Adult-Onset Dystonia-Parkinsonism

Genetic MONDO:0013060 Pathograph 42 Show in embeddings browser PLA2G6-associated neurodegeneration Neurodegenerative Disease Movement Disorder

Adult-onset dystonia-parkinsonism is an autosomal recessive PLA2G6-associated neurodegeneration spectrum disorder, usually presenting before age 30 with levodopa-responsive parkinsonism, dystonia, pyramidal signs, cognitive or psychiatric features, and variable cerebral or cerebellar atrophy and brain iron deposition.

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1
Inheritance
7
Pathophys.
33
Phenotypes
42
Pathograph
1
Genes
3
Medical Actions
10
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Adult-onset dystonia-parkinsonism is part of the autosomal recessive PLA2G6-associated neurodegeneration spectrum and is caused by biallelic pathogenic PLA2G6 variants.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"Autosomal recessive"
Orphanet lists autosomal recessive inheritance.
PMID:20301718 SUPPORT Other
"PLAN is inherited in an autosomal recessive manner."
GeneReviews supports autosomal recessive inheritance for PLAN.
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Pathophysiology

7
PLA2G6 Functional Dysregulation
Biallelic PLA2G6 variants alter group VIA calcium-independent phospholipase A2 beta function in adult PLAN. Reported parkinsonism alleles are mainly nontruncating, and biochemical assays can retain catalytic activity; altered regulation, protein interactions, or context-specific membrane homeostasis are therefore more conservative than an asserted catalytic loss-of-function mechanism.
PLA2G6 hgnc:9039 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLA2G6 (hgnc:9039). hgnc:9039 is a gene from the HUGO Gene Nomenclature Committee.
phospholipid metabolic process GO:0006644 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated phospholipid metabolic process (GO:0006644). GO:0006644 is a biological process from the Gene Ontology. ↕ DYSREGULATED
phospholipase A2 activity GO:0004623 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated phospholipase A2 activity, annotated with A2-type glycerophospholipase activity (GO:0004623). GO:0004623 is a molecular function from the Gene Ontology. ↕ DYSREGULATED
Downstream
Membrane Lipid and Retromer Homeostasis Disruption
Mitochondrial Oxidative Injury
Global Developmental Delay
Dyslexia
Show evidence (2 references)
PMID:26001724 SUPPORT Other
"Conversely, mutations associated with dystonia-parkinsonism did not impair catalytic activity."
The full-text discussion cautions against equating the adult dystonia-parkinsonism phenotype with catalytic loss of function.
PMID:34622992 SUPPORT Human Clinical
"These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration."
The adult parkinsonism series supports a mainly nontruncating variant spectrum rather than a uniform null mechanism.
Membrane Lipid and Retromer Homeostasis Disruption
Experimental loss of PLA2G6/iPLA2-VIA perturbs lipid recycling, elevates ceramides, and impairs Vps26/Vps35 retromer function, creating a membrane-fluidity and recycling defect that can compromise neuronal function.
phospholipid metabolic process GO:0006644 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated phospholipid metabolic process (GO:0006644). GO:0006644 is a biological process from the Gene Ontology. ↕ DYSREGULATED retrograde transport, endosome to Golgi GO:0042147 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retrograde transport, endosome to Golgi (GO:0042147). GO:0042147 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Progressive Neuronal Dysfunction and Neurodegeneration
Show evidence (3 references)
PMID:29909971 SUPPORT Model Organism
"We show that loss of iPLA2-VIA, the fly homolog of PLA2G6, reduces lifespan, impairs synaptic transmission, and causes neurodegeneration."
Drosophila loss-of-function data support neuronal consequences of PLA2G6 homolog disruption.
PMID:29909971 SUPPORT Model Organism
"iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances retromer function to promote protein and lipid recycling."
The model organism study directly links the PLA2G6 homolog to retromer and lipid recycling.
PMID:29909971 SUPPORT Model Organism
"Loss of iPLA2-VIA impairs retromer function, leading to a progressive increase in ceramide."
This supports the direction of retromer and lipid-homeostasis disruption.
Mitochondrial Oxidative Injury
Experimental PLA2G6 loss and a PARK14 knockin allele produce mitochondrial membrane defects, respiratory-chain dysfunction, reduced ATP synthesis, reactive oxygen species, and lipid peroxidation in model systems and patient fibroblasts.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
aerobic respiration GO:0009060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aerobic respiration (GO:0009060). GO:0009060 is a biological process from the Gene Ontology. ↓ DECREASED cellular response to oxidative stress GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Neuronal Dysfunction and Neurodegeneration
Show evidence (3 references)
PMID:26001724 SUPPORT Model Organism
"loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology."
Fly model data support mitochondrial respiratory and morphologic impairment after PLA2G6 homolog loss.
PMID:26001724 SUPPORT In Vitro
"Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species."
Patient fibroblast data support mitochondrial oxidative injury in human PLA2G6-mutant cells.
PMID:26001724 SUPPORT Other
"Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities."
The paper summarizes the integrated mechanism across its experimental systems.
Progressive Neuronal Dysfunction and Neurodegeneration
Convergent membrane-homeostasis and mitochondrial injury pathways produce progressive neuronal dysfunction across dopaminergic, pyramidal, cerebellar, autonomic, ocular-motor, bulbar, and cognitive networks. Human observations establish the multisystem phenotype, but most individual symptom routes remain mechanistically unresolved.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Basal Ganglia Dopaminergic Circuit Degeneration
Cerebral and Cerebellar Atrophy
Synuclein-Tau Proteinopathy
Iron Accumulation in Brain
Hypometric Saccades
Supranuclear Gaze Palsy
Eyelid Apraxia
Urinary Urgency
Spasticity
Dysarthria
Myoclonus
Hyperreflexia
Dysphagia
Clumsiness
Stiff Hip
Seizure
Frontotemporal Dementia
Depression
Delusion
Personality Changes
Paranoia
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment."
The human series supports progressive multisystem neurologic involvement.
Basal Ganglia Dopaminergic Circuit Degeneration
Dopaminergic nigrostriatal dysfunction and substantia nigra degeneration drive levodopa-responsive parkinsonism, bradykinesia, rigidity, tremor, dystonia, and postural instability.
dopaminergic neuron CL:0000700 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dopaminergic neuron (CL:0000700). CL:0000700 is a cell type from the Cell Ontology.
Downstream
Levodopa-Responsive Parkinsonism
Bradykinesia
Rigidity
Tremor
Postural Instability
Focal Dystonia
Progressive Extrapyramidal Movement Disorder
Hypomimic Face
Generalized Dystonia
Show evidence (3 references)
PMID:34622992 SUPPORT Human Clinical
"Presynaptic dopaminergic terminal imaging was abnormal in all where performed."
Human imaging evidence supports presynaptic dopaminergic pathway involvement in PLA2G6-related parkinsonism.
PMID:30088174 SUPPORT Model Organism
"Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons."
Knockin mouse evidence supports substantia nigra dopaminergic neuron loss downstream of a PARK14 PLA2G6 mutation.
PMID:34622992 SUPPORT Human Clinical
"Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias."
Levodopa responsiveness supports dopaminergic circuit dysfunction as a driver of motor symptoms.
Cerebral and Cerebellar Atrophy
Neurodegeneration produces cerebral and/or cerebellar atrophy on MRI; frontotemporal atrophy and hypoperfusion are particularly reported in adult-onset PLA2G6-related parkinsonism.
Downstream
Frontotemporal Cerebral Atrophy
Generalized Cerebral Atrophy
Show evidence (3 references)
PMID:18570303 SUPPORT Human Clinical
"cerebral and cerebellar atrophy on magnetic resonance imaging but absent iron in the basal ganglia."
The original adult-onset cases had MRI atrophy even without basal ganglia iron.
PMID:20938027 SUPPORT Human Clinical
"All 3 patients had early-onset l-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy."
A PLA2G6 parkinsonism series supports frontotemporal atrophy.
PMID:34622992 SUPPORT Human Clinical
"Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%."
The systematic review quantifies frequent brain atrophy and variable mineralization.
Synuclein-Tau Proteinopathy
PLA2G6-related dystonia-parkinsonism can culminate in mixed alpha-synuclein-positive Lewy pathology and hyperphosphorylated tau pathology, linking the disorder to parkinsonian neurodegeneration and neurofibrillary tangles.
Downstream
Neurofibrillary Tangles
Show evidence (3 references)
PMID:20619503 SUPPORT Human Clinical
"Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology"
Human neuropathology supports widespread Lewy pathology in PLA2G6 mutation cases.
PMID:20619503 SUPPORT Human Clinical
"In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles."
Human neuropathology supports tau accumulation and neurofibrillary tangles.
PMID:34622992 SUPPORT Human Clinical
"Brain pathology in three cases showed mixed Lewy and tau pathology."
A later systematic review confirms mixed Lewy and tau pathology in reported PLA2G6-related parkinsonism autopsies.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adult-Onset Dystonia-Parkinsonism Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

33
Digestive 1
Dysphagia FREQUENT HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0002015 | Dysphagia | Frequent (79-30%) |"
Orphanet lists dysphagia as frequent.
Genitourinary 1
Urinary Urgency FREQUENT HP:0000012 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urinary urgency (HP:0000012). HP:0000012 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"Early bladder overactivity was present in 71.9% of cases."
Systematic review of 86 cases identifies bladder overactivity as a frequent and clinically distinctive feature.
Musculoskeletal 2
Spasticity FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0001257 | Spasticity | Frequent (79-30%) |"
Orphanet lists spasticity as frequent.
PMID:20301718 SUPPORT Other
"Over time, affected persons develop both weakness and symmetric spastic tetraparesis"
GeneReviews supports spastic motor involvement in PLAN.
Rigidity FREQUENT HP:0002063 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rigidity (HP:0002063). HP:0002063 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0002063 | Rigidity | Frequent (79-30%) |"
Orphanet lists rigidity as frequent.
PMID:20301718 SUPPORT Other
"The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability."
GeneReviews supports rigidity as a common adult PLAN parkinsonian feature.
Nervous System 15
Depression OCCASIONAL HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000716 | Depression | Occasional (29-5%) |"
Orphanet lists depression as occasional.
Delusion OCCASIONAL HP:0000746 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delusion (HP:0000746). HP:0000746 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000746 | Delusion | Occasional (29-5%) |"
Orphanet lists delusion as occasional.
Personality Changes OCCASIONAL HP:0000751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Personality changes (HP:0000751). HP:0000751 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000751 | Personality changes | Occasional (29-5%) |"
Orphanet lists personality changes as occasional.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0001250 | Seizure | Occasional (29-5%) |"
Orphanet lists seizure as occasional.
Dysarthria FREQUENT HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0001260 | Dysarthria | Frequent (79-30%) |"
Orphanet lists dysarthria as frequent.
Global Developmental Delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0001263 | Global developmental delay | Occasional (29-5%) |"
Orphanet lists global developmental delay as occasional.
Generalized Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0001332 | Dystonia | Occasional (29-5%) |"
Orphanet lists dystonia as occasional.
PMID:20301718 SUPPORT Other
"Dystonia is most common in the hands and feet but may be more generalized."
GeneReviews supports variable dystonia distribution in adult PLAN.
Myoclonus OCCASIONAL HP:0001336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonus (HP:0001336). HP:0001336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0001336 | Myoclonus | Occasional (29-5%) |"
Orphanet lists myoclonus as occasional.
Tremor FREQUENT HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0001337 | Tremor | Frequent (79-30%) |"
Orphanet lists tremor as frequent.
PMID:20301718 SUPPORT Other
"The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability."
GeneReviews supports tremor as a common adult PLAN parkinsonian feature.
Hyperreflexia FREQUENT HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0001347 | Hyperreflexia | Frequent (79-30%) |"
Orphanet lists hyperreflexia as frequent.
Bradykinesia FREQUENT HP:0002067 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bradykinesia (HP:0002067). HP:0002067 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0002067 | Bradykinesia | Frequent (79-30%) |"
Orphanet lists bradykinesia as frequent.
PMID:20301718 SUPPORT Other
"The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability."
GeneReviews supports bradykinesia as a common adult PLAN parkinsonian feature.
Postural Instability FREQUENT HP:0002172 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural instability (HP:0002172). HP:0002172 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0002172 | Postural instability | Frequent (79-30%) |"
Orphanet lists postural instability as frequent.
PMID:20301718 SUPPORT Other
"The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability."
GeneReviews supports postural instability as a common adult PLAN parkinsonian feature.
Neurofibrillary Tangles FREQUENT HP:0002185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurofibrillary tangles (HP:0002185). HP:0002185 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0002185 | Neurofibrillary tangles | Frequent (79-30%) |"
Orphanet lists neurofibrillary tangles as frequent.
PMID:20619503 SUPPORT Human Clinical
"In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles."
Human neuropathology supports neurofibrillary tangles.
Frontotemporal Cerebral Atrophy FREQUENT HP:0006892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontotemporal cerebral atrophy (HP:0006892). HP:0006892 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0006892 | Frontotemporal cerebral atrophy | Frequent (79-30%) |"
Orphanet lists frontotemporal cerebral atrophy as frequent.
PMID:20938027 SUPPORT Human Clinical
"All 3 patients had early-onset l-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy."
Human PLA2G6 parkinsonism cases support frontotemporal atrophy.
Dyslexia FREQUENT HP:0010522 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyslexia (HP:0010522). HP:0010522 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0010522 | Dyslexia | Frequent (79-30%) |"
Orphanet lists dyslexia as frequent.
Other 14
Hypomimic Face FREQUENT HP:0000338 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomimic face (HP:0000338). HP:0000338 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000338 | Hypomimic face | Frequent (79-30%) |"
Orphanet lists hypomimic face as frequent.
Hypometric Saccades FREQUENT HP:0000571 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypometric saccades (HP:0000571). HP:0000571 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000571 | Hypometric saccades | Frequent (79-30%) |"
Orphanet lists hypometric saccades as frequent.
Supranuclear Gaze Palsy OCCASIONAL HP:0000605 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supranuclear gaze palsy (HP:0000605). HP:0000605 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000605 | Supranuclear gaze palsy | Occasional (29-5%) |"
Orphanet lists supranuclear gaze palsy as occasional.
Eyelid Apraxia FREQUENT HP:0000658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eyelid apraxia (HP:0000658). HP:0000658 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0000658 | Eyelid apraxia | Frequent (79-30%) |"
Orphanet lists eyelid apraxia as frequent.
Frontotemporal Dementia FREQUENT HP:0002145 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontotemporal dementia (HP:0002145). HP:0002145 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0002145 | Frontotemporal dementia | Frequent (79-30%) |"
Orphanet lists frontotemporal dementia as frequent.
Clumsiness FREQUENT HP:0002312 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clumsiness (HP:0002312). HP:0002312 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0002312 | Clumsiness | Frequent (79-30%) |"
Orphanet lists clumsiness as frequent.
Levodopa-Responsive Parkinsonism FREQUENT Parkinsonism with favorable response to dopaminergic medication HP:0002548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parkinsonism with favorable response to dopaminergic medication (HP:0002548). HP:0002548 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0002548 | Parkinsonism with favorable response to dopaminergic medication | Frequent (79-30%) |"
Orphanet lists levodopa-responsive parkinsonism as frequent.
PMID:34622992 SUPPORT Human Clinical
"Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias."
Systematic review supports levodopa responsiveness.
Focal Dystonia FREQUENT HP:0004373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal dystonia (HP:0004373). HP:0004373 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0004373 | Focal dystonia | Frequent (79-30%) |"
Orphanet lists focal dystonia as frequent.
PMID:20301718 SUPPORT Other
"Dystonia is most common in the hands and feet but may be more generalized."
GeneReviews supports frequent focal limb dystonia distribution.
Generalized Cerebral Atrophy FREQUENT Generalized cerebral atrophy/hypoplasia HP:0007058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized cerebral atrophy/hypoplasia (HP:0007058). HP:0007058 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0007058 | Generalized cerebral atrophy/hypoplasia | Frequent (79-30%) |"
Orphanet lists generalized cerebral atrophy/hypoplasia as frequent.
PMID:34622992 SUPPORT Human Clinical
"Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%."
Systematic review supports frequent cerebral atrophy.
Progressive Extrapyramidal Movement Disorder FREQUENT HP:0007153 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive extrapyramidal movement disorder (HP:0007153). HP:0007153 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0007153 | Progressive extrapyramidal movement disorder | Frequent (79-30%) |"
Orphanet lists progressive extrapyramidal movement disorder as frequent.
Paranoia OCCASIONAL HP:0011999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paranoia (HP:0011999). HP:0011999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0011999 | Paranoia | Occasional (29-5%) |"
Orphanet lists paranoia as occasional.
Iron Accumulation in Brain OCCASIONAL HP:0012675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iron accumulation in brain (HP:0012675). HP:0012675 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199351 SUPPORT Other
"| HP:0012675 | Iron accumulation in brain | Occasional (29-5%) |"
Orphanet lists brain iron accumulation as occasional.
PMID:34622992 SUPPORT Human Clinical
"Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not."
Systematic review supports brain iron as variable rather than required.
Stiff Hip FREQUENT HP:0025262 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stiff hip (HP:0025262). HP:0025262 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0025262 | Stiff hip | Frequent (79-30%) |"
Orphanet lists stiff hip as frequent.
Abnormal Circulating Creatine Kinase Concentration FREQUENT HP:0040081 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal circulating creatine kinase concentration (HP:0040081). HP:0040081 is a phenotype from the Human Phenotype Ontology.
The available Orphanet record establishes this laboratory phenotype but does not identify its tissue origin or connect it specifically to neuronal mitochondrial oxidative injury. It is intentionally left without a pathograph readout target pending source-backed evidence of the measured mechanism.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| HP:0040081 | Abnormal circulating creatine kinase concentration | Frequent (79-30%) |"
Orphanet lists abnormal circulating creatine kinase concentration as frequent.
🧬

Genetic Associations

1
PLA2G6 (Biallelic pathogenic variants)
Gene: PLA2G6 hgnc:9039 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLA2G6 (hgnc:9039). hgnc:9039 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
ORPHA:199351 SUPPORT Other
"| PLA2G6 | phospholipase A2 group VI | hgnc:9039 | Disease-causing germline mutation(s) in |"
Orphanet lists PLA2G6 as the disease-causing gene.
PMID:18570303 SUPPORT Human Clinical
"RESULTS: We identified areas of homozygosity on chromosome 22 and, subsequently, PLA2G6 mutations."
Human family mapping identified PLA2G6 mutations.
PMID:34622992 SUPPORT Human Clinical
"CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment."
Large case series and systematic review supports biallelic PLA2G6 causation.
💊

Medical Actions

3
Levodopa and dopaminergic agents
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levodopa CHEBI:15765 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levodopa, annotated with L-dopa (CHEBI:15765). CHEBI:15765 is a therapeutic agent from Chemical Entities of Biological Interest.
Levodopa or other dopaminergic agents may improve parkinsonism in adult PLAN, although early severe dyskinesias can complicate therapy.
Mechanism Target:
MODULATES Basal Ganglia Dopaminergic Circuit Degeneration — Dopaminergic therapy partially replaces downstream dopaminergic signaling.
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias."
Clinical response supports the relevance of dopaminergic motor circuits but does not directly demonstrate structural target modulation.
Target Phenotypes: Parkinsonism with favorable response to dopaminergic medication HP:0002548 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Parkinsonism with favorable response to dopaminergic medication (HP:0002548). HP:0002548 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301718 SUPPORT Other
"For individuals with adult PLAN, consider treatment with dopaminergic agents;"
GeneReviews recommends considering dopaminergic agents in adult PLAN.
PMID:34622992 SUPPORT Human Clinical
"Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias."
Human systematic review supports levodopa responsiveness and notes dyskinesia risk.
Deep brain stimulation
Action: deep brain stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is deep brain stimulation (NCIT:C21024). NCIT:C21024 is a clinical intervention from the NCI Thesaurus. Ontology label: Deep Brain Stimulation NCIT:C21024
Five reviewed patients benefited from deep brain stimulation, but the abstract did not specify treatment indications or the stimulation target.
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"Five patients benefited from deep brain stimulation."
Systematic review reports DBS benefit in five patients.
Multidisciplinary supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Supportive care addresses gait and postural instability, neuropsychiatric manifestations, feeding and aspiration risk, and musculoskeletal complications.
Target Phenotypes: Postural instability HP:0002172 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postural instability (HP:0002172). HP:0002172 is a phenotype from the Human Phenotype Ontology. Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301718 SUPPORT Other
"For individuals with adult PLAN, consider treatment with dopaminergic agents; treatment of neuropsychiatric manifestations by a psychiatrist; early care by a physical therapist and orthopedist to manage postural instability and gait difficulties and to prevent contractures as the disease progresses;"
GeneReviews supports multidisciplinary supportive management for adult PLAN.
PMID:20301718 SUPPORT Other
"feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition."
GeneReviews supports feeding modification for dysphagia and aspiration risk in adult PLAN.
🔬

