Comprehensive mutation analysis ofGLDC,AMT, andGCSHin nonketotic hyperglycinemia

Abstract

Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.

Practical difficulties in the diagnosis of transient non‐ketotic hyperglycinaemia

“…However, mutation screening, apart from the detection of a few relatively low frequency 'common' mutations, is costly and not widely available. 14 Dinopoulos et al hypothesized that milder atypical NKH cases may be due to the influence of residual GCS activity in an individual whose GCS pathways are impaired. 7 Only by confirming initial GCS enzyme deficiency, and subsequent proven GCS enzyme activity, can a diagnosis of tNKH be made, unless proven through genetic analysis.…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…A number of nonsynonymous allelic variants have been identified in patients with typical and atypical nonketotic hyperglycinemia. [70][71][72][73][74] Typical nonketotic hyperglycinemia presents with seizures, coma and apnea in neonates, whereas the rarer atypical form presents as only developmental delay with some seizures.…”

Nonketotic hyperglycinemia: novel mutation in the aminomethyl transferase gene. Case report

“…Thirty-two patients, who had mutation in AMT gene, were published in the literature up to date ( Table 1). [2][3][4][5][6][7][8] Unfortunately, because most reported mutations seem to be rare or private, it is very difficult to predict phenotype from genotype. Kure et al 6 published 11 cases with AMT mutation.…”