TY - JOUR
T1 - Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction
AU - Panneman, Daan M.
AU - Wortmann, Saskia B.
AU - Haaxma, Charlotte A.
AU - van Hasselt, Peter M.
AU - Wolf, Nicole I.
AU - Hendriks, Yvonne
AU - Küsters, Benno
AU - van Emst-de Vries, Sjenet
AU - van de Westerlo, Els
AU - Koopman, Werner J.H.
AU - Wintjes, Liesbeth
AU - van den Brandt, Frans
AU - de Vries, Maaike
AU - Lefeber, Dirk J.
AU - Smeitink, Jan A.M.
AU - Rodenburg, Richard J.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - mitochondrial disorders
KW - NGLY1
KW - OXPHOS enzyme activity
KW - Seahorse respirometry
KW - Whole exome sequencing
U2 - 10.1111/cge.13706
DO - 10.1111/cge.13706
M3 - Article
C2 - 31957011
AN - SCOPUS:85081417911
SN - 0009-9163
VL - 97
SP - 556
EP - 566
JO - Clinical Genetics
JF - Clinical Genetics
IS - 4
ER -