TY - JOUR

T1 - NANS-CDG

T2 - Delineation of the Genetic, Biochemical, and Clinical Spectrum

AU - den Hollander, Bibiche

AU - Rasing, Anne

AU - Post, Merel A.

AU - Klein, Willemijn M.

AU - Oud, Machteld M.

AU - Brands, Marion M.

AU - de Boer, Lonneke

AU - Engelke, Udo F.H.

AU - van Essen, Peter

AU - Fuchs, Sabine A.

AU - Haaxma, Charlotte A.

AU - Jensson, Brynjar O.

AU - Kluijtmans, Leo A.J.

AU - Lengyel, Anna

AU - Lichtenbelt, Klaske D.

AU - Østergaard, Elsebet

AU - Peters, Gera

AU - Salvarinova, Ramona

AU - Simon, Marleen E.H.

AU - Stefansson, Kari

AU - Thorarensen, Ólafur

AU - Ulmen, Ulrike

AU - Coene, Karlien L.M.

AU - Willemsen, Michèl A.

AU - Lefeber, Dirk J.

AU - Karnebeek, Clara D.M.van

N1 - Publisher Copyright: © Copyright © 2021 den Hollander, Rasing, Post, Klein, Oud, Brands, de Boer, Engelke, van Essen, Fuchs, Haaxma, Jensson, Kluijtmans, Lengyel, Lichtenbelt, Østergaard, Peters, Salvarinova, Simon, Stefansson, Thorarensen, Ulmen, Coene, Willemsen, Lefeber and Karnebeek.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - congenital disorder of glycosylation

KW - glycosylation

KW - intellectual developmental disorder/IDD

KW - metabolic disease

KW - N-acetyl-D-neuraminic acid

KW - sialic acid biosynthesis

KW - skeletal dysplasia

KW - thrombocytopenia

U2 - 10.3389/fneur.2021.668640

DO - 10.3389/fneur.2021.668640

M3 - Journal article

C2 - 34163424

AN - SCOPUS:85108686680

VL - 12

JO - Frontiers in Neurology

JF - Frontiers in Neurology

SN - 1664-2295

M1 - 668640

ER -