatic processes, even as total-body/serum iron indices may appear normal or elevated (a key diagnostic paradox — explains why the anemia is unresponsive to oral/parenteral iron supplementation)
Mitochondrial Fe-S cluster biogenesis failure: Reduced iron availability compromises assembly of iron-sulfur cluster-containing respiratory chain subunits (Complex I: NDUFS1, NDUFS8; Complex II: SDHB; Complex III: UQCRFS1) → decreased oxidative phosphorylation capacity (Complex I ~28% of normal, Complex II ~52% of normal activity in patient fibroblasts)
Neuronal energy failure and iron mishandling in CNS: Neurons and oligodendrocytes are particularly vulnerable to combined iron-handling and mitochondrial-bioenergetic failure; mouse data show white-matter iron deposition, axonal degeneration, and Purkinje cell loss preceding overt movement-disorder symptoms by months (LaVaute et al. 2001, PMID:11175792)
Clinical manifestation: Progressive neurodegeneration → dystonia/choreoathetosis (basal ganglia/extrapyramidal circuit dysfunction), developmental regression, cerebral atrophy, seizures
Erythroid arm (parallel/downstream branch): Erythroid precursors similarly cannot mobilize iron for heme synthesis despite adequate substrate → microcytic, hypochromic, iron-refractory anemia with elevated zinc protoporphyrin (a marker of impaired heme synthesis)

Upstream vs. downstream: The IRP2 loss-of-function lesion is the sole upstream initiating event; iron-gene misregulation and mitochondrial Fe-S cluster deficiency are intermediate/convergent nodes; neurodegeneration and anemia are parallel downstream phenotypic branches from the shared iron-misregulation node (this maps naturally onto a dismech pathophysiology node structure with a branch point).

Molecular pathways: Iron-responsive element (IRE)/iron regulatory protein (IRP) post-transcriptional regulatory system; hypoxia-inducible factor pathway (IRP1/IRP2 also regulate HIF2α mRNA translation via a 5'UTR IRE — relevant to erythropoiesis regulation and potentially to the atypical ferritin/hypoxia signaling crosstalk, PMID:24389303-adjacent literature); mitochondrial Fe-S cluster biogenesis and oxidative phosphorylation (Reactome/KEGG: "Iron uptake and transport," "Respiratory electron transport").

Cellular processes: Impaired iron trafficking/import, aberrant translational repression/derepression of iron-metabolism mRNAs, mitochondrial respiratory chain dysfunction, likely secondary oxidative stress, axonal degeneration, neuronal/oligodendrocyte iron deposition.

Protein dysfunction: Loss of function (most variants) via nonsense-mediated decay, missense-induced misfolding/proteasomal degradation, or in-frame deletion disrupting IRE-binding surface residues (e.g., Gly785Arg disrupting "a major IRE–IRP contact point").

Suggested GO terms: - GO:0006879 — cellular iron ion homeostasis - GO:0030350 — iron-responsive element binding - GO:0003729 — mRNA binding - GO:0006826 — iron ion transport - GO:0006783 — heme biosynthetic process (for the erythroid/anemia arm) - GO:0022900 — electron transport chain - GO:0016226 — iron-sulfur cluster assembly

Suggested CL terms (cell types involved): - CL:0000031 — neuron (specifically dopaminergic/basal ganglia neurons and Purkinje cells per mouse data) - CL:0000128 — oligodendrocyte (site of iron deposition in mouse white matter) - CL:0000038 — erythroid progenitor cell / CL:0000765 — erythroblast (for the anemia arm)

Molecular profiling: No transcriptomic/proteomic/metabolomic dataset specific to human NDCAMA patients was identified in this search sweep (consistent with disease rarity — n=5 patients, mostly single-family case reports with targeted functional validation rather than -omics profiling). Mouse model transcriptomic changes ("altered expression profile associated with neurological function") are noted in the 2025 D826V knock-in mouse paper but granular datasets were not retrieved here.

