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

Abstract

SUMMARY 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.

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

Amino acid synthesis deficiencies

“…The first patients with asparagine deficiency (OMIM 615574) caused by defects in asparagine synthetase (ASNS) were reported by Ruzzo et al (2013). Of nine patients from four families, the majority had an epileptic encephalopathy with intractable seizures, progressive (congenital) microcephaly, severe developmental disability, axial hypotonia and spastic tetraplegia.…”

“…Palmer et al (2015) showed in cultured skin fibroblasts of patients with asparagine deficiency that growth is restricted under conditions of limited availability of asparagine in the culture medium, and suggested that a similar mechanism may explain the central nervous system abnormalities. Ruzzo et al (2013) commented on the potential pitfalls of a biochemical diagnosis in asparagine deficiency. Apart from our traditional focus on increased asparagine levels in catabolic amino acid disorders, asparagine levels are normally low in plasma and the lower range for asparagine in CSF is set at 0 mmol/l in many laboratories.…”

Clinical whole exome sequencing from dried blood spot identifies novel genetic defect underlying asparagine synthetase deficiency

“…Ruzzo et al. studied nine children from four families presenting with similar phenotypes and reported two missense mutations‐c.1084T>G (p.F362V; NM_183356) and c.1648C>T (p.R550C; NM_183356) in the asparagine synthetase domain that dramatically reduce ASNS protein abundance 1. The authors concluded that accumulation of aspartate/glutamate secondary to ASNS depletion in the brain resulted in the neurologic impairment.…”

“…Ruzzo et al. reported the first characterization of ASNS deficiency (ASNSD) in four families presenting with congenital microcephaly, intellectual disability, progressive cerebral atrophy, intractable seizures, and recessive mutations in ASNS 1. To date, ASNS deficiency has been reported in 16 cases evaluated for a range of brain abnormalities coupled with epileptic encephalopathy and global developmental delay.…”