Progressive Mitochondrial Encephalopathy Due to the Novel Compound Heterozygous Variants c.182C>T and c.446A>AG in...

Progressive mitochondrial encephalopathy manifesting as developmental delay, regression, epilepsy, myoclonus, dystonia, and spasticity due to a novel compound heterozygous variant in NARS2 has not been reported. The patient is a 3.5-year-old female with normal psychomotor development until she experienced her first generalized status epilepticus at 4.5 months of age. After seizure control, generalized myoclonus and psychomotor regression became evident. She suffered from two other epileptic states and seizure control remained inadequate despite the use of multiple anti-seizure drugs. Neurologic examination revealed generalized hypotonia, discoordination, unstable eye contact, drooling, open mouth, myoclonus, periodic torticollis, and ankle contractions. Cerebral MRI revealed hydrocephalus ex vacuo due to diffuse cortical and subcortical atrophy bilaterally and incomplete myelination. Genetic testing at 12 months of age revealed the compound heterozygous variants chr11: 78204182C>T and chr11: 78282446A>AG in NARS2. Despite anti-seizure drugs, mitochondrial cocktail, and cannabidiol, the disease progressed to intractable seizures and severe tetraspasticity. In summary, this case demonstrates that compound heterozygous variants in NARS2 can phenotypically manifest exclusively in the brain with intractable epilepsy, myoclonus, developmental delay, regression, hypotonia, cerebral atrophy, and hypomyelination, followed by tetraspasticity and dystonia.