Neurodegeneration with brain iron accumulation 5

Summary

Neurodegeneration with brain iron accumulation 5 (MONDO:0010476) is a disease caused by WDR45 (GenCC Definitive), with 5 cohort genes and 5 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: WDR45 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 477
• Phenotypes (HPO): 22
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		68	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0000743	Frontal release signs	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002448	Progressive encephalopathy	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0012332	Abnormal autonomic nervous system physiology	Frequent (30-79%)
HP:0012675	Iron accumulation in brain	Frequent (30-79%)
HP:0012678	Iron accumulation in substantia nigra	Frequent (30-79%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation 5
Mondo ID	MONDO:0010476
OMIM	300894
Orphanet	329284
DOID	DOID:0110739
NCIT	C175210
SNOMED CT	732959007
UMLS	C3550973
MedGen	763887
GARD	0012570
Is cancer (heuristic)	no

Also known as: beta-propeller protein-associated neurodegeneration · BPAN · NBIA5 · neurodegeneration with brain iron accululation 5 · neurodegeneration with brain iron accumulation 5 · neurodegeneration with brain iron accumulation 5, X-linked dominant · neurodegeneration with brain iron accumulation caused by mutation in WDR45 · neurodegeneration with brain iron accumulation type 5 · SENDA · static encephalopathy of childhood with neurdegeneration in adulthood · static encephalopathy Of childhood with neurodegeneration In adulthood · WDR45 neurodegeneration with brain iron accumulation

Data availability: 477 ClinVar variants · 6 GenCC gene-disease records · 17 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › neurodegeneration with brain iron accumulation › neurodegeneration with brain iron accumulation 5

Related subtypes (13): pantothenate kinase-associated neurodegeneration, Woodhouse-Sakati syndrome, aceruloplasminemia, neuroferritinopathy, Kufor-Rakeb syndrome, neurodegeneration with brain iron accumulation 4, neurodegeneration with brain iron accumulation 6, PLA2G6-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, neurodegeneration with brain iron accumulation 7, neurodegeneration with brain iron accumulation 8, neurodegeneration with brain iron accumulation 9

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

477 retrieved; paginated sample, class counts are floors:

139 likely benign, 115 uncertain significance, 97 pathogenic, 45 likely pathogenic, 28 conflicting classifications of pathogenicity, 18 benign, 18 pathogenic/likely pathogenic, 15 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073994	NM_001029896.2(WDR45):c.226G>T (p.Glu76Ter)	LOC126863256	Pathogenic	criteria provided, single submitter
1075892	NM_001029896.2(WDR45):c.209del (p.Ser70fs)	LOC126863256	Pathogenic	criteria provided, single submitter
1470615	NM_001029896.2(WDR45):c.130+2T>C	LOC126863256	Pathogenic	criteria provided, single submitter
1686304	NM_001029896.2(WDR45):c.130+1G>C	LOC126863256	Pathogenic	criteria provided, single submitter
1686305	NM_001029896.2(WDR45):c.78_79del (p.Glu26fs)	LOC126863256	Pathogenic	criteria provided, single submitter
1698942	NM_001029896.2(WDR45):c.2T>C (p.Met1Thr)	LOC126863256	Pathogenic	criteria provided, multiple submitters, no conflicts
2169647	NM_001029896.2(WDR45):c.64del (p.Cys22fs)	LOC126863256	Pathogenic	criteria provided, single submitter
2704412	NM_001029896.2(WDR45):c.200del (p.Gly67fs)	LOC126863256	Pathogenic	criteria provided, single submitter
2737224	NM_001029896.2(WDR45):c.228_229del (p.Glu76fs)	LOC126863256	Pathogenic	criteria provided, single submitter
2743795	NM_001029896.2(WDR45):c.109_110insACCT (p.Leu37fs)	LOC126863256	Pathogenic	criteria provided, single submitter
280098	NM_001029896.2(WDR45):c.19C>T (p.Arg7Ter)	LOC126863256	Pathogenic	criteria provided, multiple submitters, no conflicts
3340488	NM_001029896.2(WDR45):c.229_230delinsC (p.Ile77fs)	LOC126863256	Pathogenic	criteria provided, single submitter
3654384	NM_001029896.2(WDR45):c.34del (p.Leu12fs)	LOC126863256	Pathogenic	criteria provided, single submitter
375868	NM_001029896.2(WDR45):c.55+2_55+3del	LOC126863256	Pathogenic	criteria provided, single submitter
3897654	NM_001029896.2(WDR45):c.56-1G>A	LOC126863256	Pathogenic	criteria provided, single submitter
4685506	NM_001029896.2(WDR45):c.103G>T (p.Glu35Ter)	LOC126863256	Pathogenic	criteria provided, single submitter
4711962	NM_001029896.2(WDR45):c.2dup (p.Met1fs)	LOC126863256	Pathogenic	criteria provided, single submitter
4730732	NM_001029896.2(WDR45):c.235+1G>C	LOC126863256	Pathogenic	criteria provided, single submitter
4750194	NM_001029896.2(WDR45):c.235+1G>T	LOC126863256	Pathogenic	criteria provided, single submitter
540346	NM_001029896.2(WDR45):c.131-2A>G	LOC126863256	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
567282	NM_001029896.2(WDR45):c.210_213dup (p.Pro72Ter)	LOC126863256	Pathogenic	criteria provided, single submitter
620005	NM_001029896.2(WDR45):c.2T>A (p.Met1Lys)	LOC126863256	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620358	NM_001029896.2(WDR45):c.52C>T (p.Gln18Ter)	LOC126863256	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
649495	NM_001029896.2(WDR45):c.56-2A>G	LOC126863256	Pathogenic	criteria provided, single submitter
803999	NM_001029896.2(WDR45):c.235+2T>G	LOC126863256	Pathogenic	criteria provided, single submitter
848898	NM_001029896.2(WDR45):c.183C>A (p.Asn61Lys)	LOC126863256	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
857295	NM_001029896.2(WDR45):c.226_230del (p.Glu76fs)	LOC126863256	Pathogenic	criteria provided, single submitter
871503	NM_001029896.2(WDR45):c.235+1G>A	LOC126863256	Pathogenic	criteria provided, multiple submitters, no conflicts
947175	NM_001029896.2(WDR45):c.10C>T (p.Gln4Ter)	LOC126863256	Pathogenic	criteria provided, multiple submitters, no conflicts
1070071	NM_001029896.2(WDR45):c.332_338del (p.Arg111fs)	WDR45	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 7 · 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
WDR45	Definitive	X-linked	neurodegeneration with brain iron accumulation 5	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WDR45	Orphanet:329284	Beta-propeller protein-associated neurodegeneration
WDR45	Orphanet:697160	Infantile epileptic spasms syndrome
CACNA1F	Orphanet:178333	Åland Islands eye disease
CACNA1F	Orphanet:1872	Cone rod dystrophy
CACNA1F	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
OTUD5	Orphanet:528084	Non-specific syndromic intellectual disability
AKAP4	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WDR45	HGNC:28912	ENSG00000196998	Q9Y484	WD repeat domain phosphoinositide-interacting protein 4	gencc,clinvar
CACNA1F	HGNC:1393	ENSG00000102001	O60840	Voltage-dependent L-type calcium channel subunit alpha-1F	clinvar
CCNB3	HGNC:18709	ENSG00000147082	Q8WWL7	G2/mitotic-specific cyclin-B3	clinvar
OTUD5	HGNC:25402	ENSG00000068308	Q96G74	OTU domain-containing protein 5	clinvar
AKAP4	HGNC:374	ENSG00000147081	Q5JQC9	A-kinase anchor protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WDR45	WD repeat domain phosphoinositide-interacting protein 4	Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.
CACNA1F	Voltage-dependent L-type calcium channel subunit alpha-1F	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CCNB3	G2/mitotic-specific cyclin-B3	Cyclins are positive regulatory subunits of the cyclin-dependent kinases (CDKs), and thereby play an essential role in the control of the cell cycle, notably via their destruction during cell division.
OTUD5	OTU domain-containing protein 5	Deubiquitinating enzyme that functions as a negative regulator of the innate immune system.
AKAP4	A-kinase anchor protein 4	Major structural component of sperm fibrous sheath.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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
Ion channel	1	22.3×	0.176
Protease	1	7.3×	0.259
Scaffold/PPI	1	3.5×	0.344
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDR45	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
CACNA1F	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, Ion_trans_dom
CCNB3	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
OTUD5	Protease	yes		OTU_dom, Papain-like_cys_pep_sf, Peptidase_C85-like
AKAP4	Other/Unknown	no		SPHK1-interactor_AKAP_110, AKAP_110_C, RII-bd_1

