Deficiency of Asparagine Synthetase Causes Congenital Microcephaly and a Progressive Form of Encephalopathy

We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/glutamate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs. •Recessive mutations in ASNS are responsible for a severe neurological condition•Two of the identified mutations lead to a remarkable depletion of the ASNS protein•Asns-deficient mice have structural brain abnormalities and memory deficits•Asparagine synthesis is essential for the development and function of the brain We describe a distinct neurological disorder and show that mutation of asparagine synthetase is responsible. The mouse model has structural abnormalities of the brain and deficits in learning and memory. Asparagine synthesis is essential for brain development and function.