Neurodegeneration With Brain Iron Accumulation

Genetic MONDO:0018307 Pathograph 10 iron metabolism disease neurodegenerative disease movement disorder

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of rare inherited neurodegenerative disorders unified by progressive neurologic decline and abnormal iron deposition in the globus pallidus, substantia nigra, and other basal ganglia structures.

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3
Inheritance
4
Pathophys.
12
Phenotypes
10
Pathograph
4
Genes
3
Treatments
6
Subtypes
4
Trials
1
Deep Research
👪

Inheritance

3
Autosomal recessive inheritance HP:0000007
Many NBIA subtypes, including PKAN, PLAN, MPAN, and aceruloplasminemia, are autosomal recessive.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"NBIA disorders can show an autosomal recessive, autosomal dominant or X-linked inheritance pattern."
This supports autosomal recessive inheritance as one recognized NBIA inheritance pattern.
Autosomal dominant inheritance HP:0000006
Neuroferritinopathy is an autosomal dominant NBIA subtype.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"NBIA disorders can show an autosomal recessive, autosomal dominant or X-linked inheritance pattern."
This supports autosomal dominant inheritance as one recognized NBIA inheritance pattern.
X-linked dominant inheritance HP:0001423
BPAN is an X-linked dominant NBIA subtype.
X-linked dominant inheritance
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"NBIA disorders can show an autosomal recessive, autosomal dominant or X-linked inheritance pattern."
This supports X-linked inheritance as one recognized NBIA inheritance pattern.
◆

Subtypes

6
Pantothenate kinase-associated neurodegeneration MONDO:0009319
PANK2 link
NBIA caused by pathogenic PANK2 variants and impaired CoA biosynthesis.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"PKAN is caused by a mutation in the PANK2 gene on chromosome 20 which encodes the pantothenate kinase 2 enzyme."
This directly supports PANK2-associated PKAN as an NBIA subtype.
PLA2G6-associated neurodegeneration MONDO:0017998
PLA2G6 link
NBIA caused by pathogenic PLA2G6 variants and lipid-remodeling dysfunction.
Show evidence (1 reference)
PMID:37403138 SUPPORT Human Clinical
"Phospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups."
This directly supports PLA2G6-associated neurodegeneration as a genetic NBIA subtype.
Beta-propeller protein-associated neurodegeneration MONDO:0010476
WDR45 link
NBIA caused by WDR45 variants and impaired autophagy.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"BPAN is caused by de novo mutations in the WDR45 gene located on the X chromosome."
This directly supports WDR45-associated BPAN as an NBIA subtype.
Mitochondrial membrane protein-associated neurodegeneration MONDO:0013674
C19orf12 link
NBIA caused by C19orf12 variants and mitochondrial-membrane dysfunction.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"MPAN is a monogenic NBIA disorder caused by mutations in the C19orf12 gene on chromosome 19."
This directly supports C19orf12-associated MPAN as an NBIA subtype.
Aceruloplasminemia MONDO:0011426
CP link
NBIA caused by CP variants with systemic and brain iron accumulation.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Aceruloplasminemia due to mutations in the ceruloplasmin (CP) gene on chromosome 3 is characterized by, as mentioned above, iron accumulation not only in the brain, but also in other organs including liver and pancreas."
This supports aceruloplasminemia as a CP-associated NBIA subtype with systemic iron accumulation.
Neuroferritinopathy MONDO:0011638
FTL link
Dominant NBIA subtype with brain iron overload and progressive movement disorder.
Show evidence (1 reference)
PMID:35996824 SUPPORT Human Clinical
"Neuroferritinopathy is a rare inherited neurodegenerative disease with brain iron accumulation characterized by brain iron overload resulting in progressive movement disorders."
This supports neuroferritinopathy as an inherited NBIA-spectrum disorder.
⚙

