Neurodegeneration With Brain Iron Accumulation

1. Disease Information

1.1 Overview (definition; current understanding)

Neurodegeneration with brain iron accumulation (NBIA) refers to a genetically heterogeneous group of progressive neurodegenerative disorders characterized by abnormal iron deposition in deep gray nuclei—classically the globus pallidus and substantia nigra—visible on iron-sensitive MRI sequences. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 1-2)

Direct abstract-supported statement (Frontiers in Neurology review, published 2021-04-15): NBIA is described as “a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra.” (iankova2021emergingdiseasemodifyingtherapies pages 1-2)

1.2 Key identifiers

• MONDO: MONDO_0018307 (“neurodegeneration with brain iron accumulation”) (OpenTargets Search: Neurodegeneration with brain iron accumulation)
• Other identifiers (OMIM, Orphanet, ICD-10/ICD-11, MeSH): Not retrievable from the current tool evidence set; should be filled by targeted queries to OMIM/Orphanet/MeSH/ICD resources outside this run.

1.3 Synonyms / alternative names

• “NBIA disorders” (iankova2021emergingdiseasemodifyingtherapies pages 1-2)
• Frequently referenced subtype names: PKAN, PLAN/INAD, BPAN, MPAN (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4)

1.4 Evidence source type

The characterization in this report is derived primarily from aggregated disease-level resources (peer-reviewed reviews) and cohort/registry/trial records (ClinicalTrials.gov) plus human cohort studies (PLAN cohort, chelation cohorts). (iankova2021emergingdiseasemodifyingtherapies pages 1-2, dehnavi2023phenotypeandgenotype pages 1-2, NCT02587858 chunk 1, NCT02174848 chunk 1, NCT04182763 chunk 1)

2. Etiology

2.1 Disease causal factors

NBIA is primarily genetic/monogenic in etiology, comprising multiple distinct gene-defined entities (at least ~15 monogenic disorders noted in 2021), unified by basal ganglia iron accumulation. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, uygun2025quantitativeironmeasurements pages 2-2)

While iron accumulation is a defining feature, reviews emphasize that only a subset of NBIA forms arise from primary defects in iron homeostasis genes (notably aceruloplasminemia and neuroferritinopathy), whereas many other NBIA genes map to pathways such as coenzyme A biosynthesis, lipid metabolism, and autophagy. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4)

2.2 Risk factors

• Genetic: Pathogenic variants in NBIA-associated genes (examples emphasized across sources: PANK2, PLA2G6, C19orf12, WDR45, CP, FTL, ATP13A2, FA2H, COASY). (schneider2025neurodegenerationwithbrain pages 3-4, schneider2025neurodegenerationwithbrain pages 1-2, OpenTargets Search: Neurodegeneration with brain iron accumulation)
• Consanguinity (for autosomal recessive NBIA subtypes): In the 2023 Iranian PLAN cohort, all late-onset PLAN adult cases were reported from consanguineous parents. (dehnavi2023phenotypeandgenotype pages 9-11)
• Environmental: No specific environmental risk factors were identified in the retrieved evidence; NBIA is treated as primarily genetic in the included sources.

2.3 Protective factors

Not identified in the retrieved evidence.

2.4 Gene–environment interactions

Not identified in the retrieved evidence.

3. Phenotypes

3.1 Core clinical phenotype spectrum (across NBIA)

NBIA disorders present with a broad neurologic phenotype, prominently movement disorders (dystonia, parkinsonism, chorea), pyramidal signs/spasticity, cognitive decline, neuropsychiatric features, speech disorders, and ocular abnormalities in some subtypes. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4, schneider2025neurodegenerationwithbrain pages 1-2)

3.2 Subtype-specific phenotypes with quantitative data (PLAN/INAD)

A 2023 cohort study of 25 genetically confirmed PLAN patients (18 INAD, 7 late-onset PLAN) quantified symptoms and progression. - INAD (n=18) - Initial presentation: gross motor regression in 55.55%. (dehnavi2023phenotypeandgenotype pages 4-5) - During disease course: visual disturbance 77.77%, bulbar dysfunction 77.77%, cognitive impairment 61.11%, seizures 27.77%, hearing impairment 27.77%. (dehnavi2023phenotypeandgenotype pages 4-5) - Onset: 0–108 months (mean 22.4 months). (dehnavi2023phenotypeandgenotype pages 4-5) - Progression (INAD-RS): mean decline 0.58 points/month, and “Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset.” (dehnavi2023phenotypeandgenotype pages 1-2, dehnavi2023phenotypeandgenotype pages 4-5) - Late-onset PLAN adults (n=7) - Common features: hypokinesia 6/7, hand tremor 3/7, cerebellar atrophy 4/7 (57%); iron deposition in globus pallidus and substantia nigra occurred in 1 patient in this cohort excerpt. (dehnavi2023phenotypeandgenotype pages 9-11)

