Neurodegeneration with brain iron accumulation 4

Summary

Neurodegeneration with brain iron accumulation 4 (MONDO:0013674) is a disease caused by C19orf12 (GenCC Definitive), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include isoxaflutole.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: C19orf12 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 170
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002063	Rigidity	Very frequent (80-99%)
HP:0002172	Postural instability	Very frequent (80-99%)
HP:0002378	Hand tremor	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002453	Abnormal globus pallidus morphology	Frequent (30-79%)
HP:0002607	Bowel incontinence	Frequent (30-79%)
HP:0006801	Hyperactive deep tendon reflexes	Frequent (30-79%)
HP:0007002	Motor axonal neuropathy	Frequent (30-79%)
HP:0045007	Abnormality of the substantia nigra	Frequent (30-79%)
HP:0000570	Abnormal saccadic eye movements	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation 4
Mondo ID	MONDO:0013674
OMIM	614298
Orphanet	289560
DOID	DOID:0110738
NCIT	C175707
SNOMED CT	709415008
UMLS	C3280371
MedGen	482001
GARD	0012569
Is cancer (heuristic)	no

Also known as: C19orf12 neurodegeneration with brain iron accumulation · mitochondrial Protein-associated neurodegeneration · MPAN · NBIA due to C19orf12 mutation · NBIA4 · neurodegeneration with brain iron accumulation 4 · neurodegeneration with brain iron accumulation caused by mutation in C19orf12 · neurodegeneration with brain iron accumulation due to C19orf12 mutation · neurodegeneration with brain iron accumulation type 4

Data availability: 170 ClinVar variants · 7 GenCC gene-disease records · 7 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 4

Related subtypes (13): pantothenate kinase-associated neurodegeneration, Woodhouse-Sakati syndrome, neurodegeneration with brain iron accumulation 5, aceruloplasminemia, neuroferritinopathy, Kufor-Rakeb syndrome, 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

170 retrieved; paginated sample, class counts are floors:

89 uncertain significance, 31 benign, 12 pathogenic, 10 conflicting classifications of pathogenicity, 10 likely benign, 9 pathogenic/likely pathogenic, 5 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1188836	NM_031448.6(C19orf12):c.182dup (p.Leu61fs)	C19orf12	Pathogenic	no assertion criteria provided
1344261	NM_031448.6(C19orf12):c.166del	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210552	NM_031448.6(C19orf12):c.225_226delinsTGGAGGAACAGT (p.Gln75fs)	C19orf12	Pathogenic	criteria provided, single submitter
225875	NM_031448.6(C19orf12):c.215C>T (p.Pro72Leu)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31155	NM_031448.6(C19orf12):c.171_181del (p.Gly58fs)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31156	NM_031448.6(C19orf12):c.-2C>T	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31157	NM_031448.6(C19orf12):c.172G>A (p.Gly58Arg)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31626	NM_031448.6(C19orf12):c.362T>A (p.Leu121Gln)	C19orf12	Pathogenic	no assertion criteria provided
3362869	NM_031448.6(C19orf12):c.139G>A (p.Gly47Ser)	C19orf12	Pathogenic	criteria provided, single submitter
3376956	NM_031448.6(C19orf12):c.302G>A (p.Trp101Ter)	C19orf12	Pathogenic	criteria provided, single submitter
3897647	NM_031448.6(C19orf12):c.211A>T (p.Lys71Ter)	C19orf12	Pathogenic	criteria provided, single submitter
3897648	NM_031448.6(C19orf12):c.246del (p.Ala83fs)	C19orf12	Pathogenic	criteria provided, single submitter
3897650	NM_031448.6(C19orf12):c.245del (p.Pro82fs)	C19orf12	Pathogenic	criteria provided, single submitter
3897672	NM_031448.6(C19orf12):c.271G>T (p.Glu91Ter)	C19orf12	Pathogenic	criteria provided, single submitter
425168	NM_031448.6(C19orf12):c.205C>T (p.Gln69Ter)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617481	NM_031448.6(C19orf12):c.161G>A (p.Gly54Glu)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617482	NM_031448.6(C19orf12):c.-10G>C	C19orf12	Pathogenic	no assertion criteria provided
634443	NM_031448.6(C19orf12):c.371dup (p.Met124fs)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
636274	NM_031448.6(C19orf12):c.232_233del (p.Met78fs)	C19orf12	Pathogenic	no assertion criteria provided
636275	NM_031448.6(C19orf12):c.194_204del (p.Met65fs)	C19orf12	Pathogenic	no assertion criteria provided
88866	NM_001031726.4(C19orf12):c.164_166delGGG	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3362870	NM_031448.6(C19orf12):c.-10-1G>A	C19orf12	Likely pathogenic	criteria provided, single submitter
3897649	NM_031448.6(C19orf12):c.262C>T (p.Leu88Phe)	C19orf12	Likely pathogenic	criteria provided, single submitter
402183	NM_031448.6(C19orf12):c.161G>T (p.Gly54Val)	C19orf12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
982027	NM_031448.6(C19orf12):c.240_241dup (p.Pro81fs)	C19orf12	Likely pathogenic	criteria provided, single submitter
2584363	NM_031448.6(C19orf12):c.105_106del (p.Ala37fs)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2585400	NM_031448.6(C19orf12):c.118T>G (p.Phe40Val)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286392	NM_031448.6(C19orf12):c.313G>A (p.Val105Met)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31158	NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328731	NM_031448.6(C19orf12):c.68C>T (p.Ala23Val)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
C19orf12	Definitive	Semidominant	neurodegeneration with brain iron accumulation 4	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43

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
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	gencc,clinvar

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)
C19orf12	Other/Unknown	no		C19orf12

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
endothelial cell	1
epithelial cell of pancreas	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C19orf12	584

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C19orf12	Q9NSK7	59.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
mitochondrial calcium ion homeostasis	1	991.3×	0.004	C19orf12
response to oxidative stress	1	130.6×	0.012	C19orf12
autophagy	1	110.1×	0.012	C19orf12
apoptotic process	1	28.7×	0.035	C19orf12

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
C19orf12	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	C19orf12

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)
C19orf12	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
NCT05678790	Not specified	COMPLETED	Mitochondrial Membrane Protein Neurodegeneration (MPAN)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ISOXAFLUTOLE	2	1