Diagnosis

2
PLA2G6 molecular genetic testing
Molecular genetic testing confirms the diagnosis by identifying biallelic pathogenic PLA2G6 variants in a compatible clinical presentation.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic PLA2G6 variants establish PLAN.
Show evidence (1 reference)
PMID:20301718 SUPPORT Other
"The diagnosis of PLAN is established in a proband with suggestive findings and biallelic pathogenic variants in PLA2G6 identified by molecular genetic testing."
GeneReviews supports molecular genetic confirmation.
Brain MRI
Brain MRI supports the diagnosis by identifying cerebral or cerebellar atrophy and by assessing whether basal ganglia iron or mineralization is present, recognizing that iron deposition is variable in adult-onset cases.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Results: Cerebral/cerebellar atrophy and variable iron deposition support PLA2G6-related parkinsonism.
Show evidence (2 references)
PMID:18570303 SUPPORT Human Clinical
"cerebral and cerebellar atrophy on magnetic resonance imaging but absent iron in the basal ganglia."
Original adult-onset cases support MRI atrophy and show that absent iron does not exclude the diagnosis.
PMID:34622992 SUPPORT Human Clinical
"Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%."
Systematic review supports MRI atrophy and variable mineralization.
🩻

Imaging Findings

3
Cerebral atrophy on MRI FREQUENT
Generalized cerebral atrophy is a frequent supportive MRI feature of PLA2G6-related parkinsonism, but it is not specific to this disorder.
Mri Diffuse
Generalized cerebral atrophy HP:0007058 Human Phenotype Ontology (HP) brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Generalized cerebral atrophy HP:0007058 Human Phenotype Ontology (HP)
A supportive rather than pathognomonic structural imaging feature.
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%."
The systematic review quantifies cerebral atrophy on MRI in affected people.
Cerebellar atrophy on MRI FREQUENT
Cerebellar atrophy is a frequent supportive MRI feature of PLA2G6-related parkinsonism, but it is not specific to this disorder.
Mri Diffuse
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP)
A supportive rather than pathognomonic structural imaging feature.
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%."
The systematic review quantifies cerebellar atrophy on MRI in affected people.
Variable basal-ganglia iron or mineralization on MRI OCCASIONAL
Basal-ganglia iron or mineralization is variable in adult PLAN and may be absent, so its absence does not exclude the diagnosis.
Mri
Iron accumulation in brain HP:0012675 Human Phenotype Ontology (HP) basal ganglion UBERON:0002420 Uberon multi-species anatomy ontology (UBERON) Iron accumulation in brain HP:0012675 Human Phenotype Ontology (HP)
A variable supportive feature that is not required for adult-onset PLAN.
Show evidence (2 references)
PMID:18570303 SUPPORT Human Clinical
"cerebral and cerebellar atrophy on magnetic resonance imaging but absent iron in the basal ganglia."
The original adult-onset series documents that basal-ganglia iron can be absent.
PMID:34622992 SUPPORT Human Clinical
"Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%."
The systematic review quantifies mineralization as a minority MRI finding.
📈

Progression

2
Young-adult onset
Age: Late teens to early adulthood
Adult PLAN usually begins in adolescence or early adulthood with gait, parkinsonian, dystonic, psychiatric, or cognitive manifestations; the reported median onset in the largest review was 23 years.
Show evidence (3 references)
ORPHA:199351 SUPPORT Other
"Age of onset: Adolescent"
Orphanet records adolescent onset for this disorder.
ORPHA:199351 SUPPORT Other
"Age of onset: Adult"
Orphanet also records adult onset.
PMID:34622992 SUPPORT Human Clinical
"Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features."
The systematic review characterizes the typical age and presenting manifestations.
Progressive multisystem neurologic decline
Age: Years after onset
Motor, cognitive, psychiatric, pyramidal, cerebellar, and autonomic involvement can accumulate during a relatively rapid progressive course; duration remains variable across affected individuals.
Show evidence (2 references)
PMID:20938027 SUPPORT Human Clinical
"Disease progression was relatively rapid."
A human PARK14 series directly describes the disease as relatively rapidly progressive.
PMID:34622992 SUPPORT Human Clinical
"In five deceased patients, median disease duration was 13.0 years."
Median duration in five deceased patients provides partial timing context for the progressive course.
📊

Prevalence

1
Worldwide
Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000
Orphanet records worldwide point prevalence below one per million.
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"| <1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET |"
Orphanet lists worldwide point prevalence below one per million.
{ }

