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- Title
Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia.
- Authors
Swanson, Michael A.; Coughlin, Curtis R.; Scharer, Gunter H.; Szerlong, Heather J.; Bjoraker, Kendra J.; Spector, Elaine B.; Creadon‐Swindell, Geralyn; Mahieu, Vincent; Matthijs, Gert; Hennermann, Julia B.; Applegarth, Derek A.; Toone, Jennifer R.; Tong, Suhong; Williams, Kristina; Van Hove, Johan L. K.
- Abstract
<bold>Objective: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Interpretation: </bold>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.
- Subjects
GLYCINE metabolism; GLYCINE; GENETIC mutation; PRIMATES; PROGNOSIS; PROTEINS; RESEARCH funding; PREDICTIVE tests
- Publication
Annals of Neurology, 2015, Vol 78, Issue 4, p606
- ISSN
0364-5134
- Publication type
journal article
- DOI
10.1002/ana.24485