NGLY1-congenital disorder of deglycosylation

Mendelian MONDO:0800044 Pathograph 12 Show in embeddings browser congenital disorder of deglycosylation

NGLY1-congenital disorder of deglycosylation (NGLY1-CDDG; congenital disorder of deglycosylation 1) is an autosomal recessive disorder caused by biallelic NGLY1 variants. NGLY1 encodes cytosolic N-glycanase 1, which removes N-glycans from misfolded N-linked glycoproteins retrotranslocated from the endoplasmic reticulum for degradation. Deglycosylation here is both a disposal step and a signal: with NGLY1 absent, ENGase cleaves the glycan at a different bond and leaves a single GlcNAc on the protein, whose breakdown yields the substrate biomarker GlcNAc-asparagine (GNA); and the transcription factor NFE2L1/Nrf1, which NGLY1 activates by editing glycosylated asparagines to aspartate, is left unedited, disabling the proteasome bounce-back response. The result is a multisystem neurodevelopmental disorder with developmental delay, hypotonia, a hyperkinetic movement disorder, alacrima, transient transaminase elevation, microcephaly, seizures, and a length-dependent sensorimotor neuropathy, with a published median lifespan of about 13 years. An AAV9 gene replacement therapy is in a first-in-human trial with CSF GNA as a co-primary endpoint. Which of NGLY1's several functions actually causes the phenotype is not known, and the ERAD account is under active challenge.

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1
Inheritance
5
Pathophys.
18
Phenotypes
3
Gaps
12
Pathograph
2
Genes
2
Medical Actions
2
Datasets
3
Trials
3
Models
1
References
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Classifications

ICIMD (Inherited Metabolic Disorders)
other glycan metabolism
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Inheritance

1
Autosomal recessive inheritance HP:0000007
NGLY1-CDDG is caused by biallelic pathogenic variants in NGLY1.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24651605 SUPPORT Human Clinical
"NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease."
The clinical series directly establishes autosomal recessive NGLY1 deficiency.
PMID:29419975 SUPPORT Human Clinical
"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews gives the recurrence risk that follows from the autosomal recessive mode, which the entry previously stated without quantifying.
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Discussions and Knowledge Gaps

3
Which NGLY1 substrate or function accounts for the clinical phenotype - alacrima, the hyperkinetic movement disorder, the neuropathy - and is ERAD involvement even part of the answer?
KNOWLEDGE GAP OPEN gap_ngly1_which_substrate_explains_the_phenotype
Attached to
pathophysiology#Impaired cytosolic deglycosylation of ERAD substrates pathophysiology#Failed NFE2L1 sequence editing and proteasome bounce-back failure pathophysiology#ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
The textbook account - NGLY1 deglycosylates ERAD substrates, so its loss breaks ERAD - is under direct challenge. Work on the Drosophila model states plainly that loss of NGLY1 has little effect on ERAD and does not prevent degradation of misfolded proteins, and that the physiological significance of NGLY1 in ERAD is not understood. Meanwhile the best characterized substrate, NFE2L1/Nrf1, is not an ERAD client being disposed of but a transcription factor being activated, and NGLY1 has further reported substrates and functions - NKCC1, BMP signaling, AMPK signaling, and a non-enzymatic role in aquaporin transcription - none of which has been tied to a specific clinical feature. Nothing in the literature connects any single substrate to alacrima, to the movement disorder, or to the length-dependent neuropathy. This entry therefore keeps every edge from a molecular node to the clinical consequence typed as INDIRECT_UNKNOWN_INTERMEDIATES, and curates the ERAD node as a perturbation rather than as a demonstrated degradative failure.
Proposed experiments
Substrate-specific rescue in a viable NGLY1-deficient model
exp_ngly1_substrate_specific_rescue
In the Ngly1-null rat or the inducible mouse, restore individual candidate outputs one at a time - constitutively edited Nrf1, corrected NKCC1, ENGase suppression - without restoring NGLY1 itself, and score tear production, motor phenotype, and nerve conduction separately. A feature that a single-substrate rescue corrects is a feature that substrate explains. Note the constraint the Nrf1 work supplies: mutants mimicking constitutive activation are cytotoxic, so the Nrf1 arm needs a conditional design.
Why the lacrimal gland
exp_ngly1_lacrimal_gland_mechanism
Alacrima is near-pathognomonic and among the earliest features, yet no mechanism links NGLY1 to tear production. Profile lacrimal gland tissue from a viable model for NGLY1-dependent substrates, testing in particular the reported non-enzymatic role in aquaporin transcription, which is the only proposed route with an obvious connection to secretion.
Show evidence (2 references)
PMID:40773511 SUPPORT Model Organism
"Despite this, the physiological significance of NGLY1 in ERAD is not understood."
States the gap in the ERAD account directly, from a group working on the pathway.
PMID:39137042 SUPPORT Other
"The pathophysiological basis of NGLY1 deficiency may be associated with the absence of various enzymatic and nonenzymatic roles of NGLY1"
An independent statement that the causal function is unresolved and may not be the enzymatic one at all.
Ngly1-null mice die in utero, Ngly1-null rats live to adulthood and then degenerate, and human patients survive to a median of about 13 years. Which of these is the right model of human NGLY1 deficiency, and what does the disagreement mean?
HUMAN MODEL MISMATCH OPEN mismatch_ngly1_mouse_rat_human_severity
Attached to
pathophysiology#NGLY1 N-glycanase deficiency pathophysiology#Neurodevelopmental, ocular, and hepatic dysfunction
The species spread is not a nuisance but a finding. Complete loss of the same enzyme is embryonically lethal in one rodent and compatible with adult life in another, and the mouse lethality is itself strain-dependent - outcrossing C57BL/6 to ICR partially rescues it, as does deleting Engase. Whatever makes the difference is a modifier of severity that is not NGLY1, and the same logic likely applies to the phenotypic heterogeneity seen between human patients with identical NGLY1 genotypes. The practical consequence is that a therapeutic rescue measured against mouse embryonic lethality is measured against an endpoint no patient has, while the rat's progressive adult decline is a closer match to the human course but was only characterized out to 17-18 months in 2026. Curating either rodent result as though it were a human result would overstate it.
Proposed experiments
Map the background modifiers of Ngly1-null severity
exp_ngly1_modifier_mapping_across_backgrounds
Cross the Ngly1 null onto a panel of inbred backgrounds and map the loci that convert embryonic lethality into viability. Candidate modifiers with human orthologs - SEL1L is already one such candidate from the Drosophila screen - can then be tested against severity in the patient cohort, where genotype currently predicts nothing.
Show evidence (3 references)
PMID:28426790 SUPPORT Model Organism
"a change in the genetic background of C57BL/6 mice, produced by crossing the mice with an outbred mouse strain (ICR) could partially rescue the embryonic lethality of Ngly1-deficient mice"
Shows severity in the mouse is set by background modifiers rather than by Ngly1 genotype alone.
PMID:41721346 SUPPORT Model Organism
"Notably, Ngly1⁻/⁻ mice (C57BL/6) are embryonically lethal, and prior characterization of Ngly1⁻/⁻ rats was restricted to young adult rat (~7 months old), leaving late-onset phenotypes and potential lifespan reduction unexplored."
States the species discrepancy and the gap in rat characterization that the study was designed to close.
PMID:42361657 SUPPORT Human Clinical
"Most patients carried homozygous variants, and no clear genotype-phenotype correlation was observed."
The human counterpart of the modifier problem: severity is not read off the NGLY1 genotype in patients either.
AAV9-delivered NGLY1 suppressed convulsions in Ngly1-null rats without correcting EEG abnormality or sleep fragmentation. What does the dissociation mean for what gene therapy can be expected to achieve?
KNOWLEDGE GAP OPEN gap_ngly1_gene_therapy_partial_rescue
Attached to
treatments#GS-100 (AAV9-mediated NGLY1 gene replacement) pathophysiology#Neurodevelopmental, ocular, and hepatic dysfunction
The gene-therapy programme has a strong preclinical package on motor endpoints and on the GNA biomarker, and it is easy to read that as disease-wide correction. A separate group, dosing AAV9-hNGLY1 into the same rat model, found the opposite for two other endpoints: NGLY1 protein was robustly expressed and deglycosylation activity partially restored, and non-epileptic convulsions fell, but EEG abnormalities and sleep disruption did not improve. Only partial restoration of enzymatic activity was achieved, so the dissociation may reflect dose rather than a ceiling on what restoration can fix; the alternative - that some features are already developmentally fixed by the time of dosing, or depend on a function the vector does not restore - has different implications for patient selection and for the age at which treatment is worth giving. The trial's co-primary endpoints are CSF GNA and motor function, neither of which would detect this gap.
Proposed experiments
Dose-response across endpoint classes in the Ngly1-null rat
exp_ngly1_dose_response_across_endpoint_classes
Dose AAV9-NGLY1 across a range spanning the reported partial-restoration level, and score motor function, GNA, EEG, and sleep architecture in the same animals. If EEG and sleep respond at higher restored activity, the dissociation is a dose effect; if they remain refractory at full restoration, they identify features that gene replacement cannot address.
Does the age at dosing determine which features respond
exp_ngly1_treatment_age_window
Compare dosing at weaning against dosing after the phenotype is established in the Ngly1-null rat, using the same endpoint panel. A window effect would bear directly on the 2-to-18-year enrolment range of the first-in-human trial.
Show evidence (2 references)
PMID:41176936 SUPPORT Model Organism
"While NGLY1 protein was robustly expressed in the brain with partial restoration of enzymatic deglycosylation activity, AAV9-hNGLY1-treated Ngly1-/- rats showed no significant improvement in EEG abnormalities or sleep disruption."
The negative result at the heart of this gap.
PMID:41176936 SUPPORT Model Organism
"persistent EEG seizures and sleep disturbances indicate only a partial therapeutic benefit, underscoring the need for further refinement of gene therapy strategies, as well as additional therapeutic options, for NGLY1 deficiency"
The authors' own reading, which is more cautious than the programme-level preclinical summaries.
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Pathophysiology

