1. Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.
- Author
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Panneman DM, Wortmann SB, Haaxma CA, van Hasselt PM, Wolf NI, Hendriks Y, Küsters B, van Emst-de Vries S, van de Westerlo E, Koopman WJH, Wintjes L, van den Brandt F, de Vries M, Lefeber DJ, Smeitink JAM, and Rodenburg RJ
- Subjects
- Child, Child, Preschool, Congenital Disorders of Glycosylation diagnostic imaging, Congenital Disorders of Glycosylation genetics, Congenital Disorders of Glycosylation metabolism, Congenital Disorders of Glycosylation pathology, Epilepsies, Myoclonic diagnostic imaging, Epilepsies, Myoclonic pathology, Female, Humans, Intellectual Disability diagnostic imaging, Intellectual Disability pathology, Male, Mitochondria genetics, Mitochondria pathology, Mutation genetics, Polyneuropathies diagnostic imaging, Polyneuropathies pathology, Epilepsies, Myoclonic genetics, Intellectual Disability genetics, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase genetics, Polyneuropathies genetics
- Abstract
NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
- Published
- 2020
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