Neurodegeneration with brain iron accumulation 6

Summary

Neurodegeneration with brain iron accumulation 6 (MONDO:0014290) is a disease caused by COASY (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COASY (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 288
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000722	Compulsive behaviors	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001300	Parkinsonism	Very frequent (80-99%)
HP:0002313	Spastic paraparesis	Very frequent (80-99%)
HP:0002339	Abnormal caudate nucleus morphology	Very frequent (80-99%)
HP:0002453	Abnormal globus pallidus morphology	Very frequent (80-99%)
HP:0002454	Eye of the tiger anomaly of globus pallidus	Very frequent (80-99%)
HP:0003477	Peripheral axonal neuropathy	Very frequent (80-99%)
HP:0010663	Abnormality of thalamus morphology	Very frequent (80-99%)
HP:0010994	Abnormal corpus striatum morphology	Very frequent (80-99%)
HP:0012048	Oromandibular dystonia	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation 6
Mondo ID	MONDO:0014290
OMIM	615643
Orphanet	397725
DOID	DOID:0110740
SNOMED CT	732264002
UMLS	C4517377
MedGen	1387791
GARD	0012571
Is cancer (heuristic)	no

Also known as: COASY neurodegeneration with brain iron accumulation · CoPAN · NBIA6 · neurodegeneration with brain iron accumulation 6 · neurodegeneration with brain iron accumulation caused by mutation in COASY · neurodegeneration with brain iron accumulation due to COASY mutation · neurodegeneration with brain iron accumulation type 6

Data availability: 288 ClinVar variants · 5 GenCC gene-disease records.

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 6

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 4, 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

288 retrieved; paginated sample, class counts are floors:

125 uncertain significance, 115 likely benign, 15 pathogenic, 13 conflicting classifications of pathogenicity, 7 benign, 6 benign/likely benign, 5 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100662	NM_025233.7(COASY):c.1495C>T (p.Arg499Cys)	COASY	Pathogenic	criteria provided, multiple submitters, no conflicts
100663	NM_025233.7(COASY):c.175C>T (p.Gln59Ter)	COASY	Pathogenic	no assertion criteria provided
1373025	NM_025233.7(COASY):c.1567C>T (p.Gln523Ter)	COASY	Pathogenic	criteria provided, multiple submitters, no conflicts
1418640	NM_025233.7(COASY):c.422dup (p.Tyr141Ter)	COASY	Pathogenic	criteria provided, single submitter
1899292	NM_025233.7(COASY):c.383del (p.Pro128fs)	COASY	Pathogenic	criteria provided, single submitter
2043445	NM_025233.7(COASY):c.1129C>T (p.Arg377Ter)	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2083704	NM_025233.7(COASY):c.1579C>T (p.Gln527Ter)	COASY	Pathogenic	criteria provided, single submitter
2114435	NM_025233.7(COASY):c.946C>T (p.Gln316Ter)	COASY	Pathogenic	criteria provided, single submitter
2716492	NM_025233.7(COASY):c.423C>A (p.Tyr141Ter)	COASY	Pathogenic	criteria provided, single submitter
2730066	NM_025233.7(COASY):c.545_546del (p.Gly182fs)	COASY	Pathogenic	criteria provided, single submitter
2730393	NM_025233.7(COASY):c.732_733del (p.Thr245fs)	COASY	Pathogenic	criteria provided, single submitter
2918682	NM_025233.7(COASY):c.1401_1404dup (p.Ile469fs)	COASY	Pathogenic	criteria provided, single submitter
3723340	NM_025233.7(COASY):c.183del (p.Phe62fs)	COASY	Pathogenic	criteria provided, single submitter
4704971	NM_025233.7(COASY):c.600dup (p.Asp201Ter)	COASY	Pathogenic	criteria provided, single submitter
599341	NM_025233.7(COASY):c.1486-3C>G	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
664943	NM_025233.7(COASY):c.876T>A (p.Tyr292Ter)	COASY	Pathogenic	criteria provided, single submitter
832522	NC_000017.11:g.(?42562392)(42565988_?)del	COASY	Pathogenic	criteria provided, single submitter
2050208	NM_025233.7(COASY):c.1388-2A>G	COASY	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581965	NM_025233.7(COASY):c.1387+1G>A	COASY	Likely pathogenic	criteria provided, single submitter
3779541	NM_025233.7(COASY):c.90_96del (p.Ala30_Arg31insTer)	COASY	Likely pathogenic	criteria provided, single submitter
4086116	NM_025233.7(COASY):c.112dup (p.Tyr38fs)	COASY	Likely pathogenic	criteria provided, single submitter
599340	NM_025233.7(COASY):c.641C>T (p.Ala214Val)	COASY	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1010453	NM_025233.7(COASY):c.778C>T (p.Pro260Ser)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1472390	NM_025233.7(COASY):c.1015C>T (p.Arg339Ter)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2049002	NM_025233.7(COASY):c.1112A>G (p.Lys371Arg)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2064885	NM_025233.7(COASY):c.1120A>G (p.Ile374Val)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079887	NM_025233.7(COASY):c.53dup (p.Ala19fs)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2202647	NM_025233.7(COASY):c.215A>G (p.Tyr72Cys)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2863497	NM_025233.7(COASY):c.573C>T (p.Tyr191=)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3901501	NM_025233.7(COASY):c.1357C>T (p.Arg453Ter)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
COASY	Definitive	Autosomal recessive	neurodegeneration with brain iron accumulation 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COASY	Orphanet:397725	COASY protein-associated neurodegeneration

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
COASY	HGNC:29932	ENSG00000068120	Q13057	Bifunctional coenzyme A synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COASY	Bifunctional coenzyme A synthase	Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COASY	Kinase	yes	2.7.1.24	Depp_CoAkinase, Cyt_trans-like, Rossmann-like_a/b/a_fold

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
lower esophagus mucosa	1
mucosa of transverse colon	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COASY	280	ubiquitous	marker	parotid gland, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COASY	3,273

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COASY	Q13057	89.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Coenzyme A biosynthesis	1	1427.5×	7e-04	COASY

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
coenzyme A biosynthetic process	1	1532.0×	7e-04	COASY

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COASY	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	COASY

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
COASY	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
COASY	2.7.1.24, 2.7.7.3	dephospho-CoA kinase, pantetheine-phosphate adenylyltransferase

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

1 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)
MOLIBRESIB	2	COASY

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.