5
NGLY1 N-glycanase deficiency
Biallelic NGLY1 variants abolish or markedly reduce N-glycanase 1 protein and enzymatic activity.
NGLY1 hgnc:17646 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NGLY1 (hgnc:17646). hgnc:17646 is a gene from the HUGO Gene Nomenclature Committee.
protein deglycosylation GO:0006517 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein deglycosylation (GO:0006517). GO:0006517 is a biological process from the Gene Ontology. ↓ DECREASED
peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity GO:0000224 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity (GO:0000224). GO:0000224 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired cytosolic deglycosylation of ERAD substrates Misfolded N-linked glycoproteins retrotranslocated from the ER cannot be normally deglycosylated before proteasomal degradation.
Show evidence (1 reference)
PMID:25900930 SUPPORT In Vitro
"The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts."
Patient fibroblast data support loss of N-glycanase protein as the proximal defect.
Impaired cytosolic deglycosylation of ERAD substrates
Failure to remove bulky N-glycans from ERAD substrates disrupts cytosolic processing of misfolded glycoproteins destined for proteasomal degradation.
ERAD pathway GO:0036503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ERAD pathway (GO:0036503). GO:0036503 is a biological process from the Gene Ontology. ⚠ ABNORMAL protein deglycosylation GO:0006517 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein deglycosylation (GO:0006517). GO:0006517 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation With the amidase absent there is no other route to cleave the GlcNAc-asparagine bond in the cytosol, so ENGase cleaves the glycan at a different bond instead, leaving a single GlcNAc on the protein.
Failed NFE2L1 sequence editing and proteasome bounce-back failure A subset of substrates are not being disposed of but activated: deglycosylation of NFE2L1/Nrf1 is a sequence edit that the transcription factor requires in order to work.
Neurodevelopmental, ocular, and hepatic dysfunction ERAD and deglycosylation failure causes neurologic dysfunction, abnormal tear production, and liver disease.
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome."
The clinical report places NGLY1 deficiency in the ERAD/proteasome pathway.
ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
With peptide:N-glycanase absent, the cytosol has no other way to cut the GlcNAc-asparagine bond, so endo-beta-N-acetylglucosaminidase (ENGase) cleaves between the two GlcNAc residues instead and leaves a single GlcNAc on the asparagine. The partially deglycosylated protein that results is aggregation-prone, and its eventual proteasomal breakdown yields GlcNAc-asparagine (GNA), which accumulates in cells, animal models, and patients. Two things make this node the most consequential in the entry. GNA is the disease's substrate biomarker and the pharmacodynamic endpoint that the gene-therapy programme is built on. And ENGase itself is a therapeutic target rather than a bystander: deleting Engase partially rescues the embryonic lethality of Ngly1-null mice, which is the strongest genetic evidence available that the damage is done by the diverted route and not merely by loss of the normal one.
proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology. ⚠ ABNORMAL protein deglycosylation GO:0006517 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein deglycosylation (GO:0006517). GO:0006517 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Ngly1-/- rat (Sprague Dawley, CRISPR exon 11-12 deletion) Rat measures The rat carries the same substrate biomarker as patients, in the same matrices, which is what allows a CSF endpoint to be carried from preclinical work into the trial.
Ngly1-null mouse (C57BL/6) and the Engase double knockout Mouse rescues Removing ENGase genetically removes the bypass route and rescues the phenotype, which is the causal test of that node.
Downstream
Neurodevelopmental, ocular, and hepatic dysfunction Accumulation of GNA tracks with disease across cells, rodents, and patients, and falls when NGLY1 is restored - but no step connects the catabolite to any specific clinical feature.
Show evidence (3 references)
PMID:39137042 SUPPORT Other
"Under NGLY1 deficiency, another deglycosylating enzyme known as ENGase removes N-glycans by cleaving the glycosidic bond between the 2 GlcNAc residues, leaving a single GlcNAc residue attached to the protein. This incompletely deglycosylated protein is prone to aggregation"
States the alternative reaction and the aggregation-prone product that this node represents.
PMID:34697629 SUPPORT Human Clinical
"GNA accumulation is directly linked to the absence of functional NGLY1, presenting strong potential for its use as a biomarker."
Ties the accumulating catabolite directly to loss of enzyme function.
PMID:28426790 SUPPORT Model Organism
"cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder"
Establishes ENGase as a target rather than an incidental bypass, on the strength of the Engase-deletion rescue.
Failed NFE2L1 sequence editing and proteasome bounce-back failure
Not every NGLY1 substrate is being thrown away. The ER-associated transcription factor NFE2L1/Nrf1 is activated by deglycosylation: NGLY1 converts its glycosylated asparagines to aspartate, and only after that edit at Asn574 can Nrf1 bind host cell factor C1 and O-GlcNAc transferase, reach chromatin, and drive proteasome-subunit gene expression. Without NGLY1 the edit does not happen, and the cell cannot mount the proteasome bounce-back response when the proteasome is compromised. Pathogenic patient variants, including Arg401* which accounts for roughly a fifth of alleles, misprocess NFE2L1 and impair proteasomal-subunit transcription, so this is a lesion of the human disease and not only of engineered cells. Note the counterintuitive constraint from the same work: constitutively active Nrf1 is itself cytotoxic, so a therapy that simply forced the pathway on would not be safe.
proteasome assembly GO:0043248 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome assembly (GO:0043248). GO:0043248 is a biological process from the Gene Ontology. ↓ DECREASED response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neurodevelopmental, ocular, and hepatic dysfunction A candidate route from the editing defect to clinical disease. No reported work connects failed Nrf1 activation to any specific feature of the human phenotype, so this edge is a hypothesis.
Show evidence (3 references)
PMID:41468431 SUPPORT In Vitro
"Editing of Asn574 is essential for interaction with host cell factor C1 and O-GlcNAc transferase, which is required for Nrf1 chromatin binding and sufficient proteasome expression."
The molecular route from the NGLY1-dependent edit to proteasome-subunit expression.
PMID:40643555 SUPPORT In Vitro
"Our functional and structural assessments of these variants show that they cause a profound reduction in NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1."
Shows the NFE2L1 lesion arising from real patient variants rather than from engineered enzyme removal.
PMID:40643555 SUPPORT In Vitro
"transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants"
Confirms the downstream transcriptional consequence in patient variants.
Neurodevelopmental, ocular, and hepatic dysfunction
NGLY1-CDDG presents with developmental delay, movement disorder, hypotonia, alacrima or hypolacrima, elevated liver transaminases, microcephaly, seizures, and peripheral neuropathy.
Animal models
Ngly1-/- rat (Sprague Dawley, CRISPR exon 11-12 deletion) Rat recapitulates Reproduces the neurological course including its progression and premature mortality.
Ngly1-null mouse (C57BL/6) and the Engase double knockout Mouse fails to recapitulate On the C57BL/6 background the model dies in utero, so it cannot express the postnatal multisystem phenotype that defines the human disease.
Tamoxifen-inducible Ngly1-knockout (iNgly1) mouse Mouse partially recapitulates Reproduces the motor, skeletal and cerebellar features of the human disease; the ocular and hepatic components are not among the reported readouts.
Show evidence (2 references)
PMID:24651605 SUPPORT Human Clinical
"All patients had global developmental delay, a movement disorder, and hypotonia."
The clinical series supports the neurologic branch of the phenotype.
PMID:27388694 SUPPORT Human Clinical
"decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features."
Prospective phenotyping supports the ocular, hepatic, movement, and developmental components.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for NGLY1-congenital disorder of deglycosylation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Digestive 2
Feeding difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4)."
9 of 15 is 60%, within the FREQUENT band.
Constipation FREQUENT HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4)."
6 of 15 is 40%, within the FREQUENT band.
Eye 2
Optic atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27388694 SUPPORT Human Clinical
"optic atrophy and retinal pigmentary changes/cone dystrophy"
Prospective phenotyping identified optic atrophy among ocular findings in NGLY1-CDDG.
Retinal dystrophy HP:0000556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal dystrophy (HP:0000556). HP:0000556 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27388694 SUPPORT Human Clinical
"optic atrophy and retinal pigmentary changes/cone dystrophy"
Retinal pigmentary changes and cone dystrophy support a retinal dystrophy phenotype.
Head and Neck 1
Dysmorphic facial features OBLIGATE Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"All patients presented with developmental delay and dysmorphic facial features."
Present in all 15 cohort patients, supporting the OBLIGATE band for that cohort.
Limbs 1
Short foot HP:0001773 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short foot (HP:0001773). HP:0001773 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27388694 SUPPORT Human Clinical
"small hands and feet"
Prospective phenotyping confirms small feet, represented by the HPO short foot term.
Metabolism 2
Elevated liver transaminases Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated liver transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"elevated liver transaminases (6/7)"
The clinical series reports elevated liver transaminases.
Decreased HDL cholesterol concentration HP:0003233 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased HDL cholesterol concentration (HP:0003233). HP:0003233 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10)."
Reports the low-HDL finding directly.
Musculoskeletal 2
Hypotonia OBLIGATE HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"All patients had global developmental delay, a movement disorder, and hypotonia."
The cohort states hypotonia was present in all reported patients, which supports the OBLIGATE frequency band for that cohort.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650), qualified as course progressive. HP:0002650 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:42361657 SUPPORT Human Clinical
"Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4)."
7 of 13 is 54%, within the FREQUENT band.
PMID:42114141 SUPPORT Human Clinical
"Participants in this study exhibited phenotypes previously reported, including core disease phenotypes, hypotonia, scoliosis, musculoskeletal abnormalities, abnormal electroencephalogram (EEG) results, and visual and genitourinary abnormalities."
Independent prospective confirmation of scoliosis in the natural-history cohort.
Nervous System 5
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"All patients had global developmental delay, a movement disorder, and hypotonia."
The retrospective series reports global developmental delay in all patients.
Hyperkinetic movement disorder Abnormality of movement HP:0100022 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Movement disorder, annotated with Abnormality of movement (HP:0100022). HP:0100022 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27388694 SUPPORT Human Clinical
"a complex hyperkinetic movement disorder"
The prospective study reports a complex hyperkinetic movement disorder.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"abnormal nerve conduction (3/3)."
Abnormal nerve conduction supports peripheral neuropathy.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5)."
9 of 15 is 60%, placing seizures in the FREQUENT (30-79%) band.
Abnormal EEG FREQUENT EEG abnormality HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5)."
10 of 15 is 67%, within the FREQUENT band.
Other 3
Alacrima HP:0000522 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alacrima (HP:0000522). HP:0000522 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"hypolacrima or alacrima (7/8)"
The clinical series reports hypolacrima or alacrima in most patients.
Reduced deep tendon reflexes FREQUENT Reduced tendon reflexes HP:0001315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced tendon reflexes (HP:0001315). HP:0001315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42361657 SUPPORT Human Clinical
"Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5)."
6 of 15 is 40%, within the FREQUENT band.
Hypocholesterolemia HP:0003146 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocholesterolemia (HP:0003146). HP:0003146 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42361657 SUPPORT Human Clinical
"Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10)."
Reports the hypocholesterolemia and low-HDL findings directly.
PMID:42361657 SUPPORT Human Clinical
"NGLY1 deficiency may be considered in patients with neurologic findings and dysmorphic features, especially when transient elevated transaminases and hypolipidemia are also present."
The authors' own framing of hypolipidemia as a diagnostic pointer.
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Genetic Associations