Source YAML

click to show 
name: Adult-Onset Dystonia-Parkinsonism
creation_date: "2026-05-06T17:06:40Z"
category: Genetic
parents:
- PLA2G6-associated neurodegeneration
- Neurodegenerative Disease
- Movement Disorder
disease_term:
  preferred_term: adult-onset dystonia-parkinsonism
  term:
    id: MONDO:0013060
    label: autosomal recessive Parkinson disease 14
description: >-
  Adult-onset dystonia-parkinsonism is an autosomal recessive
  PLA2G6-associated neurodegeneration spectrum disorder, usually presenting
  before age 30 with levodopa-responsive parkinsonism, dystonia, pyramidal
  signs, cognitive or psychiatric features, and variable cerebral or cerebellar
  atrophy and brain iron deposition.
references:
- reference: ORPHA:199351
  title: Adult-onset dystonia-parkinsonism
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      Orphanet defines adult-onset dystonia-parkinsonism as a rare
      neurodegenerative disease with dystonia, L-dopa-responsive parkinsonism,
      pyramidal signs, and rapid cognitive decline.
    supporting_text: >-
      A rare neurodegenerative disease usually presenting before the age of 30
      and which is characterized by dystonia, L-dopa-responsive parkinsonism,
      pyramidal signs and rapid cognitive decline.
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A rare neurodegenerative disease usually presenting before the age of 30
        and which is characterized by dystonia, L-dopa-responsive parkinsonism,
        pyramidal signs and rapid cognitive decline.
      explanation: Orphanet directly defines the disease and its core presentation.
- reference: PMID:18570303
  title: Characterization of PLA2G6 as a locus for dystonia-parkinsonism.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      Homozygosity mapping identified PLA2G6 mutations in families with
      adult-onset levodopa-responsive dystonia-parkinsonism.
    supporting_text: >-
      METHODS: We used homozygosity mapping and mutational analysis in three
      individuals from two unrelated families who presented with adult-onset
      levodopa-responsive dystonia-parkinsonism, pyramidal signs and
      cognitive/psychiatric features, and cerebral and cerebellar atrophy on
      magnetic resonance imaging but absent iron in the basal ganglia. RESULTS:
      We identified areas of homozygosity on chromosome 22 and, subsequently,
      PLA2G6 mutations.
    evidence:
    - reference: PMID:18570303
      reference_title: "Characterization of PLA2G6 as a locus for dystonia-parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        METHODS: We used homozygosity mapping and mutational analysis in three
        individuals from two unrelated families who presented with adult-onset
        levodopa-responsive dystonia-parkinsonism, pyramidal signs and
        cognitive/psychiatric features, and cerebral and cerebellar atrophy on
        magnetic resonance imaging but absent iron in the basal ganglia. RESULTS:
        We identified areas of homozygosity on chromosome 22 and, subsequently,
        PLA2G6 mutations.
      explanation: Family homozygosity mapping identified PLA2G6 mutations in the adult-onset phenotype.
- reference: PMID:16783378
  title: PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      PLA2G6 encodes a calcium-independent group VI phospholipase A2 and was
      identified in NBIA, INAD, and Karak syndrome families.
    supporting_text: >-
      We mapped a locus for infantile neuroaxonal dystrophy (INAD) and
      neurodegeneration with brain iron accumulation (NBIA) to chromosome
      22q12-q13 and identified mutations in PLA2G6, encoding a
      calcium-independent group VI phospholipase A2, in NBIA, INAD and the
      related Karak syndrome.
    evidence:
    - reference: PMID:16783378
      reference_title: "PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We mapped a locus for infantile neuroaxonal dystrophy (INAD) and
        neurodegeneration with brain iron accumulation (NBIA) to chromosome
        22q12-q13 and identified mutations in PLA2G6, encoding a
        calcium-independent group VI phospholipase A2, in NBIA, INAD and the
        related Karak syndrome.
      explanation: Human genetic mapping established PLA2G6 in the PLAN spectrum.
- reference: PMID:20938027
  title: Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      Additional PARK14 cases show early-onset L-dopa-responsive parkinsonism
      with dementia, frontotemporal atrophy, and variable iron accumulation.
    supporting_text: >-
      All 3 patients had early-onset l-dopa-responsive parkinsonism with
      dementia and frontotemporal lobar atrophy. Disease progression was
      relatively rapid. SPECT in patient B1 showed frontotemporal lobar
      hypoperfusion. MRI in patient A showed iron accumulation in the substantia
      nigra and striatum.
    evidence:
    - reference: PMID:20938027
      reference_title: "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All 3 patients had early-onset l-dopa-responsive parkinsonism with
        dementia and frontotemporal lobar atrophy. Disease progression was
        relatively rapid. SPECT in patient B1 showed frontotemporal lobar
        hypoperfusion. MRI in patient A showed iron accumulation in the substantia
        nigra and striatum.
      explanation: The human series documents the characteristic motor, cognitive, and imaging phenotype.
- reference: PMID:20301718
  title: PLA2G6-Associated Neurodegeneration.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: GeneReviews describes the typical onset and motor-cognitive presentation of adult PLAN.
    supporting_text: >-
      Adult PLAN has a variable age of onset, but most individuals present in
      early adulthood with gait disturbance or neuropsychiatric changes.
      Affected individuals consistently develop dystonia and parkinsonism
      (which may be accompanied by rapid cognitive decline) in their late teens
      to early twenties.
    evidence:
    - reference: PMID:20301718
      reference_title: "PLA2G6-Associated Neurodegeneration."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Adult PLAN has a variable age of onset, but most individuals present in
        early adulthood with gait disturbance or neuropsychiatric changes.
        Affected individuals consistently develop dystonia and parkinsonism
        (which may be accompanied by rapid cognitive decline) in their late teens
        to early twenties.
      explanation: GeneReviews summarizes the characteristic adult PLAN presentation.
- reference: PMID:20619503
  title: Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      PLA2G6-mutant dystonia-parkinsonism cases can show widespread
      alpha-synuclein-positive Lewy pathology and hyperphosphorylated tau with
      neurofibrillary tangles.
    supporting_text: >-
      Brain was available in 5 cases with an age of death ranging from 8 to 36
      years and showed widespread alpha-synuclein-positive Lewy pathology,
      which was particularly severe in the neocortex, indicating that the Lewy
      pathology spread corresponded to Braak stage 6 and was that of the
      "diffuse neocortical type". In 3 cases there was hyperphosphorylated tau
      accumulation in both cellular processes as threads and neuronal perikarya
      as pretangles and neurofibrillary tangles.
    evidence:
    - reference: PMID:20619503
      reference_title: "Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain was available in 5 cases with an age of death ranging from 8 to 36
        years and showed widespread alpha-synuclein-positive Lewy pathology,
        which was particularly severe in the neocortex, indicating that the Lewy
        pathology spread corresponded to Braak stage 6 and was that of the
        "diffuse neocortical type". In 3 cases there was hyperphosphorylated tau
        accumulation in both cellular processes as threads and neuronal perikarya
        as pretangles and neurofibrillary tangles.
      explanation: Human autopsy material directly documents the mixed Lewy and tau pathology.
- reference: PMID:34622992
  title: Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      The largest PLA2G6-related parkinsonism series supports young onset,
      complex parkinsonism, common psychiatric and bladder manifestations,
      variable iron deposition, and early severe dyskinesias.
    supporting_text: >-
      CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism
      associated with dystonia, pyramidal and cerebellar signs, myoclonus, and
      cognitive impairment. Early psychiatric manifestations and bladder
      overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic
      resonance imaging features, whereas brain iron deposition is not. Early,
      severe dyskinesias are a tell-tale sign.
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism
        associated with dystonia, pyramidal and cerebellar signs, myoclonus, and
        cognitive impairment. Early psychiatric manifestations and bladder
        overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic
        resonance imaging features, whereas brain iron deposition is not. Early,
        severe dyskinesias are a tell-tale sign.
      explanation: The human case series and systematic review summarize the adult PARK14 phenotype.
- reference: PMID:26001724
  title: Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      Experimental PLA2G6 loss models and patient fibroblasts support lipid
      peroxidation, mitochondrial dysfunction, and membrane abnormalities as a
      core mechanism.
    supporting_text: >-
      Taken together, our findings demonstrate that loss of normal PLA2G6 gene
      activity leads to lipid peroxidation, mitochondrial dysfunction and
      subsequent mitochondrial membrane abnormalities.
    evidence:
    - reference: PMID:26001724
      reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        loss of iPLA2-VIA function leads to a number of mitochondrial
        abnormalities, including mitochondrial respiratory chain dysfunction,
        reduced ATP synthesis and abnormal mitochondrial morphology.
      explanation: Drosophila loss-of-function experiments support mitochondrial dysfunction.
    - reference: PMID:26001724
      reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Similar abnormalities were seen including elevated mitochondrial lipid
        peroxidation and mitochondrial membrane defects, as well as raised levels
        of cytoplasmic and mitochondrial reactive oxygen species.
      explanation: Patient-fibroblast experiments reproduce the mitochondrial abnormalities.
- reference: PMID:29909971
  title: Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      PLA2G6/iPLA2-VIA loss impairs retromer-mediated lipid recycling and
      elevates ceramides in a Parkinsonism-relevant model.
    supporting_text: >-
      Loss of iPLA2-VIA impairs retromer function, leading to a progressive
      increase in ceramide.
    evidence:
    - reference: PMID:29909971
      reference_title: "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Loss of iPLA2-VIA impairs retromer function, leading to a progressive
        increase in ceramide.
      explanation: Drosophila experiments directly connect iPLA2-VIA loss to retromer failure and ceramide accumulation.
- reference: PMID:30088174
  title: PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model.
  found_in:
  - Adult_Onset_Dystonia_Parkinsonism-deep-research-fallback.md
  findings:
  - statement: >-
      A PARK14 PLA2G6 knockin mouse model supports dopaminergic neuron loss,
      mitochondrial dysfunction, ER stress, and mitophagy impairment.
    supporting_text: >-
      Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes
      degeneration of SNpc dopaminergic neurons by causing mitochondrial
      dysfunction, elevated ER stress, mitophagy impairment, and transcriptional
      abnormality.
    evidence:
    - reference: PMID:30088174
      reference_title: "PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes
        degeneration of SNpc dopaminergic neurons by causing mitochondrial
        dysfunction, elevated ER stress, mitophagy impairment, and transcriptional
        abnormality.
      explanation: The knockin-mouse conclusion directly links the PARK14 allele to the modeled injury cascade.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Adult-onset dystonia-parkinsonism is part of the autosomal recessive
    PLA2G6-associated neurodegeneration spectrum and is caused by biallelic
    pathogenic PLA2G6 variants.
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet lists autosomal recessive inheritance.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLAN is inherited in an autosomal recessive manner."
    explanation: GeneReviews supports autosomal recessive inheritance for PLAN.
genetic:
- name: PLA2G6
  association: Biallelic pathogenic variants
  presence: Positive
  gene_term:
    preferred_term: PLA2G6
    term:
      id: hgnc:9039
      label: PLA2G6
  notes: >-
    Biallelic PLA2G6 variants define the adult dystonia-parkinsonism phenotype;
    reported late-onset alleles are often nontruncating, contributing to
    phenotypic variability within PLAN.
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | PLA2G6 | phospholipase A2 group VI | hgnc:9039 | Disease-causing
      germline mutation(s) in |
    explanation: Orphanet lists PLA2G6 as the disease-causing gene.
  - reference: PMID:18570303
    reference_title: "Characterization of PLA2G6 as a locus for dystonia-parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RESULTS: We identified areas of homozygosity on chromosome 22 and, subsequently, PLA2G6 mutations."
    explanation: Human family mapping identified PLA2G6 mutations.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment."
    explanation: Large case series and systematic review supports biallelic PLA2G6 causation.
progression:
- phase: Young-adult onset
  age_range: Late teens to early adulthood
  notes: >-
    Adult PLAN usually begins in adolescence or early adulthood with gait,
    parkinsonian, dystonic, psychiatric, or cognitive manifestations; the
    reported median onset in the largest review was 23 years.
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adolescent"
    explanation: Orphanet records adolescent onset for this disorder.
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet also records adult onset.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Young onset (median age, 23.0 years) with parkinsonism/dystonia,
      gait/balance, and/or psychiatric/cognitive symptoms were common presenting
      features.
    explanation: The systematic review characterizes the typical age and presenting manifestations.
- phase: Progressive multisystem neurologic decline
  age_range: Years after onset
  notes: >-
    Motor, cognitive, psychiatric, pyramidal, cerebellar, and autonomic
