NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation.

Ivana Dabaj,Sophie Coutant,Stéphane Marret,Anne-Marie Guerrot,Bénédicte Sudrié-Arnaud,Pascale Saugier-Veber,Sarah Snanoudj,Gaël Nicolas,Abdellah Tebani,François Lecoquierre,Franklin Ducatez,Kimiyo Raymond,Soumeya Bekri

doi:10.3390/life11030187

Ivana Dabaj, Sophie Coutant + Show 11 more

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https://doi.org/10.3390/life11030187

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Abstract

NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay—hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima.

Highlights

NGLY1 deficiency (OMIM#615273) is a rare autosomal recessive congenital disorder ofN-linked deglycosylation (NGLY1-CDDG) related to N-Glycanase (EC 3.5.1.52) deficiency
36 cases with a confirmed molecular diagnosis have been described while the NGLY1 Foundation, a patient support and research organization for NGLY1 Deficiency (NGLY1.org), reported in 2018 sixty-three patients aged from a few months to 22 years with different ethnic backgrounds [1,3,4,5,6,7,8,9,10,11]
It has recently been shown that this catalytic function of deglycosylation is involved in the activation of proteins such as the transcription factor Nuclear Factor Erythroid 2 like 1 (NFE2L1) that regulates the proteasome, mitochondria and inflammation processes [13,14,15]

Summary

Introduction

N-linked deglycosylation (NGLY1-CDDG) related to N-Glycanase (EC 3.5.1.52) deficiency. This disease is the only congenital disorder of deglycosylation while more than 100 different congenital disorders have been reported for glycosylation [1]. The N-Glycanase cleaves the N-glycan from the asparagine residue and catalyzes the removal of N-linked oligosaccharides from misfolded glycoproteins prior to their degradation through the endoplasmic reticulum-associated degradation (ERAD) process. The decrease of aquaporin expression may underlie the hypolacrimia/alacrimia and neurological disturbances observed in NGLY1 deficiency (Figure 1A) [16]. These numerous roles of NGLY1 are certainly at the origin of the multisystemic involvement in this complex disease. We report the first case from France and provide a literature review

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