NANS-CDG:Delineation of the Genetic, Biochemical, and Clinical Spectrum
| Autor: | Bibiche den Hollander, Anne Rasing, Merel A. Post, Willemijn M. Klein, Machteld M. Oud, Marion M. Brands, Lonneke de Boer, Udo F. H. Engelke, Peter van Essen, Sabine A. Fuchs, Charlotte A. Haaxma, Brynjar O. Jensson, Leo A. J. Kluijtmans, Anna Lengyel, Klaske D. Lichtenbelt, Elsebet Østergaard, Gera Peters, Ramona Salvarinova, Marleen E. H. Simon, Kari Stefansson, Ólafur Thorarensen, Ulrike Ulmen, Karlien L. M. Coene, Michèl A. Willemsen, Dirk J. Lefeber, Clara D. M. van Karnebeek |
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| Přispěvatelé: | Paediatric Metabolic Diseases, APH - Personalized Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty glycosylation Genetic counseling Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] thrombocytopenia skeletal dysplasia Compound heterozygosity Gastroenterology Short stature 03 medical and health sciences Epilepsy congenital disorder of glycosylation All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Internal medicine medicine RC346-429 N-acetyl-D-neuraminic acid Original Research Cerebral atrophy Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] business.industry Other Research Radboud Institute for Health Sciences [Radboudumc 0] intellectual developmental disorder/IDD Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] medicine.disease metabolic disease Developmental disorder 030104 developmental biology Neurology Dysplasia sialic acid biosynthesis Neurology. Diseases of the nervous system Neurology (clinical) medicine.symptom business Congenital disorder of glycosylation 030217 neurology & neurosurgery |
| Zdroj: | den Hollander, B, Rasing, A, Post, M A, Klein, W M, Oud, M M, Brands, M M, de Boer, L, Engelke, U F H, van Essen, P, Fuchs, S A, Haaxma, C A, Jensson, B O, Kluijtmans, L A J, Lengyel, A, Lichtenbelt, K D, Østergaard, E, Peters, G, Salvarinova, R, Simon, M E H, Stefansson, K, Thorarensen, Ó, Ulmen, U, Coene, K L M, Willemsen, M A, Lefeber, D J & Karnebeek, C D M V 2021, ' NANS-CDG : Delineation of the Genetic, Biochemical, and Clinical Spectrum ', Frontiers in Neurology, vol. 12, 668640 . https://doi.org/10.3389/fneur.2021.668640 Frontiers in Neurology, 12 Frontiers in Neurology, Vol 12 (2021) Frontiers in Neurology Frontiers in neurology, 12:668640. Frontiers Media S.A. |
| ISSN: | 1664-2295 |
| Popis: | Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational cohort study to delineate the genetic, biochemical, and clinical phenotype and assess possible correlations.Methods: Medical and laboratory records were reviewed with retrospective extraction and analysis of genetic, biochemical, and clinical data (2016–2020).Results: Nine NANS-CDG patients (nine families, six countries) referred to the Radboudumc CDG Center of Expertise were included. Phenotyping confirmed the hallmark features including intellectual developmental disorder (IDD) (n = 9/9; 100%), facial dysmorphisms (n = 9/9; 100%), neurologic impairment (n = 9/9; 100%), short stature (n = 8/9; 89%), skeletal dysplasia (n = 8/9; 89%), and short limbs (n = 8/9; 89%). Newly identified features include ophthalmological abnormalities (n = 6/9; 67%), an abnormal septum pellucidum (n = 6/9; 67%), (progressive) cerebral atrophy and ventricular dilatation (n = 5/9; 56%), gastrointestinal dysfunction (n = 5/9; 56%), thrombocytopenia (n = 5/9; 56%), and hypo–low-density lipoprotein cholesterol (n = 4/9; 44%). Biochemically, elevated urinary excretion of N-acetylmannosamine (ManNAc) is pathognomonic, the concentrations of which show a significant correlation with clinical severity. Genotypically, eight novel NANS variants were identified. Three severely affected patients harbored identical compound heterozygous pathogenic variants, one of whom was initiated on experimental prenatal and postnatal treatment with oral sialic acid. This patient showed markedly better psychomotor development than the other two genotypically identical males.Conclusions: ManNAc screening should be considered in all patients with IDD, short stature with short limbs, facial dysmorphisms, neurologic impairment, and an abnormal septum pellucidum +/– congenital and neurodegenerative lesions on brain imaging, to establish a precise diagnosis and contribute to prognostication. Personalized management includes accurate genetic counseling and access to proper supports and tailored care for gastrointestinal symptoms, thrombocytopenia, and epilepsy, as well as rehabilitation services for cognitive and physical impairments. Motivated by the short-term positive effects of experimental treatment with oral sialic, we have initiated this intervention with protocolized follow-up of neurologic, systemic, and growth outcomes in four patients. Research is ongoing to unravel pathophysiology and identify novel therapeutic targets. |
| Databáze: | OpenAIRE |
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