    involvement can accumulate during a relatively rapid progressive course;
    duration remains variable across affected individuals.
  evidence:
  - reference: PMID:20938027
    reference_title: "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease progression was relatively rapid."
    explanation: A human PARK14 series directly describes the disease as relatively rapidly progressive.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five deceased patients, median disease duration was 13.0 years."
    explanation: Median duration in five deceased patients provides partial timing context for the progressive course.
pathophysiology:
- name: PLA2G6 Functional Dysregulation
  description: >-
    Biallelic PLA2G6 variants alter group VIA calcium-independent phospholipase
    A2 beta function in adult PLAN. Reported parkinsonism alleles are mainly
    nontruncating, and biochemical assays can retain catalytic activity;
    altered regulation, protein interactions, or context-specific membrane
    homeostasis are therefore more conservative than an asserted catalytic
    loss-of-function mechanism.
  genes:
  - preferred_term: PLA2G6
    term:
      id: hgnc:9039
      label: PLA2G6
  molecular_functions:
  - preferred_term: phospholipase A2 activity
    term:
      id: GO:0004623
      label: A2-type glycerophospholipase activity
    modifier: DYSREGULATED
  biological_processes:
  - preferred_term: phospholipid metabolic process
    term:
      id: GO:0006644
      label: phospholipid metabolic process
    modifier: DYSREGULATED
  downstream:
  - target: Membrane Lipid and Retromer Homeostasis Disruption
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29909971
      reference_title: "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances
        retromer function to promote protein and lipid recycling.
      explanation: >-
        The fly loss-of-function model establishes this interaction, but only
        partially supports translation to nontruncating adult PARK14 alleles.
  - target: Mitochondrial Oxidative Injury
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30088174
      reference_title: "PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        PLA2G6D331Y/D331Y mice displayed mitochondrial dysfunction and
        upregulated ROS production, which may lead to activation of apoptotic
        cascade.
      explanation: A PARK14 knockin allele directly produced mitochondrial dysfunction and oxidative stress in mice.
    - reference: PMID:26001724
      reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Similar abnormalities were seen including elevated mitochondrial lipid
        peroxidation and mitochondrial membrane defects, as well as raised levels
        of cytoplasmic and mitochondrial reactive oxygen species.
      explanation: Patient fibroblasts support the mitochondrial branch, although they do not model a neural circuit.
  - target: Global Developmental Delay
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001263 | Global developmental delay | Occasional (29-5%) |"
      explanation: >-
        Orphanet reports this developmental feature, but its relevance to adult
        PARK14 versus pre-existing or broader PLAN involvement is unresolved.
  - target: Dyslexia
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0010522 | Dyslexia | Frequent (79-30%) |"
      explanation: >-
        Orphanet reports dyslexia, but its relevance to adult PARK14 versus
        pre-existing or broader PLAN involvement is unresolved.
  evidence:
  - reference: PMID:26001724
    reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Conversely, mutations associated with dystonia-parkinsonism did not impair catalytic activity."
    explanation: >-
      The full-text discussion cautions against equating the adult
      dystonia-parkinsonism phenotype with catalytic loss of function.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These are mainly nontruncating, which may explain the phenotypic
      heterogeneity of childhood- and late-onset PLA2G6-associated
      neurodegeneration.
    explanation: >-
      The adult parkinsonism series supports a mainly nontruncating variant
      spectrum rather than a uniform null mechanism.
- name: Membrane Lipid and Retromer Homeostasis Disruption
  description: >-
    Experimental loss of PLA2G6/iPLA2-VIA perturbs lipid recycling, elevates
    ceramides, and impairs Vps26/Vps35 retromer function, creating a
    membrane-fluidity and recycling defect that can compromise neuronal
    function.
  biological_processes:
  - preferred_term: phospholipid metabolic process
    term:
      id: GO:0006644
      label: phospholipid metabolic process
    modifier: DYSREGULATED
  - preferred_term: retrograde transport, endosome to Golgi
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
    modifier: DECREASED
  downstream:
  - target: Progressive Neuronal Dysfunction and Neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lysosomal stress
    evidence:
    - reference: PMID:29909971
      reference_title: "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Reducing ceramides with drugs, including myriocin or desipramine,
        alleviates lysosomal stress and suppresses neurodegeneration.
      explanation: >-
        Rescue in the fly model supports a ceramide-linked neurodegeneration
        route, but human adult-PARK14 translation remains unproven.
  evidence:
  - reference: PMID:29909971
    reference_title: "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that loss of iPLA2-VIA, the fly homolog of PLA2G6, reduces
      lifespan, impairs synaptic transmission, and causes neurodegeneration.
    explanation: >-
      Drosophila loss-of-function data support neuronal consequences of PLA2G6
      homolog disruption.
  - reference: PMID:29909971
    reference_title: "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances
      retromer function to promote protein and lipid recycling.
    explanation: >-
      The model organism study directly links the PLA2G6 homolog to retromer
      and lipid recycling.
  - reference: PMID:29909971
    reference_title: "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of iPLA2-VIA impairs retromer function, leading to a progressive
      increase in ceramide.
    explanation: >-
      This supports the direction of retromer and lipid-homeostasis disruption.
- name: Mitochondrial Oxidative Injury
  description: >-
    Experimental PLA2G6 loss and a PARK14 knockin allele produce mitochondrial
    membrane defects, respiratory-chain dysfunction, reduced ATP synthesis,
    reactive oxygen species, and lipid peroxidation in model systems and
    patient fibroblasts.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: INCREASED
  downstream:
  - target: Progressive Neuronal Dysfunction and Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30088174
      reference_title: "PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes
        degeneration of SNpc dopaminergic neurons by causing mitochondrial
        dysfunction, elevated ER stress, mitophagy impairment, and transcriptional
        abnormality.
      explanation: The knockin model directly connects mitochondrial dysfunction to neuronal degeneration.
  evidence:
  - reference: PMID:26001724
    reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      loss of iPLA2-VIA function leads to a number of mitochondrial
      abnormalities, including mitochondrial respiratory chain dysfunction,
      reduced ATP synthesis and abnormal mitochondrial morphology.
    explanation: >-
      Fly model data support mitochondrial respiratory and morphologic
      impairment after PLA2G6 homolog loss.
  - reference: PMID:26001724
    reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Similar abnormalities were seen including elevated mitochondrial lipid
      peroxidation and mitochondrial membrane defects, as well as raised levels
      of cytoplasmic and mitochondrial reactive oxygen species.
    explanation: >-
      Patient fibroblast data support mitochondrial oxidative injury in human
      PLA2G6-mutant cells.
  - reference: PMID:26001724
    reference_title: "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Taken together, our findings demonstrate that loss of normal PLA2G6 gene
      activity leads to lipid peroxidation, mitochondrial dysfunction and
      subsequent mitochondrial membrane abnormalities.
    explanation: >-
      The paper summarizes the integrated mechanism across its experimental
      systems.
- name: Progressive Neuronal Dysfunction and Neurodegeneration
  description: >-
    Convergent membrane-homeostasis and mitochondrial injury pathways produce
    progressive neuronal dysfunction across dopaminergic, pyramidal,
    cerebellar, autonomic, ocular-motor, bulbar, and cognitive networks. Human
    observations establish the multisystem phenotype, but most individual
    symptom routes remain mechanistically unresolved.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Basal Ganglia Dopaminergic Circuit Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30088174
      reference_title: "PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons."
      explanation: The mouse model supports dopaminergic degeneration, while the intervening human route remains unresolved.
  - target: Cerebral and Cerebellar Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
        cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
      explanation: Clinical co-occurrence supports the atrophy branch but not a direct molecular route.
  - target: Synuclein-Tau Proteinopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain pathology in three cases showed mixed Lewy and tau pathology."
      explanation: Human pathology establishes the branch in some cases without proving how neurodegeneration produces it.
  - target: Iron Accumulation in Brain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
        cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
      explanation: The cohort supports variable mineralization but not its causal route from neuronal dysfunction.
  - target: Hypometric Saccades
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000571 | Hypometric saccades | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the ocular-motor route remains unresolved.
  - target: Supranuclear Gaze Palsy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000605 | Supranuclear gaze palsy | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the ocular-motor route remains unresolved.
  - target: Eyelid Apraxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000658 | Eyelid apraxia | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the ocular-motor route remains unresolved.
  - target: Urinary Urgency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early bladder overactivity was present in 71.9% of cases."
      explanation: The cohort supports common bladder dysfunction but not the intervening autonomic mechanism.
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001257 | Spasticity | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the pyramidal route remains unresolved.
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001260 | Dysarthria | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the bulbar-motor route remains unresolved.
  - target: Myoclonus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001336 | Myoclonus | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the myoclonus route remains unresolved.
  - target: Hyperreflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001347 | Hyperreflexia | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the pyramidal route remains unresolved.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0002015 | Dysphagia | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the swallowing-network route remains unresolved.
  - target: Clumsiness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0002312 | Clumsiness | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the coordination route remains unresolved.
  - target: Stiff Hip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0025262 | Stiff hip | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the musculoskeletal route remains unresolved.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001250 | Seizure | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the epileptogenic route remains unresolved.
  - target: Frontotemporal Dementia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0002145 | Frontotemporal dementia | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence without attributing dementia directly to tau pathology.
  - target: Depression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000716 | Depression | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the psychiatric route remains unresolved.
  - target: Delusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000746 | Delusion | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the psychiatric route remains unresolved.
  - target: Personality Changes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000751 | Personality changes | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the psychiatric route remains unresolved.
  - target: Paranoia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0011999 | Paranoia | Occasional (29-5%) |"
      explanation: Orphanet supports occurrence; the psychiatric route remains unresolved.
  evidence:
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism
      associated with dystonia, pyramidal and cerebellar signs, myoclonus, and
      cognitive impairment.
    explanation: The human series supports progressive multisystem neurologic involvement.
- name: Basal Ganglia Dopaminergic Circuit Degeneration
  description: >-
    Dopaminergic nigrostriatal dysfunction and substantia nigra degeneration
    drive levodopa-responsive parkinsonism, bradykinesia, rigidity, tremor,
    dystonia, and postural instability.
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  downstream:
  - target: Levodopa-Responsive Parkinsonism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Parkinsonism was levodopa responsive but complicated by early, often
        severe dyskinesias.
      explanation: Treatment response supports dopaminergic circuit relevance but not a direct route from cell loss.
  - target: Bradykinesia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0002067 | Bradykinesia | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the specific circuit route remains inferential.
  - target: Rigidity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0002063 | Rigidity | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the specific circuit route remains inferential.
  - target: Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001337 | Tremor | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the specific circuit route remains inferential.
