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NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum

Authors :
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
Source :
Frontiers in Neurology, Vol 12 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

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.

Details

Language :
English
ISSN :
16642295
Volume :
12
Database :
Directory of Open Access Journals
Journal :
Frontiers in Neurology
Publication Type :
Academic Journal
Accession number :
edsdoj.8c594ab0c7de47199c4d3dccb48830a8
Document Type :
article
Full Text :
https://doi.org/10.3389/fneur.2021.668640