Bilateral Striopallidodentate Calcinosis

👪

Inheritance

2

Autosomal dominant inheritance HP:0000006

Dominant disease accounts for the traditional PFBC families driven mainly by SLC20A2, XPR1, PDGFRB, and PDGFB.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:29955172 SUPPORT Human Clinical

"It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1."

Establishes autosomal dominant inheritance for the classical PFBC subgroup.

Autosomal recessive inheritance HP:0000007

Recessive BSPDC/PFBC now includes MYORG-, JAM2-, and NAA60-associated disease with biallelic pathogenic variants.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:38480682 SUPPORT Human Clinical

"Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC."

Confirms autosomal recessive inheritance as part of the PFBC spectrum.

◆

Subtypes

2

Autosomal Dominant PFBC

Dominant BSPDC/PFBC is most often caused by pathogenic variants in SLC20A2, XPR1, PDGFRB, or PDGFB and shows age-dependent, variably expressive motor, cognitive, and neuropsychiatric disease.

Show evidence (1 reference)

PMID:29955172 SUPPORT Human Clinical

"It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1."

Defines the dominant PFBC subgroup and its core genes.

Autosomal Recessive PFBC

Recessive BSPDC/PFBC currently includes MYORG-, JAM2-, and NAA60-associated disease and tends to have heavier calcification burden and more severe neurologic involvement than the dominant forms.

Show evidence (2 references)

PMID:31851307 SUPPORT Human Clinical

"Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention."

Supports recessive PFBC as a clinically more severe subtype grouping.

PMID:38480682 SUPPORT Human Clinical

"Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC."

Confirms that autosomal recessive PFBC extends beyond MYORG and JAM2.

⚙

Pathophysiology

2

Disrupted phosphate transport homeostasis

SLC20A2 and XPR1 directly regulate inorganic phosphate influx and efflux, while NAA60 loss secondarily reduces SLC20A2 surface abundance and phosphate uptake. Together these defects dysregulate phosphate handling in the brain microvascular environment and promote calcium-phosphate deposition.

SLC20A2 link XPR1 link NAA60 link

phosphate ion transmembrane transport link ↕ DYSREGULATED

blood-brain barrier link basal ganglion link

Downstream

Neurovascular calcium-phosphate deposition Dysregulated phosphate handling favors calcium-phosphate precipitation along deep-brain microvascular structures.

Show evidence (3 references)

PMID:32506582 SUPPORT Human Clinical

"Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC."

Supports defective phosphate import as a central dominant PFBC mechanism.

PMID:25938945 SUPPORT Human Clinical

"These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC."

Supports defective phosphate export as a complementary PFBC mechanism.

PMID:38480682 SUPPORT Human Clinical

"In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake."

Shows that NAA60-associated PFBC converges mechanistically on impaired SLC20A2-dependent phosphate uptake.

Neurovascular calcium-phosphate deposition

PFBC-linked PDGFB/PDGFRB and JAM2 defects impair pericyte-endothelial- astrocyte homeostasis, while related recessive pathways such as MYORG likely converge on the same neurovascular system. Reduced blood-brain barrier maintenance and cell-cell adhesion favor vascular and perivascular brain calcification.

brain pericyte link brain microvascular endothelial cell link astrocyte link

PDGFB link PDGFRB link JAM2 link MYORG link

maintenance of blood-brain barrier link ↓ DECREASED cell-cell adhesion link ↓ DECREASED

blood-brain barrier link basal ganglion link dentate nucleus link

Show evidence (2 references)

PMID:23913003 SUPPORT Model Organism

"The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency."

Directly supports neurovascular-unit failure as a cause of brain calcification.

PMID:31851307 SUPPORT Human Clinical

"We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit."

Supports tight-junction and neurovascular-unit disruption in recessive PFBC.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

5

Musculoskeletal 1

Intracranial calcification Intracranial calcification (HP:0430048)

Show evidence (1 reference)

PMID:31851307 SUPPORT Human Clinical

"Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms."

Supports bilateral intracranial calcification as the core disease phenotype.

Nervous System 4

Parkinsonism Parkinsonism (HP:0001300)

Show evidence (1 reference)

PMID:29955172 SUPPORT Human Clinical

"A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years)."

Quantifies parkinsonism as the leading recurrent motor phenotype in the international cohort.

Cognitive impairment Cognitive impairment (HP:0100543)

Show evidence (1 reference)

PMID:29955172 SUPPORT Human Clinical

"A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years)."

Supports cognitive impairment as a core symptomatic domain in PFBC.

Psychosis Psychosis (HP:0000709)

Show evidence (1 reference)

PMID:23122487 SUPPORT Human Clinical

"Nevertheless, purely psychiatric presentations, as demonstrated by the present case, are possible."

Supports psychosis as a legitimate presenting phenotype within the PFBC spectrum.

Seizure Seizure (HP:0001250)

Show evidence (1 reference)

PMID:31851307 SUPPORT Human Clinical

"The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages."

Supports seizures as part of the severe recessive JAM2-associated spectrum.

🧬

Genetic Associations

7

SLC20A2 (Causative)

Autosomal Dominant

Show evidence (1 reference)

PMID:32506582 SUPPORT Human Clinical

"Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC."

Establishes SLC20A2 as the major dominant phosphate-import gene in PFBC.

XPR1 (Causative)

Autosomal Dominant

Show evidence (1 reference)

PMID:25938945 SUPPORT Human Clinical

"These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC."

Directly links dominant XPR1 variants to PFBC through altered phosphate export.

PDGFRB (Causative)

Autosomal Dominant

Show evidence (1 reference)

PMID:23255827 SUPPORT Human Clinical

"Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology."

Supports PDGFRB as a causative dominant PFBC gene linked to the shared pathway.

PDGFB (Causative)

Autosomal Dominant

Show evidence (1 reference)

PMID:23913003 SUPPORT Human Clinical

"Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ."

Establishes PDGFB as a dominant PFBC gene in affected human families.

MYORG (Causative)

Autosomal Recessive

Show evidence (1 reference)

PMID:30656188 SUPPORT Human Clinical

"MYORG mutations are linked to a recessive form of primary familial brain calcification."

Establishes MYORG as a recessive PFBC gene.

JAM2 (Causative)

Autosomal Recessive

Show evidence (1 reference)

PMID:31851307 SUPPORT Human Clinical

"Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis."

Establishes JAM2 as a recessive PFBC gene and ties it to neurovascular pathology.

NAA60 (Causative)

Autosomal Recessive

Show evidence (1 reference)

PMID:38480682 SUPPORT Human Clinical

"This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning."

Establishes NAA60 as a recessive PFBC gene with a defined biochemical mechanism.

💊

Treatments

2

Dopaminergic replacement therapy

Action: Pharmacotherapy NCIT:C15986

Agent: levodopa ↗

Symptomatic dopaminergic therapy can improve PFBC-associated parkinsonism, although treatment may require adjustment because motor fluctuations and dyskinesia can emerge.

Target Phenotypes: Parkinsonism ↗

Show evidence (1 reference)

PMID:39036637 SUPPORT Human Clinical

"This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment."

Supports symptomatic dopaminergic therapy for PFBC-associated parkinsonism.

Splice-switching antisense oligonucleotide therapy

Action: antisense oligonucleotide therapy Ontology label: antisense oligonucleotide inhibitor therapy MAXO:0001593

Experimental ASO therapy for SLC20A2 haploinsufficiency restores functional SLC20A2 expression and suppresses calcification in a humanized mouse model.

Show evidence (1 reference)

PMID:39121859 SUPPORT Model Organism

"Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency."

Supports an emerging disease-modifying treatment strategy for SLC20A2-related PFBC in a preclinical model.