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system (brain — cerebral cortex, basal ganglia, cerebellum, white matter tracts) and hematopoietic system (bone marrow/erythropoiesis) - Secondary: Peripheral nervous system (peripheral neuropathy reported); possibly immune system (recurrent infections/neutropenia in one patient — needs further validation as a core feature vs. incidental) - Body systems: Nervous system (primary), hematologic system (primary), musculoskeletal (secondary — pes cavus, spasticity-related contractures)

Tissue/cell level: - White matter tracts (oligodendrocyte iron deposition, demonstrated in mouse model; corresponds to white matter volume loss on human MRI) - Cerebral cortex (atrophy) - Cerebellum — Purkinje cell loss (mouse model; not yet directly demonstrated histopathologically in human patients, who are diagnosed via imaging/genetics rather than biopsy) - Basal ganglia / extrapyramidal motor circuitry (clinical correlate of choreoathetosis/dystonia) - Bone marrow erythroid precursors

Subcellular level (GO Cellular Component): - GO:0005829 — cytosol (site of IRP2 IRE-binding activity) - GO:0005739 — mitochondrion (site of Fe-S cluster-dependent respiratory chain dysfunction) - GO:0005777 — peroxisome (not specifically implicated but part of broader iron-handling machinery in some models — verify before use)

Localization (UBERON): - UBERON:0000955 — brain - UBERON:0002316 — white matter of cerebrum / relevant white-matter tract terms - UBERON:0002037 — cerebellum - UBERON:0002420 — basal ganglion - UBERON:0002371 — bone marrow

Lateralization: Bilateral/symmetric involvement reported (consistent with a systemic metabolic/genetic disorder rather than a focal lesion).

8. Temporal Development

Onset: Infantile (reported onset ages: ~5 months [Maio 2022 patient — hypotonia/decreased movement], ~11 months [same patient — infantile spasms], and broadly "early-onset" in the other cases per the disease name itself). No adult-onset cases have been reported.
Onset pattern: Insidious/subacute — hypotonia and developmental stagnation precede overt movement disorder and seizures.
Progression: Progressive, non-remitting. Serial neuroimaging in the Costain and Cooper patients showed worsening cerebral atrophy over time.
Disease stages: No formal staging system exists (too rare); can be qualitatively described as (1) early developmental delay/hypotonia phase, (2) movement disorder emergence (dystonia/choreoathetosis) with anemia, (3) progressive neurodegeneration with seizures and cerebral atrophy, (4) severe disability/mortality (one reported death at age 10).
Progression rate: Variable but overall relatively rapid for a pediatric neurodegenerative disorder — death within the first decade reported in one case; others alive into later childhood with severe impairment.
Remission: None reported — no spontaneous or treatment-induced remission documented in any case.
Critical periods: Infancy/early childhood is the critical window of clinical presentation; no data on prenatal detectability or intervention windows.

9. Inheritance and Population

Inheritance pattern: Autosomal recessive (biallelic variants in all reported cases; parents in reported families are unaffected carriers).
Penetrance: Presumed complete for biallelic null/severe hypomorphic genotypes, based on all reported homozygous/compound-heterozygous individuals being symptomatic — though this is based on only ~5 patients, so formal penetrance estimates are not statistically robust.
Expressivity: Variable — phenotypic severity appears to correlate loosely with variant severity (complete-null Costain patient had a particularly severe/progressive phenotype; missense/hypomorphic patients show a broadly overlapping but not identical feature set — e.g., variable presence of seizures, hearing loss, immune features).
Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).
Germline mosaicism: Not reported.
Founder effects: None established; reported families are from diverse populations (Filipino, Australian, US, Chinese ×2), arguing against a single founder variant and consistent with private/family-specific variants at each report.
Consanguinity: Not explicitly reported as a feature of the published families (most cases are compound heterozygous rather than homozygous, arguing against obligate consanguinity, though this should be verified per source).
Carrier frequency: Unknown/not established — variants are presumed ultra-rare or absent from population databases (gnomAD) given only 4 known families.
Epidemiology: No formal prevalence or incidence estimate exists; this is one of the rarest reported monogenic neurodegenerative disorders (n≈5 patients in the world literature as of 2024–2025).
Population demographics: No specific ethnic/geographic enrichment identified — cases span East Asian (Chinese, 2 families), Southeast Asian (Filipino), and Oceanian/European-descent (Australian) backgrounds, plus at least one US-diagnosed case, suggesting the disorder occurs across diverse populations as private variants rather than being population-restricted.
Sex ratio: All reported patients described in this search sweep are male (16-year-old boy, 10-year-old boy who died, 7-year-old boy, 8-month-old boy) — this is a striking pattern worth flagging, though with n≈4-5 it cannot be concluded that this reflects a true sex-linked susceptibility (IREB2 is autosomal, not X-linked) rather than ascertainment bias in a tiny case series. Curators should note this as an open observation, not a mechanistic claim.
Age distribution: All reported cases are pediatric (infancy through early adolescence at presentation; one death at age 10).