2
NGLY1 (Biallelic loss-of-function variants)
Gene: NGLY1 hgnc:17646 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NGLY1 (hgnc:17646). hgnc:17646 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:25900930 SUPPORT Human Clinical
"We identified nine cases with mutations in NGLY1."
The biochemical study identifies NGLY1 mutations in affected individuals.
PMID:40643555 SUPPORT In Vitro
"the most common pathogenic NGLY1 variant, Arg401*, found in about 20% of patients"
Identifies the recurrent nonsense allele that accounts for roughly a fifth of patients.
PMID:40643555 SUPPORT Computational
"Our in silico structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390"
A structural mechanism for one missense allele, from modelling rather than from experiment - typed COMPUTATIONAL for that reason.
+ 2 more references
SEL1L (Candidate genetic modifier of phenotype severity)
Gene: SEL1L hgnc:10717 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SEL1L (hgnc:10717). hgnc:10717 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (2 references)
PMID:40773511 SUPPORT Model Organism
"the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the NGLY1 deficiency model, compared to the SEL1LS780 variant"
The modifier effect, measured in the Drosophila model.
PMID:40773511 SUPPORT Model Organism
"SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common."
The authors' own framing: a candidate in patients, not a demonstrated human modifier, hence PARTIAL and relationship_type MODIFIER.
💊

Medical Actions

2
GS-100 (AAV9-mediated NGLY1 gene replacement)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
A recombinant single-stranded AAV9 vector delivering a functional copy of human NGLY1, given as a single intracerebroventricular dose. The route is the finding, not an implementation detail: in the Ngly1-null rat, ICV and IV+ICV administration improved behaviour while intravenous-only did not, and adding IV to ICV added nothing - which is the evidence that the CNS is the primary therapeutic target organ. Preclinical work showed dose-dependent CNS biodistribution, reduced CSF and brain GNA, and improved motor function, with CSF GNA reduction correlating with behavioural improvement. Safety studies in wild-type rats and non-human primates found no adverse effects at or near the clinical starting dose, supporting an FDA IND. This is an investigational therapy with no human efficacy data yet.
Mechanism Target:
ACTIVATES NGLY1 N-glycanase deficiency — Restores NGLY1 expression and enzymatic activity at the trigger node, rather than acting on any downstream consequence.
Show evidence (1 reference)
PMID:34120625 SUPPORT Model Organism
"restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain"
Direct restoration of the deficient enzyme at the trigger node.
INHIBITS ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation — Restoring the amidase removes the need for the ENGase bypass, and the GNA catabolite falls in CSF and brain.
Show evidence (1 reference)
PMID:36320418 SUPPORT Model Organism
"GS-100 delivered by ICV or IV+ICV significantly reduced levels of the substrate biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn or GNA) in CSF and brain tissue compared with untreated Ngly1-/- rats."
Direct measurement of the biomarker response to treatment.
Show evidence (3 references)
PMID:40687377 SUPPORT Model Organism
"In pharmacology studies using Ngly1 -/- rats, intracerebroventricular (i.c.v.) administration of GS-100 showed dose-dependent biodistribution, increased hNGLY1 mRNA expression, reduced disease biomarker N-acetylglucosamine-asparagine (GNA), improved motor function, and prevented phenotype progression."
The preclinical efficacy package supporting the IND.
PMID:40687377 SUPPORT Model Organism
"These nonclinical data supported the Food and Drug Administration approval of an Investigational New Drug application for a first-in-human phase 1/2/3 dose-escalation clinical trial."
Establishes the regulatory status - investigational, not approved.
PMID:36320418 SUPPORT Model Organism
"ICV and IV + ICV administration of GS-100 resulted in behavioral improvements in rotarod and rearing tests, whereas IV-only administration did not."
The route-dependence result that makes intracerebroventricular delivery the chosen route.
N-acetylglucosamine (GlcNAc) supplementation for alacrima
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: N-acetylglucosamine CHEBI:59640 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses N-acetylglucosamine (CHEBI:59640). CHEBI:59640 is a therapeutic agent from Chemical Entities of Biological Interest.
An oral dietary supplement tested specifically against the tear-production deficit rather than against the disease as a whole, in a randomized double-blind placebo-controlled phase II study. Alacrima is the target because insufficient tear production causes progressive eye damage. No efficacy result is curated here; the trial record establishes only that the question was asked in a controlled design.
Show evidence (1 reference)
clinicaltrials:NCT05402345 SUPPORT Human Clinical
"This study is being done to see if the dietary supplement, GlcNAc, improves tear production in patients with NGLY1-CDDG."
Establishes the intervention and its target symptom; supports the existence of the trial, not an efficacy claim.
🔬

Biochemical Markers

2
Aspartylglycosamine in dried blood spots
Context: Aspartylglycosamine is increased in dried blood spots and is proposed as a small-molecule biomarker of NGLY1-CDDG.
Show evidence (1 reference)
PMID:31311714 SUPPORT Human Clinical
"We identified aspartylglycosamine as the only significantly increased compound"
The metabolomics study supports aspartylglycosamine as a biochemical readout.
GlcNAc-asparagine (GNA) in plasma, urine and CSF
Context: GlcNAc-Asn, also written GNA and reported in earlier work as aspartylglycosamine, is the substrate biomarker of NGLY1 deficiency. It is the terminal catabolite of the ENGase bypass route, so its concentration is an inverse readout of NGLY1 function. It is elevated in patient plasma and urine, in dried blood spots, and in the plasma and CSF of the Ngly1-null rat; it is stable over time; and it falls with gene-therapy treatment, which is what makes it usable as a pharmacodynamic endpoint rather than only a diagnostic marker. CSF GNA is a co-primary endpoint of the first-in-human GS-100 trial.
Pathograph Readouts
Readout Of ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation Positive Diagnostic
GNA concentration is the direct measurement of the catabolite this node represents.
Show evidence (3 references)
PMID:34697629 SUPPORT Human Clinical
"We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls."
Establishes GNA as the analyte with the clearest patient-control separation.
PMID:34697629 SUPPORT Human Clinical
"it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and patients (plasma and urine)"
Establishes the matrices in which GNA is measurable and its cross-species conservation.
PMID:42114141 SUPPORT Human Clinical
"Liver transaminase and biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA) levels were elevated in all participants."
Prospective natural-history confirmation that GNA is elevated in every participant.
🔬

Diagnosis

2
Molecular genetic confirmation of biallelic NGLY1 variants
NGLY1-CDDG is a molecular diagnosis. Identification of biallelic pathogenic NGLY1 variants in a proband with the clinical picture establishes it; no biochemical assay is diagnostic in its place.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic NGLY1 variants in a proband establish the diagnosis.
Show evidence (1 reference)
PMID:29419975 SUPPORT Human Clinical
"The diagnosis of NGLY1-CDDG is established in a proband by the identification of biallelic pathogenic variants in NGLY1 on molecular genetic testing."
GeneReviews states the diagnostic criterion directly.
Standard CDG serum screening does not detect NGLY1-CDDG (Negative)
A clinically critical negative. NGLY1-CDDG is a disorder of de-glycosylation, not of glycan synthesis, so the serum screens used to triage the congenital disorders of glycosylation are not informative here and a normal result does not exclude it. Screening an NGLY1-CDDG proband the way a CDG proband would be screened yields a false negative.
serum transferrin glycoform screening NCIT:C15419 NCI Thesaurus (NCIT)
Results: Serum transferrin glycoform analysis and N/O glycan profiling are unreliable for NGLY1-CDDG; proceed to molecular genetic testing.
Show evidence (1 reference)
PMID:29419975 SUPPORT Human Clinical
"Typical serum screening tests for congenital disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG."
GeneReviews states the negative screening result explicitly.
📈

Progression

1
Progressive developmental divergence with relatively stable individual function
Age: infancy onward; symptom onset averages about 4 months
A one-year prospective natural-history study of 15 participants - roughly 10% of the identified patient population - found profound global developmental delay across communication, gross and fine motor, and cognitive domains. The pattern it documents is specific and easy to misread: individual measurements were mostly stable over the year, while age-equivalent scores diverged further from neurotypical peers, meaning the gap widens because development does not keep pace rather than because function is lost. Most patients never walk and do not develop verbal communication. Peripheral and auditory neuropathy in the 2026 multicenter cohort were observed to appear over time rather than at presentation, so the disease continues to accrue features after diagnosis.
Show evidence (4 references)
PMID:42114141 SUPPORT Human Clinical
"Age-equivalent scores identified a widening developmental gap between participants and neurotypical peers over time, indicating delayed milestone achievement and/or regression."
The core progression finding of the prospective study.
PMID:42114141 SUPPORT Human Clinical
"Although fluctuations were observed, measurements for individual participants were mostly stable over the course of the NHS."
The counterpart finding that keeps the widening gap from being read as rapid individual decline over one year.
PMID:42361657 SUPPORT Human Clinical
"Peripheral and auditory neuropathy findings were observed over time."
Establishes that neuropathy accrues after presentation.
+ 1 more reference
📊

Prevalence

2
United States
Birth Prevalence 0.025 per 100,000 <1 in 1,000,000
Reported as an estimated incidence of about 1 in 4 million live births, normalized here to 0.025 per 100,000 births. The source labels this an incidence estimate; it is recorded as a birth prevalence because the denominator is live births.
Show evidence (1 reference)
PMID:40687377 SUPPORT Human Clinical
"In the United States, the estimated incidence of NGLY1 deficiency is approximately 1 in 4 million live births."
The source of the birth-prevalence estimate.
Worldwide
Cases In Literature Ultra Rare
Roughly 150 diagnosed patients worldwide and 42 in the United States as of 2025. The worldwide figure is cited as unpublished data in the source, so it is recorded as a case count rather than as a rate.
Show evidence (1 reference)
PMID:40687377 SUPPORT Human Clinical
"There are currently 42 patients diagnosed with NGLY1 deficiency in the US and ∼150 patients who have been diagnosed with the disease worldwide"
The reported diagnosed-patient counts.
📊

Related Datasets

2
NGLY1-dependent conversion of N-glycosylated N to D is essential for transcription of proteasome genes geo:GSE301626
Transcriptomic profiling of HeLa cells expressing glycan-less Nrf1 mutants (9NA and 9ND) in which all nine putative N-glycosylation sites were replaced, isolating the sequence-editing-specific contribution to Nrf1 function. This is the primary dataset behind the NFE2L1 sequence-editing node in this entry.
human BULK RNA SEQ n=9
PMID:41468431
Found by GEO DataSets search and verified against NCBI E-utilities on 2026-08-20; title, sample count, and organism are GEO's own values. DIRECT relevance - the series is the deposited data of the cited NGLY1 paper, not a gene-name match.
Single-nucleus transcriptomics of inducible Ngly1-/- cerebellum geo:GSE295078
Single-nucleus RNA sequencing of cerebella from Ngly1fl/fl, iNgly1-/- and iNgly1-/-Sting1-/- mice, examining cell-type-specific effects of NGLY1 deficiency and the contribution of the STING pathway. The Sting1 double knockout arm is what makes the series informative rather than descriptive: it tests whether an inflammatory pathway mediates the neurodegeneration.
mouse SINGLE CELL RNA SEQ n=6
PMID:40644312
Found by GEO DataSets search and verified against NCBI E-utilities on 2026-08-20. DIRECT relevance - an Ngly1 knockout series in the inducible mouse model this entry curates. The associated publication (PMID:40644312, STING-driven noninflammatory neurodegeneration) is not yet curated as evidence in this entry; the dataset is recorded here without inheriting any claim from it.
🔬

Clinical Trials

3
NCT06199531 PHASE_III ACTIVE_NOT_RECRUITING
First-in-human, open-label, single-arm, dose-finding phase 1/2/3 study of a single intracerebroventricular dose of GS-100 in patients aged 2 to 18 years. Registered as phase 3 on ClinicalTrials.gov although the protocol spans phases 1 through 3.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Movement disorder HP:0100022 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Movement disorder, annotated with Abnormality of movement (HP:0100022). HP:0100022 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06199531 SUPPORT Human Clinical
"A non-randomized, open-label, Phase 1/2/3 study of a single intracerebroventricular (ICV) administration of a gene replacement therapy (GS-100) in participants who are 2 to 18 years old with NGLY1 Deficiency."
The registered design of the first-in-human gene-therapy trial.
NCT05402345 PHASE_II ACTIVE_NOT_RECRUITING
Randomized, multicenter, double-blind, placebo-controlled phase II study of oral GlcNAc for tear production in NGLY1-CDDG.
Target Phenotypes: Alacrima HP:0000522 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Alacrima (HP:0000522). HP:0000522 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT05402345 SUPPORT Human Clinical
"In patients with NGLY1-CDDG, the disorder can lead to eye damage due to not being able to produce enough tears."
Establishes the trial's rationale and target phenotype.
NCT06122766 NOT_APPLICABLE COMPLETED
Observational study characterizing the NGLY1 movement disorder and clinical features, motivated by the fact that the hyperkinetic movement disorder had only been described qualitatively.
Target Phenotypes: Movement disorder HP:0100022 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Movement disorder, annotated with Abnormality of movement (HP:0100022). HP:0100022 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06122766 SUPPORT Human Clinical
"The hyperkinetic movement disorder in NGLY1 Deficiency is highly complex and has been qualitatively described to include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements."
Documents the movement-disorder phenomenology this observational study set out to quantify.
🐁

