neurodegeneration with brain iron accumulation 2A

Summary

neurodegeneration with brain iron accumulation 2A (MONDO:0024457) is a disease caused by PLA2G6 (GenCC Definitive), with 2 cohort genes and 4 clinical trials. Top therapeutic interventions include desipramine.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PLA2G6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 905
• Phenotypes (HPO): 52
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

52 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0002361	Psychomotor deterioration	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001285	Spastic tetraparesis	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002191	Progressive spasticity	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002454	Eye of the tiger anomaly of globus pallidus	Frequent (30-79%)
HP:0002483	Bulbar signs	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0003134	Abnormality of peripheral nerve conduction	Frequent (30-79%)
HP:0003405	Diffuse axonal swelling	Frequent (30-79%)
HP:0003444	EMG: chronic denervation signs	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0012675	Iron accumulation in brain	Frequent (30-79%)
HP:0012698	Cerebellar gliosis	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0005968	Temperature instability	Occasional (5-29%)
HP:0011951	Aspiration pneumonia	Occasional (5-29%)
HP:0012043	Pendular nystagmus	Occasional (5-29%)
HP:0012332	Abnormal autonomic nervous system physiology	Occasional (5-29%)
HP:0100710	Impulsivity	Occasional (5-29%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0005949	Apneic episodes in infancy	Very rare (<1-4%)
HP:0010545	Downbeat nystagmus	Very rare (<1-4%)
HP:0025331	Upgaze palsy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation 2A
Mondo ID	MONDO:0024457
MeSH	C536071
OMIM	256600
Orphanet	35069
DOID	DOID:0110735
NCIT	C84927
SNOMED CT	52713000
UMLS	C0270724
MedGen	82852
GARD	0003957
Is cancer (heuristic)	no

Also known as: Hunter Carpenter Macdonald syndrome · Hunter-Carpenter-McDonald syndrome · INAD · inaD · INAD1 · infantile neuroaxonal dystrophy · infantile neuroaxonal dystrophy/atypical neuroaxonal dystrophy · KARAK syndrome, included · NBIA2A · NBIA2a · neuroaxonal dystrophy presenting with neonatal dysmorphic features, early onset of peripheral gangrene · neurodegeneration with brain iron accumulation 2A · neurodegeneration with brain iron accumulation type 2A · neurodegeneration with brain iron accumulation type 2a · neurodegeneration, PLA2G6-associated · neurodegeneration, Pla2G6-associated · neurodegeneration, Pla2g6-associated · phospholipase A2-associated neurodegeneration · PLAN · Seitelberger disease

Data availability: 905 ClinVar variants · 5 GenCC gene-disease records · 10 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 › PLA2G6-associated neurodegeneration › neurodegeneration with brain iron accumulation 2A

Related subtypes (2): neurodegeneration with brain iron accumulation 2B, autosomal recessive Parkinson disease 14

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

600 retrieved; paginated sample, class counts are floors:

