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parkinsonism-dystonia 3, childhood-onset - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

parkinsonism-dystonia 3, childhood-onset

MONDO:0030676

Also known as:PKDYS3

Overview

GeneticsAutosomal recessive · WARS2 (chr 1)

ResearchLimited published research (5 articles)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Hyperkinetic movements, Hypertonia, Action tremor, and Dystonia and others; and common findings: Ataxia, Depression, Anxiety, and Intellectual disability and others. 24 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	15	Action tremor, Dystonia, Global brain atrophy

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

WARS2 function has not been fully characterized.

Parkinsonism-dystonia 3, childhood-onset is associated with mutations in the WARS2 gene on chromosome 1.

GeneReviews

Clinical Guidance

Several genotype-phenotype correlations have been observed. Biallelic loss-of-function WARS2 pathogenic variants are typically associated with neonatal- or infantile-onset DEE. However, at least two individuals with biallelic loss-of-function WARS2 variants had levodopa-responsive parkinsonism/dystonia . . Evidence suggests that the common WARS2 variant c.37TG (p.Trp13Gly) is a hypomorphic variant that is disease causing only when in the compound heterozygous state with a loss-of-function variant. While individuals with the hypomorphic p.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

No consensus clinical diagnostic criteria for WARS2 deficiency have been published.

Suggestive Findings

WARS2 deficiency should be considered in a proband with the following clinical, laboratory and imaging findings, and family history.

Epilepsy Spectrum – Neonatal or Infantile Onset

Clinical findings

Initial manifestations:

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for parkinsonism-dystonia 3, childhood-onset. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for WARS2 deficiency have been published. Evaluations Following Initial Diagnosis The evaluations recommended to determine the extent of disease and needs of an individual diagnosed with WARS2-related epilepsy are summarized in and of an individual with WARS2-related movement disorder in . Note: It is often not necessary to repeat evaluations performed as part of the evaluation that led to the diagnosis. Table 3a. WARS2-Related Epilepsy: Recommended Evaluations Following Initial Diagnosis

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Because most infants and young children with WARS2-related developmental and epileptic encephalopathy are severely affected and may be hospitalized for prolonged periods from the onset of disease manifestations, they should be reviewed regularly by senior clinical specialists if they are hospitalized. The recommendations regarding frequency of follow up (for WARS2-related epilepsy) and (for WARS2-related movement disorder) pertain to outpatient visits only.

Table 5a.

WARS2-Related Epilepsy: Recommended Surveillance

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for parkinsonism-dystonia 3, childhood-onset.

5 publications have been identified in PubMed for parkinsonism-dystonia 3, childhood-onset. Research spans Basic Science / Preclinical (40%), Review / Meta-Analysis (20%), and Case Report / Case Series (20%).

Recent Publications

Kalita S (2025). [PMID: 40977440](https://pubmed.ncbi.nlm.nih.gov/40977440/). *Annals of Indian Academy of Neurology*. [Review / Meta-Analysis]
Calakos N (2025). [PMID: 39467044](https://pubmed.ncbi.nlm.nih.gov/39467044/). *Movement disorders : official journal of the Movement Disorder Society*. [Basic Science / Preclinical]
Graziola F (2025). [PMID: 39992063](https://pubmed.ncbi.nlm.nih.gov/39992063/). *Movement disorders clinical practice*. [Case Report / Case Series]
Keles MN (2025). [PMID: 40531829](https://pubmed.ncbi.nlm.nih.gov/40531829/). *PloS one*. [Epidemiology / Natural History]
Zech M (2025). [PMID: 39937650](https://pubmed.ncbi.nlm.nih.gov/39937650/). *Brain : a journal of neurology*. [Basic Science / Preclinical]

Data assembled from 6 of 12 sources · Last updated Sep 20, 2026, 5:38 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:619738

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

Differential Diagnosis

Epilepsy Spectrum Developmental and epileptic encephalopathy (DEE). Because the phenotype of WARS2-related DEE is indistinguishable from many other inherited disorders with neonatal- or infantile-onset encephalopathy, all neurodevelopmental disorders, epileptic encephalopathy syndromes, and mitochondrial disorders should be considered in the differential diagnosis. See the Primary Mitochondrial Disorders Overview and the following OMIM Phenotypic Series: • Intellectual disability without other distinctive findings: OMIM Autosomal Dominant, Autosomal Recessive, and Syndromic X-linked Intellectual Developmental Disorder Phenotypic Series. • DEE: OMIM Developmental and Epileptic Encephalopathy Phenotypic Series Additionally, the infantile-onset disorders in have overlapping phenotypic features with WARS2-related DEE, including increased serum lactate, developmental delay, intellectual disability, seizures, and muscle involvement. Table 2a. Selected Genes of Interest in the Differential Diagnosis of WARS2-Related Developmental and Epileptic Encephalopathy

Gene	Disorder	MOI	Features of This Disorder
GNB1 encephalopathy	AD	ID/DD, behavioral issues, seizures, abnormal muscle tone, movement disorders, GI findings	Movement disorders less common; Macrocephaly; Infantile-onset hypotonia that develops into hypertonia spasticity GNAO1
GNAO1-related disorder	AD	Severe seizure onset shortly after birth; May be assoc w/prominent movement disorder; No distinguishing brain MRI findings	Movement disorder may be severe; most persons show mixed pattern of permanent or paroxysmal hyperkinetic hypertonic movements that affect the whole body.; Overlap between movement disorders epilepsy in most affected persons
LIAS	LIAS-related hyperglycinemia, lactic acidosis, seizures (OMIM 614462)	AR	Hypotonia seizures assoc w/ serum glycine lactate in 1st days of life; DD; Death in childhood
LRPPRC	Mitochondrial complex IV deficiency, nuclear type 5 (OMIM 220111)	AR	ID/DD w/speech delay, hypotonia, ataxia, seizures; serum lactate
MECP2	MECP2-related severe neonatal encephalopathy (See MECP2 Disorders.)	XL	ID, seizures, rigidity, muscle hypotonia, microcephaly; Early death due to respiratory failure

Source: GeneReviews — "WARS2 Deficiency"

System/Concern	Evaluation	Comment
Constitutional	Measure length, weight, head circumference	Plot these measurements serially on growth charts.
Neuromuscular	By pediatric neurologist	Assess functional neurologic status.; Brain imaging; EEG if seizures are suspected Orthopedics/ physical medicine rehab/ PT OT eval
Respiratory	Referral to pediatric pulmonologist for children w/evidence of respiratory function	Assessment may incl consideration of tracheostomy artificial ventilation (see Ethics consultation). Gastrointestinal/
Feeding	Gastroenterology/ nutrition/ feeding team eval	To incl eval for GI dysmotility, aspiration risk, nutritional status; Consider eval for gastrostomy tube placement to manage dysphagia /or increased risk of aspiration.
Ophthalmologic	Pediatric ophthalmologist	To incl eval for:; Ptosis strabismus; Visual acuity; Evidence of optic atrophy/pigmentary retinal changes Consider obtaining baseline photographs to document ptosis.
Cardiovascular	Eval for cardiomyopathy	Psychiatric/
Psychologic	Assessment of emotional, behavioral, social development	Indicated if signs of neuropsychiatric manifestations are present such as aggressiveness /or sleep disturbance
Genetic counseling	By genetics professionals1	To inform families re nature, MOI, implications of WARS2 deficiency to facilitate medical personal decision making Family support resources
Ethics consultation	Clinical ethics services	Assess health care decisions in the context of the best interest of the child the values preferences of the family.; For difficult life-prolonging decisions or for clarification of treatment options, consider seeking further opinions from independent clinical teams.
WARS2-Related Movement Disorder: Recommended Evaluations Following Initial Diagnosis System/Concern	Evaluation	Comment
Neurologic	Assessment by neurologist for cerebellar motor dysfunction (gait postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, smooth pursuit)	Use standardized scale to establish baseline for ataxia (e.g., SARA). Assess for parkinsonism.
Activities of Daily Living	By physical medicine rehab/ OT PT	To assess gross motor fine motor skills, gait, ambulation, need for adaptive devices, need for ongoing PT/OT
Ophthalmologic	Complete eye exam	Assess for best corrected visual acuity, nystagmus, ptosis.; Consider referral for corrective measures incl prisms /or surgery.
Dysarthria	Eval by speech-language pathologist	To determine need for speech-language therapy /or alternative means of communication Feeding

Kisho

parkinsonism-dystonia 3, childhood-onset

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Differential Diagnosis

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Neurologic status incl possible seizures/ subclinical status epilepticus

Musculoskeletal

Development

Gastrointestinal

Growth

Respiratory

Family/Community

Latest News & Developments

Glutaric aciduria type 1 presenting with Parkinsonism with presynaptic dopaminergic dysfunction in an adult female: a case report.

Exploring the genetic spectrum of parkinsonism in Brazil.

Early assessment, diagnosis and treatment of Parkinsonism and Related Syndromes study (ExPRESS): a protocol for an observational study on incident parkinsonism.

parkinsonism-dystonia 3, childhood-onset

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Differential Diagnosis

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Neurologic status incl possible seizures/ subclinical status epilepticus

Musculoskeletal

Development

Gastrointestinal

Growth

Respiratory

Family/Community

Latest News & Developments

Glutaric aciduria type 1 presenting with Parkinsonism with presynaptic dopaminergic dysfunction in an adult female: a case report.

Exploring the genetic spectrum of parkinsonism in Brazil.

Early assessment, diagnosis and treatment of Parkinsonism and Related Syndromes study (ExPRESS): a protocol for an observational study on incident parkinsonism.