Neuroferritinopathy

Summary

Neuroferritinopathy (MONDO:0011638) is a disease caused by FTL (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FTL (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 172
• Phenotypes (HPO): 43
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		90	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0002134	Abnormality of the basal ganglia	Very frequent (80-99%)
HP:0012343	Decreased serum ferritin	Very frequent (80-99%)
HP:0012675	Iron accumulation in brain	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0002339	Abnormal caudate nucleus morphology	Frequent (30-79%)
HP:0002454	Eye of the tiger anomaly of globus pallidus	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0004373	Focal dystonia	Frequent (30-79%)
HP:0012678	Iron accumulation in substantia nigra	Frequent (30-79%)
HP:0012690	T2 hypointense thalamus	Frequent (30-79%)
HP:0012696	Abnormal thalamic MRI signal intensity	Frequent (30-79%)
HP:0031959	Leg dystonia	Frequent (30-79%)
HP:0031982	Abnormal putamen morphology	Frequent (30-79%)
HP:0100321	Abnormality of the dentate nucleus	Frequent (30-79%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001348	Brisk reflexes	Occasional (5-29%)
HP:0001621	Weak voice	Occasional (5-29%)
HP:0001686	Loss of voice	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0002356	Writer’s cramp	Occasional (5-29%)
HP:0002395	Lower limb hyperreflexia	Occasional (5-29%)
HP:0007350	Hyperreflexia in upper limbs	Occasional (5-29%)
HP:0007772	Impaired smooth pursuit	Occasional (5-29%)
HP:0010530	Palatal myoclonus	Occasional (5-29%)
HP:0031960	Arm dystonia	Occasional (5-29%)
HP:0000709	Psychosis	Very rare (<1-4%)
HP:0000727	Frontal lobe dementia	Very rare (<1-4%)
HP:0002322	Resting tremor	Very rare (<1-4%)
HP:0002922	Increased CSF protein concentration	Very rare (<1-4%)
HP:0003487	Babinski sign	Very rare (<1-4%)
HP:0007123	Subcortical dementia	Very rare (<1-4%)
HP:0025331	Upgaze palsy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neuroferritinopathy
Mondo ID	MONDO:0011638
MeSH	C548080
OMIM	606159
Orphanet	157846
DOID	DOID:0110737
SNOMED CT	699299001
UMLS	C1853578
MedGen	381211
GARD	0010686
Is cancer (heuristic)	no

Also known as: adult basal ganglia disease · basal ganglia disease adult-onset · ferritin-related neurodegeneration · hereditary ferritinopathy · NBIA3 · neurodegeneration with brain iron accumulation 3 · neurodegeneration with brain iron accumulation type 3 · neuroferritinopathy

Data availability: 172 ClinVar variants · 4 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 › Huntington disease and related disorders › Huntington disease-like syndrome › neuroferritinopathy

Related subtypes (9): Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, Huntington disease-like 3, spinocerebellar ataxia type 17, neuroacanthocytosis, Huntington disease-like syndrome due to C9ORF72 expansions, childhood-onset benign chorea with striatal involvement

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

172 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 31 likely benign, 12 pathogenic, 7 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 4 likely pathogenic, 4 benign/likely benign, 3 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1320267	NM_000146.4(FTL):c.485_489dup (p.Glu164fs)	FTL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16474	NM_000146.4(FTL):c.-160A>G	FTL	Pathogenic	criteria provided, multiple submitters, no conflicts
16476	NM_000146.4(FTL):c.-168G>A	FTL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16479	NM_000146.4(FTL):c.-168G>T	FTL	Pathogenic	criteria provided, multiple submitters, no conflicts
16480	NM_000146.4(FTL):c.-161C>T	FTL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16481	NM_000146.4(FTL):c.-164C>A	FTL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16485	NM_000146.4(FTL):c.-168G>C	FTL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16486	NM_000146.4(FTL):c.286G>A (p.Ala96Thr)	FTL	Pathogenic	no assertion criteria provided
16487	NM_000146.4(FTL):c.498_499dup (p.Phe167fs)	FTL	Pathogenic	no assertion criteria provided
16489	NM_000146.4(FTL):c.458dup (p.His153fs)	FTL	Pathogenic	no assertion criteria provided
1686694	NM_000146.4(FTL):c.-150C>A	FTL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698387	NM_000146.4(FTL):c.460dup (p.Arg154fs)	FTL	Pathogenic	criteria provided, single submitter
2041512	NM_000146.4(FTL):c.460_461delinsCCA (p.Arg154fs)	FTL	Pathogenic	criteria provided, single submitter
2197338	NM_000146.4(FTL):c.-151A>G	FTL	Pathogenic	criteria provided, single submitter
3897670	NM_000146.4(FTL):c.351delinsTTT (p.Gly118fs)	FTL	Pathogenic	criteria provided, single submitter
3897671	NM_000146.4(FTL):c.501dup (p.Glu168fs)	FTL	Pathogenic	criteria provided, single submitter
647521	NM_000146.4(FTL):c.-157G>A	FTL	Pathogenic	criteria provided, single submitter
963917	NM_000146.4(FTL):c.-167C>T	FTL	Pathogenic	criteria provided, multiple submitters, no conflicts
39583	NM_000146.4(FTL):c.89C>T (p.Thr30Ile)	LOC130064892	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1052512	NM_000146.4(FTL):c.-166T>C	FTL	Likely pathogenic	criteria provided, single submitter
16482	NM_000146.4(FTL):c.-149G>C	FTL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
16488	NM_000146.4(FTL):c.469_484dup (p.Leu162fs)	FTL	Likely pathogenic	criteria provided, single submitter
2138316	NM_000146.4(FTL):c.-153G>A	FTL	Likely pathogenic	criteria provided, single submitter
1049905	NM_000146.4(FTL):c.155T>G (p.Phe52Cys)	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156439	NM_000146.4(FTL):c.169G>A (p.Glu57Lys)	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158603	NM_000146.4(FTL):c.*8C>T	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1595257	NM_000146.4(FTL):c.-121C>T	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893264	NM_000146.4(FTL):c.362G>A (p.Arg121His)	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
894480	NM_000146.4(FTL):c.103-14A>C	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
96689	NM_000146.4(FTL):c.1A>G (p.Met1Val)	FTL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 4 · 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
FTL	Strong	Autosomal dominant	neuroferritinopathy	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FTL	Orphanet:157846	Neuroferritinopathy
FTL	Orphanet:163	Hereditary hyperferritinemia-cataract syndrome
FTL	Orphanet:254704	Genetic hyperferritinemia without iron overload
FTL	Orphanet:440731	L-ferritin deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FTL	HGNC:3999	ENSG00000087086	P02792	Ferritin light chain	gencc,clinvar
NOX1	HGNC:7889	ENSG00000007952	Q9Y5S8	NADPH oxidase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FTL	Ferritin light chain	Stores iron in a soluble, non-toxic, readily available form.
NOX1	NADPH oxidase 1	NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FTL	Other/Unknown	no		Ferritin, Ferritin_DPS_dom, Ferritin-like_diiron
NOX1	Other/Unknown	no		Cyt_b245_heavy_chain, FAD-bd_8, Fe_red_NAD-bd_6

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
gall bladder	1
stromal cell of endometrium	1
colonic mucosa	1
mucosa of sigmoid colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FTL	134	ubiquitous	marker	stromal cell of endometrium, blood, gall bladder
NOX1	155	tissue_specific	marker	rectum, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FTL	2,767
NOX1	2,080

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FTL	P02792	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NOX1	Q9Y5S8	90.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
WNT5:FZD7-mediated leishmania damping	1	475.8×	0.012	NOX1
Scavenging by Class A Receptors	1	300.5×	0.012	FTL
RHO GTPases Activate NADPH Oxidases	1	228.4×	0.012	NOX1
Iron uptake and transport	1	173.0×	0.012	FTL
Golgi Associated Vesicle Biogenesis	1	100.2×	0.016	FTL
RAC3 GTPase cycle	1	59.5×	0.022	NOX1
RAC1 GTPase cycle	1	30.5×	0.037	NOX1
Neutrophil degranulation	1	11.5×	0.085	FTL

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of integrin biosynthetic process	1	2808.7×	0.002	NOX1
hydrogen peroxide metabolic process	1	2106.5×	0.002	NOX1
oxygen metabolic process	1	2106.5×	0.002	NOX1
regulation of systemic arterial blood pressure by renin-angiotensin	1	1685.2×	0.002	NOX1
cellular response to hyperoxia	1	1685.2×	0.002	NOX1
positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	1685.2×	0.002	NOX1
NADP+ metabolic process	1	766.0×	0.004	NOX1
respiratory burst	1	648.1×	0.005	NOX1
iron ion transport	1	443.5×	0.006	FTL
intrinsic apoptotic signaling pathway in response to oxidative stress	1	421.3×	0.006	NOX1
superoxide anion generation	1	337.0×	0.006	NOX1
positive regulation of vascular endothelial growth factor production	1	247.8×	0.008	NOX1
positive regulation of smooth muscle cell proliferation	1	165.2×	0.011	NOX1
JNK cascade	1	135.9×	0.013	NOX1
intracellular iron ion homeostasis	1	122.1×	0.013	FTL
regulation of blood pressure	1	110.9×	0.013	NOX1
defense response	1	108.0×	0.013	NOX1
positive regulation of JNK cascade	1	81.8×	0.016	NOX1
extracellular matrix organization	1	61.1×	0.021	NOX1
angiogenesis	1	31.2×	0.037	NOX1
cell migration	1	30.8×	0.037	NOX1
inflammatory response	1	18.9×	0.057	NOX1
positive regulation of cell population proliferation	1	16.8×	0.061	NOX1
signal transduction	1	8.0×	0.121	NOX1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOX1	4	3
FTL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBSELEN	3	NOX1
SETANAXIB	2	NOX1
ISUZINAXIB	2	NOX1
PHENOTHIAZINE	2	NOX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOX1	32	Binding:20, Functional:12

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
EBSELEN	3	NOX1
SETANAXIB	2	NOX1
ISUZINAXIB	2	NOX1
PHENOTHIAZINE	2	NOX1

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	1	NOX1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FTL

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)
FTL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry