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Genet Med. 2017 Feb;19(2):160-168. doi: 10.1038/gim.2016.75. Epub 2016 Jul 7.

Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation.

Author information

1
Medical Genetics Branch National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
2
Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
3
Division of Genetics and Developmental Biology, National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Maryland, USA.
4
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
5
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
6
Electromyography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
7
Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
8
Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
9
Pediatric and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, Maryland, USA.
10
Immunology Service, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
11
Genetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
12
Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
13
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
14
Speech and Language Pathology Section, Department of Rehabilitation Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
15
Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
16
Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
17
Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Abstract

PURPOSE:

The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the β-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG).

METHODS:

Prospective natural history protocol.

RESULTS:

In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSF) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features.

CONCLUSION:

Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.Genet Med 19 2, 160-168.

PMID:
27388694
DOI:
10.1038/gim.2016.75
[Indexed for MEDLINE]

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