  - target: Postural Instability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0002172 | Postural instability | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the specific circuit route remains inferential.
  - target: Focal Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0004373 | Focal dystonia | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; dystonia is not reduced to dopaminergic cell loss.
  - target: Progressive Extrapyramidal Movement Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0007153 | Progressive extrapyramidal movement disorder | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the exact circuit route remains inferential.
  - target: Hypomimic Face
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0000338 | Hypomimic face | Frequent (79-30%) |"
      explanation: Orphanet supports occurrence; the specific circuit route remains inferential.
  - target: Generalized Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:199351
      reference_title: "Adult-onset dystonia-parkinsonism"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| HP:0001332 | Dystonia | Occasional (29-5%) |"
      explanation: Orphanet supports dystonia occurrence; generalized distribution is separately supported at phenotype level.
  evidence:
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presynaptic dopaminergic terminal imaging was abnormal in all where performed."
    explanation: >-
      Human imaging evidence supports presynaptic dopaminergic pathway
      involvement in PLA2G6-related parkinsonism.
  - reference: PMID:30088174
    reference_title: "PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons."
    explanation: >-
      Knockin mouse evidence supports substantia nigra dopaminergic neuron loss
      downstream of a PARK14 PLA2G6 mutation.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parkinsonism was levodopa responsive but complicated by early, often
      severe dyskinesias.
    explanation: >-
      Levodopa responsiveness supports dopaminergic circuit dysfunction as a
      driver of motor symptoms.
- name: Cerebral and Cerebellar Atrophy
  description: >-
    Neurodegeneration produces cerebral and/or cerebellar atrophy on MRI;
    frontotemporal atrophy and hypoperfusion are particularly reported in
    adult-onset PLA2G6-related parkinsonism.
  downstream:
  - target: Frontotemporal Cerebral Atrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20938027
      reference_title: "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All 3 patients had early-onset l-dopa-responsive parkinsonism with
        dementia and frontotemporal lobar atrophy.
      explanation: Human imaging directly supports the frontotemporal-atrophy manifestation.
  - target: Generalized Cerebral Atrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
        cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
      explanation: The cohort directly documents cerebral atrophy on MRI.
  evidence:
  - reference: PMID:18570303
    reference_title: "Characterization of PLA2G6 as a locus for dystonia-parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebral and cerebellar atrophy on magnetic resonance imaging but absent
      iron in the basal ganglia.
    explanation: >-
      The original adult-onset cases had MRI atrophy even without basal ganglia
      iron.
  - reference: PMID:20938027
    reference_title: "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 3 patients had early-onset l-dopa-responsive parkinsonism with
      dementia and frontotemporal lobar atrophy.
    explanation: >-
      A PLA2G6 parkinsonism series supports frontotemporal atrophy.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
      cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
    explanation: >-
      The systematic review quantifies frequent brain atrophy and variable
      mineralization.
- name: Synuclein-Tau Proteinopathy
  description: >-
    PLA2G6-related dystonia-parkinsonism can culminate in mixed
    alpha-synuclein-positive Lewy pathology and hyperphosphorylated tau
    pathology, linking the disorder to parkinsonian neurodegeneration and
    neurofibrillary tangles.
  downstream:
  - target: Neurofibrillary Tangles
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20619503
      reference_title: "Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 3 cases there was hyperphosphorylated tau accumulation in both cellular
        processes as threads and neuronal perikarya as pretangles and
        neurofibrillary tangles.
      explanation: Human neuropathology directly supports neurofibrillary tangles in the mixed proteinopathy branch.
  evidence:
  - reference: PMID:20619503
    reference_title: "Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain was available in 5 cases with an age of death ranging from 8 to 36
      years and showed widespread alpha-synuclein-positive Lewy pathology
    explanation: >-
      Human neuropathology supports widespread Lewy pathology in PLA2G6
      mutation cases.
  - reference: PMID:20619503
    reference_title: "Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 3 cases there was hyperphosphorylated tau accumulation in both cellular
      processes as threads and neuronal perikarya as pretangles and
      neurofibrillary tangles.
    explanation: >-
      Human neuropathology supports tau accumulation and neurofibrillary
      tangles.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain pathology in three cases showed mixed Lewy and tau pathology."
    explanation: >-
      A later systematic review confirms mixed Lewy and tau pathology in
      reported PLA2G6-related parkinsonism autopsies.
phenotypes:
- category: Craniofacial
  name: Hypomimic Face
  description: Hypomimia is a frequent facial motor manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypomimic face
    term:
      id: HP:0000338
      label: Hypomimic face
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000338 | Hypomimic face | Frequent (79-30%) |"
    explanation: Orphanet lists hypomimic face as frequent.
- category: Ophthalmologic
  name: Hypometric Saccades
  description: Hypometric saccades are frequent ocular motor findings.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypometric saccades
    term:
      id: HP:0000571
      label: Hypometric saccades
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000571 | Hypometric saccades | Frequent (79-30%) |"
    explanation: Orphanet lists hypometric saccades as frequent.
- category: Ophthalmologic
  name: Supranuclear Gaze Palsy
  description: Supranuclear gaze palsy is an occasional ocular motor feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Supranuclear gaze palsy
    term:
      id: HP:0000605
      label: Supranuclear gaze palsy
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000605 | Supranuclear gaze palsy | Occasional (29-5%) |"
    explanation: Orphanet lists supranuclear gaze palsy as occasional.
- category: Ophthalmologic
  name: Eyelid Apraxia
  description: Eyelid apraxia is a frequent ocular motor manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Eyelid apraxia
    term:
      id: HP:0000658
      label: Eyelid apraxia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000658 | Eyelid apraxia | Frequent (79-30%) |"
    explanation: Orphanet lists eyelid apraxia as frequent.
- category: Psychiatric
  name: Depression
  description: Depression is an occasional psychiatric feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000716 | Depression | Occasional (29-5%) |"
    explanation: Orphanet lists depression as occasional.
- category: Psychiatric
  name: Delusion
  description: Delusions are occasional psychiatric manifestations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Delusion
    term:
      id: HP:0000746
      label: Delusion
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000746 | Delusion | Occasional (29-5%) |"
    explanation: Orphanet lists delusion as occasional.
- category: Psychiatric
  name: Personality Changes
  description: Personality changes are occasional psychiatric manifestations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Personality changes
    term:
      id: HP:0000751
      label: Personality changes
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000751 | Personality changes | Occasional (29-5%) |"
    explanation: Orphanet lists personality changes as occasional.
- category: Urologic
  name: Urinary Urgency
  description: >-
    Early bladder overactivity is a frequent and clinically distinctive feature
    of PLA2G6-related parkinsonism.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Urinary urgency
    term:
      id: HP:0000012
      label: Urinary urgency
  evidence:
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early bladder overactivity was present in 71.9% of cases."
    explanation: >-
      Systematic review of 86 cases identifies bladder overactivity as a
      frequent and clinically distinctive feature.
- category: Neurologic
  name: Seizure
  description: Seizures are occasional neurologic manifestations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001250 | Seizure | Occasional (29-5%) |"
    explanation: Orphanet lists seizure as occasional.
- category: Neurologic
  name: Spasticity
  description: Spasticity is a frequent pyramidal motor feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001257 | Spasticity | Frequent (79-30%) |"
    explanation: Orphanet lists spasticity as frequent.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Over time, affected persons develop both weakness and symmetric spastic
      tetraparesis
    explanation: GeneReviews supports spastic motor involvement in PLAN.
- category: Neurologic
  name: Dysarthria
  description: Dysarthria is a frequent bulbar or motor speech manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001260 | Dysarthria | Frequent (79-30%) |"
    explanation: Orphanet lists dysarthria as frequent.
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: Global developmental delay is an occasional feature in the broader PLAN spectrum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001263 | Global developmental delay | Occasional (29-5%) |"
    explanation: Orphanet lists global developmental delay as occasional.
- category: Neurologic
  name: Generalized Dystonia
  description: Dystonia may be generalized in some individuals.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001332 | Dystonia | Occasional (29-5%) |"
    explanation: Orphanet lists dystonia as occasional.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dystonia is most common in the hands and feet but may be more generalized."
    explanation: GeneReviews supports variable dystonia distribution in adult PLAN.
- category: Neurologic
  name: Myoclonus
  description: Myoclonus is an occasional movement manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001336 | Myoclonus | Occasional (29-5%) |"
    explanation: Orphanet lists myoclonus as occasional.
- category: Neurologic
  name: Tremor
  description: Tremor is a frequent parkinsonian motor manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001337 | Tremor | Frequent (79-30%) |"
    explanation: Orphanet lists tremor as frequent.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common features of parkinsonism in these individuals are
      bradykinesia, resting tremor, rigidity, and postural instability.
    explanation: GeneReviews supports tremor as a common adult PLAN parkinsonian feature.
- category: Neurologic
  name: Hyperreflexia
  description: Hyperreflexia is a frequent pyramidal sign.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001347 | Hyperreflexia | Frequent (79-30%) |"
    explanation: Orphanet lists hyperreflexia as frequent.
- category: Gastrointestinal
  name: Dysphagia
  description: Dysphagia is a frequent bulbar manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002015 | Dysphagia | Frequent (79-30%) |"
    explanation: Orphanet lists dysphagia as frequent.
- category: Neurologic
  name: Rigidity
  description: Rigidity is a frequent parkinsonian motor manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002063 | Rigidity | Frequent (79-30%) |"
    explanation: Orphanet lists rigidity as frequent.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common features of parkinsonism in these individuals are
      bradykinesia, resting tremor, rigidity, and postural instability.
    explanation: GeneReviews supports rigidity as a common adult PLAN parkinsonian feature.
- category: Neurologic
  name: Bradykinesia
  description: Bradykinesia is a frequent parkinsonian motor manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002067 | Bradykinesia | Frequent (79-30%) |"
    explanation: Orphanet lists bradykinesia as frequent.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common features of parkinsonism in these individuals are
      bradykinesia, resting tremor, rigidity, and postural instability.
    explanation: GeneReviews supports bradykinesia as a common adult PLAN parkinsonian feature.
- category: Neurologic
  name: Frontotemporal Dementia
  description: Frontotemporal dementia is a frequent cognitive manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Frontotemporal dementia
    term:
      id: HP:0002145
      label: Frontotemporal dementia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002145 | Frontotemporal dementia | Frequent (79-30%) |"
    explanation: Orphanet lists frontotemporal dementia as frequent.
- category: Neurologic
  name: Postural Instability
  description: Postural instability is a frequent parkinsonian motor manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Postural instability
    term:
      id: HP:0002172
      label: Postural instability
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002172 | Postural instability | Frequent (79-30%) |"
    explanation: Orphanet lists postural instability as frequent.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common features of parkinsonism in these individuals are
      bradykinesia, resting tremor, rigidity, and postural instability.
    explanation: GeneReviews supports postural instability as a common adult PLAN parkinsonian feature.
- category: Neurologic
  name: Neurofibrillary Tangles
  description: Neurofibrillary tangles are frequent neuropathologic findings.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Neurofibrillary tangles
    term:
      id: HP:0002185
      label: Neurofibrillary tangles
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002185 | Neurofibrillary tangles | Frequent (79-30%) |"
    explanation: Orphanet lists neurofibrillary tangles as frequent.
  - reference: PMID:20619503
    reference_title: "Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 3 cases there was hyperphosphorylated tau accumulation in both cellular
      processes as threads and neuronal perikarya as pretangles and
      neurofibrillary tangles.
    explanation: Human neuropathology supports neurofibrillary tangles.