Animal Models

3
Ngly1-/- rat (Sprague Dawley, CRISPR exon 11-12 deletion)
The workhorse model of the disease and the one the gene-therapy programme is built on. Unlike the mouse, it is viable, and it reproduces the human features that matter for an endpoint: motor and gait deficits, impaired spatial learning, peripheral axon loss, and elevated GNA in plasma and CSF. Longitudinal work out to 17-18 months added a progressive, lethal course - about half the animals dead or euthanized by 9-10 months, roughly 92% reduction in rotarod latency, widespread neuroinflammation, and loss of spinal motor neurons - which is what makes it a model of a progressive neurodegenerative disease rather than a static one.
Species
Rat
Genotype
Ngly1 homozygous deletion of exons 11-12 and the 3' polyA region
Publication
PMID:41721346
Pathograph links
Neurodevelopmental, ocular, and hepatic dysfunction recapitulates fidelity: moderate Reproduces the neurological course including its progression and premature mortality.
Limitations: The rat's terminal course is not a documented feature of every human patient; the human median lifespan of about 13 years is cited from published clinical data rather than measured alongside the rodent. Ocular and hepatic components of the human phenotype are not the readouts this model is characterized on, so the RECAPITULATES claim rests on the neurological arm.
Readouts
Rotarod latency
Direction: DECREASED
Interpretation: Motor performance decline with age in the null animals.
Show evidence (1 reference)
PMID:41721346 SUPPORT Model Organism
"Surviving animals displayed phenotypes mirroring human NGLY1 Deficiency disease progression, such as worsening motor deficits (~92% reduction in rotarod latency and ~82% reduction in rearing)"
Reports the motor measurements and their magnitude.
Survival
Direction: DECREASED
Interpretation: Premature mortality, the endpoint that distinguishes the aged rat from earlier young-adult characterizations.
Show evidence (1 reference)
PMID:41721346 SUPPORT Model Organism
"By 9-10 months of age, ~50% of the Ngly1⁻/⁻ rats had either died or met humane euthanasia criteria due to a severe decline in health."
Reports the survival measurement directly.
Spinal motor neuron and peripheral axon counts
Direction: DECREASED
Interpretation: The neuropathological substrate of the motor decline, and the structural correlate of the human sensorimotor neuropathy.
Show evidence (1 reference)
PMID:41721346 SUPPORT Model Organism
"histopathological examination of Ngly1⁻/⁻ rats identified significant neuropathological abnormalities that were not present in the control cohorts, including loss of peripheral axons and spinal motor neurons"
Reports the histopathological measurement.
Show evidence (1 reference)
PMID:41721346 SUPPORT Model Organism
"The findings reported here demonstrate that Ngly1⁻/⁻ rats recapitulate the severe, progressive course of NGLY1 Deficiency, including neurodegenerative deterioration, motor deficits, and premature mortality."
The authors' own statement that the model is informative for the human disease course.
ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation measures fidelity: high The rat carries the same substrate biomarker as patients, in the same matrices, which is what allows a CSF endpoint to be carried from preclinical work into the trial.
Limitations: GNA is a readout of enzyme function, not of clinical benefit; the correlation between GNA reduction and behavioural improvement in this model is the basis for treating it as a surrogate, and that surrogacy is not yet established in humans.
Readouts
CSF and brain GNA
Direction: INCREASED
Interpretation: Elevated in untreated null animals and reduced by gene transfer, which is what makes it a pharmacodynamic marker.
Show evidence (1 reference)
PMID:40687377 SUPPORT Model Organism
"Reductions in GNA within central nervous system (CNS) tissues and cerebrospinal fluid (CSF) correlated significantly with improvements, suggesting that CSF GNA may serve as a clinical biomarker of therapeutic activity."
Reports the biomarker measurement and its correlation with benefit.
Ngly1-null mouse (C57BL/6) and the Engase double knockout
A negative and a genetic result rather than a phenotyping platform. The Ngly1-null mouse is embryonically lethal on a C57BL/6 background, which human NGLY1 deficiency is not, so on its own it fails as a model of the human disease. Its value is what rescues it: additionally deleting Engase partially rescues the lethality, and outcrossing to ICR partially rescues it too. Viable mixed-background animals then show a severe phenotype reminiscent of patients, and those defects are again suppressed by Engase deletion. This is the strongest genetic evidence that the damage in NGLY1 deficiency is done by the diverted ENGase route rather than by the absence of deglycosylation as such.
Species
Mouse
Genotype
Ngly1 knockout on C57BL/6; Ngly1/Engase double knockout
Publication
PMID:28426790
Pathograph links
Neurodevelopmental, ocular, and hepatic dysfunction fails to recapitulate fidelity: low On the C57BL/6 background the model dies in utero, so it cannot express the postnatal multisystem phenotype that defines the human disease.
Limitations: The failure is background-dependent, not absolute: a mixed C57BL/6-ICR background yields viable animals with a phenotype resembling patients. A strain-specific embryonic lethality with no human counterpart means any rescue measured against it is measured against the wrong endpoint, which is the core translational problem with this model.
Show evidence (1 reference)
PMID:28426790 SUPPORT Model Organism
"we analyzed Ngly1-deficient mice and found that they are embryonic lethal in C57BL/6 background"
The embryonic lethality that human patients do not have, and which this model therefore fails to recapitulate.
ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation rescues fidelity: moderate Removing ENGase genetically removes the bypass route and rescues the phenotype, which is the causal test of that node.
Limitations: Germline deletion from conception is not the same intervention as pharmacological inhibition in a diagnosed patient, and the rescue is partial. No ENGase inhibitor has been tested in a human.
Readouts
Survival of Ngly1-null animals
Direction: RESTORED
Interpretation: Partial restoration of viability on removing the bypass enzyme.
Show evidence (1 reference)
PMID:28426790 SUPPORT Model Organism
"the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice"
Reports the rescue and its mechanism.
Show evidence (1 reference)
PMID:28426790 SUPPORT Model Organism
"cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder"
The authors' framing of the rescue as therapeutically informative for this node.
Tamoxifen-inducible Ngly1-knockout (iNgly1) mouse
An inducible knockout that sidesteps the embryonic lethality of the constitutive C57BL/6 null and produces a postnatal phenotype - elevated GlcNAc-Asn, motor deficits, kyphosis, Purkinje cell loss, gait abnormality - in which systemic gene therapy can be tested. Systemic AAV.PHPeB delivery corrected multiple features at 8 weeks and near-completely normalized the neurological phenotype over a year.
Species
Mouse
Genotype
Tamoxifen-inducible Ngly1 knockout on C57BL/6
Publication
PMID:39137042
Pathograph links
Neurodevelopmental, ocular, and hepatic dysfunction partially recapitulates fidelity: moderate Reproduces the motor, skeletal and cerebellar features of the human disease; the ocular and hepatic components are not among the reported readouts.
Limitations: Adult-inducible knockout does not model a congenital, developmental disease - the animal develops normally before the gene is removed, which is the opposite of the patient's situation. The therapeutic result also does not transfer as reported: AAV.PHPeB's CNS tropism is mouse-specific and, as the authors state, does not translate to primates.
Readouts
Neurological phenotype after systemic gene transfer
Direction: RESTORED
Interpretation: Durable near-complete normalization over a year, the strongest efficacy result in any NGLY1 model.
Show evidence (1 reference)
PMID:39137042 SUPPORT Model Organism
"another cohort of AAV.PHPeB-treated iNgly1 mice were monitored over a year and showed near-complete normalization of the neurological aspects of the disease phenotype, demonstrating the durability of gene therapy"
Reports the treatment response and its durability.
Show evidence (1 reference)
PMID:39137042 SUPPORT Model Organism
"we first characterized a tamoxifen-inducible Ngly1-knockout (iNgly1) C57BL/6J mouse model, which exhibited symptoms recapitulating human disease, including elevation of the biomarker GlcNAc-Asn, motor deficits, kyphosis, Purkinje cell loss, and gait abnormalities"
The model's characterized phenotype.
{ }