Pathophysiology

4
Genetic pathway heterogeneity
NBIA is not a single linear biochemical disorder; causal genes converge from several pathways, including CoA biosynthesis, lipid metabolism, iron homeostasis, autophagy, mitochondrial function, and incompletely understood pathways.
PANK2 link PLA2G6 link C19orf12 link WDR45 link
coenzyme A biosynthetic process link ↕ DYSREGULATED lipid metabolic process link ↕ DYSREGULATED autophagy link ↕ DYSREGULATED
Downstream
Basal ganglia iron accumulation Diverse upstream genetic mechanisms converge on abnormal brain iron deposition.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Dysfunctions in several pathophysiological pathways have been identified to be involved in NBIA disorders, including (1) coenzyme A biosynthesis, (2) lipid metabolism, (3) iron homeostasis, (4) autophagy and (5) other pathways of yet unknown function"
This supports modeling NBIA as multiple genetic pathway classes rather than one mechanism.
Basal ganglia iron accumulation
The shared imaging and biochemical hallmark is excess iron in the globus pallidus, substantia nigra, and basal ganglia, detectable by MRI and quantitative susceptibility mapping.
neuron link glial cell link
intracellular iron ion homeostasis link ↕ DYSREGULATED
globus pallidus link substantia nigra link
Downstream
Oxidative stress and neuronal injury Iron dyshomeostasis promotes oxidative stress and other neuronal injury pathways.
Show evidence (2 references)
PMID:33935938 SUPPORT Human Clinical
"Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra."
This directly supports basal ganglia iron deposition as the defining NBIA hallmark.
PMID:40817817 SUPPORT Human Clinical
"QSM is a sensitive and noninvasive tool for detecting and quantifying iron accumulation in NBIA."
This supports quantitative in vivo detection of NBIA brain iron accumulation.
Oxidative stress and neuronal injury
Brain iron overload is associated with reactive oxygen species, protein aggregation, autophagy-lysosomal dysfunction, neuroinflammation, and ferroptosis-like neuronal injury.
neuron link
response to oxidative stress link ↑ INCREASED neuron apoptotic process link ↑ INCREASED
Downstream
Progressive motor and cognitive decline Neuronal injury in basal ganglia and related networks drives progressive neurologic decline.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Iron dyshomeostasis with iron overload is associated with increased production of radical oxygen species and oxidative stress, protein misfolding and aggregation, dysfunction of the autophagy-lysosomal pathway, neuroinflammation and ferroptosis (iron-dependent apoptosis)"
This supports oxidative and proteostatic injury downstream of iron dyshomeostasis.
Progressive motor and cognitive decline
Progressive basal ganglia and neurodegenerative injury manifests as worsening movement disorder, pyramidal features, speech disorders, cognitive decline, and ocular abnormalities.
neuron link
Show evidence (1 reference)
PMID:34909266 SUPPORT Human Clinical
"NBIA disorders comprise a group of rare but devastating inherited neurological diseases with unifying features of progressive cognitive and motor decline, and increased iron deposition in the basal ganglia."
This directly links inherited NBIA disorders with progressive cognitive and motor decline.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neurodegeneration With Brain Iron Accumulation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Endocrine 1
Diabetes mellitus Diabetes mellitus (HP:0000819)
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"A valuable characteristic of this disorder is that systemic manifestations such as anemia and diabetes mellitus usually occur a decade prior to the onset of neurological symptoms"
This review supports diabetes mellitus as a systemic manifestation of aceruloplasminemia that may precede neurologic onset.
Eye 1
Visual impairment Visual impairment (HP:0000505)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 PARTIAL Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities."
The review supports ocular abnormalities broadly; visual impairment is a conservative HPO mapping for clinically relevant ocular involvement.
Musculoskeletal 1
Spasticity Spasticity (HP:0001257)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities."
This directly lists spasticity among pyramidal NBIA manifestations.
Nervous System 9
Dystonia Dystonia (HP:0001332)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea)"
This directly lists dystonia in the NBIA movement-disorder spectrum.
Parkinsonism Parkinsonism (HP:0001300)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea)"
This directly lists parkinsonism in the NBIA movement-disorder spectrum.
Chorea Chorea (HP:0002072)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea)"
This directly lists chorea in the NBIA movement-disorder spectrum.
Dysarthria Dysarthria (HP:0001260)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 PARTIAL Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities."
The review cites speech disorders broadly; dysarthria is the HPO mapping used for neurologic speech impairment.
Cognitive impairment Cognitive impairment (HP:0100543)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities."
This directly lists cognitive decline in the NBIA clinical spectrum.
Intellectual disability Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"BPAN is characterized by childhood-onset seizures and developmental delay with loss of expressive language skills, stereotypies, behavioral abnormalities and intellectual disabilities."
This review directly identifies intellectual disability as part of the BPAN clinical presentation.
Developmental regression Developmental regression (HP:0002376)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37403138 SUPPORT Human Clinical
"Among 18 patients with INAD, gross motor regression was the most common presenting symptom."
Gross motor regression supports developmental regression as an infantile PLAN/INAD manifestation.
Ataxia Ataxia (HP:0001251)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37403138 SUPPORT Human Clinical
"Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features."
The abstract's ataxic gait finding supports ataxia in adult PLAN.
Cerebellar atrophy Cerebellar atrophy (HP:0001272)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37403138 SUPPORT Human Clinical
"Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%."
This cohort directly supports cerebellar atrophy in PLA2G6-associated neurodegeneration.
🧬

Genetic Associations

4
PANK2 (Causal variants)
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"PKAN is caused by a mutation in the PANK2 gene on chromosome 20 which encodes the pantothenate kinase 2 enzyme."
This directly identifies PANK2 as causal for PKAN.
PLA2G6 (Causal variants)
Show evidence (1 reference)
PMID:37403138 SUPPORT Human Clinical
"Phospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups."
This directly identifies PLA2G6 as causal for PLAN.
C19orf12 (Causal variants)
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"MPAN is a monogenic NBIA disorder caused by mutations in the C19orf12 gene on chromosome 19."
This directly identifies C19orf12 as causal for MPAN.
WDR45 (Causal variants)
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"BPAN is caused by de novo mutations in the WDR45 gene located on the X chromosome."
This directly identifies WDR45 as causal for BPAN.
💊

Treatments

3
Symptomatic and supportive care
Action: supportive care MAXO:0000950
Current routine management remains largely symptomatic, addressing movement disorder, spasticity, speech/swallowing needs, and functional support.
Show evidence (1 reference)
PMID:26739693 SUPPORT Human Clinical
"Treatment for NBIA disorders remains symptomatic but a placebo-controlled double-blind study is underway."
This review supports symptomatic management as the established care baseline.
Deferiprone iron chelation
Action: Pharmacotherapy NCIT:C15986
Agent: deferiprone ↗
Deferiprone is an investigational or off-label disease-modifying strategy aimed at lowering brain iron; evidence supports radiologic improvement and possible clinical stabilization in subsets rather than broad cure.
Mechanism Target:
MODULATES Basal ganglia iron accumulation — Deferiprone is intended to chelate brain iron.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron."
This supports the target mechanism for iron chelation therapy.
Show evidence (2 references)
PMID:33935938 PARTIAL Human Clinical
"demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression."
This supports deferiprone as potentially disease-modifying but not definitively curative.
PMID:35956138 PARTIAL Human Clinical
"Our results show the progressive decrease in the cerebral accumulation of iron evaluated by MRI and a substantial stability of the overall clinical neurological picture without a significant correlation between clinical and radiological findings."
This long-term cohort supports MRI iron reduction and clinical stability, with the caveat that radiologic and clinical outcomes did not correlate significantly.
CoA-Z substrate replacement
Action: Pharmacotherapy NCIT:C15986
CoA-Z is an investigational PKAN substrate-bypass strategy intended to address PANK2-related CoA biosynthesis deficiency.
Mechanism Target:
BYPASSES Genetic pathway heterogeneity — CoA-Z targets the PKAN CoA-biosynthesis branch of NBIA pathophysiology.
Show evidence (1 reference)
PMID:33935938 SUPPORT Human Clinical
"To test the effect in humans, a compound called CoA-Z (not to be mistaken with the enzyme COASY) was developed."
This supports CoA-Z as a human investigational strategy for the PKAN branch of NBIA.
Show evidence (1 reference)
PMID:33935938 PARTIAL Human Clinical
"To test the effect in humans, a compound called CoA-Z (not to be mistaken with the enzyme COASY) was developed."
This supports CoA-Z as an investigational human PKAN treatment strategy.
🔬

Clinical Trials

4
NCT01741532 PHASE_III COMPLETED
Randomized double-blind placebo-controlled deferiprone trial in PKAN.
Target Phenotypes: Dystonia ↗
Show evidence (1 reference)
clinicaltrials:NCT01741532 SUPPORT Human Clinical
"A multi-center, placebo controlled, double-blind trial comparing the efficacy and safety of 18 months of treatment with deferiprone versus placebo in patients with PKAN."
This trial record directly describes the randomized deferiprone PKAN trial.
NCT02174848 PHASE_III COMPLETED
Long-term deferiprone extension for PKAN patients completing the earlier trial.
Target Phenotypes: Dystonia ↗
Show evidence (1 reference)
clinicaltrials:NCT02174848 SUPPORT Human Clinical
"Patients with PKAN will be treated with the iron chelator deferiprone for 18 months."
This trial record directly supports the deferiprone long-term extension study.
NCT04182763 PHASE_II COMPLETED
CoA-Z vitamin-metabolite trial for PKAN.
Target Phenotypes: Dystonia ↗
Show evidence (1 reference)
clinicaltrials:NCT04182763 SUPPORT Human Clinical
"The purpose of this study is to learn more about how people with the condition pantothenate kinase-associated neurodegeneration (PKAN) respond to a specialized study product."
This trial record supports CoA-Z as an investigational PKAN study product.
NCT02587858 UNKNOWN
NBIAready natural-history collection for patient-reported outcome measures.
Show evidence (1 reference)
clinicaltrials:NCT02587858 SUPPORT Human Clinical
"The purpose of this study is to learn more about Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders."
This trial record supports the NBIAready natural-history resource for NBIA outcome tracking.
{ }

