A number sign (#) is used with this entry because of evidence that mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and with or without seizures (NEMMLAS) is caused by homozygous or compound heterozygous mutation in the WARS2 gene (604733) on chromosome 1p12.

Biallelic mutation in the WARS2 gene also causes childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738), which has overlapping features.

NEMMLAS is an autosomal recessive multisystemic disorder characterized by delayed psychomotor development, intellectual disability, and abnormal motor function, including hypotonia, dystonia, ataxia, and spasticity. Patient tissues may show deficiencies in one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes, but this is not a constant finding (summary by Wortmann et al., 2017).

Musante et al. (2017) reported 2 teenaged sisters, born of consanguineous Iranian parents (family 2), with delayed psychomotor development, moderate intellectual disability (IQ range, 41-46), speech impairment, and aggressive behavior. The sisters also had movement abnormalities, including muscle weakness, ataxia that became apparent in childhood, and athetosis. Brain imaging and laboratory studies were apparently not performed. They had an affected brother who died of an infectious disease.

Theisen et al. (2017) reported a 24-year-old man, born of unrelated parents of European ancestry, with infantile-onset leukoencephalopathy. He showed hypoglycemia and transient thrombocytopenia at birth, followed by delayed development with profound intellectual disability, absent speech, and inability to achieve crawling, standing, or walking. Additional neurologic findings included axial hypotonia, spastic quadriplegia with diffuse muscle atrophy, dysmetria, hyperreflexia, tremor, nystagmus, exotropia, and amblyopia with difficulty tracking. At age 6 months, he developed multifocal seizures that were intermittently controlled throughout life, but became treatment resistant and resulted in death at age 24 years. Serial brain imaging showed initially delayed myelination, diffuse cerebral atrophy, paucity of white matter, enlarged ventricles, and nonspecific periventricular white matter signal abnormalities.

Wortmann et al. (2017) reported 6 patients from 5 unrelated families with a complex multisystemic neurodevelopmental disorder. The patients were of various ethnicities, including Serbian, Dutch, French, Iraqi, and Canadian. All had delayed development and intellectual disability with some highly variable features. Four of the children died; 1 died of multiorgan failure at age 23 days, 2 brothers from a second family who had severe epilepsy died at ages 3.5 years and 18 months, and a girl from another family died in an epileptic seizure at age 3 years. The patients presented at birth or early infancy with hypotonia, seizures, abnormal movements, delayed development or impaired swallowing, lactic acidosis, and/or hypoglycemia. Additional features included intrauterine growth retardation, hypertonia, brisk reflexes, and dystonic movements. Three patients had seizures, including 2 with a clinical diagnosis of West syndrome, and 1 had suspected seizures. One patient had cardiomyopathy and retinitis pigmentosa. The least severely affected patient was a 10-year-old girl with delayed speech and fine motor skills, walking at age 7.5 years, ataxia, mild spasticity, rigidity, intellectual disability, and mild optic atrophy without visual impairment. Brain imaging of all patients revealed varying abnormalities, including white matter defects, absent or delayed myelination, and cerebral and cerebellar atrophy. Most patients had increased serum lactate, but there was a varying degree of abnormalities in mitochondrial oxidative phosphorylation (OXPHOS) activity in tissue. Mild enzyme deficiencies were observed in muscle of 1 patient and in muscle and fibroblasts of another, while the most severely affected individual showed severe combined complex I and IV deficiency in liver, but normal levels in muscle. However, muscle and fibroblasts from another patient showed normal OXPHOS activity. Overall, the phenotype was consistent with a mitochondrial encephalopathy with a broad phenotypic spectrum ranging from severe neonatal lactic acidosis and early death to an attenuated course with intellectual disability.

Maffezzini et al. (2019) reported 2 sisters, born of unrelated Swedish parents, with NEMMLAS confirmed by genetic analysis. They both had intrauterine growth retardation and were delivered early by C-section. The girls, who were 15 and 10.5 years of age at the time of the report, presented in the first year of life with global developmental delay, axial hypotonia, peripheral spasticity with hyperreflexia, and ataxia. They had moderate to severe intellectual disability, but the older sister was able to attend a special school. The older sister had visual impairment and developed seizures at age 8 years, whereas the other had normal vision and no seizures. Both had strabismus. Brain imaging showed decreased white matter. Serum and CSF lactate was elevated in the older sister, but not in the younger. Patient fibroblasts and skeletal muscle biopsies did not show OXPHOS defects, although in vitro studies in yeast and patient-derived induced neuroepithelial cells indicated mitochondrial dysfunction.

Ilinca et al. (2022) reported a 22-year-old Swedish woman who had onset of persistent seizures in the neonatal period, increased muscle tone and limb tremor, difficulty walking, and juvenile parkinsonism that was responsive to levodopa. She developed levodopa-induced dyskinesia, cervical and truncal dystonia, scoliosis, and myoclonic jerks. Brain imaging showed a thin corpus callosum, mildly reduced cerebral and cerebellar volume, and transient white matter hyperintensities.

The transmission pattern of NEMMLAS in the families reported by Musante et al. (2017), Theisen et al. (2017), and Wortmann et al. (2017) was consistent with autosomal recessive inheritance.

In 2 sisters, born of consanguineous Iranian parents (family 2), with NEMMLAS, Musante et al. (2017) identified compound heterozygous mutations in the WARS2 gene (c.325delC, 604733.0001 and W13G, 604733.0002). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the W13G mutation resulted in impaired localization of the WARS2 mutant protein to the mitochondria. Musante et al. (2017) suggested that the W13G variant may be a hypomorphic polymorphism that becomes significant only when paired with a loss-of-function allele. Of note, overexpression of wildtype WARS2 resulted in decreased SDHA (600857) compared to cells overexpressing the mutant protein; SDHA is part of the mitochondrial respiratory chain.

In a 24-year-old man with NEMMLAS, Theisen et al. (2017) identified compound heterozygous mutations in the WARS2 gene (K313M, 604733.0003 and Lys100del, 604733.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%).

In 6 patients from 5 unrelated families with NEMMLAS, Wortmann et al. (2017) identified homozygous or compound heterozygous mutations in the WARS2 gene (see, e.g., 604733.0003; 604733.0005-604733.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 6 missense mutations, 1 frameshift, and 1 insertion/deletion. Cells derived from several unrelated patients showed decreased or absent WARS2 protein levels compared to controls. In addition, cells derived from 2 sibs showed a clear decrease in charged mt-tRNA(Trp), while total mt-tRNA(Trp) levels appeared normal. These findings suggested that the defect in WARS2 causes improper aminoacylation of tRNA(Trp), leading to abnormalities in mitochondrial oxidative phosphorylation (OXPHOS) protein synthesis. However, OXPHOS activities in most patient cells were normal, with the exception of 1 severely affected individual and mild changes in some tissues of 2 other patients. Wortmann et al. (2017) postulated that the OXPHOS defect may be apparent in the central nervous system, but such tissue was not available for study.

In 2 sisters, born of unrelated Swedish parents, with NEMMLAS, Maffezzini et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: K313M (604733.0003) and V278G (604733.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast resulted in variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function.

In a 22-year-old Swedish woman with NEMMLAS, Ilinca et al. (2022) identified compound heterozygosity for the K313M and V278G mutations in the WARS2 gene. Functional studies of the variant and studies of patient cells were not performed.