3.3 MRI / neuroradiology phenotypes

• MRI is central for NBIA diagnosis and subtype pattern recognition; iron-sensitive sequences (e.g., T2, SWI) and quantitative mapping (R2 or QSM) can detect and quantify brain iron. (uygun2025quantitativeironmeasurements pages 2-2, romano2022longtermneuroradiologicaland pages 1-2)
• PKAN hallmark: “eye-of-the-tiger” sign. (spaull2021towardsprecisiontherapies pages 6-8, romano2022longtermneuroradiologicaland pages 1-2)
• PLAN/INAD: early cerebellar atrophy is common and may precede obvious basal ganglia iron in some cases; iron deposition in globus pallidus/substantia nigra can occur. (dehnavi2023phenotypeandgenotype pages 4-5)
• BPAN: reports describe a characteristic midbrain/substantia nigra pattern (T1 hyperintense halo) in association with iron changes. (spaull2021towardsprecisiontherapies pages 6-8)

3.4 Suggested HPO terms (non-exhaustive)

Based on phenotypes emphasized in retrieved evidence: - Dystonia — HP:0001332 - Parkinsonism / Bradykinesia — HP:0001300, HP:0002067 - Spasticity — HP:0001257 - Cognitive impairment — HP:0100543 - Developmental regression / psychomotor regression — HP:0002376 - Cerebellar atrophy — HP:0001272 - Ataxia / gait ataxia — HP:0001251 - Bulbar dysfunction / dysphagia / dysarthria — HP:0002015, HP:0001260 - Seizures — HP:0001250 - Visual impairment — HP:0000505

(HP codes are suggested ontology mappings; the evidence supports the clinical concepts but does not itself provide HPO annotations.) (iankova2021emergingdiseasemodifyingtherapies pages 1-2, dehnavi2023phenotypeandgenotype pages 4-5)

3.5 Quality of life impact

NBIA is typically progressive with severe disability and premature mortality in many forms; published sources in the retrieved evidence characterize the conditions as “devastating,” with progressive motor and cognitive decline. (spaull2021towardsprecisiontherapies pages 2-4, uygun2025quantitativeironmeasurements pages 2-2)

4. Genetic / Molecular Information

4.1 Causal genes and subtype architecture

Authoritative reviews and datasets emphasize the major NBIA entities and genes: - PKAN: PANK2 (schneider2025neurodegenerationwithbrain pages 1-2, marupudi2024genetictargetsand pages 3-4) - PLAN/INAD: PLA2G6 (dehnavi2023phenotypeandgenotype pages 1-2, dehnavi2023phenotypeandgenotype pages 4-5) - MPAN: C19orf12 (schneider2025neurodegenerationwithbrain pages 3-4, marupudi2024genetictargetsand pages 3-4) - BPAN: WDR45 (X-linked dominant) (spaull2021towardsprecisiontherapies pages 6-8, marupudi2024genetictargetsand pages 4-5) - Aceruloplasminemia: CP (schneider2025neurodegenerationwithbrain pages 3-4) - Neuroferritinopathy: FTL (dominant) (schneider2025neurodegenerationwithbrain pages 3-4)

OpenTargets disease–target associations for NBIA (MONDO_0018307) also highlight PLA2G6, PANK2, C19orf12, ATP13A2, WDR45, CP, COASY among top associated targets (evidence sizes shown). (OpenTargets Search: Neurodegeneration with brain iron accumulation)

4.2 Variant classes and ACMG classification (PLAN example)

In the 2023 PLAN cohort (25 individuals), PLA2G6 variant spectrum included: 15 missense (75%), 2 nonsense (10%), 1 frameshift (5%), 2 splice-site (10%); ACMG classifications: 40% pathogenic, 50% likely pathogenic, 10% VUS. Only two variants had gnomAD allele frequencies reported in that paper excerpt (0.0059% and 0.0007%). (dehnavi2023phenotypeandgenotype pages 9-11)

4.3 Inheritance patterns

• Many NBIA subtypes are autosomal recessive (e.g., PKAN, PLAN, MPAN, aceruloplasminemia). (spaull2021towardsprecisiontherapies pages 6-8, marupudi2024genetictargetsand pages 3-4)
• Some NBIA forms are autosomal dominant (e.g., neuroferritinopathy/FTL) or X-linked dominant (BPAN/WDR45). (schneider2025neurodegenerationwithbrain pages 3-4, marupudi2024genetictargetsand pages 4-5)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

Not identified in the retrieved evidence.