Source YAML

click to show 
name: Neurodegeneration With Brain Iron Accumulation
creation_date: "2026-05-10T18:42:10Z"
updated_date: "2026-05-10T19:42:23Z"
category: Genetic
description: >-
  Neurodegeneration with brain iron accumulation (NBIA) is a genetically
  heterogeneous group of rare inherited neurodegenerative disorders unified by
  progressive neurologic decline and abnormal iron deposition in the globus
  pallidus, substantia nigra, and other basal ganglia structures.
disease_term:
  preferred_term: neurodegeneration with brain iron accumulation
  term:
    id: MONDO:0018307
    label: neurodegeneration with brain iron accumulation
synonyms:
- NBIA
- Hallervorden-Spatz syndrome
parents:
- iron metabolism disease
- neurodegenerative disease
- movement disorder
prevalence:
- population: Global
  notes: Combined NBIA prevalence has been estimated at 1-9 per 1,000,000.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are considered ultrarare with a combined estimated prevalence of
      1–9 per 1,000,000
    explanation: >-
      This review provides the aggregate rare-disease prevalence estimate for
      NBIA disorders.
progression:
- phase: Progressive neurodegenerative course
  notes: >-
    NBIA disorders typically progress with early disability, worsening movement
    disorder, and cognitive or psychiatric involvement.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease course is progressive, with early disability and decreasing
      quality of life.
    explanation: >-
      This directly characterizes the overall NBIA disease course.
- phase: PLAN/INAD functional decline
  subtype: PLAN
  notes: >-
    PLA2G6-associated neurodegeneration has quantified infantile progression
    with rapid INAD-RS decline.
  evidence:
  - reference: PMID:37403138
    reference_title: Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Considering the INAD-RS total score, the mean rate of progression was
      0.58 points per month of symptoms
    explanation: >-
      This cohort provides quantitative progression data for the PLAN/INAD
      subtype.
has_subtypes:
- name: PKAN
  display_name: Pantothenate kinase-associated neurodegeneration
  subtype_term:
    preferred_term: pantothenate kinase-associated neurodegeneration
    term:
      id: MONDO:0009319
      label: pantothenate kinase-associated neurodegeneration
  description: NBIA caused by pathogenic PANK2 variants and impaired CoA biosynthesis.
  genes:
  - preferred_term: PANK2
    term:
      id: hgnc:15894
      label: PANK2
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PKAN is caused by a mutation in the PANK2 gene on chromosome 20 which
      encodes the pantothenate kinase 2 enzyme.
    explanation: >-
      This directly supports PANK2-associated PKAN as an NBIA subtype.
- name: PLAN
  display_name: PLA2G6-associated neurodegeneration
  subtype_term:
    preferred_term: PLA2G6-associated neurodegeneration
    term:
      id: MONDO:0017998
      label: PLA2G6-associated neurodegeneration
  description: NBIA caused by pathogenic PLA2G6 variants and lipid-remodeling dysfunction.
  genes:
  - preferred_term: PLA2G6
    term:
      id: hgnc:9039
      label: PLA2G6
  evidence:
  - reference: PMID:37403138
    reference_title: Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phospholipase-associated neurodegeneration (PLAN) caused by mutations in
      the PLA2G6 gene is a rare neurodegenerative disorder that presents with
      four sub-groups.
    explanation: >-
      This directly supports PLA2G6-associated neurodegeneration as a genetic
      NBIA subtype.
- name: BPAN
  display_name: Beta-propeller protein-associated neurodegeneration
  subtype_term:
    preferred_term: beta-propeller protein-associated neurodegeneration
    term:
      id: MONDO:0010476
      label: neurodegeneration with brain iron accumulation 5
  description: NBIA caused by WDR45 variants and impaired autophagy.
  genes:
  - preferred_term: WDR45
    term:
      id: hgnc:28912
      label: WDR45
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BPAN is caused by de novo mutations in the WDR45 gene located on the X
      chromosome.
    explanation: >-
      This directly supports WDR45-associated BPAN as an NBIA subtype.
- name: MPAN
  display_name: Mitochondrial membrane protein-associated neurodegeneration
  subtype_term:
    preferred_term: mitochondrial membrane protein-associated neurodegeneration
    term:
      id: MONDO:0013674
      label: neurodegeneration with brain iron accumulation 4
  description: NBIA caused by C19orf12 variants and mitochondrial-membrane dysfunction.
  genes:
  - preferred_term: C19orf12
    term:
      id: hgnc:25443
      label: C19orf12
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPAN is a monogenic NBIA disorder caused by mutations in the C19orf12
      gene on chromosome 19.
    explanation: >-
      This directly supports C19orf12-associated MPAN as an NBIA subtype.
- name: Aceruloplasminemia
  subtype_term:
    preferred_term: aceruloplasminemia
    term:
      id: MONDO:0011426
      label: aceruloplasminemia
  description: NBIA caused by CP variants with systemic and brain iron accumulation.
  genes:
  - preferred_term: CP
    term:
      id: hgnc:2295
      label: CP
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aceruloplasminemia due to mutations in the ceruloplasmin (CP) gene on
      chromosome 3 is characterized by, as mentioned above, iron accumulation
      not only in the brain, but also in other organs including liver and
      pancreas.
    explanation: >-
      This supports aceruloplasminemia as a CP-associated NBIA subtype with
      systemic iron accumulation.
- name: Neuroferritinopathy
  subtype_term:
    preferred_term: neuroferritinopathy
    term:
      id: MONDO:0011638
      label: neuroferritinopathy
  description: Dominant NBIA subtype with brain iron overload and progressive movement disorder.
  genes:
  - preferred_term: FTL
    term:
      id: hgnc:3999
      label: FTL
  evidence:
  - reference: PMID:35996824
    reference_title: Conservative Iron Chelation for Neuroferritinopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuroferritinopathy is a rare inherited neurodegenerative disease with
      brain iron accumulation characterized by brain iron overload resulting in
      progressive movement disorders.
    explanation: >-
      This supports neuroferritinopathy as an inherited NBIA-spectrum disorder.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Many NBIA subtypes, including PKAN, PLAN, MPAN, and aceruloplasminemia, are
    autosomal recessive.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NBIA disorders can show an autosomal recessive, autosomal dominant or
      X-linked inheritance pattern.
    explanation: >-
      This supports autosomal recessive inheritance as one recognized NBIA
      inheritance pattern.
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Neuroferritinopathy is an autosomal dominant NBIA subtype.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NBIA disorders can show an autosomal recessive, autosomal dominant or
      X-linked inheritance pattern.
