Lethal NARS2-Related Disorder Associated With Rapidly Progressive Intractable Epilepsy and Global Brain Atrophy.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Infantile epileptic encephalopathy (IEE) is a complex neurological disorder with over 200 associated genes.
• Diagnostic challenges arise from phenotypic variability and uncertain prognoses in IEE.
• Recent studies link biallelic variants in NARS2, encoding a mitochondrial aminoacyl-tRNA synthetase, to neurodegenerative conditions including epilepsy.

Observation:

• Two infant brothers presented with severe, refractory focal status epilepticus leading to lethal epileptic encephalopathy.
• Initial diagnostic evaluations, including extensive metabolic, infectious, chromosomal, and genetic testing, were inconclusive for the first infant.
• Both siblings exhibited rapid brain atrophy on MRI, indicating a rapidly progressive neurological decline.

Findings:

• Novel biallelic variants in the NARS2 gene were identified via rapid whole exome sequencing in both brothers.
• Specific variants, c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile), were confirmed in the older sibling.
• NARS2 protein analysis suggested a significant biological impact of these identified variants.

Implications:

• NARS2-related disorder should be considered in infants with refractory seizures and rapid brain atrophy.
• Standard metabolic screening may not detect NARS2-related disorders, necessitating advanced genetic testing.
• Rapid whole exome sequencing can expedite diagnosis, improve prognosis, and guide medical management in severe pediatric epilepsy cases.