5. Environmental Information

No NBIA-specific environmental or infectious drivers were identified in the retrieved evidence; the dominant explanatory framework in the retrieved sources is genetic causation with downstream metabolic and cellular pathway disruption. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4)

6. Mechanism / Pathophysiology

6.1 Mechanistic themes (cross-NBIA)

Retrieved reviews converge on several pathway “classes”: - Coenzyme A (CoA) biosynthesis defects (notably PKAN) (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 5-6) - Lipid metabolism / membrane remodeling defects (notably PLAN) (iankova2021emergingdiseasemodifyingtherapies pages 1-2, marupudi2024genetictargetsand pages 3-4) - Autophagy dysfunction (notably BPAN/WDR45) (spaull2021towardsprecisiontherapies pages 6-8, schneider2025neurodegenerationwithbrain pages 3-4) - Mitochondrial dysfunction as a common downstream theme across multiple subtypes (schneider2025neurodegenerationwithbrain pages 1-2, marupudi2024genetictargetsand pages 7-8) - Iron homeostasis primary defects in a subset (aceruloplasminemia, neuroferritinopathy) (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 3-4)

A proposed unifying hypothesis cited in reviews is impairment in transferrin receptor (TfR1) recycling/palmitoylation affecting cellular iron handling, although the causal linkage between iron accumulation and neurodegeneration is not fully proven. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4)

6.2 Causal chains (examples)

• PKAN (PANK2 loss-of-function) → impaired pantothenate phosphorylation → CoA deficiency → mitochondrial/metabolic dysfunction and oxidative stress → basal ganglia neurodegeneration with iron accumulation detectable on MRI. (marupudi2024genetictargetsand pages 3-4, spaull2021towardsprecisiontherapies pages 5-6)
• PLAN/INAD (PLA2G6 dysfunction) → defective phospholipase/lipid remodeling → axonal spheroids and neuroaxonal dystrophy pathology → neurodegeneration with cerebellar atrophy and variable iron deposition. (marupudi2024genetictargetsand pages 3-4, dehnavi2023phenotypeandgenotype pages 4-5)
• BPAN (WDR45) → impaired autophagy → iron overload plus mitochondrial dysfunction and reduced ferritin reported in reviews. (spaull2021towardsprecisiontherapies pages 6-8)

6.3 Biochemical and cellular processes (ontology suggestions)

GO Biological Process (suggested) - iron ion homeostasis; cellular iron ion homeostasis - autophagy - lipid metabolic process; phospholipid catabolic process - mitochondrial organization; oxidative phosphorylation - response to oxidative stress; lipid peroxidation

GO Cellular Component (suggested) - mitochondrion; mitochondria-associated membranes - lysosome - autophagosome

Cell Ontology (CL) cell types implicated by phenotype/anatomy (suggested) - striatal medium spiny neuron; pallidal neuron (basal ganglia neuronal types) - dopaminergic neuron (substantia nigra) - astrocyte; oligodendrocyte (for iron handling and white matter findings)

(These are suggested mappings; specific GO/CL term IDs were not provided in the retrieved texts.) (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 1-2, dehnavi2023phenotypeandgenotype pages 4-5)

6.4 Iron as a mechanistic driver and oxidative stress

A 2024 chelator-focused review states that brain iron accumulation in NBIA is “hypothesized to be the cause of oxidative stress, leading to the degeneration of brain tissue.” (Marupudi & Xiong, 2024-03, DOI: 10.1021/acsbiomedchemau.3c00066) (marupudi2024genetictargetsand pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/system level

Primary: central nervous system (movement disorder and cognitive/psychiatric decline). (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 1-2)

7.2 Regional neuroanatomy

• Globus pallidus and substantia nigra are the canonical sites of iron deposition across NBIA. (iankova2021emergingdiseasemodifyingtherapies pages 1-2)
• Cerebellum: cerebellar atrophy is prominent in PLAN/INAD cohorts. (dehnavi2023phenotypeandgenotype pages 4-5)

UBERON suggestions - globus pallidus; substantia nigra; cerebellum; basal ganglia

8. Temporal Development

8.1 Onset patterns

NBIA has wide onset range (infancy through adulthood), depending on subtype and even within gene-defined entities (e.g., PLAN spectrum). (spaull2021towardsprecisiontherapies pages 6-8, dehnavi2023phenotypeandgenotype pages 1-2)

PLAN cohort onset data: in INAD, onset ranged from 0 to 108 months (mean 22.4 months). (dehnavi2023phenotypeandgenotype pages 4-5)