10. Diagnostics

Laboratory tests: - Complete blood count: microcytic, hypochromic anemia (variably mild-to-moderate) - Iron studies: serum ferritin variably normal/low-normal or elevated (not a consistent single-direction marker across reported patients — see Section 3); serum iron/transferrin reported as normal in at least one patient (Cooper 2019) - Zinc protoporphyrin IX: elevated (marker of impaired heme synthesis / functional iron deficiency at the erythroid level) — reported in Costain and Maio patients - Key diagnostic clue: anemia unresponsive to iron supplementation — should prompt consideration of a functional (rather than true) iron-deficiency mechanism

Biomarkers: No validated circulating biomarker beyond the above CBC/iron-study pattern; IRP2 protein/IRE-binding activity assays in patient-derived lymphoblasts (research-use, not clinical-grade) have been used to functionally confirm pathogenicity.

Imaging: Brain MRI showing progressive cerebral atrophy, white matter volume loss, and (in one patient) a thickened corpus callosum. No single pathognomonic imaging pattern (e.g., no classic NBIA-type basal ganglia iron signal reported on standard MRI sequences in the human cases reviewed, though iron-sensitive sequences such as SWI were not specifically discussed in the search results retrieved — recommend follow-up).

Genetic testing: - Whole exome sequencing (trio) is the diagnostic modality used in all reported cases — appropriate given the extreme rarity and absence of any commercial single-gene or panel test specifically targeting IREB2 at the time of these reports. - Given the disorder's novelty (first described 2019), IREB2 may not yet be included on standard "NBIA" or "pediatric neurodegeneration/movement disorder" gene panels — worth flagging as a genetic-testing-access gap. - No newborn screening, carrier screening, or prenatal testing program exists given disease rarity and recency of description.

Clinical criteria: No formal consensus diagnostic criteria have been published (disease too recently described / too rare); diagnosis is currently genetic-confirmation-based (biallelic IREB2 variants) plus compatible phenotype (developmental delay, choreoathetosis/dystonia, iron-refractory microcytic anemia, progressive cerebral atrophy).

Differential diagnosis: Other genetic causes of infantile neurodegeneration with movement disorder, including: - Classic NBIA (Neurodegeneration with Brain Iron Accumulation) disorders (PANK2, PLA2G6, WDR45, etc.) — mechanistically and clinically overlapping (iron-related neurodegeneration with dystonia) but genetically and (per current data) neuroimaging-pattern distinct (classic NBIA shows T2 basal ganglia iron signal; IREB2-NDCAMA's iron-handling defect is a functional deficiency rather than regional accumulation*, an important mechanistic contrast worth explicit note in any dismech mechanistic_hypotheses/discussion) - Dystonic cerebral palsy (a clinical label sometimes applied before genetic diagnosis, per the Porras 2024 mouse paper's description of the index patient) - Other causes of iron-refractory iron-deficiency-like anemia (e.g., IRIDA/TMPRSS6-related iron-refractory iron deficiency anemia — mechanistically distinct, worth differentiating) - Mitochondrial disorders with combined respiratory chain defects

Screening: None established.