{ }

Source YAML

click to show

name: Bilateral Striopallidodentate Calcinosis
creation_date: "2026-04-14T08:30:00Z"
updated_date: "2026-04-22T20:53:03Z"
category: Mendelian
description: >-
  Bilateral striopallidodentate calcinosis (BSPDC), commonly discussed in
  recent literature as primary familial brain calcification (PFBC), is a
  genetically heterogeneous cerebral microvascular calcification disorder
  defined by bilateral calcium phosphate deposition in the basal ganglia and
  other brain regions including the dentate nuclei, thalamus, cerebellum, and
  subcortical white matter. The spectrum includes autosomal dominant and
  autosomal recessive forms caused by defects in phosphate transport and
  neurovascular-unit homeostasis, with age-dependent penetrance and wide
  clinical variation ranging from incidental imaging findings to parkinsonism,
  cognitive impairment, psychosis, seizures, and other movement disorders.
disease_term:
  preferred_term: bilateral striopallidodentate calcinosis
  term:
    id: MONDO:0008947
    label: bilateral striopallidodentate calcinosis
parents:
- Basal Ganglia Disorder
- Neurodegenerative Disease
- Hereditary Neurological Disease
synonyms:
- BSPDC
- PFBC
- Primary Familial Brain Calcification
- primary familial brain calcification
- idiopathic basal ganglia calcification
- Fahr disease
notes: >-
  This entry is intentionally curated at the disease/root level for
  MONDO:0008947 rather than split into multiple premature gene-specific pages.
  The page captures the dominant and recessive BSPDC/PFBC spectrum in one
  place, with subtype heterogeneity documented under `has_subtypes` and
  gene-level heterogeneity documented under `genetic`. The current
  PMID-supported core gene set curated here is SLC20A2, XPR1, PDGFRB, PDGFB,
  MYORG, JAM2, and NAA60. Secondary causes of basal ganglia calcification are
  outside scope for this disease-level entry.
has_subtypes:
- name: Autosomal Dominant PFBC
  classification: inheritance
  description: >-
    Dominant BSPDC/PFBC is most often caused by pathogenic variants in SLC20A2,
    XPR1, PDGFRB, or PDGFB and shows age-dependent, variably expressive motor,
    cognitive, and neuropsychiatric disease.
  evidence:
  - reference: PMID:29955172
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1."
    explanation: Defines the dominant PFBC subgroup and its core genes.
- name: Autosomal Recessive PFBC
  classification: inheritance
  description: >-
    Recessive BSPDC/PFBC currently includes MYORG-, JAM2-, and
    NAA60-associated disease and tends to have heavier calcification burden and
    more severe neurologic involvement than the dominant forms.
  evidence:
  - reference: PMID:31851307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention."
    explanation: Supports recessive PFBC as a clinically more severe subtype grouping.
  - reference: PMID:38480682
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC."
    explanation: Confirms that autosomal recessive PFBC extends beyond MYORG and JAM2.
progression:
- phase: Variable onset and age-dependent expressivity
  notes: >-
    Symptoms may begin in childhood or late adulthood, and some genetically
    affected individuals remain asymptomatic despite calcifications on imaging.
  evidence:
  - reference: PMID:29955172
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years)."
    explanation: Supports age-dependent penetrance and broad onset variability.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Dominant disease accounts for the traditional PFBC families driven mainly
    by SLC20A2, XPR1, PDGFRB, and PDGFB.
  evidence:
  - reference: PMID:29955172
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1."
    explanation: Establishes autosomal dominant inheritance for the classical PFBC subgroup.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Recessive BSPDC/PFBC now includes MYORG-, JAM2-, and NAA60-associated
    disease with biallelic pathogenic variants.
  evidence:
  - reference: PMID:38480682
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC."
    explanation: Confirms autosomal recessive inheritance as part of the PFBC spectrum.
genetic:
- name: SLC20A2
  gene_term:
    preferred_term: SLC20A2
    term:
      id: hgnc:10947
      label: SLC20A2
  association: Causative
  features: >-
    SLC20A2 encodes the PiT-2 inorganic phosphate importer and is the major
    cause of autosomal dominant PFBC. Loss of expression or regulatory
    haploinsufficiency lowers phosphate uptake and promotes phosphate
    dysregulation in brain microvascular tissue.
  inheritance:
  - name: Autosomal Dominant
  evidence:
  - reference: PMID:32506582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC."
    explanation: Establishes SLC20A2 as the major dominant phosphate-import gene in PFBC.
- name: XPR1
  gene_term:
    preferred_term: XPR1
    term:
      id: hgnc:12827
      label: XPR1
  association: Causative
  features: >-
    XPR1 encodes a phosphate exporter. Pathogenic dominant variants impair