8.2 Progression

Progression is typically neurodegenerative and progressive. Quantitative longitudinal metric (INAD-RS) in the PLAN cohort: mean decline 0.58 points/month; a large fraction of functional loss accrued within 5 years from onset. (dehnavi2023phenotypeandgenotype pages 1-2, dehnavi2023phenotypeandgenotype pages 4-5)

9. Inheritance and Population

9.1 Overall NBIA prevalence

A 2021 review reports combined NBIA prevalence of approximately 1–9 per 1,000,000. (iankova2021emergingdiseasemodifyingtherapies pages 1-2)

9.2 Subtype epidemiology — PLAN genetic prevalence (2024)

A 2024 study estimated PLAN genetic prevalence using ClinVar/HGMD/gnomAD allele frequencies: - Overall genetic prevalence (including pathogenic and/or conflicting variants): 1 in 987,267 to 1 in 1,570,079 pregnancies. (Kurtovic‑Kozaric et al., 2024-10, DOI: 10.1186/s13023-024-03275-x) (kurtovickozaric2024anestimationof pages 1-2) - Highest estimated prevalence: - African/African-American: 1 in 421,960 to 1 in 365,197 - East Asian: 1 in 683,978 to 1 in 190,771 (kurtovickozaric2024anestimationof pages 1-2) - Carrier frequency estimates: approximately 1 in 497 to 1 in 627 individuals. (kurtovickozaric2024anestimationof pages 4-6) - Global burden projection: 82–127 affected births/year based on global births. (kurtovickozaric2024anestimationof pages 4-6)

Interpretation from that paper: the authors emphasize likely underdiagnosis and the need for expanded sequencing in non-European populations. (kurtovickozaric2024anestimationof pages 1-2)

10. Diagnostics

10.1 Clinical and imaging diagnostics

• MRI is a primary diagnostic modality; iron-sensitive sequences identify characteristic patterns, sometimes before overt clinical features. (schneider2025neurodegenerationwithbrain pages 3-4, romano2022longtermneuroradiologicaland pages 1-2)
• Quantitative approaches:
• R2* relaxometry used to quantify pallidal iron and track response to chelation in NBIA cohorts. (romano2022longtermneuroradiologicaland pages 2-4)
• QSM highlighted as potentially more sensitive for early detection/quantitation of iron. (uygun2025quantitativeironmeasurements pages 2-2)

10.2 Genetic testing strategy

Diagnosis is suspected from phenotype + MRI and confirmed by genetic testing; recommended approaches include single-gene testing when phenotype/MRI is highly characteristic (e.g., PKAN eye-of-the-tiger), multigene panels, or WES/WGS for broader heterogeneity. (spaull2021towardsprecisiontherapies pages 2-4)

PLAN cohort confirms real-world approach: whole-exome sequencing followed by Sanger co-segregation, ACMG classification, and MAF checks in gnomAD. (dehnavi2023phenotypeandgenotype pages 2-4, dehnavi2023phenotypeandgenotype pages 9-11)

10.3 Differential diagnosis

Not systematically extracted in the retrieved evidence.

11. Outcome / Prognosis

Quantitative survival estimates were not retrieved. However, NBIA is consistently described as progressive and severely disabling, often with premature mortality in severe childhood-onset forms. (spaull2021towardsprecisiontherapies pages 2-4, uygun2025quantitativeironmeasurements pages 2-2)

12. Treatment

12.1 Symptomatic vs disease-modifying treatment landscape

Reviews consistently state that NBIA treatment is largely symptomatic and that proven disease-modifying treatments remain limited, motivating mechanistically targeted (precision) therapies. (spaull2021towardsprecisiontherapies pages 2-4, marupudi2024genetictargetsand pages 1-2)

12.2 Iron chelation (deferiprone and others)

Deferiprone (DFP) is repeatedly highlighted because it can cross the blood–brain barrier and has been tested in PKAN and other NBIA contexts. (romano2022longtermneuroradiologicaland pages 1-2)

Prospective long-term NBIA cohort (Romano et al., 2022-08, DOI: 10.3390/jcm11154524): - Dose: 15 mg/kg BID (30 mg/kg/day) (romano2022longtermneuroradiologicaland pages 2-4) - Follow-up: 5.5 ± 2.3 years (range 2.4–9.6) (romano2022longtermneuroradiologicaland pages 2-4) - Quantitative MRI outcome: GPi R2 decreased significantly (left 47.6 ± 6.4 Hz → 37.3 ± 5.8 Hz; right 48.4 ± 6.2 Hz → 37.9 ± 6.6 Hz*, both p<0.0001). (romano2022longtermneuroradiologicaland pages 4-7) - Clinical outcome: “substantial stability” overall; correlation between radiology and clinical measures not significant. (romano2022longtermneuroradiologicaland pages 1-2, romano2022longtermneuroradiologicaland pages 4-7)