Source YAML

click to show 
name: NGLY1-congenital disorder of deglycosylation
creation_date: "2026-07-06T06:04:18Z"
description: >-
  NGLY1-congenital disorder of deglycosylation (NGLY1-CDDG; congenital disorder
  of deglycosylation 1) is an autosomal recessive disorder caused by biallelic
  NGLY1 variants. NGLY1 encodes cytosolic N-glycanase 1, which removes N-glycans
  from misfolded N-linked glycoproteins retrotranslocated from the endoplasmic
  reticulum for degradation. Deglycosylation here is both a disposal step and a
  signal: with NGLY1 absent, ENGase cleaves the glycan at a different bond and
  leaves a single GlcNAc on the protein, whose breakdown yields the substrate
  biomarker GlcNAc-asparagine (GNA); and the transcription factor NFE2L1/Nrf1,
  which NGLY1 activates by editing glycosylated asparagines to aspartate, is
  left unedited, disabling the proteasome bounce-back response. The result is a
  multisystem neurodevelopmental disorder with developmental delay, hypotonia,
  a hyperkinetic movement disorder, alacrima, transient transaminase elevation,
  microcephaly, seizures, and a length-dependent sensorimotor neuropathy, with
  a published median lifespan of about 13 years. An AAV9 gene replacement
  therapy is in a first-in-human trial with CSF GNA as a co-primary endpoint.
  Which of NGLY1's several functions actually causes the phenotype is not
  known, and the ERAD account is under active challenge.
category: Mendelian
disease_term:
  preferred_term: congenital disorder of deglycosylation 1
  term:
    id: MONDO:0800044
    label: congenital disorder of deglycosylation 1
synonyms:
- NGLY1 deficiency
- NGLY1-CDDG
- congenital disorder of deglycosylation 1
- congenital disorder of glycosylation type IV
parents:
- congenital disorder of deglycosylation
references:
- reference: PMID:29419975
  title: NGLY1-Related Congenital Disorder of Deglycosylation.
  tags:
  - GeneReviews
  findings: []
classifications:
  icimd_category:
  - classification_value: other_glycan_metabolism
    notes: >-
      The local ICIMD enum folds the specific deglycosylation subgroup into the
      broader other_glycan_metabolism value.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: NGLY1-CDDG is caused by biallelic pathogenic variants in NGLY1.
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NGLY1 deficiency is a novel autosomal recessive disorder of the
      endoplasmic reticulum-associated degradation pathway associated with
      neurological dysfunction, abnormal tear production, and liver disease.
    explanation: >-
      The clinical series directly establishes autosomal recessive NGLY1
      deficiency.
  - reference: PMID:29419975
    reference_title: NGLY1-Related Congenital Disorder of Deglycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At conception, each sib of an affected individual has a 25% chance of
      being affected, a 50% chance of being an asymptomatic carrier, and a 25%
      chance of being unaffected and not a carrier.
    explanation: >-
      GeneReviews gives the recurrence risk that follows from the autosomal
      recessive mode, which the entry previously stated without quantifying.
pathophysiology:
- name: NGLY1 N-glycanase deficiency
  conforms_to: "cytosolic_deglycosylation#Cytosolic Deglycosylation Enzyme Deficiency"
  description: >-
    Biallelic NGLY1 variants abolish or markedly reduce N-glycanase 1 protein
    and enzymatic activity.
  role: trigger
  genes:
  - preferred_term: NGLY1
    term:
      id: hgnc:17646
      label: NGLY1
  molecular_functions:
  - preferred_term: peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity
    modifier: DECREASED
    term:
      id: GO:0000224
      label: peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity
  biological_processes:
  - preferred_term: protein deglycosylation
    modifier: DECREASED
    term:
      id: GO:0006517
      label: protein deglycosylation
  evidence:
  - reference: PMID:25900930
    reference_title: "A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in
      patient-derived fibroblasts.
    explanation: >-
      Patient fibroblast data support loss of N-glycanase protein as the
      proximal defect.
  downstream:
  - target: Impaired cytosolic deglycosylation of ERAD substrates
    description: >-
      Misfolded N-linked glycoproteins retrotranslocated from the ER cannot be
      normally deglycosylated before proteasomal degradation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25900930
      reference_title: "A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of
        misfolded N-linked glycoproteins retrotranslocated into the cytosol.
      explanation: >-
        The biochemical study defines the NGLY1-dependent substrate and
        reaction.
- name: Impaired cytosolic deglycosylation of ERAD substrates
  conforms_to: "cytosolic_deglycosylation#Impaired Cytosolic Deglycosylation of Retrotranslocated Glycoproteins"
  description: >-
    Failure to remove bulky N-glycans from ERAD substrates disrupts cytosolic
    processing of misfolded glycoproteins destined for proteasomal degradation.
  role: central_effector
  biological_processes:
  - preferred_term: ERAD pathway
    modifier: ABNORMAL
    term:
      id: GO:0036503
      label: ERAD pathway
  - preferred_term: protein deglycosylation
    modifier: DECREASED
    term:
      id: GO:0006517
      label: protein deglycosylation
  chemical_entities:
  - preferred_term: N-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The endoplasmic reticulum-associated degradation pathway is responsible
      for the translocation of misfolded proteins across the endoplasmic
      reticulum membrane into the cytosol for subsequent degradation by the
      proteasome.
    explanation: >-
      The clinical report places NGLY1 deficiency in the ERAD/proteasome
      pathway.
  downstream:
  - target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
    description: >-
      With the amidase absent there is no other route to cleave the
      GlcNAc-asparagine bond in the cytosol, so ENGase cleaves the glycan at a
      different bond instead, leaving a single GlcNAc on the protein.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36320418
      reference_title: "AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the absence of NGLY1, there are no alternative mechanisms for
        cleaving this bond in the cytosol, thus the glycan is cleaved at an
        alternative bond leaving a partially deglycosylated protein that
        retains the GlcNAc-Asn bond.
      explanation: >-
        States the diversion to the ENGase route and its product, which is what
        this edge represents.
  - target: Failed NFE2L1 sequence editing and proteasome bounce-back failure
    description: >-
      A subset of substrates are not being disposed of but activated:
      deglycosylation of NFE2L1/Nrf1 is a sequence edit that the transcription
      factor requires in order to work.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41468431
      reference_title: "NFE2L1/Nrf1 forms a coactivator complex post-peptide:N-glycanase-mediated sequence editing and mitigates proteasome dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Nrf proteins are the only transcription factors that undergo sequence
        editing for transcriptional activation.
      explanation: >-
        Establishes that this branch is an activation step rather than a
        degradative one, and that it is specific to the Nrf transcription
        factors.
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    description: >-
      ERAD and deglycosylation failure causes neurologic dysfunction, abnormal
      tear production, and liver disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
  conforms_to: "cytosolic_deglycosylation#Cytosolic Glycan Catabolite Dysregulation"
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    With peptide:N-glycanase absent, the cytosol has no other way to cut the
    GlcNAc-asparagine bond, so endo-beta-N-acetylglucosaminidase (ENGase)
    cleaves between the two GlcNAc residues instead and leaves a single GlcNAc
    on the asparagine. The partially deglycosylated protein that results is
    aggregation-prone, and its eventual proteasomal breakdown yields
    GlcNAc-asparagine (GNA), which accumulates in cells, animal models, and
    patients. Two things make this node the most consequential in the entry.
    GNA is the disease's substrate biomarker and the pharmacodynamic endpoint
    that the gene-therapy programme is built on. And ENGase itself is a
    therapeutic target rather than a bystander: deleting Engase partially
    rescues the embryonic lethality of Ngly1-null mice, which is the strongest
    genetic evidence available that the damage is done by the diverted route
    and not merely by loss of the normal one.
  biological_processes:
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: ABNORMAL
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  - preferred_term: protein deglycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006517
      label: protein deglycosylation
  evidence:
  - reference: PMID:39137042
    reference_title: "Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Under NGLY1 deficiency, another deglycosylating enzyme known as ENGase
      removes N-glycans by cleaving the glycosidic bond between the 2 GlcNAc
      residues, leaving a single GlcNAc residue attached to the protein. This
      incompletely deglycosylated protein is prone to aggregation
    explanation: >-
      States the alternative reaction and the aggregation-prone product that
      this node represents.
  - reference: PMID:34697629
    reference_title: "GlcNAc-Asn is a biomarker for NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GNA accumulation is directly linked to the absence of functional NGLY1,
      presenting strong potential for its use as a biomarker.
    explanation: >-
      Ties the accumulating catabolite directly to loss of enzyme function.
  - reference: PMID:28426790
    reference_title: "Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cytoplasmic ENGase represents one of the potential therapeutic targets
      for this genetic disorder
    explanation: >-
      Establishes ENGase as a target rather than an incidental bypass, on the
      strength of the Engase-deletion rescue.
  downstream:
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    description: >-
      Accumulation of GNA tracks with disease across cells, rodents, and
      patients, and falls when NGLY1 is restored - but no step connects the
      catabolite to any specific clinical feature.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34697629
      reference_title: "GlcNAc-Asn is a biomarker for NGLY1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Elevated GNA levels differentiate patients from controls, are stable
        over time and correlate with changes in NGLY1 activity.
      explanation: >-
        Supports GNA as a marker of enzyme function, not as a cause of any
        phenotype, which is why this edge stays weakly typed.