    explanation: >-
      This supports autosomal dominant inheritance as one recognized NBIA
      inheritance pattern.
- name: X-linked dominant inheritance
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
  description: BPAN is an X-linked dominant NBIA subtype.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NBIA disorders can show an autosomal recessive, autosomal dominant or
      X-linked inheritance pattern.
    explanation: >-
      This supports X-linked inheritance as one recognized NBIA inheritance
      pattern.
genetic:
- name: PANK2
  association: Causal variants
  presence: Positive
  gene_term:
    preferred_term: PANK2
    term:
      id: hgnc:15894
      label: PANK2
  subtype: PKAN
  notes: Biallelic PANK2 variants disrupt mitochondrial pantothenate kinase activity.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PKAN is caused by a mutation in the PANK2 gene on chromosome 20 which
      encodes the pantothenate kinase 2 enzyme.
    explanation: This directly identifies PANK2 as causal for PKAN.
- name: PLA2G6
  association: Causal variants
  presence: Positive
  gene_term:
    preferred_term: PLA2G6
    term:
      id: hgnc:9039
      label: PLA2G6
  subtype: PLAN
  notes: PLA2G6 variants cause PLAN/INAD and dystonia-parkinsonism phenotypes.
  evidence:
  - reference: PMID:37403138
    reference_title: Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phospholipase-associated neurodegeneration (PLAN) caused by mutations in
      the PLA2G6 gene is a rare neurodegenerative disorder that presents with
      four sub-groups.
    explanation: This directly identifies PLA2G6 as causal for PLAN.
- name: C19orf12
  association: Causal variants
  presence: Positive
  gene_term:
    preferred_term: C19orf12
    term:
      id: hgnc:25443
      label: C19orf12
  subtype: MPAN
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPAN is a monogenic NBIA disorder caused by mutations in the C19orf12
      gene on chromosome 19.
    explanation: This directly identifies C19orf12 as causal for MPAN.
- name: WDR45
  association: Causal variants
  presence: Positive
  gene_term:
    preferred_term: WDR45
    term:
      id: hgnc:28912
      label: WDR45
  subtype: BPAN
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BPAN is caused by de novo mutations in the WDR45 gene located on the X
      chromosome.
    explanation: This directly identifies WDR45 as causal for BPAN.
pathophysiology:
- name: Genetic pathway heterogeneity
  description: >-
    NBIA is not a single linear biochemical disorder; causal genes converge from
    several pathways, including CoA biosynthesis, lipid metabolism, iron
    homeostasis, autophagy, mitochondrial function, and incompletely understood
    pathways.
  genes:
  - preferred_term: PANK2
    term:
      id: hgnc:15894
      label: PANK2
  - preferred_term: PLA2G6
    term:
      id: hgnc:9039
      label: PLA2G6
  - preferred_term: C19orf12
    term:
      id: hgnc:25443
      label: C19orf12
  - preferred_term: WDR45
    term:
      id: hgnc:28912
      label: WDR45
  biological_processes:
  - preferred_term: coenzyme A biosynthetic process
    term:
      id: GO:0015937
      label: coenzyme A biosynthetic process
    modifier: DYSREGULATED
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: DYSREGULATED
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysfunctions in several pathophysiological pathways have been identified
      to be involved in NBIA disorders, including (1) coenzyme A biosynthesis,
      (2) lipid metabolism, (3) iron homeostasis, (4) autophagy and (5) other
      pathways of yet unknown function
    explanation: >-
      This supports modeling NBIA as multiple genetic pathway classes rather
      than one mechanism.
  downstream:
  - target: Basal ganglia iron accumulation
    description: Diverse upstream genetic mechanisms converge on abnormal brain iron deposition.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33935938
      reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dysfunctions in several pathophysiological pathways have been identified
        to be involved in NBIA disorders, including (1) coenzyme A biosynthesis,
        (2) lipid metabolism, (3) iron homeostasis, (4) autophagy and (5) other
        pathways of yet unknown function
      explanation: >-
        This supports diverse genetic pathway classes as upstream contributors
        to NBIA mechanisms.
- name: Basal ganglia iron accumulation
  description: >-
    The shared imaging and biochemical hallmark is excess iron in the globus
    pallidus, substantia nigra, and basal ganglia, detectable by MRI and
    quantitative susceptibility mapping.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  locations:
  - preferred_term: globus pallidus
    term:
      id: UBERON:0001875
      label: globus pallidus
  - preferred_term: substantia nigra
    term:
      id: UBERON:0002038
      label: substantia nigra
  biological_processes:
  - preferred_term: intracellular iron ion homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous
      group of progressive neurodegenerative diseases characterized by iron
      deposition in the globus pallidus and the substantia nigra.
    explanation: >-
      This directly supports basal ganglia iron deposition as the defining NBIA
      hallmark.
  - reference: PMID:40817817
    reference_title: "Quantitative Iron Measurements in the Basal Ganglia of NBIA Patients Using QSM: Insights From a Tertiary Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      QSM is a sensitive and noninvasive tool for detecting and quantifying iron
      accumulation in NBIA.
    explanation: >-
      This supports quantitative in vivo detection of NBIA brain iron
      accumulation.
  downstream:
  - target: Oxidative stress and neuronal injury
    description: Iron dyshomeostasis promotes oxidative stress and other neuronal injury pathways.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33935938
      reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Iron dyshomeostasis with iron overload is associated with increased
        production of radical oxygen species and oxidative stress, protein
        misfolding and aggregation, dysfunction of the autophagy-lysosomal
        pathway, neuroinflammation and ferroptosis (iron-dependent apoptosis)
      explanation: >-
        This directly supports oxidative and related injury pathways downstream
        of iron dyshomeostasis.
- name: Oxidative stress and neuronal injury
  description: >-
    Brain iron overload is associated with reactive oxygen species, protein
    aggregation, autophagy-lysosomal dysfunction, neuroinflammation, and
    ferroptosis-like neuronal injury.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron dyshomeostasis with iron overload is associated with increased
      production of radical oxygen species and oxidative stress, protein
      misfolding and aggregation, dysfunction of the autophagy-lysosomal
      pathway, neuroinflammation and ferroptosis (iron-dependent apoptosis)
    explanation: >-
      This supports oxidative and proteostatic injury downstream of iron
      dyshomeostasis.
  downstream:
  - target: Progressive motor and cognitive decline
    description: Neuronal injury in basal ganglia and related networks drives progressive neurologic decline.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34909266
      reference_title: Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        NBIA disorders comprise a group of rare but devastating inherited
        neurological diseases with unifying features of progressive cognitive
        and motor decline, and increased iron deposition in the basal ganglia.
      explanation: >-
        This directly links basal-ganglia iron deposition with progressive
        cognitive and motor decline in NBIA.
- name: Progressive motor and cognitive decline
  description: >-
    Progressive basal ganglia and neurodegenerative injury manifests as
    worsening movement disorder, pyramidal features, speech disorders, cognitive
    decline, and ocular abnormalities.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:34909266
    reference_title: Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NBIA disorders comprise a group of rare but devastating inherited
      neurological diseases with unifying features of progressive cognitive and
      motor decline, and increased iron deposition in the basal ganglia.
    explanation: >-
      This directly links inherited NBIA disorders with progressive cognitive
      and motor decline.
phenotypes:
- name: Dystonia
  category: Neurologic
  description: Dystonia is a core extrapyramidal movement disorder manifestation of NBIA.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea)
    explanation: >-
      This directly lists dystonia in the NBIA movement-disorder spectrum.
- name: Parkinsonism
  category: Neurologic
  description: Parkinsonism is part of the extrapyramidal movement-disorder spectrum.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea)
    explanation: >-
      This directly lists parkinsonism in the NBIA movement-disorder spectrum.
- name: Chorea
  category: Neurologic
  description: Chorea can occur as another extrapyramidal movement abnormality.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea)
    explanation: >-
      This directly lists chorea in the NBIA movement-disorder spectrum.
- name: Spasticity
  category: Neurologic
  description: Pyramidal involvement can manifest as spasticity.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea), pyramidal involvement (e.g.,
      spasticity), speech disorders, cognitive decline, psychomotor retardation,
      and ocular abnormalities.
    explanation: >-
      This directly lists spasticity among pyramidal NBIA manifestations.
- name: Dysarthria
  category: Neurologic
  description: Speech impairment is part of the neurologic presentation.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea), pyramidal involvement (e.g.,
      spasticity), speech disorders, cognitive decline, psychomotor retardation,
      and ocular abnormalities.
    explanation: >-
      The review cites speech disorders broadly; dysarthria is the HPO mapping
      used for neurologic speech impairment.
- name: Cognitive impairment
  category: Neuropsychiatric
  description: Cognitive decline is common across NBIA disorders.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea), pyramidal involvement (e.g.,
      spasticity), speech disorders, cognitive decline, psychomotor retardation,
      and ocular abnormalities.
    explanation: >-
      This directly lists cognitive decline in the NBIA clinical spectrum.
- name: Intellectual disability
  category: Neurodevelopmental
  subtype: BPAN
  description: >-
    BPAN commonly includes intellectual disability and developmental delay
    before later adult neurodegeneration.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BPAN is characterized by childhood-onset seizures and developmental delay
      with loss of expressive language skills, stereotypies, behavioral
      abnormalities and intellectual disabilities.
    explanation: >-
      This review directly identifies intellectual disability as part of the
      BPAN clinical presentation.
- name: Developmental regression
  category: Neurodevelopmental
  subtype: PLAN
  description: Infantile PLAN/INAD frequently presents with loss of motor milestones.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37403138
    reference_title: Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 18 patients with INAD, gross motor regression was the most common
      presenting symptom.
    explanation: >-
      Gross motor regression supports developmental regression as an infantile
      PLAN/INAD manifestation.
- name: Ataxia
  category: Neurologic
  subtype: PLAN
  description: Ataxia is reported in adult PLAN and related NBIA presentations.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37403138
    reference_title: Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and
      cognitive impairment were the most frequent clinical features.
    explanation: >-
      The abstract's ataxic gait finding supports ataxia in adult PLAN.
- name: Cerebellar atrophy
  category: Neuroimaging
  subtype: PLAN
  description: Cerebellar atrophy is a prominent imaging feature in PLAN/INAD.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37403138
    reference_title: Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Various brain imaging abnormalities were also observed in 26 imaging
      series of these patients with cerebellar atrophy being the most common
      finding in more than 50%.
    explanation: >-
      This cohort directly supports cerebellar atrophy in PLA2G6-associated
      neurodegeneration.
- name: Visual impairment
  category: Ophthalmologic
  description: Ocular abnormalities and visual dysfunction occur in the NBIA spectrum.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration with Brain Iron Accumulation disorders present with a
      wide spectrum of clinical symptoms such as movement disorder signs
      (dystonia, parkinsonism, chorea), pyramidal involvement (e.g.,
      spasticity), speech disorders, cognitive decline, psychomotor retardation,
      and ocular abnormalities.
    explanation: >-
      The review supports ocular abnormalities broadly; visual impairment is a
      conservative HPO mapping for clinically relevant ocular involvement.
- name: Diabetes mellitus
  category: Metabolic
  subtype: Aceruloplasminemia
  description: >-
    Aceruloplasminemia can include diabetes mellitus as a systemic
    pre-neurologic manifestation of iron accumulation.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A valuable characteristic of this disorder is that systemic manifestations
      such as anemia and diabetes mellitus usually occur a decade prior to the
      onset of neurological symptoms
    explanation: >-
      This review supports diabetes mellitus as a systemic manifestation of
      aceruloplasminemia that may precede neurologic onset.
diagnosis:
- name: Brain MRI for iron deposition
  description: >-
    Brain MRI, especially iron-sensitive approaches, identifies basal-ganglia
