WARS2 Deficiency

Excerpt

Clinical characteristics: The current (but limited) understanding of the WARS2 deficiency phenotypic spectrum, based on 29 individuals from 24 families reported to date, can be viewed as a clustering of hallmark features within the broad phenotypes of epilepsy and movement disorder.

The epilepsy spectrum encompasses neonatal- or infantile-onset developmental and epileptic encephalopathy (DEE) and other less well described seizure types. DEE manifests mostly in the neonatal period or within the first year of life. Seizures are generally difficult to control and may lead to status epilepticus and death. Over time the following become evident: global developmental delay, mild-to-severe intellectual disability, speech impairment (slurred and slow speech, dysarthria or no speech production but preserved receptive speech), weakness and muscle atrophy, motor hyperactivity with athetosis, and neuropsychiatric manifestations including aggressiveness and sleep disorders.

The movement disorder spectrum encompasses the overlapping phenotypes of levodopa-responsive parkinsonism/dystonia and progressive myoclonus-ataxia/hyperkinetic movement disorder and is primarily associated with childhood or early adulthood onset.

Of note, the continua within and between the epilepsy spectrum and the movement disorder spectrum remain to be determined pending reporting of more individuals with WARS2 deficiency.

Diagnosis/testing: The diagnosis of WARS2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in WARS2 identified by molecular genetic testing. Of note, to date all individuals with a childhood- or early adulthood-onset movement disorder have the hypomorphic WARS2 variant c.37T>G (p.Trp13Gly) in trans with a WARS2 pathogenic variant.

Management: Treatment of manifestations: There is no known cure for WARS2 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Supportive treatment of WARS2-related DEE ideally involves multidisciplinary care by specialists in child neurology (treatment of seizures), nutrition/feeding, pulmonology, physical therapy, developmental pediatrics, social work, medical ethics, and medical genetics. Supportive treatment of WARS2-related movement disorders ideally involves multidisciplinary care by specialists in neurology (treatment of movement disorders), physiatry, physical therapy, occupational therapy, speech-language pathology (including consideration of augmentative and alternative communication), developmental pediatrics, mental health, social work, and medical genetics. Of note, individuals with parkinsonism show an overall good response to dopaminergic therapy, mostly to levodopa (alternatively, dopamine receptor agonists).

Surveillance: Because most infants and young children with WARS2-related DEE are severely affected and may be hospitalized for prolonged periods, it is recommended that they be reviewed regularly by senior clinical specialists when hospitalized. For individuals with a WARS2-related movement disorder, it is recommended that monitoring of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations follow the recommendations of the treating specialists.

Agents/circumstances to avoid: Valproic acid has caused severe hepatopathy and neurologic deterioration in one individual with WARS2-related DEE.

Genetic counseling: WARS2 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a WARS2 pathogenic variant or hypomorphic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic variants, a 50% chance of inheriting one variant, and a 25% chance of inheriting neither of the familial WARS2 variants. Sibs who inherit:

1. Biallelic loss-of-function pathogenic variants are likely to have WARS2-related epilepsy;

2. A WARS2 loss-of-function pathogenic variant in trans with the hypomorphic WARS2 variant are likely to have a WARS2-related movement disorder;

3. One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;

4. Neither of the familial WARS2 variants are unaffected and not carriers.

Once the WARS2 deficiency-related variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.