    phosphate efflux and reinforce phosphate homeostasis as a central disease
    axis in BSPDC/PFBC.
  inheritance:
  - name: Autosomal Dominant
  evidence:
  - reference: PMID:25938945
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC."
    explanation: Directly links dominant XPR1 variants to PFBC through altered phosphate export.
- name: PDGFRB
  gene_term:
    preferred_term: PDGFRB
    term:
      id: hgnc:8804
      label: PDGFRB
  association: Causative
  features: >-
    PDGFRB encodes the platelet-derived growth factor receptor beta. Reduced
    receptor function implicates pericyte biology, angiogenic signaling, and
    phosphate-regulatory neurovascular pathways in PFBC.
  inheritance:
  - name: Autosomal Dominant
  evidence:
  - reference: PMID:23255827
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology."
    explanation: Supports PDGFRB as a causative dominant PFBC gene linked to the shared pathway.
- name: PDGFB
  gene_term:
    preferred_term: PDGFB
    term:
      id: hgnc:8800
      label: PDGFB
  association: Causative
  features: >-
    PDGFB is the major ligand for PDGFRB. Endothelial PDGF-B loss is linked to
    pericyte deficiency, blood-brain barrier compromise, and brain
    calcification.
  inheritance:
  - name: Autosomal Dominant
  evidence:
  - reference: PMID:23913003
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ."
    explanation: Establishes PDGFB as a dominant PFBC gene in affected human families.
- name: MYORG
  gene_term:
    preferred_term: MYORG
    term:
      id: hgnc:19918
      label: MYORG
  association: Causative
  features: >-
    MYORG encodes an astrocyte-associated glycosidase-family protein and causes
    recessive PFBC. Current evidence links MYORG-associated disease to
    neurovascular signaling pathways related to PDGFRB biology.
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:30656188
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYORG mutations are linked to a recessive form of primary familial brain calcification."
    explanation: Establishes MYORG as a recessive PFBC gene.
- name: JAM2
  gene_term:
    preferred_term: JAM2
    term:
      id: hgnc:14686
      label: JAM2
  association: Causative
  features: >-
    JAM2 encodes a junctional adhesion protein enriched in neurovascular-unit
    cell types. Biallelic loss disrupts cell-cell adhesion and neurovascular
    integrity in severe recessive PFBC.
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:31851307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis."
    explanation: Establishes JAM2 as a recessive PFBC gene and ties it to neurovascular pathology.
- name: NAA60
  gene_term:
    preferred_term: NAA60
    term:
      id: hgnc:25875
      label: NAA60
  association: Causative
  features: >-
    NAA60 encodes a Golgi-localized N-terminal acetyltransferase. Recessive
    loss of NAA60 impairs transmembrane-protein acetylation, lowers cell-surface
    SLC20A2, and reduces phosphate uptake.
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:38480682
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning."
    explanation: Establishes NAA60 as a recessive PFBC gene with a defined biochemical mechanism.
pathophysiology:
- name: Disrupted phosphate transport homeostasis
  description: >-
    SLC20A2 and XPR1 directly regulate inorganic phosphate influx and efflux,
    while NAA60 loss secondarily reduces SLC20A2 surface abundance and
    phosphate uptake. Together these defects dysregulate phosphate handling in
    the brain microvascular environment and promote calcium-phosphate
    deposition.
  genes:
  - preferred_term: SLC20A2
    term:
      id: hgnc:10947
      label: SLC20A2
  - preferred_term: XPR1
    term:
      id: hgnc:12827
      label: XPR1
  - preferred_term: NAA60
    term:
      id: hgnc:25875
      label: NAA60
  biological_processes:
  - preferred_term: phosphate ion transmembrane transport
    term:
      id: GO:0035435
      label: phosphate ion transmembrane transport
    modifier: DYSREGULATED
  locations:
  - preferred_term: blood-brain barrier
    term:
      id: UBERON:0000120
      label: blood brain barrier
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  evidence:
  - reference: PMID:32506582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC."
    explanation: Supports defective phosphate import as a central dominant PFBC mechanism.
  - reference: PMID:25938945
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC."
    explanation: Supports defective phosphate export as a complementary PFBC mechanism.
  - reference: PMID:38480682
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake."
    explanation: Shows that NAA60-associated PFBC converges mechanistically on impaired SLC20A2-dependent phosphate uptake.
  downstream:
  - target: Neurovascular calcium-phosphate deposition
    description: Dysregulated phosphate handling favors calcium-phosphate precipitation along deep-brain microvascular structures.
- name: Neurovascular calcium-phosphate deposition
  description: >-
    PFBC-linked PDGFB/PDGFRB and JAM2 defects impair pericyte-endothelial-