    iron accumulation and characteristic subtype patterns.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  results: Globus pallidus and substantia nigra iron deposition support NBIA diagnosis.
  evidence:
  - reference: PMID:35956138
    reference_title: Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging (MRI) allows diagnosis of this condition, and
      genetic molecular testing can confirm the diagnosis to better understand
      the intracellular damage mechanism involved.
    explanation: >-
      This directly supports MRI and genetic testing in NBIA diagnosis.
- name: Molecular genetic testing
  description: >-
    Molecular genetic testing confirms subtype diagnosis and identifies the
    affected NBIA gene.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Pathogenic variants in an NBIA gene confirm the molecular subtype.
  evidence:
  - reference: PMID:35956138
    reference_title: Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging (MRI) allows diagnosis of this condition, and
      genetic molecular testing can confirm the diagnosis to better understand
      the intracellular damage mechanism involved.
    explanation: >-
      This directly supports genetic molecular testing as confirmatory for
      NBIA.
treatments:
- name: Symptomatic and supportive care
  description: >-
    Current routine management remains largely symptomatic, addressing movement
    disorder, spasticity, speech/swallowing needs, and functional support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:26739693
    reference_title: Neurodegeneration with Brain Iron Accumulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment for NBIA disorders remains symptomatic but a
      placebo-controlled double-blind study is underway.
    explanation: >-
      This review supports symptomatic management as the established care
      baseline.
- name: Deferiprone iron chelation
  description: >-
    Deferiprone is an investigational or off-label disease-modifying strategy
    aimed at lowering brain iron; evidence supports radiologic improvement and
    possible clinical stabilization in subsets rather than broad cure.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deferiprone
      term:
        id: CHEBI:68554
        label: deferiprone
  target_mechanisms:
  - target: Basal ganglia iron accumulation
    treatment_effect: MODULATES
    description: Deferiprone is intended to chelate brain iron.
    evidence:
    - reference: PMID:33935938
      reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A general mechanistic approach for treatment of NBIA disorders is with
        iron chelators which bind and remove iron.
      explanation: >-
        This supports the target mechanism for iron chelation therapy.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      demonstrating radiological improvement with reduction of iron load in the
      basal ganglia and a trend to slowing of disease progression.
    explanation: >-
      This supports deferiprone as potentially disease-modifying but not
      definitively curative.
  - reference: PMID:35956138
    reference_title: Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results show the progressive decrease in the cerebral accumulation of
      iron evaluated by MRI and a substantial stability of the overall clinical
      neurological picture without a significant correlation between clinical
      and radiological findings.
    explanation: >-
      This long-term cohort supports MRI iron reduction and clinical stability,
      with the caveat that radiologic and clinical outcomes did not correlate
      significantly.
- name: CoA-Z substrate replacement
  description: >-
    CoA-Z is an investigational PKAN substrate-bypass strategy intended to
    address PANK2-related CoA biosynthesis deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Genetic pathway heterogeneity
    treatment_effect: BYPASSES
    description: CoA-Z targets the PKAN CoA-biosynthesis branch of NBIA pathophysiology.
    evidence:
    - reference: PMID:33935938
      reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        To test the effect in humans, a compound called CoA-Z (not to be mistaken
        with the enzyme COASY) was developed.
      explanation: >-
        This supports CoA-Z as a human investigational strategy for the PKAN
        branch of NBIA.
  evidence:
  - reference: PMID:33935938
    reference_title: Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To test the effect in humans, a compound called CoA-Z (not to be mistaken
      with the enzyme COASY) was developed.
    explanation: >-
      This supports CoA-Z as an investigational human PKAN treatment strategy.
clinical_trials:
- name: NCT01741532
  phase: PHASE_III
  status: COMPLETED
  description: Randomized double-blind placebo-controlled deferiprone trial in PKAN.
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: clinicaltrials:NCT01741532
    reference_title: "A Randomized, Double-blind, Placebo-controlled Trial of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A multi-center, placebo controlled, double-blind trial comparing the
      efficacy and safety of 18 months of treatment with deferiprone versus
      placebo in patients with PKAN.
    explanation: >-
      This trial record directly describes the randomized deferiprone PKAN
      trial.
- name: NCT02174848
  phase: PHASE_III
  status: COMPLETED
  description: Long-term deferiprone extension for PKAN patients completing the earlier trial.
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: clinicaltrials:NCT02174848
    reference_title: Long-term Safety and Efficacy Study of Deferiprone in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with PKAN will be treated with the iron chelator deferiprone for
      18 months.
    explanation: >-
      This trial record directly supports the deferiprone long-term extension
      study.
- name: NCT04182763
  phase: PHASE_II
  status: COMPLETED
  description: CoA-Z vitamin-metabolite trial for PKAN.
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: clinicaltrials:NCT04182763
    reference_title: A Phase 2 Study of a Vitamin Metabolite for PKAN
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to learn more about how people with the
      condition pantothenate kinase-associated neurodegeneration (PKAN) respond
      to a specialized study product.
    explanation: >-
      This trial record supports CoA-Z as an investigational PKAN study product.
- name: NCT02587858
  status: UNKNOWN
  description: NBIAready natural-history collection for patient-reported outcome measures.
  evidence:
  - reference: clinicaltrials:NCT02587858
    reference_title: "NBIAready: Online Collection of Natural History Patient-reported Outcome Measures"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to learn more about Neurodegeneration with
      Brain Iron Accumulation (NBIA) Disorders.
    explanation: >-
      This trial record supports the NBIAready natural-history resource for
      NBIA outcome tracking.
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 42 citations 2026-05-10T14:55:06.244448

