This article was originally published here
Ann Neurol. 2022 May 26. doi: 10.1002/ana.26423. Online ahead of print.
OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed.
METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of International Working Group on Neurotransmitter related Disorders were studied with in silico analyses, pathogenicity scores and molecular modeling of GLDC and AMT variants.
RESULTS: Symptom onset (p<0· 01) and diagnosis occur earlier in life in severe NKH (p<0· 01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset-age ≥3 months (66% specificity, 100% sensitivity, AUC = 0·87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤0· 09 (57% specificity, 100% sensitivity, AUC = 0·88) are sensitive indicators for attenuated NKH while CSF glycine concentration ≥116· 5 μmol/L (100% specificity, 93% sensitivity, AUC = 0·97) and CSF/plasma glycine ratio ≥0· 15 (100% specificity, 64% sensitivity, AUC = 0·88) are specific for severe forms. A ratio threshold of 0· 128 discriminates the overlapping range. We present ten new GLDC variants. Two mild variants resulted in attenuated, while two severe variants or one mild and one severe variant lead to severe phenotype. Based on clinical, biochemical and genetic parameter we propose a severity prediction model.
INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. This article is protected by copyright. All rights reserved.