ASNS – Asparagine Synthetase Deficiency

Asparagine Synthetase Deficiency (ASNSD) is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ASNS. It presents with severe congenital microcephaly, progressive cerebral atrophy, intractable seizures, and spastic quadriplegia (PMID:25663424).

Multiple case reports and series have described over 50 affected individuals from more than 20 unrelated families with homozygous or compound heterozygous ASNS variants, including missense and loss-of-function alleles, segregating with disease in both consanguineous and non-consanguineous pedigrees (PMID:25663424, PMID:27469131). A recurrent pathogenic variant, c.1193A>C (p.Tyr398Ser), has been identified in multiple siblings and confirmed as deleterious by enzyme activity assays.

The phenotypic spectrum encompasses primary microcephaly (HP:0000252), severe global developmental delay (HP:0001263), spastic tetraplegia (HP:0002510), and progressive cerebral atrophy with simplified gyral patterns on MRI. Seizure types range from infantile spasms to status epilepticus.

Functional studies in patient-derived fibroblasts, inducible pluripotent stem cells, and ASNS-null cell lines demonstrate that ASNS variants markedly reduce enzymatic activity and impair cell proliferation in asparagine-deprived medium, effects that are rescued by wild-type ASNS expression, confirming a loss-of-function mechanism (PMID:29279279, PMID:36613999).

Therapeutic trials of oral asparagine supplementation in small cohorts have shown stabilization of neurodevelopment and attenuated disease progression in some patients (PMID:31123592), whereas others experienced worsening seizures upon treatment (PMID:27268761).

References

• JIMD reports • 2015 • Asparagine Synthetase Deficiency: New Inborn Errors of Metabolism. PMID:25663424
• JIMD reports • 2017 • Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype. PMID:27469131
• Molecular genetics and metabolism • 2018 • Characterization of a novel variant in siblings with Asparagine Synthetase Deficiency. PMID:29279279
• International journal of molecular sciences • 2022 • Analysis of Enzyme Activity and Cellular Function for the N80S and S480F Asparagine Synthetase Variants Expressed in a Child with Asparagine Synthetase Deficiency. PMID:36613999
• Human genome variation • 2019 • Clinical outcomes of two patients with a novel pathogenic variant in ASNS: response to asparagine supplementation and review of the literature. PMID:31123592
• Pediatric neurology • 2016 • Worsening of Seizures After Asparagine Supplementation in a Child with Asparagine Synthetase Deficiency. PMID:27268761

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