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

Subtype (common name) Gene(s) Inheritance Core clinical features Characteristic MRI features Pathway/mechanism themes Notable disease-modifying/experimental therapies or trials
PKAN (pantothenate kinase-associated neurodegeneration) PANK2 Autosomal recessive Progressive dystonia, rigidity/bradykinesia, spasticity, dysarthria, postural instability, feeding/communication difficulty; classic childhood-onset and atypical later-onset forms (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 1-2, marupudi2024genetictargetsand pages 3-4) Iron accumulation in globus pallidus; classic “eye-of-the-tiger” sign; MRI R2* used to quantify pallidal iron (spaull2021towardsprecisiontherapies pages 6-8, romano2022longtermneuroradiologicaland pages 1-2, NCT01741532 chunk 2) Defective CoA biosynthesis, mitochondrial dysfunction, impaired dopamine metabolism, lipid peroxidation/possible ferroptosis, downstream iron dyshomeostasis (spaull2021towardsprecisiontherapies pages 5-6, marupudi2024genetictargetsand pages 3-4) Deferiprone phase 3 TIRCON/NCT01741532 and extension NCT02174848; radiologic iron reduction with trend to slower progression. Fosmetpantotenate phase 3 NCT03041116 terminated/negative. CoA-Z completed NCT04182763. 4′-phosphopantetheine and PZ-2891 discussed as precision approaches (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4, marupudi2024genetictargetsand pages 5-6, NCT02174848 chunk 1, NCT04182763 chunk 1)
PLAN / INAD (PLA2G6-associated neurodegeneration; infantile neuroaxonal dystrophy spectrum) PLA2G6 Autosomal recessive Infantile psychomotor/gross motor regression, bulbar dysfunction, visual disturbance, cognitive impairment; later-onset dystonia-parkinsonism with hypokinesia, tremor, ataxic gait, cognitive/psychiatric features (iankova2021emergingdiseasemodifyingtherapies pages 1-2, dehnavi2023phenotypeandgenotype pages 1-2, dehnavi2023phenotypeandgenotype pages 4-5) Early cerebellar atrophy common; may show iron deposition in globus pallidus/substantia nigra; white-matter/callosal abnormalities and optic atrophy reported (spaull2021towardsprecisiontherapies pages 6-8, dehnavi2023phenotypeandgenotype pages 2-4, dehnavi2023phenotypeandgenotype pages 4-5) Lipid metabolism/phospholipase dysfunction, axonal spheroids, mitochondrial dysfunction, lipid peroxidation, α-synuclein/tau-related pathology (spaull2021towardsprecisiontherapies pages 6-8, marupudi2024genetictargetsand pages 3-4) No proven disease-modifying therapy; D-PUFA proposed to reduce mitochondrial lipid peroxidation; desipramine repurposing discussed for infantile neuroaxonal dystrophy; gene therapy remains preclinical (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 2-4)
MPAN (mitochondrial membrane protein-associated neurodegeneration) C19orf12 Usually autosomal recessive; rare monoallelic cases reported Dystonia-parkinsonism, optic atrophy, axonal neuropathy, cognitive/psychiatric features; Lewy body pathology described (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 6-8, marupudi2024genetictargetsand pages 3-4) T2 hypointensity/iron-related signal in globus pallidus and substantia nigra; basal ganglia iron accumulation (spaull2021towardsprecisiontherapies pages 6-8, marupudi2024genetictargetsand pages 3-4) Mitochondrial membrane dysfunction, lipid metabolism abnormalities, iron dyshomeostasis (iankova2021emergingdiseasemodifyingtherapies pages 1-2, marupudi2024genetictargetsand pages 3-4) No established disease-modifying therapy; deferiprone reported in case literature with variable response (iankova2021emergingdiseasemodifyingtherapies pages 1-2, marupudi2024genetictargetsand pages 5-6)
BPAN (beta-propeller protein-associated neurodegeneration) WDR45 X-linked dominant Developmental delay/intellectual disability followed later by parkinsonism-dystonia; cognitive decline and neuropsychiatric features (iankova2021emergingdiseasemodifyingtherapies pages 1-2, spaull2021towardsprecisiontherapies pages 6-8) T2 hypointensity in globus pallidus/substantia nigra with characteristic T1 hyperintense halo in the substantia nigra / midbrain halo pattern (spaull2021towardsprecisiontherapies pages 6-8) Defective autophagy, reduced ferritin, mitochondrial dysfunction, iron overload (spaull2021towardsprecisiontherapies pages 6-8) No proven disease-modifying therapy; small studies/case experience with deferiprone showed mixed clinical effects (spaull2021towardsprecisiontherapies pages 6-8)
Aceruloplasminemia CP Autosomal recessive Neurologic disease with movement disorder/cognitive features; systemic iron overload with diabetes often prominent at presentation (schneider2025neurodegenerationwithbrain pages 3-4) Brain iron accumulation; systemic iron deposition can involve retina, pancreas, liver (schneider2025neurodegenerationwithbrain pages 3-4) Direct iron-homeostasis defect due to absent/defective ferroxidase activity and impaired iron mobilization (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 3-4) No established causal therapy in gathered evidence; iron chelation is part of general NBIA disease-modifying rationale, but subtype-specific trial evidence not detailed here (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 3-4)
Neuroferritinopathy FTL Autosomal dominant Progressive movement disorder phenotype within NBIA spectrum (schneider2025neurodegenerationwithbrain pages 3-4, marchand2022conservativeironchelation pages 1-2) Brain iron overload with MRI R2* tracking regional iron burden (marchand2022conservativeironchelation pages 2-3, marchand2022conservativeironchelation pages 4-5) Direct iron-homeostasis defect from abnormal ferritin configuration/iron storage (iankova2021emergingdiseasemodifyingtherapies pages 1-2, schneider2025neurodegenerationwithbrain pages 3-4) Deferiprone conservative chelation (30 mg/kg/day) in small series/cases: stabilization or improvement in some patients, R2* reductions in some regions, but neutropenia risk requires monitoring (marchand2022conservativeironchelation pages 2-3, marchand2022conservativeironchelation pages 3-4, marchand2022conservativeironchelation pages 1-2)

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

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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.

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  16. (marupudi2024genetictargetsand pages 4-5): 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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  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.