A number sign (#) is used with this entry because of evidence that childhood-onset parkinsonism-dystonia-3 (PKDYS3) is caused by homozygous or compound heterozygous mutation in the WARS2 gene (604733) on chromosome 1p12.

Biallelic mutation in the WARS2 gene also causes NEMMLAS (617710), which shows overlapping features, but is a more severe disorder in general.

Childhood-onset parkinsonism-dystonia-3 (PKDYS3) is an autosomal recessive neurodegenerative disorder with onset in infancy or early childhood. Affected individuals present with progressive movement abnormalities, including parkinsonism with tremor, dystonia, myoclonus ataxia, and hyperkinetic movements such as ballismus. The parkinsonism features may be responsive to treatment with levodopa, although many patients develop levodopa-induced dyskinesia. Some patients may have mild cognitive impairment or psychiatric disturbances (summary by Burke et al., 2018 and Skorvanek et al., 2022).

For a discussion of genetic heterogeneity of PKDYS, see 613135.

Burke et al. (2018) reported a 17-year-old boy who presented with infantile-onset levodopa-responsive parkinsonism at 2 years of age. He was conceived by in vitro fertilization and born at 37 weeks' gestation. He initially presented with tremor and intermittent dystonia that progressed from 1 leg to involve all limbs. He also had expressive language delay. Treatment with levodopa was initially effective, and he had a stable period of several years with normal skill development. However, he eventually developed more advanced features of parkinsonism with dystonia, dyskinesia, and stooped posture. Brain imaging showed progressive generalized brain atrophy. Muscle biopsy showed mild variation in fiber size, slightly decreased mtDNA content (76%), and normal COX staining. Electron microscopy showed proliferation of subsarcolemmal mitochondria. Activities of the mitochondrial respiratory chain complexes were normal. At age 10 years, he underwent deep brain stimulation (DBS) leading to a substantial improvement in the motor complications.

Hubers et al. (2019) reported a 31-year-old man who presented to a movement clinic at age 30 with a severe hyperkinetic movement disorder that began around 15 months of age and coincided with a loss of early acquired skills. He had uncontrollable ballistic, dystonic, and choreic movements that progressed with age. He had cognitive impairment and could communicate nonverbally at a basic level. Brain imaging showed cerebellar atrophy without signs of leukodystrophy. Serum lactate had been intermittently elevated in childhood, but later normalized. The patient did not have seizures, which may have accounted for his long survival. The findings expanded the phenotype associated with biallelic WARS2 mutations affecting mitochondrial function to include juvenile hyperkinetic movement disorders.

Skorvanek et al. (2022) reported 6 patients from 4 unrelated families with PKDYS3. The patients, who ranged from 8 to 33 years of age, had onset of symptoms between infancy and 12 years. There was phenotypic variability. Two sibs in family 1, of Slovak origin, presented at 10 and 12 years of age with parkinsonism, including tremor, bradykinesia, and rigidity, associated with an abnormal DAT scan; brain MRI was normal. The disorder was progressive, and 1 developed cervical dystonia. One sib had normal cognition, and the other had mild intellectual disability, but both developed significant psychiatric disorders, including psychosis, depression, anxiety, and apathy. The Czech sibs in family 2 presented in childhood with myoclonus ataxia, dystonia, and action tremor. Both had cognitive impairment. The remaining patients had growth retardation associated with variable ataxia, dystonia, myoclonus, chorea, and tremor. Patient 5 from family 3, of Swiss origin, had a rapidly progressive phenotype with dysphagia requiring a feeding tube; he was wheelchair-bound by 8 years of age. A few patients had hypertonia and spasticity. Brain imaging was normal in all. None had seizures. Levodopa was used in a few patients with variable effectiveness.

The transmission pattern of PKDYS3 in the family reported by Burke et al. (2018) was consistent with autosomal recessive inheritance.

In a 17-year-old boy with PKDYS3, Burke et al. (2018) identified compound heterozygous missense mutations in the WARS2 gene: W13G (604733.0002) and S228W (604733.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration.

In a 31-year-old man with PKDYS3, Hubers et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: W13G and G50D (604733.0009). The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that W13G is considered a hypomorphic allele that is pathogenic when found in association with another more deleterious WARS2 variant.

In 6 patients from 4 unrelated families with PKDYS3, Skorvanek et al. (2022) identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (604733.0011). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (604733.0004) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (604733.0009) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; 604733.0012) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. Overall, the findings indicated that biallelic loss-of-function or hypomorphic mutations in the WARS2 gene lead to mitochondrial dysfunction and disease.