title: Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia.
abstract: OBJECTIVE
  Nonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed.
  
  
  METHODS
  We reviewed 124 patients stratified by developmental outcome for biochemical and molecular predictive factors. Missense mutations were expressed to quantify residual activity using a new assay.
  
  
  RESULTS
  Patients with severe nonketotic hyperglycinemia required multiple anticonvulsants, whereas patients with developmental quotient (DQ) > 30 did not require anticonvulsants. Brain malformations occurred mainly in patients with severe nonketotic hyperglycinemia (71%) but rarely in patients with attenuated nonketotic hyperglycinemia (7.5%). Neonatal presentation did not correlate with outcome, but age at onset ≥ 4 months was associated with attenuated nonketotic hyperglycinemia. Cerebrospinal fluid (CSF) glycine levels and CSF:plasma glycine ratio correlated inversely with DQ; CSF glycine > 230 μM indicated severe outcome and CSF:plasma glycine ratio ≤ 0.08 predicted attenuated outcome. The glycine index correlated strongly with outcome. Molecular analysis identified 99% of mutant alleles, including 96 novel mutations. Mutations near the active cleft of the P-protein maintained stable protein levels. Presence of 1 mutation with residual activity was necessary but not sufficient for attenuated outcome; 2 such mutations conferred best outcome. Divergent outcomes for the same genotype indicate a contribution of other genetic or nongenetic factors.
  
  
  CONCLUSIONS
  Accurate prediction of outcome is possible in most patients. A combination of 4 factors available neonatally predicted 78% of severe and 49% of attenuated patients, and a score based on mutation severity predicted outcome with 70% sensitivity and 97% specificity.
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Swanson
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Gunter H
authors.initials: GH
authors.lastname: Scharer
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Szerlong
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Kendra J
authors.initials: KJ
authors.lastname: Bjoraker
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Elaine B
authors.initials: EB
authors.lastname: Spector
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Geralyn
authors.initials: G
authors.lastname: Creadon-Swindell
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mahieu
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, Germany.
authors.forename: Julia B
authors.initials: JB
authors.lastname: Hennermann
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Applegarth
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Toone
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Suhong
authors.initials: S
authors.lastname: Tong
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Kristina
authors.initials: K
authors.lastname: Williams
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO.
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D005998:Glycine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D017433:Protein Structure, Secondary
chemical_list: D005998:Glycine