- category: Neurologic
  name: Clumsiness
  description: Clumsiness is a frequent motor coordination manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Clumsiness
    term:
      id: HP:0002312
      label: Clumsiness
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002312 | Clumsiness | Frequent (79-30%) |"
    explanation: Orphanet lists clumsiness as frequent.
- category: Neurologic
  name: Levodopa-Responsive Parkinsonism
  description: Parkinsonism frequently responds to dopaminergic medication.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Parkinsonism with favorable response to dopaminergic medication
    term:
      id: HP:0002548
      label: Parkinsonism with favorable response to dopaminergic medication
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0002548 | Parkinsonism with favorable response to dopaminergic
      medication | Frequent (79-30%) |
    explanation: Orphanet lists levodopa-responsive parkinsonism as frequent.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parkinsonism was levodopa responsive but complicated by early, often
      severe dyskinesias.
    explanation: Systematic review supports levodopa responsiveness.
- category: Neurologic
  name: Focal Dystonia
  description: Focal dystonia is frequent and often affects hands or feet.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Focal dystonia
    term:
      id: HP:0004373
      label: Focal dystonia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0004373 | Focal dystonia | Frequent (79-30%) |"
    explanation: Orphanet lists focal dystonia as frequent.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dystonia is most common in the hands and feet but may be more generalized."
    explanation: GeneReviews supports frequent focal limb dystonia distribution.
- category: Neurologic
  name: Frontotemporal Cerebral Atrophy
  description: Frontotemporal cerebral atrophy is frequent on neuroimaging.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Frontotemporal cerebral atrophy
    term:
      id: HP:0006892
      label: Frontotemporal cerebral atrophy
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0006892 | Frontotemporal cerebral atrophy | Frequent (79-30%) |"
    explanation: Orphanet lists frontotemporal cerebral atrophy as frequent.
  - reference: PMID:20938027
    reference_title: "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 3 patients had early-onset l-dopa-responsive parkinsonism with
      dementia and frontotemporal lobar atrophy.
    explanation: Human PLA2G6 parkinsonism cases support frontotemporal atrophy.
- category: Neurologic
  name: Generalized Cerebral Atrophy
  description: Generalized cerebral atrophy or hypoplasia is frequent on neuroimaging.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized cerebral atrophy/hypoplasia
    term:
      id: HP:0007058
      label: Generalized cerebral atrophy/hypoplasia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0007058 | Generalized cerebral atrophy/hypoplasia | Frequent
      (79-30%) |
    explanation: Orphanet lists generalized cerebral atrophy/hypoplasia as frequent.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
      cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
    explanation: Systematic review supports frequent cerebral atrophy.
- category: Neurologic
  name: Progressive Extrapyramidal Movement Disorder
  description: Progressive extrapyramidal movement disorder is a frequent motor phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Progressive extrapyramidal movement disorder
    term:
      id: HP:0007153
      label: Progressive extrapyramidal movement disorder
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0007153 | Progressive extrapyramidal movement disorder | Frequent
      (79-30%) |
    explanation: Orphanet lists progressive extrapyramidal movement disorder as frequent.
- category: Neurodevelopmental
  name: Dyslexia
  description: Dyslexia is a frequent neurodevelopmental feature in Orphanet.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dyslexia
    term:
      id: HP:0010522
      label: Dyslexia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0010522 | Dyslexia | Frequent (79-30%) |"
    explanation: Orphanet lists dyslexia as frequent.
- category: Psychiatric
  name: Paranoia
  description: Paranoia is an occasional psychiatric feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Paranoia
    term:
      id: HP:0011999
      label: Paranoia
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0011999 | Paranoia | Occasional (29-5%) |"
    explanation: Orphanet lists paranoia as occasional.
- category: Neurologic
  name: Iron Accumulation in Brain
  description: Brain iron accumulation is occasional and may be absent in adult cases.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Iron accumulation in brain
    term:
      id: HP:0012675
      label: Iron accumulation in brain
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0012675 | Iron accumulation in brain | Occasional (29-5%) |"
    explanation: Orphanet lists brain iron accumulation as occasional.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebro/cerebellar atrophy are frequent magnetic resonance imaging
      features, whereas brain iron deposition is not.
    explanation: >-
      Systematic review supports brain iron as variable rather than required.
- category: Musculoskeletal
  name: Stiff Hip
  description: Stiff hip is a frequent musculoskeletal manifestation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Stiff hip
    term:
      id: HP:0025262
      label: Stiff hip
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0025262 | Stiff hip | Frequent (79-30%) |"
    explanation: Orphanet lists stiff hip as frequent.
- category: Biochemical
  name: Abnormal Circulating Creatine Kinase Concentration
  description: Abnormal circulating creatine kinase concentration is frequent.
  frequency: FREQUENT
  notes: >-
    The available Orphanet record establishes this laboratory phenotype but
    does not identify its tissue origin or connect it specifically to neuronal
    mitochondrial oxidative injury. It is intentionally left without a
    pathograph readout target pending source-backed evidence of the measured
    mechanism.
  phenotype_term:
    preferred_term: Abnormal circulating creatine kinase concentration
    term:
      id: HP:0040081
      label: Abnormal circulating creatine kinase concentration
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0040081 | Abnormal circulating creatine kinase concentration |
      Frequent (79-30%) |
    explanation: >-
      Orphanet lists abnormal circulating creatine kinase concentration as
      frequent.
imaging_findings:
- name: Cerebral atrophy on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Generalized cerebral atrophy
    term:
      id: HP:0007058
      label: Generalized cerebral atrophy/hypoplasia
  description: >-
    Generalized cerebral atrophy is a frequent supportive MRI feature of
    PLA2G6-related parkinsonism, but it is not specific to this disorder.
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  spatial_extent: DIFFUSE
  phenotype_term:
    preferred_term: Generalized cerebral atrophy
    term:
      id: HP:0007058
      label: Generalized cerebral atrophy/hypoplasia
  diagnostic: false
  frequency: FREQUENT
  notes: A supportive rather than pathognomonic structural imaging feature.
  evidence:
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
      cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
    explanation: The systematic review quantifies cerebral atrophy on MRI in affected people.
- name: Cerebellar atrophy on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  description: >-
    Cerebellar atrophy is a frequent supportive MRI feature of PLA2G6-related
    parkinsonism, but it is not specific to this disorder.
  located_in:
    preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  spatial_extent: DIFFUSE
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  diagnostic: false
  frequency: FREQUENT
  notes: A supportive rather than pathognomonic structural imaging feature.
  evidence:
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
      cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
    explanation: The systematic review quantifies cerebellar atrophy on MRI in affected people.
- name: Variable basal-ganglia iron or mineralization on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Iron accumulation in brain
    term:
      id: HP:0012675
      label: Iron accumulation in brain
  description: >-
    Basal-ganglia iron or mineralization is variable in adult PLAN and may be
    absent, so its absence does not exclude the diagnosis.
  located_in:
    preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  phenotype_term:
    preferred_term: Iron accumulation in brain
    term:
      id: HP:0012675
      label: Iron accumulation in brain
  diagnostic: false
  frequency: OCCASIONAL
  notes: A variable supportive feature that is not required for adult-onset PLAN.
  evidence:
  - reference: PMID:18570303
    reference_title: "Characterization of PLA2G6 as a locus for dystonia-parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebral and cerebellar atrophy on magnetic resonance imaging but absent
      iron in the basal ganglia.
    explanation: The original adult-onset series documents that basal-ganglia iron can be absent.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
      cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
    explanation: The systematic review quantifies mineralization as a minority MRI finding.
diagnosis:
- name: PLA2G6 molecular genetic testing
  description: >-
    Molecular genetic testing confirms the diagnosis by identifying biallelic
    pathogenic PLA2G6 variants in a compatible clinical presentation.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: PLA2G6
        term:
          id: hgnc:9039
          label: PLA2G6
  results: Biallelic pathogenic PLA2G6 variants establish PLAN.
  evidence:
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of PLAN is established in a proband with suggestive findings
      and biallelic pathogenic variants in PLA2G6 identified by molecular
      genetic testing.
    explanation: GeneReviews supports molecular genetic confirmation.
- name: Brain MRI
  description: >-
    Brain MRI supports the diagnosis by identifying cerebral or cerebellar
    atrophy and by assessing whether basal ganglia iron or mineralization is
    present, recognizing that iron deposition is variable in adult-onset cases.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Cerebral/cerebellar atrophy and variable iron deposition support PLA2G6-related parkinsonism.
  evidence:
  - reference: PMID:18570303
    reference_title: "Characterization of PLA2G6 as a locus for dystonia-parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebral and cerebellar atrophy on magnetic resonance imaging but absent
      iron in the basal ganglia.
    explanation: >-
      Original adult-onset cases support MRI atrophy and show that absent iron
      does not exclude the diagnosis.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging findings included cerebral (49.3%) and/or
      cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%.
    explanation: Systematic review supports MRI atrophy and variable mineralization.
treatments:
- name: Levodopa and dopaminergic agents
  description: >-
    Levodopa or other dopaminergic agents may improve parkinsonism in adult
    PLAN, although early severe dyskinesias can complicate therapy.
  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 with favorable response to dopaminergic medication
    term:
      id: HP:0002548
      label: Parkinsonism with favorable response to dopaminergic medication
  target_mechanisms:
  - target: Basal Ganglia Dopaminergic Circuit Degeneration
    treatment_effect: MODULATES
    description: Dopaminergic therapy partially replaces downstream dopaminergic signaling.
    evidence:
    - reference: PMID:34622992
      reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Parkinsonism was levodopa responsive but complicated by early, often
        severe dyskinesias.
      explanation: >-
        Clinical response supports the relevance of dopaminergic motor circuits
        but does not directly demonstrate structural target modulation.
  evidence:
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For individuals with adult PLAN, consider treatment with dopaminergic agents;"
    explanation: GeneReviews recommends considering dopaminergic agents in adult PLAN.
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parkinsonism was levodopa responsive but complicated by early, often
      severe dyskinesias.
    explanation: Human systematic review supports levodopa responsiveness and notes dyskinesia risk.
- name: Deep brain stimulation
  description: >-
    Five reviewed patients benefited from deep brain stimulation, but the
    abstract did not specify treatment indications or the stimulation target.
  treatment_term:
    preferred_term: deep brain stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  evidence:
  - reference: PMID:34622992
    reference_title: "Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients benefited from deep brain stimulation."
    explanation: Systematic review reports DBS benefit in five patients.
- name: Multidisciplinary supportive care
  description: >-
    Supportive care addresses gait and postural instability, neuropsychiatric
    manifestations, feeding and aspiration risk, and musculoskeletal
    complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Postural instability
    term:
      id: HP:0002172
      label: Postural instability
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For individuals with adult PLAN, consider treatment with dopaminergic
      agents; treatment of neuropsychiatric manifestations by a psychiatrist;
      early care by a physical therapist and orthopedist to manage postural
      instability and gait difficulties and to prevent contractures as the
      disease progresses;
    explanation: >-
      GeneReviews supports multidisciplinary supportive management for adult
      PLAN.
  - reference: PMID:20301718
    reference_title: "PLA2G6-Associated Neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition."
    explanation: GeneReviews supports feeding modification for dysphagia and aspiration risk in adult PLAN.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  percentage: <1 / 1 000 000
  notes: Orphanet records worldwide point prevalence below one per million.
  evidence:
  - reference: ORPHA:199351
    reference_title: "Adult-onset dystonia-parkinsonism"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| <1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET |"
    explanation: Orphanet lists worldwide point prevalence below one per million.
📚

