A Novel WARS2 Mutation in a Swiss Family With Predominant Generalized Dystonia Responsive to Trihexyphenidyl

Dear Editor,

Biallelic mutations of WARS2, which encodes the mitochondrial tryptophanyl-tRNA synthetase, were first described in an intellectual disability consanguineous Iranian family in 2017.1 Subsequent reports described a broad phenotype of patients carrying biallelic WARS2 mutations with developmental delay, variety of movement disorders, neuropsychiatric manifestations, leukoencephalopathy, epilepsy, dysmorphic features, and short stature.1, 2, 3, 4, 5, 6, 7 The most severely affected patients have NEMMLAS, which is a neurodevelopmental mitochondrial disorder presenting with abnormal movements and lactic acidosis, with or without seizures (MIM #617710).1, 2, 3, 4

Here we report a nonconsanguineous Swiss family with two affected siblings presenting with predominant dystonia that responded to trihexyphenidyl and who carried a novel missense WARS2 mutation.

Patient 1: The 36-year-old male patient was born after an uneventful pregnancy. His early psychomotor development was delayed, with walking at 3 years and speech delay. He first received medical attention in childhood because of mental retardation and gait abnormalities. His walk was unsteady due to right-foot inversion and left-foot eversion. MRI at age 16 years demonstrated cerebellar atrophy. The follow-up during childhood and early adulthood did not document evidence of disease progression.

At the age of 18 years he experienced repeated falls triggered by emotional stimuli. There were no epileptic seizures and EEG did not reveal epileptic discharges. The falls were described as sudden body stiffness and falling backward without loss of consciousness, so we interpreted them as dystonic in nature.

At the age of 34 years he presented with cognitive impairment, high-arched palate, severe dysarthria, mild left-sided asymmetric bradykinesia and rigidity, cervical dystonia, right-foot dystonia, and striatal toe, but the Babinski sign was absent. There was no ataxia in the finger-to-nose and knee-to-heel tests. There were also no oculomotor disturbances. Brain MRI at 33 years showed the previously known cerebellar atrophy. The patient had mild signs of parkinsonism. However, the impaired gait was due to dystonia, causing right-foot inversion and axial dystonia (see Supplementary Video 1 in the online-only Data Supplement) leading to repeated falls backward. In addition, the patient reported night cramps that were lessened by trihexyphenidyl. Treatment with L-dopa at up to 300 mg daily moderately improved the gait, but this was discontinued due to sedation. In contrast, the administration of trihexyphenidyl 5 mg three times daily led to significant improvement of the dystonia and was well tolerated.

Patient 2: The 4-years-younger sister of patient 1 also had delayed psychomotor development. She was able to walk at 2.5 years of age, and her speech was delayed. Similarly to her brother, her gait had been impaired since early childhood because of dystonia of the feet. She also experienced repeated falling backward and forward at the age of 19 years triggered by emotional stimuli. The falls were not associated with loss of consciousness and were described by the mother as “falling like a board.” There were no epileptic discharges in EEG. Brain MRI at the age of 19 years demonstrated vermis atrophy. L-dopa treatment was initiated, but data on the daily dosage were missing from the available medical records, and so the response could not be reliably evaluated retrospectively. However, the patient was switched to trihexyphenidyl, which resulted in improvement of the gait disturbances, and the daily dosage was gradually increased to 15 mg. There was no significant disease progression during pediatric follow-up.

At the age of 32 years she presented with cognitive impairment, high-arched palate, and short stature. Her dystonia was less severe than that in her brother. However, she had more severe dysarthria and speech developmental arrest, being only able to speak single words. There was intermittent cervical dystonia, and dystonic gait with inversion of the right knee and eversion of the right foot. There were no oculomotor or cerebellar disturbances. Tendon reflexes were brisk and the Babinski sign was absent. Transient interruption of trihexyphenidyl treatment significantly worsened the dystonic gait disorder, with repeated falls occurring.

We performed whole-exome sequencing and found that both siblings are compound heterozygous for the previously described WARS2 maternally inherited variant c.37T>G/p. (Trp13Gly),1 and the newly identified paternally inherited variant c.161G>A/p.(Gly54Glu). The latter missense variant leads to substitution of a highly conserved glycine to glutamate at position 54 (Fig. 1). This variant is not listed in the public databases. Mutation taster, SIFT, CADD, and PP2 predicted deleterious effect of this substitution at the protein level. It is located in the tryptophan-tRNA ligase domain, which is crucial for enzyme function.

Fig. 1
Multiple sequence alignment of WARS2 across different species showing the highly conserved glycine at position 54.

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Both mutations were confirmed using targeted Sanger sequencing and segregate with the disease phenotype.

We report a Swiss family with biallelic WARS2 mutations in two affected siblings. The two patients presented a similar phenotype with generalized dystonia and psychomotor developmental delay, but without epilepsy or cerebellar ataxia. Previous reports of patients have described a variety of movement disorders including infantile-onset parkinsonism that responded to L-dopa.5, 6, 7 Interestingly, our patients shared the same pathogenic p.(Trp13Gly) variant and a relatively mild phenotype (“hypomorphic variant”1, 7), but did not respond to L-dopa at a daily dosage of up to 300 mg (patient 1). Side effects in this patient meant that the dosage could not be increased, but a response to higher dosages could not be excluded since some previously reported patients showed benefit at daily L-dopa dosages of up to 1,000 mg.7

However, both of our patients demonstrated excellent response to trihexyphenidyl, an anticholinergic agent, enabling the brother to walk independently indoors and with a walker outdoors. Moreover, transient interruption of trihexyphenidyl severely impeded the walking ability of the sister. In addition, both siblings demonstrated significant reductions in falling frequency when the trihexyphenidyl dosage was increased. The benefit of trihexyphenidyl was sustained over a follow-up lasting more than 10 years, with no evidence of disease progression.

Similarly to other mitochondrial disorders, WARS2 mutant patients frequently present with extrapyramidal symptoms. However, in contrast to other mitochondrial diseases (e.g., Leigh syndrome and POLG-associated encephalopathy), our patients as well as previously reported cases2, 5, 6, 7 have not demonstrated basal ganglia abnormalities in brain MRI.

This report further supports the hypomorphic nature of the WARS2 p.(Trp13Gly) variant. We suggest trying an anticholinergic agent in cases that exhibit an insufficient response or intolerance to L-dopa. Our report and the cases in the literature indicate that WARS2 mutations frequently present with dystonia and parkinsonism. Therefore, WARS2 should be included in gene panels for movement disorders.