Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation

• Published in: Annals of neurology Vol. 59; no. 2; pp. 411 - 415
• Main Authors: Korman, Stanley H., Wexler, Isaiah D., Gutman, Alisa, Rolland, Marie-Odile, Kanno, Junko, Kure, Shigeo
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-02-2006; Willey-Liss
• Subjects: Aldehydes - cerebrospinal fluid; Amino Acid Oxidoreductases - metabolism; Biological and medical sciences; Carrier Proteins - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diseases of striated muscles. Neuromuscular diseases; DNA Mutational Analysis - methods; Epoxy Compounds - cerebrospinal fluid; Excitatory Amino Acid Antagonists - therapeutic use; Female; Follow-Up Studies; Glycine Dehydrogenase - genetics; Humans; Hyperglycinemia, Nonketotic - cerebrospinal fluid; Hyperglycinemia, Nonketotic - drug therapy; Hyperglycinemia, Nonketotic - genetics; Infant, Newborn; Ketamine - therapeutic use; Medical sciences; Multienzyme Complexes - metabolism; Mutation; Neurology; Prospective Studies; Sodium Benzoate - therapeutic use; Transferases - metabolism; Nervous system diseases; Treatment; Hyperglycinemia; Metabolic diseases; Mutation; Enzymopathy; Aminoacid disorder; Genetic disease
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20759

Objective
To determine whether the devastating outcome of neonatal‐onset glycine encephalopathy (NKH) could be improved by instituting treatment immediately at birth rather than after symptoms are already well established.
Methods
A newborn with NKH diagnosed prenatally following the neonatal death of a previous affected sibling was treated from birth with oral sodium benzoate (250mg/kg/day) and the NMDA receptor antagonist ketamine (15mg/kg/day) immediately after sampling cord blood and cerebrospinal fluid (CSF) for glycine determination. Glycine cleavage system (CGS) activity was determined in placental tissue. Mutation analysis was performed by sequencing all GLDC, GCSH and AMT exons.
Results
CSF glycine (99 μmol/L, reference 3.8–8.0) was already markedly elevated at birth. GCS activity in placental tissue was severely reduced (2.6% of controls). A novel homozygous GLDC c.482A→G(Y161C) missense mutation was identified. Neonatal hypotonia and apnea did not occur but the long‐term outcome was poor, with intractable seizures and severe psychomotor retardation. This contrasts with the favorable outcome with early treatment in variant NKH with mild GCS deficiency (Ann Neuol 2004;56:139–143).
Interpretation
Prospective treatment with this regimen can favorably modify the early neonatal course of severe NKH but does not prevent the poor long‐term outcome, suggesting glycine‐induced prenatal injury and/or ongoing postnatal damage. Ann Neurol 2006