[P1-165] Asparagine Synthetase Deficiency: The First Japanese Case Report and Review of Literature
[Introduction] Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder characterized by severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures. [Methodology] Two Japanese children with progressive microcephaly were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions. The clinical presentations of our patients were compared with those of reported cases. [Results] Even though the clinical presentations of two Japanese cases were very similar to reported cases, there are some differences between two patients. Progressive microcephaly was noted during the prenatal period in patient 1 but only after birth in patient 2. Patient 1 developed generalized tonic seizures at 7 months of age, while patient 2 had repeated generalized tonic, myoclonic, and tonic–clonic seizures at 3 months of age. Despite the administration of multiple anti-epileptic drugs, it was difficult to control seizures of patient 1, while sodium valproate and clobazam were temporarily effective in patient 2. Both patients had novel compound heterozygous ASNS mutations: patient 1 had p.L145S and p.L247W, while patient 2 carried p.V489D and p.W541Cfs*5, respectively. Three of the four mutations were predicted to affect protein folding, and in silico analyses suggested that they would be pathogenic. [Conclusions] We report the first two Japanese patients with ASNS deficiency. Disease severity appears to vary among patients. Future analysis of the function of these missense mutations could be performed with an enzyme activity assay.