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.
Highlights
The clinical spectrum of mitochondrial disorders (MDs) is extremely broad and there are numerous underlying biochemical and genetic defects associated with this type of disorders
N-glycanase 1 (NGLY1) is an enzyme involved in the removal of N-glycans from glycoproteins, which precedes the proteolytic degradation of glycosylated proteins via the endoplasmatic reticulum-associated degradation (ERAD) pathway
We report four patients with biallelic variants in NGLY1 who presented with myoclonus epilepsy, peripheral neuropathy, and metabolic markers suggestive for mitochondrial dysfunction
Summary
The clinical spectrum of mitochondrial disorders (MDs) is extremely broad and there are numerous underlying biochemical and genetic defects associated with this type of disorders. While suggestive for a MD, clinical signs like infantile myoclonus epilepsy, intellectual disability, and muscular hypotonia1,2) show clinical overlap with other (neuro)muscular and (neuro)metabolic disorders. This overlap is evident in recently published patients with an impaired function of N-glycanase 1 (NGLY1). This genetic defect causes a broad clinical spectrum including hypo-/alacrima, developmental delay, elevated liver enzymes, diminished deep tendon reflexes, and epileptic seizures.. Molecular testing revealed further mitochondrial morphological and functional alterations which have not yet been described for this patient group Taken together, these results provide evidence for a possible role for NGLY1 in mitochondrial function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
