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

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.

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

“…Loss of N-glycanase 1 in worms, MEFs, and fibroblasts and muscle biopsies from NGLY1 deficiency patients results in functional abnormalities in mitochondria, including a reduction in oxidative phosphorylation, basal OCR and maximal OCR, and an increase in oxidative stress [7,12,13]. Moreover, Ngly1 -/-MEFs showed mitochondrial fragmentation [13].…”

“…The cytoplasmic enzyme N-glycanase 1 (NGLY1) catalyzes the removal of N-linked glycans from glycoproteins and is thought to operate as part of the endoplasmic reticulum-associated degradation (ERAD) pathway [1]. Recessive mutations in human NGLY1 result in a genetic disorder with various phenotypes including developmental delay, seizures, hypo-/alacrima, elevated liver enzymes, diminished deep tendon reflexes, muscle weakness, orthopedic manifestations, and chronic constipation [2][3][4][5][6][7][8]. This disease is a congenital disorder of deglycosylation (OMIM # 615273) and is commonly referred to as NGLY1 deficiency.…”

“…Studies in tissue samples from NGLY1 deficiency patients, patient fibroblasts, Ngly1 -/ mouse embryonic fibroblasts (MEFs) and C. elegans mutants for the NGLY1 homolog (png-1 -/-) have shown structural and functional abnormalities in mitochondria [7,12]. Moreover, Ngly1 -/-MEFs fail to properly clear damaged mitochondria via mitophagy [13].…”

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

“…Our literature search identified 36 patients with pathogenic variants in NGLY1. The molecular and clinical overviews of reported cases [1,[3][4][5][6][7][8][9][10][11]23,[25][26][27][28] are summarized in Figures 1B and 2A and detailed in the supplementary Table S1. The most frequently associated clinical signs are psychomotor retardation (36/36), abnormal movements (30/30), hypolacrima or alacrima (30/30) and cytolysis (30/30).…”

Integration and comparison of multi-omics profiles of NGLY1 deficiency plasma and cellular models to identify clinically relevant molecular phenotypes

“…Symptoms arise in infancy and vary between individual patients. Most patients do not survive past childhood 7,8 and no therapeutic options have been developed thus far. As revealed by whole exome sequencing, the disorder is caused by a mutation in NGLY1 gene which encodes the cytosolic enzyme N-glycanase1 (NGLY1) responsible for protein deglycosylation, a process necessary for the endoplasmic reticulum associated degradation (ERAD) of misfolded or damaged glycoproteins 1,[9][10][11][12] .…”