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 the 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, area under the curve [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, whereas CSF glycine concentration ≥ 116.5μmol/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 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, 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. ANN NEUROL 2022;92:292-303.

1st Department of Pediatrics Aristotle University of Thessaloniki Thessaloniki Greece

Bioinformatics and Medical Statistics Group Faculty of Science and Technology Vic University University of Central Catalonia Barcelona Spain

Children's Hospital University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Neurology Washington University School of Medicine St Louis MO USA

Department of Neurometabolism and Metabolic Disorders University Hospital of Nantes Nantes France

Department of Pediatric Neurology Virgen de la Arrixaca Hospital Murcia Spain

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Dietmar Hopp Metabolic Center University Children's Hospital Heidelberg Heidelberg Germany

Division of Biochemical Genetics Department of Pediatrics University of British Columbia BC Children's Hospital Vancouver British Columbia Canada

Inborn Errors of Metabolism and Child Neurology Unit Department of Pediatrics Germans Trias i Pujol Hospital Badalona and Faculty of Medicine Autonomous University of Barcelona Barcelona Spain

Inborn Errors of Metabolism Unit Department of Neurology Recerca Sant Joan de Déu Institute CIBERER ISCIII and MetabERN Barcelona Spain

Metabolic Diseases Unit Miguel Servet University Hospital Zaragoza Spain

University Children's Hospital Heidelberg Division of Child Neurology and Metabolic Disorders Heidelberg Germany

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