    astrocyte homeostasis, while related recessive pathways such as MYORG
    likely converge on the same neurovascular system. Reduced blood-brain
    barrier maintenance and cell-cell adhesion favor vascular and perivascular
    brain calcification.
  genes:
  - preferred_term: PDGFB
    term:
      id: hgnc:8800
      label: PDGFB
  - preferred_term: PDGFRB
    term:
      id: hgnc:8804
      label: PDGFRB
  - preferred_term: JAM2
    term:
      id: hgnc:14686
      label: JAM2
  - preferred_term: MYORG
    term:
      id: hgnc:19918
      label: MYORG
  cell_types:
  - preferred_term: brain pericyte
    term:
      id: CL:2000043
      label: brain pericyte
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: maintenance of blood-brain barrier
    term:
      id: GO:0035633
      label: maintenance of blood-brain barrier
    modifier: DECREASED
  - preferred_term: cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: DECREASED
  locations:
  - preferred_term: blood-brain barrier
    term:
      id: UBERON:0000120
      label: blood brain barrier
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  - preferred_term: dentate nucleus
    term:
      id: UBERON:0002132
      label: dentate nucleus
  evidence:
  - reference: PMID:23913003
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency."
    explanation: Directly supports neurovascular-unit failure as a cause of brain calcification.
  - reference: PMID:31851307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit."
    explanation: Supports tight-junction and neurovascular-unit disruption in recessive PFBC.
phenotypes:
- category: Neurological
  name: Intracranial calcification
  description: >-
    Bilateral intracranial calcification involving the basal ganglia and other
    deep brain regions is the defining radiographic hallmark of the disorder.
  phenotype_term:
    preferred_term: Intracranial calcification
    term:
      id: HP:0430048
      label: Intracranial calcification
  evidence:
  - reference: PMID:31851307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms."
    explanation: Supports bilateral intracranial calcification as the core disease phenotype.
- category: Neurological
  name: Parkinsonism
  description: >-
    Parkinsonism is one of the most common symptomatic motor manifestations in
    clinically affected BSPDC/PFBC carriers.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:29955172
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years)."
    explanation: Quantifies parkinsonism as the leading recurrent motor phenotype in the international cohort.
- category: Neurological
  name: Cognitive impairment
  description: >-
    Cognitive impairment is a common symptomatic domain across the BSPDC/PFBC
    spectrum.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:29955172
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years)."
    explanation: Supports cognitive impairment as a core symptomatic domain in PFBC.
- category: Psychiatric
  name: Psychosis
  description: >-
    Psychosis can be part of the BSPDC/PFBC phenotype and may occasionally
    dominate the initial presentation.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:23122487
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, purely psychiatric presentations, as demonstrated by the present case, are possible."
    explanation: Supports psychosis as a legitimate presenting phenotype within the PFBC spectrum.
- category: Neurological
  name: Seizure
  subtype: Autosomal Recessive PFBC
  description: >-
    Seizures occur in a subset of severe recessive PFBC cases, particularly
    those with extensive cortical calcification.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31851307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages."
    explanation: Supports seizures as part of the severe recessive JAM2-associated spectrum.
treatments:
- name: Dopaminergic replacement therapy
  description: >-
    Symptomatic dopaminergic therapy can improve PFBC-associated parkinsonism,
    although treatment may require adjustment because motor fluctuations and
    dyskinesia can emerge.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_phenotypes:
  - preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:39036637
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment."
    explanation: Supports symptomatic dopaminergic therapy for PFBC-associated parkinsonism.
- name: Splice-switching antisense oligonucleotide therapy
  description: >-
    Experimental ASO therapy for SLC20A2 haploinsufficiency restores functional
    SLC20A2 expression and suppresses calcification in a humanized mouse model.
  treatment_term:
    preferred_term: antisense oligonucleotide therapy
    term:
      id: MAXO:0001593
      label: antisense oligonucleotide inhibitor therapy
  evidence:
  - reference: PMID:39121859
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency."
    explanation: Supports an emerging disease-modifying treatment strategy for SLC20A2-related PFBC in a preclinical model.

