Integrative approach to predict severity in nonketotic hyperglycinemia

• Verfasst von: Kuseyri Hübschmann, Oya [VerfasserIn]
• Verfasst von: Juliá-Palacios, Natalia Alexandra [VerfasserIn]
• Verfasst von: Olivella, Mireia [VerfasserIn]
• Verfasst von: Guder, Philipp [VerfasserIn]
• Verfasst von: Zafeiriou, Dimitrios I. [VerfasserIn]
• Verfasst von: Horvath, Gabriela Ana [VerfasserIn]
• Verfasst von: Kulhánek, Jan [VerfasserIn]
• Verfasst von: Pearson, Toni S. [VerfasserIn]
• Verfasst von: Kuster, Alice [VerfasserIn]
• Verfasst von: Cortès-Saladelafont, Elisenda [VerfasserIn]
• Verfasst von: Ibáñez, Salvador [VerfasserIn]
• Verfasst von: García-Jiménez, Maria Concepción [VerfasserIn]
• Verfasst von: Honzík, Tomáš [VerfasserIn]
• Verfasst von: Santer, René [VerfasserIn]
• Verfasst von: Jeltsch, Kathrin [VerfasserIn]
• Verfasst von: Garbade, Sven [VerfasserIn]
• Verfasst von: Hoffmann, Georg F. [VerfasserIn]
• Verfasst von: Opladen, Thomas [VerfasserIn]
• Verfasst von: García-Cazorla, Ángeles [VerfasserIn]
• Titel: Integrative approach to predict severity in nonketotic hyperglycinemia
• Verf.angabe: Oya Kuseyri Hübschmann, MD, Natalia Alexandra Juliá-Palacios, MD, Mireia Olivella, PhD, Philipp Guder, MD, Dimitrios I. Zafeiriou, MD, Gabriella Horvath, MD, Jan Kulhánek, MD, Toni S. Pearson, MD, Alice Kuster, MD, Elisenda Cortès-Saladelafont, MD, Salvador Ibáñez, MD, Maria Concepción García-Jiménez, MD, Tomáš Honzík, MD, René Santer, MD, Kathrin Jeltsch, PhD, Sven F. Garbade, PhD, Georg F. Hoffmann, MD, Thomas Opladen, MD, and Ángeles García-Cazorla, MD
• E-Jahr: 2022
• Jahr: August 2022
• Umfang: 12 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 09.08.2023
• Titel Quelle: Enthalten in: Annals of neurology
• Ort Quelle: Hoboken, NJ : Wiley-Blackwell, 1977
• Jahr Quelle: 2022
• Band/Heft Quelle: 92(2022), 2 vom: Aug., Seite 292-303
• ISSN Quelle: 1531-8249
• DOI: doi:10.1002/ana.26423
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1854991752

Abstract

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