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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. INTERPRETATION: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.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Swanson MA,Coughlin CR Jr,Scharer GH,Szerlong HJ,Bjoraker KJ,Spector EB,Creadon-Swindell G,Mahieu V,Matthijs G,Hennermann JB,Applegarth DA,Toone JR,Tong S,Williams K,Van Hove JL

doi

10.1002/ana.24485

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

606-18

issue

eissn

0364-5134

issn

1531-8249

journal_volume

pub_type

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Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia.