Background N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. The functional NMDA receptors are heterotetramers consisting mainly of two GluN1 and two GluN2 subunits. GluN2 is encoded by the GRIN2D gene. A few case series have shown that GRIN2D variants are linked to developmental and epileptic encephalopathy. In this article, we report a novel GRIN2D variant, namely c.2021C > A (p.T674K) in a neonate with intractable epileptic encephalopathy. Case presentation A 12-day-old boy who had stiffness of the lower and upper extremities since birth was transferred from a local hospital to our department. On admission, the patient presented with head tilting backwards, staring, apnea and hypertonia of limbs. Video electroencephalogram showed continuous, generalized or multi-focal spike-wave and spike-and-slow wave discharges and hypsarrhythmia. A treatment regimen composed of phenobarbital, midazolam, levetiracetam and clonazepam was administered, which however led to only partial control of the seizure. Whole-exome sequencing identified c.2021C > A (p.T674K) in GRIN2D in the patient while such a mutation was not detected in the parents. The patient was hospitalized for 1 month and died of sudden cardio-respiratory arrest 2 weeks after discharge. Conclusions A novel variant of GRIN2D was identified in a neonate with epileptic encephalopathy. Epilepsy associated with this GRIN2D mutation is refractory to conventional anti-epileptic medications.

Nonketotic hyperglycinemia (NKH) is a lethal autosomal recessive disease resulting from alterations in glycine metabolism, commonly caused by mutations in glycine decarboxylase (GLDC). The symptoms of NKH usually manifest in the neonatal period, and can be categorized into severe NKH and attenuated NKH based on the clinical outcome. To date, only a few NKH cases have been reported in China. We here report a case of a neonate with severe NKH carrying a novel compound heterozygous variant in GLDC. The patient was a 68-h-old girl who had progressive lethargy, no crying, and poor sucking ability from birth, and was therefore transferred to our department. On admission, the patient was supported by intubation and ventilation and presented with profound coma. Metabolic investigation indicated a markedly increased glycine concentration both in the plasma and cerebrospinal fluid (CSF). Symptomatic treatments were administered, but the patient's condition did not improve substantially. Whole-exome sequencing identified compound heterozygous mutations (c.1261G>C, p.G421R and c.450 C>G, p.N150K) in GLDC, which were inherited from the mother and the father, respectively. The patient was hospitalized for 8 days in our department and died 2 days after discharge. We further summarize the clinical features, genetic characteristics, administered treatment, and prognosis of previously reported Chinese NKH patients for context. Our results highlight that due to the non-specific clinical phenotypes of NKH and difficulty in obtaining CSF samples, genetic testing is a crucial tool, not only for a diagnosis but also for predicting the clinical outcome and can potentially help to determine the optimal therapeutic strategy.

Background: Classical Galactosemia (CG) is a rare autosomal recessive metabolic disease caused by mutations in the galactose-1-phosphate uridyl transferase ( GALT ) gene. This study aim to identify pathogenic mutations underlying classic galactosemia in two Chinese families. Methods: We collected blood samples from two Chinese families and extracted genomic DNA. High-throughput sequencing, sanger sequencing, and bioinformatics analysis were used to investigate the molecular cause of manifestations in the two Chinese families. Results: We found compound heterozygous mutations (c.396C>G; p.His132Gln and c.974C>T; p.Pro325Leu) in family 1 and a homozygous missense variant (c.974C>T; p.Pro325Leu) in family 2. Bioinformatics and Sanger sequencing were performed to verify the identified variants. Conclusion: The present study identified the GALT mutations as a genetic etiology in the two Chinese families with classic galactosemia and expanded the phenotypic and mutational spectrum of GALT . Our findings could be useful in providing evidence for prenatal interventions and more precise pharmacological treatments to patients. High-throughput sequencing conducted in our study is a convenient and useful tool for clinical diagnosis of galactosemia and other associated genetic disorders.

Glutathione synthetase deficiency (GSSD) is an autosomal-recessive metabolic disorder caused by glutathione synthetase (GSS) gene mutations. No more than 90 cases of GSSD have been reported worldwide; thus, the spectrum of GSS mutations and the genotype–phenotype association remain unclear. Here, we present a severely affected infant carrying a compound heterozygous GSS variation, c.491G > A, and a novel variant of c.1343_1348delTACTTC. We also summarize the clinical manifestations, treatment protocol, prognosis, and genetic characteristics of previously reported GSSD cases in China. In this case study, our patient presented with tachypnea, jaundice, intractable metabolic acidosis, and hemolytic anemia. Urinary-organic acid analysis revealed elevated 5-oxoproline levels. Further, this patient showed improved outcomes owing to early diagnosis and the timely administration of vitamins C and E. Therefore, our study indicates that in clinical cases of unexplained hemolytic anemia and metabolic acidosis, GSSD should be considered. Additionally, genetic testing and antioxidant application might help identify GSSD and improve the prognosis.