Reply

Kure and colleagues report three patients in whom they attribute transient hyperglycinemia to heterozygosity in a component of the glycine cleavage system (GCS). One mutant P-protein (GLDC) allele was identified in each of two patients and one mutant H-protein (GCSH) allele in the third. The latter is reported to have normal GCS activity in lymphoblasts and B6 responsive seizures. No follow-up plasma or CSF glycine levels are reported for any of the patients to document the transience of the hyperglycinemia. Transient hyperglycinemia has not been reported in any families with glycine encephalopathy (nonketotic hyperglycinemia [NKH]), nor have we seen it in more than 100 families with NKH that we have evaluated, nor has a report of familial transient hyperglycinemia been described. The basis of transient hyperglycinemia remains unknown, although the hypothesis of heterozygosity for one or more components of the GCS plus other genetic and environmental factors is attractive. Recently, A.H. had the privilege of evaluating Patient 1 of Kure and colleagues in clinic. In contrast with the report, she is a normocephalic (occipitofrontal circumference, 49.5cm, 25–50th percentile) 3-year-old white female with a development quotient of 30, persistent seizures (0–20/day), a markedly abnormal electroencephalogram, and a fasting plasma glycine of 820 mol/L taking 350mg/kg/day of sodium benzoate. She has NKH, and there is nothing transient about it. The identified GLDC mutation is a premature termination codon in exon 20 (W805X). Because the number of nucleotides in exon 20 is not a multiple of 3 precluding the possibility of nonsense mediated alternative splicing, the most likely effect of this mutation is markedly reduced mRNA because of nonsense mediated mRNA decay and not a profoundly truncated polypeptide of P-protein. The second mutation was either missed by the methods used or is a promoter or deep intronic mutation that was not detected. The article by Kure and colleagues should not be used to counsel families at 25% risk of an infant with NKH that their carrier children may be affected with transient NKH, because there are no data to support this. Our data plus the lack of documentation of the transient nature of the hyperglycinemia question the validity of their diagnosis. Second, heterozygosity at the disease gene locus is uncertain in the absence of exhaustive survey for a mutation and appropriate family studies. Nevertheless, the idea that heterozygosity for certain mutant alleles (most likely a missense mutation with a dominant negative capability) is an interesting one that would necessitate additional experimental validation, including family studies. Alternatively, the idea of a digenic cause with mutations in multiple components of the GCS also merits investigation. This is particularly attractive for Patient 3 who is B6 responsive (the cofactor for P-protein) but has a mutation in GCSH. Additional information regarding Patients 2 and 3 in this study is necessary to substantiate the claims of transient NKH. Furthermore, the lack of detection of a second mutation never provides certainty that it is not there. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium