Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia

Summary

Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (MONDO:0032758) is a disease caused by IREB2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: IREB2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
Mondo ID	MONDO:0032758
OMIM	618451
UMLS	C5193104
MedGen	1676579
GARD	0027271
Is cancer (heuristic)	no

Also known as: NDCAMA

Data availability: 14 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

14 retrieved; paginated sample, class counts are floors:

6 benign, 6 uncertain significance, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
633460	NM_004136.4(IREB2):c.1255C>T (p.Arg419Ter)	IREB2	Likely pathogenic	criteria provided, single submitter
633461	NM_004136.4(IREB2):c.1069G>T (p.Gly357Ter)	IREB2	Likely pathogenic	criteria provided, single submitter
3064391	NM_004136.4(IREB2):c.128G>A (p.Arg43Gln)	IREB2	Uncertain significance	criteria provided, single submitter
3068104	NM_004136.4(IREB2):c.824G>A (p.Ser275Asn)	IREB2	Uncertain significance	criteria provided, single submitter
3891403	NM_004136.4(IREB2):c.68A>G (p.Lys23Arg)	IREB2	Uncertain significance	criteria provided, single submitter
3891404	NM_004136.4(IREB2):c.7G>C (p.Ala3Pro)	IREB2	Uncertain significance	criteria provided, single submitter
694293	NM_004136.4(IREB2):c.2353G>A (p.Gly785Arg)	IREB2	Uncertain significance	criteria provided, single submitter
694294	NM_004136.4(IREB2):c.1329_1331del (p.Ser444del)	IREB2	Uncertain significance	criteria provided, single submitter
1300039	NM_004136.4(IREB2):c.629+22A>C	IREB2	Benign	criteria provided, multiple submitters, no conflicts
1300040	NM_004136.4(IREB2):c.883+19A>G	IREB2	Benign	criteria provided, multiple submitters, no conflicts
1300041	NM_004136.4(IREB2):c.1739T>C (p.Ile580Thr)	IREB2	Benign	criteria provided, multiple submitters, no conflicts
1300042	NM_004136.4(IREB2):c.2472+12A>C	IREB2	Benign	criteria provided, multiple submitters, no conflicts
1300043	NM_004136.4(IREB2):c.2616C>T (p.Ala872=)	IREB2	Benign	criteria provided, multiple submitters, no conflicts
1300044	NM_004136.4(IREB2):c.2781+23T>C	IREB2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IREB2	Strong	Autosomal recessive	neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia	3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IREB2	HGNC:6115	ENSG00000136381	P48200	Iron-responsive element-binding protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IREB2	Iron-responsive element-binding protein 2	RNA-binding protein that binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5’-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3’-UTR of transferrin receptor mRNA.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IREB2	Other/Unknown	no		AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase/IRP2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
palpebral conjunctiva	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IREB2	272	ubiquitous	marker	tibia, germinal epithelium of ovary, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IREB2	3,944

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IREB2	P48200	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Iron uptake and transport	1	346.1×	0.006	IREB2
Transport of small molecules	1	25.1×	0.040	IREB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete protoporphyrinogen IX biosynthetic process	1	1685.2×	0.002	IREB2
erythrocyte homeostasis	1	1296.3×	0.002	IREB2
intestinal absorption	1	1203.7×	0.002	IREB2
multicellular organismal-level iron ion homeostasis	1	581.1×	0.003	IREB2
mRNA stabilization	1	366.4×	0.004	IREB2
osteoclast differentiation	1	343.9×	0.004	IREB2
intracellular iron ion homeostasis	1	244.2×	0.005	IREB2
post-embryonic development	1	205.5×	0.005	IREB2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IREB2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IREB2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IREB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.