References & Deep Research

References

10
ORPHA:199351
Adult-onset dystonia-parkinsonism
1 finding
Orphanet defines adult-onset dystonia-parkinsonism as a rare neurodegenerative disease with dystonia, L-dopa-responsive parkinsonism, pyramidal signs, and rapid cognitive decline.
"A rare neurodegenerative disease usually presenting before the age of 30 and which is characterized by dystonia, L-dopa-responsive parkinsonism, pyramidal signs and rapid cognitive decline."
Show evidence (1 reference)
ORPHA:199351 SUPPORT Other
"A rare neurodegenerative disease usually presenting before the age of 30 and which is characterized by dystonia, L-dopa-responsive parkinsonism, pyramidal signs and rapid cognitive decline."
Orphanet directly defines the disease and its core presentation.
PMID:18570303
Characterization of PLA2G6 as a locus for dystonia-parkinsonism.
1 finding
Homozygosity mapping identified PLA2G6 mutations in families with adult-onset levodopa-responsive dystonia-parkinsonism.
"METHODS: We used homozygosity mapping and mutational analysis in three individuals from two unrelated families who presented with adult-onset levodopa-responsive dystonia-parkinsonism, pyramidal signs and cognitive/psychiatric features, and cerebral and cerebellar atrophy on magnetic resonance..."
Show evidence (1 reference)
PMID:18570303 SUPPORT Human Clinical
"METHODS: We used homozygosity mapping and mutational analysis in three individuals from two unrelated families who presented with adult-onset levodopa-responsive dystonia-parkinsonism, pyramidal signs and cognitive/psychiatric features, and cerebral and cerebellar atrophy on magnetic resonance..."
Family homozygosity mapping identified PLA2G6 mutations in the adult-onset phenotype.
PMID:16783378
PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.
1 finding
PLA2G6 encodes a calcium-independent group VI phospholipase A2 and was identified in NBIA, INAD, and Karak syndrome families.
"We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome."
Show evidence (1 reference)
PMID:16783378 SUPPORT Human Clinical
"We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome."
Human genetic mapping established PLA2G6 in the PLAN spectrum.
PMID:20938027
Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism.
1 finding
Additional PARK14 cases show early-onset L-dopa-responsive parkinsonism with dementia, frontotemporal atrophy, and variable iron accumulation.
"All 3 patients had early-onset l-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy. Disease progression was relatively rapid. SPECT in patient B1 showed frontotemporal lobar hypoperfusion. MRI in patient A showed iron accumulation in the substantia nigra and striatum."
Show evidence (1 reference)
PMID:20938027 SUPPORT Human Clinical
"All 3 patients had early-onset l-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy. Disease progression was relatively rapid. SPECT in patient B1 showed frontotemporal lobar hypoperfusion. MRI in patient A showed iron accumulation in the substantia nigra and striatum."
The human series documents the characteristic motor, cognitive, and imaging phenotype.
PMID:20301718
PLA2G6-Associated Neurodegeneration.
1 finding
GeneReviews describes the typical onset and motor-cognitive presentation of adult PLAN.
"Adult PLAN has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties."
Show evidence (1 reference)
PMID:20301718 SUPPORT Other
"Adult PLAN has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties."
GeneReviews summarizes the characteristic adult PLAN presentation.
PMID:20619503
Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.
1 finding
PLA2G6-mutant dystonia-parkinsonism cases can show widespread alpha-synuclein-positive Lewy pathology and hyperphosphorylated tau with neurofibrillary tangles.
"Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the "diffuse..."
Show evidence (1 reference)
PMID:20619503 SUPPORT Human Clinical
"Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the "diffuse..."
Human autopsy material directly documents the mixed Lewy and tau pathology.
PMID:34622992
Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.
1 finding
The largest PLA2G6-related parkinsonism series supports young onset, complex parkinsonism, common psychiatric and bladder manifestations, variable iron deposition, and early severe dyskinesias.
"CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance..."
Show evidence (1 reference)
PMID:34622992 SUPPORT Human Clinical
"CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance..."
The human case series and systematic review summarize the adult PARK14 phenotype.
PMID:26001724
Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction.
1 finding
Experimental PLA2G6 loss models and patient fibroblasts support lipid peroxidation, mitochondrial dysfunction, and membrane abnormalities as a core mechanism.
"Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities."
Show evidence (2 references)
PMID:26001724 SUPPORT Model Organism
"loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology."
Drosophila loss-of-function experiments support mitochondrial dysfunction.
+ 1 more reference
PMID:29909971
Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain.
1 finding
PLA2G6/iPLA2-VIA loss impairs retromer-mediated lipid recycling and elevates ceramides in a Parkinsonism-relevant model.
"Loss of iPLA2-VIA impairs retromer function, leading to a progressive increase in ceramide."
Show evidence (1 reference)
PMID:29909971 SUPPORT Model Organism
"Loss of iPLA2-VIA impairs retromer function, leading to a progressive increase in ceramide."
Drosophila experiments directly connect iPLA2-VIA loss to retromer failure and ceramide accumulation.
PMID:30088174
PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model.
1 finding
A PARK14 PLA2G6 knockin mouse model supports dopaminergic neuron loss, mitochondrial dysfunction, ER stress, and mitophagy impairment.
"Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality."
Show evidence (1 reference)
PMID:30088174 SUPPORT Model Organism
"Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality."
The knockin-mouse conclusion directly links the PARK14 allele to the modeled injury cascade.

Deep Research

1
Adult-Onset Dystonia-Parkinsonism Deep Research Fallback ▸

Adult-Onset Dystonia-Parkinsonism Deep Research Fallback

Provider Attempts

  • falcon: timeout 75s just research-disorder falcon Adult_Onset_Dystonia_Parkinsonism was terminated by timeout with signal 15 before returning content.
  • openai: timeout 75s just research-disorder openai Adult_Onset_Dystonia_Parkinsonism was terminated by timeout with signal 15 before returning content.
  • perplexity: timeout 75s just research-disorder perplexity Adult_Onset_Dystonia_Parkinsonism failed immediately with an API quota/401 error.

Because the preferred deep-research providers did not return usable content in bounded attempts, this fallback records the literature scope used for curation. All YAML evidence was taken from generated Orphanet and PubMed reference caches, not from hand-created reference text.

Literature Scope

Adult-onset dystonia-parkinsonism corresponds to Orphanet ORPHA:199351 and MONDO:0013060. Orphanet defines it as a rare neurodegenerative disease usually presenting before age 30 with dystonia, L-dopa-responsive parkinsonism, pyramidal signs, and rapid cognitive decline. Orphanet also provides the autosomal recessive inheritance, PLA2G6 gene association, point prevalence, and HPO phenotype frequency table used for the phenotype section.

The original locus paper used homozygosity mapping and mutational analysis in families with adult-onset levodopa-responsive dystonia-parkinsonism, pyramidal signs, cognitive/psychiatric features, and cerebral/cerebellar atrophy to identify PLA2G6 mutations. A subsequent PARK14 phenotype-spectrum study found compound heterozygous PLA2G6 mutations in early-onset L-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy, with variable iron accumulation.

GeneReviews frames PLA2G6-associated neurodegeneration as an age-related continuum and describes adult PLAN as gait disturbance or neuropsychiatric onset followed by dystonia and parkinsonism in the late teens to early twenties. It supports diagnosis by biallelic pathogenic PLA2G6 variants, autosomal recessive inheritance, consideration of dopaminergic agents for adult PLAN, and multidisciplinary supportive management.

The largest PLA2G6-related parkinsonism systematic review describes young onset with parkinsonism/dystonia, gait/balance, psychiatric/cognitive symptoms, frequent pyramidal signs, myoclonus, cognitive impairment, levodopa responsiveness complicated by dyskinesias, DBS benefit in some patients, cerebral/cerebellar atrophy, variable mineralization, abnormal presynaptic dopaminergic terminal imaging, and mixed Lewy/tau pathology in autopsied cases.

Mechanistically, PLA2G6 encodes calcium-independent group VI phospholipase A2. Experimental evidence supports membrane lipid and retromer disruption, ceramide elevation, mitochondrial respiratory-chain dysfunction, reduced ATP synthesis, abnormal mitochondrial morphology, lipid peroxidation, elevated ROS, patient-fibroblast mitochondrial membrane defects, and dopaminergic neuron degeneration in a PARK14 knockin mouse model. Human neuropathology supports widespread alpha-synuclein-positive Lewy pathology and hyperphosphorylated tau with neurofibrillary tangles.

Curation Decisions

  • Used ORPHA:199351 for disease scope, inheritance, prevalence, gene mapping, and HPO phenotype frequencies.
  • Used MONDO:0013060 as the disease term, preserving its canonical label "autosomal recessive Parkinson disease 14" while using the Orphanet name as the display/preferred term.
  • Represented brain iron accumulation as occasional and variable, not required, because adult-onset series report absent iron in some cases and systematic review data indicate mineralization in a minority.
  • Added levodopa/dopaminergic therapy, DBS, and multidisciplinary supportive care only where cached evidence directly supported those interventions.
  • Avoided unsupported disease-modifying therapy claims; experimental deuterated polyunsaturated fatty acid rescue in models was kept out of the treatment section because it is not established clinical care for this disorder.