Neuroferritinopathy case series (Marchand et al., 2022-08, DOI: 10.1002/mds.29145): - Deferiprone 30 mg/kg/day in 4 patients, with reports including >11-year stabilization in one patient and marked improvements in some individuals; hematologic risk (neutropenia) observed and requires monitoring. (marchand2022conservativeironchelation pages 3-4, marchand2022conservativeironchelation pages 1-2)

Other chelators discussed in the 2024 review include deferoxamine and deferasirox; limitations include BBB penetration and toxicity concerns, and new delivery methods (intranasal and nanocarriers) are proposed to improve CNS targeting. (marupudi2024genetictargetsand pages 1-2, marupudi2024genetictargetsand pages 5-6, marupudi2024genetictargetsand pages 7-8)

12.3 Substrate replacement / pathway-bypass strategies (PKAN)

• A 2021 review reports that a randomized controlled trial of fosmetpantotenate did not show significant benefit and extensions were terminated early. (iankova2021emergingdiseasemodifyingtherapies pages 1-2)
• ClinicalTrials.gov confirms fosmetpantotenate study NCT03041116 listed as terminated (trial details limited in our extracted clinical-trial chunk set). (spaull2021towardsprecisiontherapies pages 2-4)
• CoA-Z (OHSU) is an investigational product intended to bypass metabolic defects in PKAN; trial NCT04182763 is completed with 77 participants, with a randomized double-blind phase followed by open-label period and safety/molecular endpoints. (NCT04182763 chunk 1)

12.4 PLAN-targeted approaches

A 2021 review highlights deuterated polyunsaturated fatty acids (D-PUFA) to reduce mitochondrial lipid peroxidation in PLAN and discusses desipramine repurposing in infantile neuroaxonal dystrophy to block ceramide accumulation, with gene replacement in preclinical stage. (iankova2021emergingdiseasemodifyingtherapies pages 1-2)

12.5 Clinical trials and real-world implementations

Key NBIA clinical trial and infrastructure resources identified in this evidence set: - TIRCON: an international NBIA network reported to include a global patient registry/biobank with baseline and follow-up data of >400 NBIA patients and to have run a randomized deferiprone trial in PKAN. (uygun2025quantitativeironmeasurements pages 2-2) - NBIAready natural history patient-reported outcomes study: NCT02587858, observational; estimated enrollment 300; online assessments every ~6 months for 5–10 years. (NCT02587858 chunk 1) - Deferiprone in PKAN: NCT01741532 (MRI R2* brain iron change over 18 months as key endpoint) and extension NCT02174848 (Phase 3, 68 participants; BAD scale, PGI-I; safety endpoints). (NCT01741532 chunk 2, NCT02174848 chunk 1)

12.6 MAXO term suggestions (treatments/actions)

• Iron chelation therapy (e.g., deferiprone) — “iron chelation”
• Magnetic resonance imaging (diagnostic imaging)
• Whole-exome sequencing / genome sequencing (genetic diagnostic procedure)
• Symptomatic dystonia management (e.g., baclofen, botulinum toxin; noted in case-report literature but not a primary evidence focus here) (schneider2025neurodegenerationwithbrain pages 1-2)

(MAXO IDs not provided in the retrieved evidence; terms are suggested for mapping.)

13. Prevention

No primary prevention strategies were identified in the retrieved evidence. For genetic NBIA, prevention in practice is typically via genetic counseling and reproductive options; the retrieved evidence supports the role of genetic testing and counseling but does not provide prevention-specific programs or guidelines. (schneider2025neurodegenerationwithbrain pages 3-4)

14. Other Species / Natural Disease

Not identified in the retrieved evidence.

15. Model Organisms

The retrieved evidence set includes review-level statements that animal and cell models are used to evaluate candidate therapies (e.g., 4′-phosphopantetheine in PKAN models; D-PUFA in PLAN models; preclinical gene replacement), but detailed model organism phenotypes were not extracted in the current snippets. (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4)

2023–2024 Developments (prioritized)

1) 2024: Therapeutic delivery and chelator engineering focus — A 2024 ACS review synthesizes chelator options for NBIA and emphasizes future directions such as intranasal delivery and nanocarrier approaches to bypass BBB and reduce systemic toxicity, alongside gene-therapy modalities (ASO, AAV, CRISPR). (Marupudi & Xiong, 2024-03, DOI: 10.1021/acsbiomedchemau.3c00066) (marupudi2024genetictargetsand pages 5-6, marupudi2024genetictargetsand pages 6-7, marupudi2024genetictargetsand pages 7-8)

