In this study, we describe the screening of the entire GLDC gene in 3 NKH families by D-HPLC analysis of all 25 exons, identifying two point mutations and two large deletions (exon 8 and exons 2-15) using a combination of D-HPLC analysis, long range PCR, Southern blot and sequencing.
The in vitro expression analysis of the identified GLDC mutations revealed considerable residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even in neonatal-onset nonketotic hyperglycinemia.
Three of four nonketotic hyperglycinemia patients homozygous for a novel GLDC mutation (A802V) were treated by assisted respiration and/or sodium benzoate with or without ketamine and had transient neonatal or absent symptoms and normal developmental outcome, despite persisting biochemical evidence of nonketotic hyperglycinemia.
Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH).
Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psiGLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia.
Using CRISPR/Cas9, we knocked out the gldc gene and showed that gldc-/- fish recapitulate GE on a molecular level and present a motor phenotype reminiscent of severe GE symptoms.
The two variants of GLDC gene identified probably underlie the pathogenesis of non-ketotic hyperglycinemia in this family, and also enrich the mutational spectrum of GLDC gene.
The diagnosis of nonketotic hyperglycinemia was made biochemically and was confirmed by genetic studies, which revealed two missense mutations (one not previously described) within the glycine decarboxylase gene, GLDC.
A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem.
Two novel heterozygous missense mutations (c.1130C>T (p.A377V) and c.2081_2088del (p.A694DfsX11) in exons 8 and 18) in the glycine decarboxylase gene confirmed the diagnosis of nonketotic hyperglycinemia.
Nonketotic hyperglycinemia (NKH) is a neuro-metabolic disorder caused by a deficiency in the glycine cleavage system (GCS) and glycine transporter 1 (GlyT1).