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References & Deep Research

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Cyberian Codex ▸

Question

codex-local-synthesis 13 citations 2026-04-14T08:20:00Z

Question

Codex secondary synthesis for disorder curation.

Curation Summary

Disease anchor: MONDO:0008947 (bilateral striopallidodentate calcinosis), with exact MONDO synonyms including PFBC, Primary Familial Brain Calcification, and narrow synonym Fahr disease.
Curation strategy: keep one disease/root page and document heterogeneity inside it. Do not split into multiple premature gene pages.
YAML evidence policy: only PMID-backed abstract quotes that can survive validate-references.

Disease Framing

BSPDC/PFBC is the same broad disease spectrum for this curation purpose.
The 2025 Brain review (PMID:40344186) states: To date, seven genes have been linked to PFBC.
Recent literature supports two high-level subtype buckets for the parent page:
Autosomal dominant PFBC: SLC20A2, XPR1, PDGFRB, PDGFB
Autosomal recessive PFBC: MYORG, JAM2, NAA60
I did not promote older, less stable candidate-gene mentions into the YAML unless I had direct and current PMID-backed support consistent with the current core-gene set.

Mechanistic Synthesis

Shared mechanism 1: phosphate transport dysregulation.
SLC20A2 is the major dominant phosphate-import gene (PMID:32506582).
XPR1 adds the complementary phosphate-export defect (PMID:25938945).
NAA60 converges on the same axis by lowering cell-surface SLC20A2 and extracellular phosphate uptake (PMID:38480682).
Shared mechanism 2: neurovascular-unit dysfunction.
PDGFB / PDGFRB connect PFBC to endothelial-pericyte biology and blood-brain barrier maintenance (PMID:23913003, PMID:23255827).
JAM2 makes the neurovascular-unit hypothesis explicit through impaired cell-cell adhesion (PMID:31851307).
MYORG is likely in the same broader pathway family, but the most validator-safe abstract wording is still more cautious (PMID:30656188).
Emerging mechanistic theme not over-modeled in YAML:
PMID:40344186 links NAA60 and SLC20A2 to Golgi integrity and highlights Golgi fragmentation as an emerging PFBC topic.

Phenotype Synthesis

Core parent-page phenotypes best supported by abstract-level quotes:
intracranial calcification / bilateral basal ganglia and extra-basal calcification
parkinsonism
cognitive impairment
psychosis / psychiatric presentation
Heterogeneity point worth preserving:
recessive disease is generally more severe and can include seizures and heavier cortical involvement (PMID:31851307).
I avoided overcommitting to additional phenotypes unless I had a clean HPO mapping plus an exact abstract sentence.

Treatment Synthesis

Current clinically supported treatment remains symptomatic rather than disease-modifying.
PMID:39036637 supports dopaminergic replacement therapy for PFBC-associated parkinsonism.
The strongest emerging precision-treatment paper is subtype-specific and preclinical.
PMID:39121859 shows ASO-mediated splice correction as a potential therapy for SLC20A2 haploinsufficiency.
I kept treatment modeling conservative:
one symptomatic pharmacotherapy entry
one experimental ASO entry

YAML Decisions

Included:
one spectrum/root disorder page
two inheritance-level subtypes
seven causative genes with direct support
two shared mechanism nodes
four core phenotypes plus one recessive-severity phenotype
one symptomatic and one experimental treatment
Deliberately not included:
separate gene-specific disorder pages
secondary/idiopathic basal ganglia calcification syndromes outside MONDO:0008947
weaker or unstable gene claims not anchored by current direct PMID evidence

PMID Set Used For YAML

PMID:23122487
PMID:23255827
PMID:23913003
PMID:25938945
PMID:29955172
PMID:30656188
PMID:31851307
PMID:32506582
PMID:38480682
PMID:39036637
PMID:39121859
PMID:40344186

Bilateral Striopallidodentate Calcinosis

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Mechanistic Synthesis

Phenotype Synthesis

Treatment Synthesis

YAML Decisions

PMID Set Used For YAML