Neonatal hypotonia with burst suppression pattern reveals non ketotic hyperglycinemia associated with P-protein deficiency

Background: Non-ketotic hyperglycinemia (NKH, MIM#605899) is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage system (GCS).

Case report:: The female baby was born at term to a GII, PI mother (non-consanguineous parents with unremarkable family history) after an uneventful pregnancy (birth weight: 3510 gr). APGAR scores were 9 and 10. Vital signs were normal. On day two of life the newborn became progressively lethargic with generalised muscular hypotonia, a weak suck, absent deep tendon reflexes, extreme sleepiness, and insufficient respiratory drive, which mandated intubation and mechanical ventilation. Routine clinical chemistry was normal. An ultrasound scan of the brain did not reveal any intracranial pathology. An amplitude-integrated EEG showed continuous burst suppression pattern. Of interest, the neonate did not have manifest seizures. A lumbar puncture yielded normal results for white cell count, protein, glucose and lactate. The analysis of amino acids in CSF and plasma yielded the diagnosis of NKH: glycine in CSF: 360.1µmol/l, (reference value: 5.9–8.5µmol/l); plasma glycine: 2196µmol/l; (reference value: 224–514µmol/l) and ratio CSF/plasma: 0.16 (normal <0.04). The diagnosis of NKH was then confirmed by direct sequencing of all exons and intron-exons boundaries of GLDC gene using DNA extracted from leukocytes. The child is compound heterozygous for 2 sequence modifications: the substitution of an adenine by a guanine at position 1654 on the cDNA (c.1654A>G) leading to the replacement of a methionine by a valine at position 552 on the protein (p.Met552Val) and the substitution of a guanine by an adenine at position 2311 (c.2311G>A) leading to the replacement of a glycine by an arginine at position 771 on the protein (p.Gly771Arg). These sequence modifications were then screened in DNA from each parent: the mother carries the p.Gly771Arg mutation and the father, the p.Met552Val.

Conclusion: We report a new genetic mutation in a neonate with NKH. NKH should be taken into the differenzial diagnosis of neonatal hypotonia.