2) 2023: Quantitative natural history metrics in PLAN/INAD — The 2023 Orphanet cohort reports INAD-RS progression (0.58 points/month) and symptom frequencies, supporting more standardized endpoints for trials and care. (Dehnavi et al., 2023-07, DOI: 10.1186/s13023-023-02780-9) (dehnavi2023phenotypeandgenotype pages 4-5)

3) 2024: Global genetic prevalence estimates for PLAN — PLAN prevalence and carrier frequencies were estimated from gnomAD and variant databases with population-stratified projections; results highlight underdiagnosis and the need for sequencing in underrepresented ancestries. (Kurtovic‑Kozaric et al., 2024-10, DOI: 10.1186/s13023-024-03275-x) (kurtovickozaric2024anestimationof pages 1-2, kurtovickozaric2024anestimationof pages 4-6)

Visual evidence (figure/table)

A key synthesis figure and tables summarizing NBIA genes, pathways, and trialed/in-development therapies were retrieved from Spaull et al. 2021 (Figure 1 and Tables 1–2). (spaull2021towardsprecisiontherapies media e9e8d758, spaull2021towardsprecisiontherapies media efb687c0, spaull2021towardsprecisiontherapies media 7e7d49af, spaull2021towardsprecisiontherapies media c661aa84)

Cross-subtype comparison table

Table: Compact comparison of the principal NBIA disorders, summarizing genes, inheritance, hallmark phenotypes, MRI signatures, mechanisms, and disease-modifying or investigational therapies supported by the gathered evidence.

Evidence limitations and gaps (important for knowledge base curation)

• This run did not retrieve OMIM/Orphanet/ICD/MeSH entries directly; MONDO was available via OpenTargets. (OpenTargets Search: Neurodegeneration with brain iron accumulation)
• Several key randomized trial results (e.g., published deferiprone RCT results in Lancet Neurology referenced in trial record/reviews) were not directly retrieved as full papers in this run; consequently, effect-size estimates beyond MRI/scale descriptions in the extracted records are limited. (NCT01741532 chunk 2, iankova2021emergingdiseasemodifyingtherapies pages 1-2)
• Environmental factors, protective factors, gene–environment interactions, and systematic differential diagnosis lists were not present in the retrieved evidence set.

URLs and publication dates (selected key sources)

• Marupudi N, Xiong MP. Genetic Targets and Applications of Iron Chelators for NBIA. ACS Bio & Med Chem Au. 2024-03. https://doi.org/10.1021/acsbiomedchemau.3c00066 (marupudi2024genetictargetsand pages 1-2)
• Dehnavi AZ et al. Phenotype and genotype heterogeneity of PLAN. Orphanet J Rare Dis. 2023-07. https://doi.org/10.1186/s13023-023-02780-9 (dehnavi2023phenotypeandgenotype pages 1-2)
• Kurtovic‑Kozaric A et al. Global genetic prevalence of PLAN. Orphanet J Rare Dis. 2024-10. https://doi.org/10.1186/s13023-024-03275-x (kurtovickozaric2024anestimationof pages 1-2)
• Romano N et al. Long-term deferiprone in NBIA. J Clin Med. 2022-08. https://doi.org/10.3390/jcm11154524 (romano2022longtermneuroradiologicaland pages 2-4)
• ClinicalTrials.gov: NCT04182763 (CoA‑Z in PKAN) (posted 2019; completed 2025) https://clinicaltrials.gov/study/NCT04182763 (NCT04182763 chunk 1)
• ClinicalTrials.gov: NCT02174848 (TIRCON-EXT deferiprone extension) (posted 2014; completed 2018; results posted 2019) https://clinicaltrials.gov/study/NCT02174848 (NCT02174848 chunk 1)
• ClinicalTrials.gov: NCT02587858 (NBIAready natural history PROs) (posted 2015) https://clinicaltrials.gov/study/NCT02587858 (NCT02587858 chunk 1)

References

1. (iankova2021emergingdiseasemodifyingtherapies pages 1-2): Vassilena Iankova, Ivan Karin, Thomas Klopstock, and Susanne A. Schneider. Emerging disease-modifying therapies in neurodegeneration with brain iron accumulation (nbia) disorders. Frontiers in Neurology, Apr 2021. URL: https://doi.org/10.3389/fneur.2021.629414, doi:10.3389/fneur.2021.629414. This article has 87 citations and is from a peer-reviewed journal.

2. (schneider2025neurodegenerationwithbrain pages 1-2): Susanne A. Schneider. Neurodegeneration with brain iron accumulation. Current Neurology and Neuroscience Reports, 16:1-9, Jan 2025. URL: https://doi.org/10.1007/s11910-015-0608-3, doi:10.1007/s11910-015-0608-3. This article has 38 citations and is from a domain leading peer-reviewed journal.

3. (OpenTargets Search: Neurodegeneration with brain iron accumulation): Open Targets Query (Neurodegeneration with brain iron accumulation, 15 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

4. (spaull2021towardsprecisiontherapies pages 2-4): Robert V.V. Spaull, Audrey K.S. Soo, Penelope Hogarth, Susan J. Hayflick, and Manju A. Kurian. Towards precision therapies for inherited disorders of neurodegeneration with brain iron accumulation. Tremor and Other Hyperkinetic Movements, Nov 2021. URL: https://doi.org/10.5334/tohm.661, doi:10.5334/tohm.661. This article has 30 citations and is from a peer-reviewed journal.

5. (dehnavi2023phenotypeandgenotype pages 1-2): Ali Zare Dehnavi, Maryam Bemanalizadeh, Seyyed Mohammad Kahani, Mahmoud Reza Ashrafi, Mohammad Rohani, Mehran Beiraghi Toosi, Morteza Heidari, Sareh Hosseinpour, Behnam Amini, Shaghayegh Zokaei, Zahra Rezaei, Hajar Aryan, Man Amanat, Hassan Vahidnezhad, Pouria Mohammadi, Masoud Garshasbi, and Ali Reza Tavasoli. Phenotype and genotype heterogeneity of pla2g6-associated neurodegeneration in a cohort of pediatric and adult patients. Orphanet Journal of Rare Diseases, Jul 2023. URL: https://doi.org/10.1186/s13023-023-02780-9, doi:10.1186/s13023-023-02780-9. This article has 19 citations and is from a peer-reviewed journal.

6. (NCT02587858 chunk 1): Susan J. Hayflick. NBIAready: Online Collection of Natural History Patient-reported Outcome Measures. Susan J. Hayflick. 2015. ClinicalTrials.gov Identifier: NCT02587858

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9. (uygun2025quantitativeironmeasurements pages 2-2): Özge Uygun, A. Özcan, Fuat Kaan Aras, Evrim Bozdemir, S. U. Ugur Iseri, Murat Gültekin, N. H. Akçakaya, Orkhan Mammadov, Gülay Kır, Dilek İnce Günal, Neşe Tuncer, Fatma Betül Özdilek, Banu Özen Barut, Ercan Köse, Hülya Apaydın, Asuman Ali, S. Çağırıcı, Pınar Topaloğlu, Alp Dinçer, and Zuhal Yapıcı. Quantitative iron measurements in the basal ganglia of nbia patients using qsm: insights from a tertiary center. Annals of clinical and translational neurology, Aug 2025. URL: https://doi.org/10.1002/acn3.70161, doi:10.1002/acn3.70161. This article has 1 citations and is from a peer-reviewed journal.

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12. (dehnavi2023phenotypeandgenotype pages 4-5): Ali Zare Dehnavi, Maryam Bemanalizadeh, Seyyed Mohammad Kahani, Mahmoud Reza Ashrafi, Mohammad Rohani, Mehran Beiraghi Toosi, Morteza Heidari, Sareh Hosseinpour, Behnam Amini, Shaghayegh Zokaei, Zahra Rezaei, Hajar Aryan, Man Amanat, Hassan Vahidnezhad, Pouria Mohammadi, Masoud Garshasbi, and Ali Reza Tavasoli. Phenotype and genotype heterogeneity of pla2g6-associated neurodegeneration in a cohort of pediatric and adult patients. Orphanet Journal of Rare Diseases, Jul 2023. URL: https://doi.org/10.1186/s13023-023-02780-9, doi:10.1186/s13023-023-02780-9. This article has 19 citations and is from a peer-reviewed journal.

13. (romano2022longtermneuroradiologicaland pages 1-2): Nicola Romano, Giammarco Baiardi, Valeria Maria Pinto, Sabrina Quintino, Barbara Gianesin, Riccardo Sasso, Andrea Diociasi, Francesca Mattioli, Roberta Marchese, Giovanni Abbruzzese, Antonio Castaldi, and Gian Luca Forni. Long-term neuroradiological and clinical evaluation of nbia patients treated with a deferiprone based iron-chelation therapy. Journal of Clinical Medicine, 11:4524, Aug 2022. URL: https://doi.org/10.3390/jcm11154524, doi:10.3390/jcm11154524. This article has 21 citations.

14. (spaull2021towardsprecisiontherapies pages 6-8): Robert V.V. Spaull, Audrey K.S. Soo, Penelope Hogarth, Susan J. Hayflick, and Manju A. Kurian. Towards precision therapies for inherited disorders of neurodegeneration with brain iron accumulation. Tremor and Other Hyperkinetic Movements, Nov 2021. URL: https://doi.org/10.5334/tohm.661, doi:10.5334/tohm.661. This article has 30 citations and is from a peer-reviewed journal.

15. (marupudi2024genetictargetsand pages 3-4): Neharika Marupudi and May P. Xiong. Genetic targets and applications of iron chelators for neurodegeneration with brain iron accumulation. ACS Bio & Med Chem Au, 4:119-130, Mar 2024. URL: https://doi.org/10.1021/acsbiomedchemau.3c00066, doi:10.1021/acsbiomedchemau.3c00066. This article has 22 citations.

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17. (spaull2021towardsprecisiontherapies pages 5-6): Robert V.V. Spaull, Audrey K.S. Soo, Penelope Hogarth, Susan J. Hayflick, and Manju A. Kurian. Towards precision therapies for inherited disorders of neurodegeneration with brain iron accumulation. Tremor and Other Hyperkinetic Movements, Nov 2021. URL: https://doi.org/10.5334/tohm.661, doi:10.5334/tohm.661. This article has 30 citations and is from a peer-reviewed journal.

18. (marupudi2024genetictargetsand pages 7-8): Neharika Marupudi and May P. Xiong. Genetic targets and applications of iron chelators for neurodegeneration with brain iron accumulation. ACS Bio & Med Chem Au, 4:119-130, Mar 2024. URL: https://doi.org/10.1021/acsbiomedchemau.3c00066, doi:10.1021/acsbiomedchemau.3c00066. This article has 22 citations.

19. (marupudi2024genetictargetsand pages 1-2): Neharika Marupudi and May P. Xiong. Genetic targets and applications of iron chelators for neurodegeneration with brain iron accumulation. ACS Bio & Med Chem Au, 4:119-130, Mar 2024. URL: https://doi.org/10.1021/acsbiomedchemau.3c00066, doi:10.1021/acsbiomedchemau.3c00066. This article has 22 citations.

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22. (romano2022longtermneuroradiologicaland pages 2-4): Nicola Romano, Giammarco Baiardi, Valeria Maria Pinto, Sabrina Quintino, Barbara Gianesin, Riccardo Sasso, Andrea Diociasi, Francesca Mattioli, Roberta Marchese, Giovanni Abbruzzese, Antonio Castaldi, and Gian Luca Forni. Long-term neuroradiological and clinical evaluation of nbia patients treated with a deferiprone based iron-chelation therapy. Journal of Clinical Medicine, 11:4524, Aug 2022. URL: https://doi.org/10.3390/jcm11154524, doi:10.3390/jcm11154524. This article has 21 citations.

23. (dehnavi2023phenotypeandgenotype pages 2-4): Ali Zare Dehnavi, Maryam Bemanalizadeh, Seyyed Mohammad Kahani, Mahmoud Reza Ashrafi, Mohammad Rohani, Mehran Beiraghi Toosi, Morteza Heidari, Sareh Hosseinpour, Behnam Amini, Shaghayegh Zokaei, Zahra Rezaei, Hajar Aryan, Man Amanat, Hassan Vahidnezhad, Pouria Mohammadi, Masoud Garshasbi, and Ali Reza Tavasoli. Phenotype and genotype heterogeneity of pla2g6-associated neurodegeneration in a cohort of pediatric and adult patients. Orphanet Journal of Rare Diseases, Jul 2023. URL: https://doi.org/10.1186/s13023-023-02780-9, doi:10.1186/s13023-023-02780-9. This article has 19 citations and is from a peer-reviewed journal.

24. (romano2022longtermneuroradiologicaland pages 4-7): Nicola Romano, Giammarco Baiardi, Valeria Maria Pinto, Sabrina Quintino, Barbara Gianesin, Riccardo Sasso, Andrea Diociasi, Francesca Mattioli, Roberta Marchese, Giovanni Abbruzzese, Antonio Castaldi, and Gian Luca Forni. Long-term neuroradiological and clinical evaluation of nbia patients treated with a deferiprone based iron-chelation therapy. Journal of Clinical Medicine, 11:4524, Aug 2022. URL: https://doi.org/10.3390/jcm11154524, doi:10.3390/jcm11154524. This article has 21 citations.

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35. (marchand2022conservativeironchelation pages 4-5): Felix Marchand, Caroline Moreau, Gregory Kuchcinski, Vincent Huin, Luc Defebvre, and David Devos. Conservative iron chelation for neuroferritinopathy. Movement Disorders, 37:1948-1952, Aug 2022. URL: https://doi.org/10.1002/mds.29145, doi:10.1002/mds.29145. This article has 19 citations and is from a highest quality peer-reviewed journal.