N-Glycanase 1 Deficiency Is a Rare Cause of Pediatric Neurodegeneration With Neuronal Inclusions and Liver Steatosis

Stuut, Thomas; Popescu, Oana; Oviedo, Angélica

doi:10.7759/cureus.19126

Cited by 3 publications

(6 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Table 1 lists the reported patients, along with their gender, age at the time of publication, genotype at the NGLY1 locus, reported phenotypes, and reference(s). Although the initial clinical triad of hypo/alacrima, choreoathetosis, and elevated liver transaminases has been observed in subsequent patients [ 18 , 19 ], additional findings have complicated the picture, indicating that NGLY1 deficiency affects more organ systems than originally described [ 11 , 12 , 20 , 21 , 22 ].…”

Section: Patient Phenotypes In Ngly1 Deficiencymentioning

confidence: 99%

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology

Pandey

Adams

Han

et al. 2022

Cells

View full text Add to dashboard Cite

N-Glycanase 1 (NGLY1) is a cytosolic enzyme involved in removing N-linked glycans of misfolded N-glycoproteins and is considered to be a component of endoplasmic reticulum-associated degradation (ERAD). The 2012 identification of recessive NGLY1 mutations in a rare multisystem disorder has led to intense research efforts on the roles of NGLY1 in animal development and physiology, as well as the pathophysiology of NGLY1 deficiency. Here, we present a review of the NGLY1-deficient patient phenotypes, along with insights into the function of this gene from studies in rodent and invertebrate animal models, as well as cell culture and biochemical experiments. We will discuss critical processes affected by the loss of NGLY1, including proteasome bounce-back response, mitochondrial function and homeostasis, and bone morphogenetic protein (BMP) signaling. We will also cover the biologically relevant targets of NGLY1 and the genetic modifiers of NGLY1 deficiency phenotypes in animal models. Together, these discoveries and disease models have provided a number of avenues for preclinical testing of potential therapeutic approaches for this disease.

show abstract

Section: Patient Phenotypes In Ngly1 Deficiencymentioning

confidence: 99%

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology

Pandey

Adams

Han

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…7 Additional patients continue to be identified through next-generation sequencing. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] The predominant and most debilitating features of NGLY1 deficiency are neurologic, affecting both the central and peripheral nervous system. In published cases, 23/48 (47.9%) individuals have comorbid epilepsy, although clinical details are limited.…”

Section: Introductionmentioning

confidence: 99%

“…Additional patients continue to be identified through next‐generation sequencing 8–24 . The predominant and most debilitating features of NGLY1 deficiency are neurologic, affecting both the central and peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

Delineating the epilepsy phenotype of NGLY1 deficiency

Levy

Frater

Gallentine

et al. 2022

J of Inher Metab Disea

View full text Add to dashboard Cite

We delineated the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort. We collected detailed clinical and electroencephalographic data from 29 individuals with bi‐allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in‐person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping. Of 29 individuals (mean 11.4 years, range 3–27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. Electroencephalogram (EEGs) were abnormal in 80% (12/15) of participants with or without epilepsy, although encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays. In summary, epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated.

show abstract

“…9,10,26 Defects in NGLY1 show accumulation of undegraded protein aggregates that may damage cells in the brain, eyes, and liver. 9,[27][28][29] The measurement of NGLY1 activity by using a BODIPY-labeled asialo glycopeptide has been developed and NGLY1 mutants show reduced activity. 30 However, when the endogenous NGLY1 activity was measured using glycosylated hepta-cyclopeptide, the test lacked specificity.…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of NGLY1, a cytosolic enzyme, endo‐β‐N‐acetylglucosaminidase (ENGase) catalyzes the deglycosylation of misfolded glycoproteins in the cytosol and generates N‐GlcNAc proteins, which is lethal to cells 9,10,26 . Defects in NGLY1 show accumulation of undegraded protein aggregates that may damage cells in the brain, eyes, and liver 9,27–29 …”

Section: Introductionmentioning

confidence: 99%

N‐glycoproteomics reveals distinct glycosylation alterations in NGLY1‐deficient patient‐derived dermal fibroblasts

Budhraja

Saraswat

Graef

et al. 2022

J of Inher Metab Disea

View full text Add to dashboard Cite

Congenital disorders of glycosylation are genetic disorders that occur due to defects in protein and lipid glycosylation pathways. A deficiency of N-glycanase 1, encoded by the NGLY1 gene, results in a congenital disorder of deglycosylation. The NGLY1 enzyme is mainly involved in cleaving N-glycans from misfolded, retrotranslocated glycoproteins in the cytosol from the endoplasmic reticulum before their proteasomal degradation or activation. Despite the essential role of NGLY1 in deglycosylation pathways, the exact consequences of NGLY1 deficiency on global cellular protein glycosylation have not yet been investigated. We undertook a multiplexed tandem mass tags-labeling-based quantitative glycoproteomics and proteomics analysis of fibroblasts from NGLY1-deficient individuals carrying different biallelic pathogenic variants in NGLY1. This quantitative mass spectrometric analysis detected 8041 proteins and defined a proteomic signature of differential expression across affected individuals and controls. Proteins that showed significant differential expression included phospholipid phosphatase 3, stromal cellderived factor 1, collagen alpha-1 (IV) chain, hyaluronan and proteoglycan link protein 1, and thrombospondin-1. We further detected a total of 3255 Nglycopeptides derived from 550 glycosylation sites of 407 glycoproteins by multiplexed N-glycoproteomics. Several extracellular matrix glycoproteins and adhesion molecules showed altered abundance of N-glycopeptides. Overall, we observed distinct alterations in specific glycoproteins, but our data revealed no global accumulation of glycopeptides in the patient-derived fibroblasts, despite the genetic defect in NGLY1. Our findings highlight new molecular and system-level insights for understanding NGLY1-CDDG.

show abstract

N-Glycanase 1 Deficiency Is a Rare Cause of Pediatric Neurodegeneration With Neuronal Inclusions and Liver Steatosis

Cited by 3 publications

References 4 publications

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology

Delineating the epilepsy phenotype of NGLY1 deficiency

N‐glycoproteomics reveals distinct glycosylation alterations in NGLY1‐deficient patient‐derived dermal fibroblasts

Contact Info

Product

Resources

About