Clinical and genetic analysis of nonketotic hyperglycinemia:A case report

BACKGROUND Nonketotic hyperglycinemia(NKH)is a rare autosomal recessive genetic disorder of abnormal glycine metabolism caused by insufficient activity of the glycine cleavage enzyme system.Glycine is believed to function mainly as an inhibitory neurotransmitter,but it can also act as a co-agonist of the N-methyl-D-aspartate(NMDA)receptor.The accumulation of a large amount of glycine in the brain leads to neuronal and axonal injury via overactivation of NMDA receptors located in the hippocampus,cerebral cortex,olfactory bulb,and cerebellum and to stimulation of the inhibitory function of glycine receptors located in the spinal cord and brain stem,resulting in central apnea,hiccups,and hypotonia in the early stage of the disease.CASE SUMMARY The child described in this report had typical clinical manifestations of NKH,such as hiccups,disturbance of consciousness,hypotonia,and convulsions,within the first week after birth.Whole-exome genetic testing revealed that the child had a compound heterozygous mutation,namely,c.395C>A(p.S132X)and c.2182G>A(p.G728R),in the GLDC gene,and he was diagnosed with NKH.For treatment,we administered an oral levetiracetam solution and added topiramate and prednisone for epilepsy control,but the epilepsy remained uncontrollable.Ketogenic diet therapy was started at 6 mo of age,his seizures were significantly reduced,and there were no obvious adverse reactions during ketogenic treatment.Furthermore,we found that with the development of the disease,high levels of serum glycine decreased or even disappeared without intervention,and as the disease progressed,the corpus callosum became dysplastic.CONCLUSION This case shows that plasma glycine levels cannot be used to evaluate the prognosis of NKH,that the development of the corpus callosum can be affected by NKH,and that a ketogenic diet may be effective for seizure control in NKH patients.

Novel mutations in PDE6B causing human retinitis pigmentosa

AIM: To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS: Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE5B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS: We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T6041) in PDE5B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION: We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE9B contribute to the genetic heterogeneity of RP.