Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction

Daan M. Panneman, Saskia B. Wortmann, Charlotte A. Haaxma, Peter M. van Hasselt, Nicole I. Wolf, Yvonne Hendriks, Benno Küsters, Sjenet van Emst-de Vries, Els van de Westerlo, Werner J.H. Koopman, Liesbeth Wintjes, Frans van den Brandt, Maaike de Vries, Dirk J. Lefeber, Jan A.M. Smeitink, Richard J. Rodenburg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)556-566
Number of pages11
JournalClinical Genetics
Volume97
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020

Cite this

Panneman, D. M., Wortmann, S. B., Haaxma, C. A., van Hasselt, P. M., Wolf, N. I., Hendriks, Y., ... Rodenburg, R. J. (2020). Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction. Clinical Genetics, 97(4), 556-566. https://doi.org/10.1111/cge.13706