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.

Source: GeneReviews — "WARS2 Deficiency"

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:

• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.

Note: For the purposes of this GeneReview, DEE is defined as severe seizure onset shortly after birth (often called infantile epileptic spasms syndrome).

Source: GeneReviews — "WARS2 Deficiency"

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

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

Source: GeneReviews — "WARS2 Deficiency"

Clinical Guidance

Valproic acid can cause severe hepatopathy and neurologic deterioration, as reported in one individual with WARS2-related DEE .

Source: GeneReviews — "WARS2 Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "WARS2 Deficiency"

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

System/Concern | Evaluation | Suggested Frequency of Outpatient Surveillance After Initial Assessment

Neurologic status incl possible seizures/ subclinical status epilepticus

| • Eval of seizure status by pediatric neurologist; to incl EEG video EEG monitoring

• Without seizure correlates, routine EEG is not indicated.

• Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.

| At each visit (or per treating clinician)

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, need for adaptive devises

Development

| Monitor developmental progress educational needs.

Gastrointestinal

| • Assessment of feeding

• Monitoring of stool frequency

• Dietary assessment to maintain adequate nutrition growth

Growth

| Assessment of nutritional status, height, weight, body mass index

Respiratory

| Monitor for evidence of aspiration, respiratory insufficiency.

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other...

Source: GeneReviews — "WARS2 Deficiency"