311 likely benign, 156 uncertain significance, 47 conflicting classifications of pathogenicity, 29 pathogenic, 28 pathogenic/likely pathogenic, 13 likely pathogenic, 10 benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012697	NM_003560.4(PLA2G6):c.2349G>A (p.Trp783Ter)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012698	NM_003560.4(PLA2G6):c.2251G>T (p.Glu751Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
1028628	NM_003560.4(PLA2G6):c.1933C>T (p.Arg645Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
1076982	NC_000022.10:g.(?38528818)(38539315_?)dup	PLA2G6	Pathogenic	criteria provided, single submitter
1180814	NM_003560.4(PLA2G6):c.1893G>A (p.Trp631Ter)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1197568	NM_003560.4(PLA2G6):c.1798C>T (p.Arg600Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298894	NM_003560.4(PLA2G6):c.1771C>T (p.Arg591Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453196	NC_000022.10:g.(?38565205)(38565433_?)del	PLA2G6	Pathogenic	criteria provided, single submitter
1459347	NC_000022.10:g.(?38528818)(38536196_?)del	PLA2G6	Pathogenic	criteria provided, single submitter
159728	NM_003560.4(PLA2G6):c.1117G>A (p.Gly373Arg)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159730	NC_000022.10:g.38522454delG	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
159731	NM_003560.4(PLA2G6):c.1442T>A (p.Leu481Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159738	NM_003560.4(PLA2G6):c.1612C>T (p.Arg538Cys)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159739	NM_003560.4(PLA2G6):c.1613G>A (p.Arg538His)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159741	NM_003560.4(PLA2G6):c.1634A>G (p.Lys545Arg)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159742	NM_003560.4(PLA2G6):c.1674del (p.Leu560fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159748	NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159749	NM_003560.4(PLA2G6):c.1903C>T (p.Arg635Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
159762	NM_003560.4(PLA2G6):c.2233C>T (p.Arg745Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159764	NM_003560.4(PLA2G6):c.2327_2328del (p.Thr776fs)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
159775	NM_003560.4(PLA2G6):c.673C>T (p.His225Tyr)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159778	NM_003560.4(PLA2G6):c.755del (p.Asn252fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686076	NM_003560.4(PLA2G6):c.1969G>A (p.Ala657Thr)	PLA2G6	Pathogenic	criteria provided, single submitter
1686077	NM_003560.4(PLA2G6):c.1474_1478del (p.Ile492fs)	PLA2G6	Pathogenic	criteria provided, single submitter
1686078	NM_003560.4(PLA2G6):c.1069G>A (p.Ala357Thr)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686079	NM_003560.4(PLA2G6):c.437dup (p.Cys146fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722386	NM_003560.4(PLA2G6):c.1511C>T (p.Ser504Leu)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208712	NM_003560.4(PLA2G6):c.1019_1025del (p.Gly340fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211909	NM_003560.4(PLA2G6):c.1349-2A>G	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121380	NM_003560.4(PLA2G6):c.1460del (p.Gly487fs)	PLA2G6	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
PLA2G6	Definitive	Autosomal recessive	neurodegeneration with brain iron accumulation 2A	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLA2G6	Orphanet:199351	Adult-onset dystonia-parkinsonism
PLA2G6	Orphanet:35069	Infantile neuroaxonal dystrophy

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
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	gencc,clinvar
ANKRD54	HGNC:25185	ENSG00000100124	Q6NXT1	Ankyrin repeat domain-containing protein 54	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLA2G6	85/88 kDa calcium-independent phospholipase A2	Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.
ANKRD54	Ankyrin repeat domain-containing protein 54	Plays an important role in regulating intracellular signaling events associated with erythroid terminal differentiation.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase
ANKRD54	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf

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
right uterine tube	2
left lobe of thyroid gland	1
right lobe of thyroid gland	1
kidney epithelium	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLA2G6	232	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
ANKRD54	247	ubiquitous	marker	right uterine tube, kidney epithelium, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLA2G6	1,769
ANKRD54	1,122

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLA2G6	O60733	86.16
ANKRD54	Q6NXT1	68.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
Acyl chain remodeling of CL	1	1903.3×	0.003	PLA2G6
Role of phospholipids in phagocytosis	1	456.8×	0.003	PLA2G6
Acyl chain remodelling of PC	1	423.0×	0.003	PLA2G6
Acyl chain remodelling of PE	1	393.8×	0.003	PLA2G6
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.005	PLA2G6

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
platelet activating factor metabolic process	1	2808.7×	0.002	PLA2G6
cardiolipin acyl-chain remodeling	1	2106.5×	0.002	PLA2G6
phosphatidylethanolamine catabolic process	1	2106.5×	0.002	PLA2G6
phosphatidic acid metabolic process	1	1404.3×	0.002	PLA2G6
positive regulation of ceramide biosynthetic process	1	1203.7×	0.002	PLA2G6
phosphatidylcholine catabolic process	1	648.1×	0.003	PLA2G6
regulation of intracellular signal transduction	1	443.5×	0.004	ANKRD54
Fc-gamma receptor signaling pathway involved in phagocytosis	1	351.1×	0.005	PLA2G6
positive regulation of erythrocyte differentiation	1	255.3×	0.006	ANKRD54
nucleocytoplasmic transport	1	195.9×	0.006	ANKRD54
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.006	PLA2G6
antibacterial humoral response	1	165.2×	0.007	PLA2G6
chemotaxis	1	68.0×	0.015	PLA2G6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
PLA2G6	1	2
ANKRD54	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARESPLADIB	2	PLA2G6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLA2G6	47	Binding:47
ANKRD54	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G6	3.1.1.4	phospholipase A2

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

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)
VARESPLADIB	2	PLA2G6

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	PLA2G6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANKRD54

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)
ANKRD54	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03726996	PHASE4	TERMINATED	Desipramine in Infantile Neuroaxonal Dystrophy (INAD).
NCT03570931	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy
NCT06203106	Not specified	RECRUITING	NYSCF Scientific Discovery Biobank
NCT03999814	Not specified	COMPLETED	Natural History of Infantile Neuroaxonal Dystrophy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DESIPRAMINE	4	1