11. Outcome/Prognosis

Survival/mortality: At least one reported death (age 10, progressive neurological disease) among 5 reported patients; no formal survival statistics exist given case-series-only data.
Morbidity/function: Severe and progressive functional impairment reported in all surviving patients — non-ambulatory, minimal-to-absent speech, need for full supportive care.
Complications: Seizures (including infantile spasms/hypsarrhythmia), recurrent infections/neutropenia (one patient), feeding intolerance.
Recovery potential: No evidence of spontaneous recovery or disease reversal in any reported patient; cellular/functional rescue has only been demonstrated in vitro (lentiviral gene restoration in patient lymphoblasts), not in vivo.
Prognostic factors: Variant severity (complete null vs. hypomorphic missense) may correlate with phenotype severity, but sample size is too small for statistical confirmation.

12. Treatment

No disease-modifying or FDA-approved therapy currently exists. Management to date has been supportive/symptomatic (standard pediatric neurodegeneration supportive care — physical/occupational/speech therapy, seizure management, nutritional support). Suggested NCIT terms for these general supportive categories: NCIT:C15747 (Supportive Care), NCIT:C15302 (Physical Therapy), NCIT:C121351 (Occupational Therapy), NCIT:C159273 (Speech Therapy).

Important negative/mechanistic treatment finding: The authors of the key mechanistic papers explicitly caution that iron chelation therapy would likely not be therapeutic (and could be harmful), because the underlying defect is a functional cytosolic iron deficiency, not iron overload — despite normal/elevated serum ferritin in some patients. This is an important mechanism-informed treatment caveat for curators to capture (e.g., as a discussions entry with kind: KNOWLEDGE_GAP or a treatment-avoidance note), since a naive reading of elevated ferritin could otherwise misleadingly suggest chelation.

Experimental/preclinical therapeutic leads (model-organism evidence only, not yet tested in human patients): - TEMPOL (a stable nitroxide antioxidant) — dietary TEMPOL in Ireb2−/− mice activates latent IRE-binding activity of the paralog IRP1, correcting TfR1 stabilization and ferritin repression in brain tissue, and "markedly attenuated" progression of the neuromuscular/neurodegenerative phenotype, though it did not correct the microcytic anemia (Ghosh et al. 2008, PNAS, PMID:18685102). This represents a proof-of-concept pharmacological strategy (paralog-activation rather than gene replacement) that has not been translated to human patients. - Proteasome inhibition — in the 2024 Chinese-pedigree functional study, proteasome inhibitors partially restored IRP2 expression in cells carrying the p.Asp826Val degradation-prone variant, "highlighting a promising therapeutic target for patients with IRP2 deficiency" — an in vitro finding only. - Gene replacement (research tool, not therapy): Lentiviral-mediated restoration of wild-type IREB2 expression fully reverses the cellular/molecular phenotype in patient-derived lymphoblasts (Costain 2019; Maio 2022) — proof of principle for a gene-therapy approach (suggested therapeutic_modality: GENE_THERAPY if/when this reaches clinical translation), but no in vivo human gene therapy trial exists. - HIF2 inhibition: A related but mechanistically distinct line of mouse work ("Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2," PMID:34675764) suggests that pharmacological HIF2α inhibition may ameliorate the Ireb2-deficient mouse neurological phenotype, consistent with the IRP-HIF2α mechanistic link described in Section 6 — another preclinical-only lead.

Clinical trials: No IREB2/NDCAMA-specific trials identified in ClinicalTrials.gov in this search sweep (consistent with disease rarity/recency).

Treatment strategy: No treatment algorithm exists; management is individualized supportive care by pediatric neurology/genetics teams.

13. Prevention

Primary prevention: None available (no way to prevent occurrence in an at-risk family beyond genetic counseling).
Secondary prevention/screening: No population or genetic screening program exists (disease too rare/recently described); once a proband is identified, cascade carrier testing of at-risk relatives and prenatal/preimplantation genetic testing could in principle be offered for future pregnancies in a known-carrier family, per standard practice for autosomal recessive Mendelian disorders — not specifically documented as having been performed in the literature reviewed.
Genetic counseling: Standard autosomal recessive recurrence-risk counseling (25% recurrence risk per pregnancy for carrier-carrier couples) applies once a family's causal variants are known. Suggested NCIT term: NCIT:C15240 (Genetic Counseling).
Public health/behavioral/prophylaxis: Not applicable to this Mendelian disorder.

14. Other Species / Natural Disease

Taxonomy: No naturally-occurring veterinary/companion-animal cases of IREB2-deficiency neurodegeneration have been identified in this search sweep (OMIA search not independently performed here — recommend a direct OMIA check before asserting absence).
Orthologous gene: Mouse Ireb2 (MGI:1928268), NCBI Gene (mouse) — extensively studied via targeted knockout (see Section 15).
Comparative biology: The mouse Ireb2−/− phenotype (adult-onset ataxia, bradykinesia, tremor, white-matter iron deposition, Purkinje cell loss — LaVaute et al. 2001, PMID:11175792) served as the original discovery/hypothesis-generating model that motivated the eventual search for and identification of human patients — a textbook example of mouse-to-human translational disease-gene discovery, worth explicitly capturing in the dismech entry's provenance/discussion.

15. Model Organisms

Mouse — the dominant model system for this gene:

Global Ireb2−/− knockout (LaVaute et al. 2001, Nat Genet 27:209–214, PMID:11175792): First description; adult-onset movement disorder (ataxia, bradykinesia, tremor) with white-matter and neuronal iron deposition preceding symptom onset by months; misregulation of intestinal iron metabolism; established IRP2 as essential for CNS iron homeostasis and motor function.
A contrasting/discordant Irp2-deficient mouse line (Nature Genetics 2006, DOI referenced as "ng0906-967," "Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse"): Showed no overt neurodegeneration or brain iron accumulation, only mild motor coordination/balance deficits — an important discordance across independently generated knockout lines that later behavioral studies (Porras et al. 2024) sought to resolve with more sensitive testing.
Behavioral deep-phenotyping (Porras et al. 2024, Curr Res Neurobiol, PMID:39239479): Using rotarod, hanging-wire, hot/cold-plate, Barnes maze, and touchscreen reversal-learning assays, demonstrated significant motor, somatosensory, and executive/cognitive dysfunction in Irp2-null mice, explicitly motivated by ("The research was motivated by") the discovery of the first human IREB2-deficient patient — a direct example of reverse-translational model refinement following a human genetic discovery.
Pharmacological rescue model (Ghosh et al. 2008, PNAS, PMID:18685102): TEMPOL dietary supplementation corrects the neurodegenerative phenotype (not the anemia) via IRP1 paralog activation — see Section 12.
Motor neuron/mitochondrial model (PLOS ONE 2011, "Iron Insufficiency Compromises Motor Neurons and Their Mitochondrial Function in Irp2-Null Mice"): Direct evidence of mitochondrial dysfunction in motor neurons, mechanistically bridging to the human patient-fibroblast Complex I/II findings.
Patient-variant knock-in mouse model (2025, Acta Biochim Biophys Sin, DOI 10.3724/abbs.2025176): A CRISPR-Cas9-engineered Ireb2 D826V/D826V mouse (recapitulating the exact c.2477A>T/p.Asp826Val variant from the 2024 Chinese NDCAMA pedigree) — the first patient-variant-specific (rather than null-allele) mouse model, showing impaired spatial learning/memory (Morris water maze), reduced motor activity (open field test), Y-maze deficits, reduced Ireb2 protein levels, and dysregulated iron metabolism — the most disease-relevant genetic model currently available, and a strong candidate for future preclinical therapeutic testing.
Parkinson's-disease-adjacent model (Jia et al. 2022, Cell Death Dis, DOI 10.1038/s41419-022-04704-0): Otud3-knockout mice (loss of an IRP2-stabilizing deubiquitylase) show nigral iron accumulation and nigrostriatal dopaminergic degeneration resembling Parkinson's disease — relevant as a mechanistically adjacent model connecting IRP2 stability/regulation to a distinct (sporadic, adult-onset) neurodegenerative phenotype; useful context but should not be conflated with the pediatric NDCAMA Mendelian syndrome itself.

Model characteristics/limitations: The existence of two independently generated Ireb2−/− mouse lines with discordant neurodegeneration phenotypes (LaVaute line: overt neurodegeneration; the other line: minimal pathology) is a notable human-model-mismatch-relevant consideration — worth flagging explicitly in any dismech HUMAN_MODEL_MISMATCH discussion, since it shows that genetic background/allele design details significantly affect phenotype penetrance even within the mouse, which should inform caution in extrapolating any single mouse dataset directly to human severity/course.

Other model systems: No zebrafish, Drosophila, C. elegans, or iPSC-derived organoid models specific to IREB2/NDCAMA were identified in this search sweep; patient-derived lymphoblast cell lines (Epstein-Barr-virus-transformed) are the primary human cellular model used across all clinical reports for functional variant validation.

Summary Table of Key Citations

Citation	PMID	Key Contribution
LaVaute et al. 2001, Nat Genet 27:209–214	11175792	First mouse Ireb2−/− neurodegeneration model
Ghosh et al. 2008, PNAS 105:12028–33	18685102	TEMPOL rescue via IRP1 activation
Costain et al. 2019, Brain 142:1195–1202	30915432	First human patient (R419X/G357X), NDCAMA established
Cooper et al. 2019, Brain 142:e40 (letter)	not independently confirmed — verify	Second human patient (Gly785Arg/Ser444del)
Reply, Costain/Rouault, Brain 142:e41	31243430	Response to Cooper letter
DeMeo et al. 2009, Am J Hum Genet 85:493–502	19800047	IREB2 as COPD susceptibility gene (distinct entity)
Maio et al. 2022, Brain Commun 4:fcac102	35602653	Third patient (missense), mitochondrial Complex I/II defect
Jia et al. 2022, Cell Death Dis 13:418	not independently confirmed — verify	OTUD3-IRP2-Parkinson's link
Porras et al. 2024, Curr Res Neurobiol	39239479	Deep behavioral phenotyping of Irp2-null mice
Chinese pedigree 2024, Orphanet J Rare Dis	not independently confirmed — verify	Fourth/fifth patient (Ile371Val/Asp826Val)
D826V knock-in mouse 2025, Acta Biochim Biophys Sin	not independently confirmed — verify	Patient-variant-specific mouse model

Curator note on citation verification: Several PMIDs above are flagged "not independently confirmed" — per dismech's evidence-verification SOP, each of these must be independently confirmed via just fetch-reference PMID:XXXX (or direct PubMed lookup to first obtain the correct PMID) before any snippet is committed to a KB entry. Do not treat any PMID/quote in this report as pre-verified for dismech curation purposes — this report is a research lead document, not a validated evidence source.

Sources: - Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome (Costain et al. 2019) - IREB2-associated neurodegeneration (Cooper et al. 2019) - Reply: IREB2-associated neurodegeneration - Disruption of cellular iron homeostasis by IREB2 missense variants (Maio et al. 2022) - Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree (2024) - OMIM #618451 — NDCAMA - OMIM *147582 — IREB2 - MedGen C5193104 - Targeted deletion of Ireb2 causes neurodegenerative disease in mice (LaVaute et al. 2001) - Tempol-mediated activation of latent iron regulatory protein activity (Ghosh et al. 2008) - Ablation of Iron Regulatory Protein 2 produces a neurological disorder in mice (Porras et al. 2024) - Iron homeostasis in the brain: complete IRP2 deficiency without symptomatic neurodegeneration in mouse - Deubiquitylase OTUD3 prevents Parkinson's disease through stabilizing IRP2 - The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice (2025) - Integration of Genomic and Genetic Approaches Implicates IREB2 as a COPD Susceptibility Gene (DeMeo et al. 2009) - IREB2 Gene - GeneCards - Iron Insufficiency Compromises Motor Neurons in Irp2-Null Mice

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References & Deep Research

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Deep Research

IREB2-Related Neurodegeneration (Neurodegeneration, Early-Onset, with Choreoathetoid Movements and Microcytic Anemia — NDCAMA): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Core/most-consistent phenotypes (reported in ≥4/5 patients)

Additional reported features

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table of Key Citations