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
apex of heart	1
mucosa of stomach	1
parotid gland	1
right hemisphere of cerebellum	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
secondary oocyte	1
cardiac muscle of right atrium	1
upper arm skin	1
left testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDR45	293	ubiquitous	marker	apex of heart, mucosa of stomach, granulocyte
CACNA1F	143	tissue_specific	marker	parotid gland, granulocyte, right hemisphere of cerebellum
CCNB3	156	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte
OTUD5	259	ubiquitous	marker	upper arm skin, cardiac muscle of right atrium, granulocyte
AKAP4	62	tissue_specific	marker	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCNB3	2,576
CACNA1F	1,616
OTUD5	1,385
WDR45	1,233
AKAP4	1,149

Intra-cohort edges

A	B	Sources
AKAP4	CCNB3	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR45	Q9Y484	3
OTUD5	Q96G74	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CACNA1F	O60840	67.46
AKAP4	Q5JQC9	53.52
CCNB3	Q8WWL7	42.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulators of DDX58/IFIH1 signaling	1	163.1×	0.011	OTUD5
Ovarian tumor domain proteases	1	139.3×	0.011	OTUD5
Macroautophagy	1	57.7×	0.017	WDR45

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nucleophagy	1	674.1×	0.021	WDR45
negative regulation of voltage-gated calcium channel activity	1	674.1×	0.021	CACNA1F
positive regulation of TORC2 signaling	1	421.3×	0.021	OTUD5
neural crest cell differentiation	1	306.4×	0.021	OTUD5
glycophagy	1	280.9×	0.021	WDR45
pexophagy	1	210.7×	0.021	WDR45
protein localization to phagophore assembly site	1	198.3×	0.021	WDR45
positive regulation of autophagosome assembly	1	160.5×	0.021	WDR45
autophagy of mitochondrion	1	146.5×	0.021	WDR45
cell surface receptor protein serine/threonine kinase signaling pathway	1	146.5×	0.021	AKAP4
sperm flagellum assembly	1	134.8×	0.021	AKAP4
detection of light stimulus involved in visual perception	1	129.6×	0.021	CACNA1F
protein K48-linked deubiquitination	1	129.6×	0.021	OTUD5
protein K63-linked deubiquitination	1	124.8×	0.021	OTUD5
calcium ion import across plasma membrane	1	108.7×	0.021	CACNA1F
negative regulation of type I interferon production	1	99.1×	0.021	OTUD5
regulation of immune response	1	99.1×	0.021	OTUD5
establishment of protein localization	1	86.4×	0.023	AKAP4
positive regulation of TORC1 signaling	1	59.1×	0.032	OTUD5
meiotic cell cycle	1	48.9×	0.037	CCNB3
autophagosome assembly	1	44.9×	0.038	WDR45
G1/S transition of mitotic cell cycle	1	40.1×	0.040	CCNB3
cellular response to starvation	1	38.7×	0.040	WDR45
single fertilization	1	36.6×	0.040	AKAP4
protein deubiquitination	1	35.5×	0.040	OTUD5
establishment of localization in cell	1	32.1×	0.043	AKAP4
response to lipopolysaccharide	1	25.0×	0.052	OTUD5
negative regulation of canonical Wnt signaling pathway	1	23.6×	0.052	OTUD5
flagellated sperm motility	1	23.4×	0.052	AKAP4
autophagy	1	22.0×	0.054	WDR45

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CACNA1F	BEPRIDIL
CCNB3	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1F	48	4
CCNB3	17	4
WDR45	0	0
OTUD5	0	0
AKAP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1F
IMIPRAMINE	4	CACNA1F
HALOFANTRINE	4	CACNA1F
DROPERIDOL	4	CACNA1F
SAQUINAVIR	4	CACNA1F
DULOXETINE	4	CACNA1F
DIAZEPAM	4	CACNA1F
SERTINDOLE	4	CACNA1F
QUINIDINE	4	CACNA1F
LAMIVUDINE	4	CACNA1F
PIMOZIDE	4	CACNA1F
PHENYTOIN	4	CACNA1F
TERFENADINE	4	CACNA1F
CISAPRIDE	4	CACNA1F
SOLIFENACIN	4	CACNA1F
NIFEDIPINE	4	CACNA1F
DILTIAZEM	4	CACNA1F
NILOTINIB	4	CACNA1F
ASTEMIZOLE	4	CACNA1F
TERODILINE	4	CACNA1F
CLOZAPINE	4	CACNA1F
MIBEFRADIL	4	CACNA1F
DOFETILIDE	4	CACNA1F
THIORIDAZINE	4	CACNA1F
PAROXETINE	4	CACNA1F
DONEPEZIL	4	CACNA1F
IBUTILIDE	4	CACNA1F
SUNITINIB	4	CACNA1F
HALOPERIDOL	4	CACNA1F
DASATINIB	4	CACNA1F

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CACNA1F	221	Binding:135, Functional:79, Toxicity:5, ADMET:2
CCNB3	148	Binding:147, Functional:1
OTUD5	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CACNA1F	221
CCNB3	148

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	CACNA1F
IMIPRAMINE	4	CACNA1F
HALOFANTRINE	4	CACNA1F
DROPERIDOL	4	CACNA1F
SAQUINAVIR	4	CACNA1F
DULOXETINE	4	CACNA1F
DIAZEPAM	4	CACNA1F
SERTINDOLE	4	CACNA1F
QUINIDINE	4	CACNA1F
LAMIVUDINE	4	CACNA1F
PIMOZIDE	4	CACNA1F
PHENYTOIN	4	CACNA1F
TERFENADINE	4	CACNA1F
CISAPRIDE	4	CACNA1F
SOLIFENACIN	4	CACNA1F
NIFEDIPINE	4	CACNA1F
DILTIAZEM	4	CACNA1F
NILOTINIB	4	CACNA1F
ASTEMIZOLE	4	CACNA1F
TERODILINE	4	CACNA1F
CLOZAPINE	4	CACNA1F
MIBEFRADIL	4	CACNA1F
DOFETILIDE	4	CACNA1F
THIORIDAZINE	4	CACNA1F
PAROXETINE	4	CACNA1F
DONEPEZIL	4	CACNA1F
IBUTILIDE	4	CACNA1F
SUNITINIB	4	CACNA1F
HALOPERIDOL	4	CACNA1F
DASATINIB	4	CACNA1F

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CACNA1F, CCNB3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	OTUD5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	WDR45, AKAP4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WDR45	0	—
OTUD5	1	—
AKAP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03572114	Not specified	UNKNOWN	Imaging Neuromelanin and Iron in Dystonia/Parkinsonism