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Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.
Kuseyri Hübschmann, Oya; Juliá-Palacios, Natalia Alexandra; Olivella, Mireia; Guder, Philipp; Zafeiriou, Dimitrios I; Horvath, Gabriella; Kulhánek, Jan; Pearson, Toni S; Kuster, Alice; Cortès-Saladelafont, Elisenda; Ibáñez, Salvador; García-Jiménez, Maria Concepción; Honzík, Tomás; Santer, René; Jeltsch, Kathrin; Garbade, Sven F; Hoffmann, Georg F; Opladen, Thomas; García-Cazorla, Ángeles.
Afiliación
  • Kuseyri Hübschmann O; University Children's Hospital Heidelberg, Division of Child Neurology and Metabolic Disorders, Heidelberg, Germany.
  • Juliá-Palacios NA; Inborn Errors of Metabolism Unit, Department of Neurology, Recerca Sant Joan de Déu Institute, CIBERER-ISCIII and MetabERN, Barcelona, Spain.
  • Olivella M; Bioinformatics and Medical Statistics Group, Faculty of Science and Technology, Vic University-University of Central Catalonia, Barcelona, Spain.
  • Guder P; Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Zafeiriou DI; First Department of Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  • Horvath G; Division of Biochemical Genetics, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, British Columbia, Canada.
  • Kulhánek J; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • Pearson TS; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
  • Kuster A; Department of Neurometabolism and Metabolic Disorders, University Hospital of Nantes, Nantes, France.
  • Cortès-Saladelafont E; Inborn Errors of Metabolism Unit, Department of Neurology, Recerca Sant Joan de Déu Institute, CIBERER-ISCIII and MetabERN, Barcelona, Spain.
  • Ibáñez S; 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.
  • García-Jiménez MC; Department of Pediatric Neurology, Virgen de la Arrixaca Hospital, Murcia, Spain.
  • Honzík T; Metabolic Diseases Unit, Miguel Servet University Hospital, Zaragoza, Spain.
  • Santer R; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • Jeltsch K; Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Garbade SF; University Children's Hospital Heidelberg, Division of Child Neurology and Metabolic Disorders, Heidelberg, Germany.
  • Hoffmann GF; Dietmar-Hopp Metabolic Center, University Children's Hospital Heidelberg, Heidelberg, Germany.
  • Opladen T; University Children's Hospital Heidelberg, Division of Child Neurology and Metabolic Disorders, Heidelberg, Germany.
  • García-Cazorla Á; University Children's Hospital Heidelberg, Division of Child Neurology and Metabolic Disorders, Heidelberg, Germany.
Ann Neurol ; 92(2): 292-303, 2022 08.
Article en En | MEDLINE | ID: mdl-35616651
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hiperglicinemia no Cetósica Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Ann Neurol Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hiperglicinemia no Cetósica Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Ann Neurol Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos