Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Issue 4 (10th August 2015)

• Record Type: Journal Article
• 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.
• Is Part Of: Annals of neurology. Volume 78:Issue 4(2015:Oct.)
• Page Start: 606
• Page End: 618
• Publication Date: 2015-08-10
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24485
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24485-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="ana24485-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="ana24485-sec-0003" sec-type="section"> <title>Results</title> <p>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.</p> </sec> <sec id="ana24485-sec-0004" sec-type="section"> <title>Interpretation</title> <p>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. Ann Neurol 2015;78:606–618</p> </sec> </abstract>