- name: Failed NFE2L1 sequence editing and proteasome bounce-back failure
  conforms_to: "cytosolic_deglycosylation#Loss of Deglycosylation-Dependent Substrate Activation"
  biological_scale: CELLULAR
  role: effector
  description: >-
    Not every NGLY1 substrate is being thrown away. The ER-associated
    transcription factor NFE2L1/Nrf1 is activated by deglycosylation: NGLY1
    converts its glycosylated asparagines to aspartate, and only after that
    edit at Asn574 can Nrf1 bind host cell factor C1 and O-GlcNAc transferase,
    reach chromatin, and drive proteasome-subunit gene expression. Without
    NGLY1 the edit does not happen, and the cell cannot mount the proteasome
    bounce-back response when the proteasome is compromised. Pathogenic patient
    variants, including Arg401* which accounts for roughly a fifth of alleles,
    misprocess NFE2L1 and impair proteasomal-subunit transcription, so this is
    a lesion of the human disease and not only of engineered cells. Note the
    counterintuitive constraint from the same work: constitutively active Nrf1
    is itself cytotoxic, so a therapy that simply forced the pathway on would
    not be safe.
  biological_processes:
  - preferred_term: proteasome assembly
    modifier: DECREASED
    term:
      id: GO:0043248
      label: proteasome assembly
  - preferred_term: response to oxidative stress
    modifier: ABNORMAL
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:41468431
    reference_title: "NFE2L1/Nrf1 forms a coactivator complex post-peptide:N-glycanase-mediated sequence editing and mitigates proteasome dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Editing of Asn574 is essential for interaction with host cell factor C1
      and O-GlcNAc transferase, which is required for Nrf1 chromatin binding and
      sufficient proteasome expression.
    explanation: >-
      The molecular route from the NGLY1-dependent edit to proteasome-subunit
      expression.
  - reference: PMID:40643555
    reference_title: "Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our functional and structural assessments of these variants show that
      they cause a profound reduction in NGLY1 activity, severely reduced
      expression of NGLY1 protein, and misprocessing of the transcription
      factor NFE2L1.
    explanation: >-
      Shows the NFE2L1 lesion arising from real patient variants rather than
      from engineered enzyme removal.
  - reference: PMID:40643555
    reference_title: "Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      transcription of proteasomal subunits and NGLY1 mRNA splicing are
      impaired by some of these variants
    explanation: >-
      Confirms the downstream transcriptional consequence in patient variants.
  downstream:
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    description: >-
      A candidate route from the editing defect to clinical disease. No
      reported work connects failed Nrf1 activation to any specific feature of
      the human phenotype, so this edge is a hypothesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neurodevelopmental, ocular, and hepatic dysfunction
  conforms_to: "cytosolic_deglycosylation#Neurodevelopmental and Multisystem Dysfunction"
  description: >-
    NGLY1-CDDG presents with developmental delay, movement disorder, hypotonia,
    alacrima or hypolacrima, elevated liver transaminases, microcephaly,
    seizures, and peripheral neuropathy.
  role: consequence
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had global developmental delay, a movement disorder, and
      hypotonia.
    explanation: >-
      The clinical series supports the neurologic branch of the phenotype.
  - reference: PMID:27388694
    reference_title: "Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased tear production, transient transaminitis, small feet, a complex
      hyperkinetic movement disorder, and varying degrees of global developmental
      delay with relatively preserved socialization are the most consistent
      features.
    explanation: >-
      Prospective phenotyping supports the ocular, hepatic, movement, and
      developmental components.
phenotypes:
- name: Global developmental delay
  description: Developmental delay is consistently reported in NGLY1-CDDG.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had global developmental delay, a movement disorder, and
      hypotonia.
    explanation: The retrospective series reports global developmental delay in all patients.
- name: Hypotonia
  frequency: OBLIGATE
  description: Hypotonia is a core neurologic feature reported in the original cohort.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had global developmental delay, a movement disorder, and
      hypotonia.
    explanation: >-
      The cohort states hypotonia was present in all reported patients, which
      supports the OBLIGATE frequency band for that cohort.
- name: Alacrima
  description: Decreased or absent tear production is a characteristic feature.
  phenotype_term:
    preferred_term: Alacrima
    term:
      id: HP:0000522
      label: Alacrima
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypolacrima or alacrima (7/8)
    explanation: The clinical series reports hypolacrima or alacrima in most patients.
- name: Hyperkinetic movement disorder
  description: Hyperkinetic movement disorder is among the most consistent features.
  phenotype_term:
    preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:27388694
    reference_title: "Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a complex hyperkinetic movement disorder
    explanation: The prospective study reports a complex hyperkinetic movement disorder.
- name: Optic atrophy
  description: Optic atrophy is part of the prospective ocular phenotype.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:27388694
    reference_title: "Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      optic atrophy and retinal pigmentary changes/cone dystrophy
    explanation: >-
      Prospective phenotyping identified optic atrophy among ocular findings in
      NGLY1-CDDG.
- name: Retinal dystrophy
  description: Retinal pigmentary changes and cone dystrophy are reported ocular findings.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:27388694
    reference_title: "Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      optic atrophy and retinal pigmentary changes/cone dystrophy
    explanation: >-
      Retinal pigmentary changes and cone dystrophy support a retinal dystrophy
      phenotype.
- name: Short foot
  description: Small feet are among the confirmed morphologic features of NGLY1-CDDG.
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  evidence:
  - reference: PMID:27388694
    reference_title: "Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      small hands and feet
    explanation: >-
      Prospective phenotyping confirms small feet, represented by the HPO short
      foot term.
- name: Elevated liver transaminases
  description: Transient transaminitis is a recurrent hepatic feature.
  phenotype_term:
    preferred_term: Elevated liver transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  reports_on:
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Transient transaminitis measures the hepatic dysfunction component of NGLY1-CDDG.
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated liver transaminases (6/7)
    explanation: The clinical series reports elevated liver transaminases.
- name: Peripheral neuropathy
  description: Peripheral neuropathy is part of the NGLY1-CDDG neurologic spectrum.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:24651605
    reference_title: "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal nerve conduction (3/3).
    explanation: Abnormal nerve conduction supports peripheral neuropathy.
- name: Seizures
  frequency: FREQUENT
  description: >-
    Seizures were reported in 9 of 15 patients in the 2026 multicenter cohort.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common neurological findings included abnormal EEG (10/15), seizures
      (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon
      reflexes (6/15), and peripheral neuropathy (3/5).
    explanation: >-
      9 of 15 is 60%, placing seizures in the FREQUENT (30-79%) band.
- name: Abnormal EEG
  frequency: FREQUENT
  description: >-
    EEG abnormality was the single most common neurological finding in the 2026
    cohort, present in 10 of 15 patients and exceeding the frequency of clinical
    seizures.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common neurological findings included abnormal EEG (10/15), seizures
      (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon
      reflexes (6/15), and peripheral neuropathy (3/5).
    explanation: >-
      10 of 15 is 67%, within the FREQUENT band.
- name: Reduced deep tendon reflexes
  frequency: FREQUENT
  description: >-
    Reduced deep tendon reflexes, consistent with the sensorimotor neuropathy,
    in 6 of 15 patients.
  phenotype_term:
    preferred_term: Reduced tendon reflexes
    term:
      id: HP:0001315
      label: Reduced tendon reflexes
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common neurological findings included abnormal EEG (10/15), seizures
      (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon
      reflexes (6/15), and peripheral neuropathy (3/5).
    explanation: >-
      6 of 15 is 40%, within the FREQUENT band.
- name: Feeding difficulties
  frequency: FREQUENT
  description: >-
    Feeding difficulty was the most common non-neurological feature in the 2026
    cohort, in 9 of 15 patients.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frequent non-neurological features included feeding difficulties (9/15),
      scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and
      auditory neuropathy (2/4).
    explanation: >-
      9 of 15 is 60%, within the FREQUENT band.
- name: Scoliosis
  frequency: FREQUENT
  description: >-
    Scoliosis in 7 of 13 assessed patients. It is one of the features the
    natural-history study describes as emerging over time rather than being
    present at diagnosis.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frequent non-neurological features included feeding difficulties (9/15),
      scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and
      auditory neuropathy (2/4).
    explanation: >-
      7 of 13 is 54%, within the FREQUENT band.
  - reference: PMID:42114141
    reference_title: "Natural history of NGLY1 deficiency: motor function & clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants in this study exhibited phenotypes previously reported,
      including core disease phenotypes, hypotonia, scoliosis, musculoskeletal
      abnormalities, abnormal electroencephalogram (EEG) results, and visual and
      genitourinary abnormalities.
    explanation: >-
      Independent prospective confirmation of scoliosis in the natural-history
      cohort.
- name: Constipation
  frequency: FREQUENT
  description: Constipation in 6 of 15 patients in the 2026 cohort.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frequent non-neurological features included feeding difficulties (9/15),
      scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and
      auditory neuropathy (2/4).
    explanation: >-
      6 of 15 is 40%, within the FREQUENT band.
- name: Hypocholesterolemia
  description: >-
    Low total cholesterol in 7 of 10 patients tested and low HDL in 5 of 10, a
    laboratory pattern the 2026 cohort proposes as a diagnostic clue when it
    accompanies transient transaminase elevation.
  phenotype_term:
    preferred_term: Hypocholesterolemia
    term:
      id: HP:0003146
      label: Hypocholesterolemia
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated transaminases were the most common laboratory abnormality
      (12/14) and were transient in most patients (9/12), followed by low total
      cholesterol (7/10) and HDL levels (5/10).
    explanation: >-
      Reports the hypocholesterolemia and low-HDL findings directly.
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NGLY1 deficiency may be considered in patients with neurologic findings
      and dysmorphic features, especially when transient elevated transaminases
      and hypolipidemia are also present.
    explanation: >-
      The authors' own framing of hypolipidemia as a diagnostic pointer.
- name: Decreased HDL cholesterol concentration
  description: Low HDL cholesterol in 5 of 10 patients tested.
  phenotype_term:
    preferred_term: Decreased HDL cholesterol concentration
    term:
      id: HP:0003233
      label: Decreased HDL cholesterol concentration
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated transaminases were the most common laboratory abnormality
      (12/14) and were transient in most patients (9/12), followed by low total
      cholesterol (7/10) and HDL levels (5/10).
    explanation: Reports the low-HDL finding directly.
- name: Dysmorphic facial features
  frequency: OBLIGATE
  description: >-
    All 15 patients in the 2026 multicenter cohort had dysmorphic facial
    features, alongside developmental delay.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with developmental delay and dysmorphic facial
      features.
    explanation: >-
      Present in all 15 cohort patients, supporting the OBLIGATE band for that
      cohort.
biochemical:
- name: Aspartylglycosamine in dried blood spots
  context: >-
    Aspartylglycosamine is increased in dried blood spots and is proposed as a
    small-molecule biomarker of NGLY1-CDDG.
  evidence:
  - reference: PMID:31311714
    reference_title: "Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified aspartylglycosamine as the only significantly increased
      compound
    explanation: >-
      The metabolomics study supports aspartylglycosamine as a biochemical
      readout.
- name: GlcNAc-asparagine (GNA) in plasma, urine and CSF
  context: >-
    GlcNAc-Asn, also written GNA and reported in earlier work as
    aspartylglycosamine, is the substrate biomarker of NGLY1 deficiency. It is
    the terminal catabolite of the ENGase bypass route, so its concentration is
    an inverse readout of NGLY1 function. It is elevated in patient plasma and
    urine, in dried blood spots, and in the plasma and CSF of the Ngly1-null
    rat; it is stable over time; and it falls with gene-therapy treatment,
    which is what makes it usable as a pharmacodynamic endpoint rather than
    only a diagnostic marker. CSF GNA is a co-primary endpoint of the
    first-in-human GS-100 trial.
  readouts:
  - target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      GNA concentration is the direct measurement of the catabolite this node
      represents.
  evidence:
  - reference: PMID:34697629
    reference_title: "GlcNAc-Asn is a biomarker for NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is
      the analyte most closely associated with NGLY1 deficiency, showing
      consistent separation in levels between patients and controls.
    explanation: >-
      Establishes GNA as the analyte with the clearest patient-control
      separation.
  - reference: PMID:34697629
    reference_title: "GlcNAc-Asn is a biomarker for NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient
      cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and
      patients (plasma and urine)
    explanation: >-
      Establishes the matrices in which GNA is measurable and its
      cross-species conservation.
  - reference: PMID:42114141
    reference_title: "Natural history of NGLY1 deficiency: motor function & clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver transaminase and biomarker N-acetylglucosamine-asparagine
      (GlcNAc-Asn; GNA) levels were elevated in all participants.
    explanation: >-
      Prospective natural-history confirmation that GNA is elevated in every
      participant.
genetic:
- name: NGLY1
  association: Biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: NGLY1
    term:
      id: hgnc:17646
      label: NGLY1
  evidence:
  - reference: PMID:25900930
    reference_title: "A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified nine cases with mutations in NGLY1.
    explanation: The biochemical study identifies NGLY1 mutations in affected individuals.
  - reference: PMID:40643555
    reference_title: "Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the most common pathogenic NGLY1 variant, Arg401*, found in about 20% of
      patients
    explanation: >-
      Identifies the recurrent nonsense allele that accounts for roughly a
      fifth of patients.
  - reference: PMID:40643555
    reference_title: "Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Our in silico structural analysis shows that the Arg390Gln substitution
      results in destabilization of NGLY1 structure due to a loss of an ionic
      interaction network of Arg390
    explanation: >-
      A structural mechanism for one missense allele, from modelling rather
      than from experiment - typed COMPUTATIONAL for that reason.
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 10 distinct variants, including two novel variants
      c.629delA (p.(Lys210SerfsTer14)) and c.1036C > T (p.(Gln346Ter)).
    explanation: >-
      Extends the allelic spectrum with two novel loss-of-function variants.
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients carried homozygous variants, and no clear
      genotype-phenotype correlation was observed.
    explanation: >-
      A negative result worth keeping: genotype does not predict phenotype in
      this cohort, which is the backdrop for the modifier work below.
- name: SEL1L
  association: Candidate genetic modifier of phenotype severity
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  notes: >-
    NGLY1 deficiency is phenotypically heterogeneous even between patients
    carrying identical NGLY1 genotypes, which points to modifiers. Natural
    variants in the cytoplasmic tail of SEL1L, a component of the ERAD
    retrotranslocation complex, rescue lethality in a Drosophila model of the
    disease and improve resistance to ER stress in an NGLY1-activity-dependent
    manner. SEL1L is proposed as a candidate modifier in patients; it has not
    been shown to modify human disease.
  gene_term:
    preferred_term: SEL1L
    term:
      id: hgnc:10717
      label: SEL1L
  evidence:
  - reference: PMID:40773511
    reference_title: "Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the
      NGLY1 deficiency model, compared to the SEL1LS780 variant
    explanation: >-
      The modifier effect, measured in the Drosophila model.
  - reference: PMID:40773511
    reference_title: "Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SEL1L is a strong candidate modifier gene in patients, where variability
      in presentation is common.
    explanation: >-
      The authors' own framing: a candidate in patients, not a demonstrated
      human modifier, hence PARTIAL and relationship_type MODIFIER.
prevalence:
- population: United States
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.025
  notes: >-
    Reported as an estimated incidence of about 1 in 4 million live births,
    normalized here to 0.025 per 100,000 births. The source labels this an
    incidence estimate; it is recorded as a birth prevalence because the
    denominator is live births.
  evidence:
  - reference: PMID:40687377
    reference_title: "Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the United States, the estimated incidence of NGLY1 deficiency is
      approximately 1 in 4 million live births.
    explanation: The source of the birth-prevalence estimate.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Roughly 150 diagnosed patients worldwide and 42 in the United States as of
    2025. The worldwide figure is cited as unpublished data in the source, so
    it is recorded as a case count rather than as a rate.
  evidence:
  - reference: PMID:40687377
    reference_title: "Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are currently 42 patients diagnosed with NGLY1 deficiency in the US
      and ∼150 patients who have been diagnosed with the disease worldwide
    explanation: The reported diagnosed-patient counts.
progression:
- phase: Progressive developmental divergence with relatively stable individual function
  age_range: infancy onward; symptom onset averages about 4 months
  notes: >-
    A one-year prospective natural-history study of 15 participants - roughly
    10% of the identified patient population - found profound global
    developmental delay across communication, gross and fine motor, and
    cognitive domains. The pattern it documents is specific and easy to
    misread: individual measurements were mostly stable over the year, while
    age-equivalent scores diverged further from neurotypical peers, meaning the
    gap widens because development does not keep pace rather than because
    function is lost. Most patients never walk and do not develop verbal
    communication. Peripheral and auditory neuropathy in the 2026 multicenter
    cohort were observed to appear over time rather than at presentation, so
    the disease continues to accrue features after diagnosis.
  evidence:
  - reference: PMID:42114141
    reference_title: "Natural history of NGLY1 deficiency: motor function & clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age-equivalent scores identified a widening developmental gap between
      participants and neurotypical peers over time, indicating delayed
      milestone achievement and/or regression.
    explanation: The core progression finding of the prospective study.
  - reference: PMID:42114141
    reference_title: "Natural history of NGLY1 deficiency: motor function & clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although fluctuations were observed, measurements for individual
      participants were mostly stable over the course of the NHS.
    explanation: >-
      The counterpart finding that keeps the widening gap from being read as
      rapid individual decline over one year.
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral and auditory neuropathy findings were observed over time.
    explanation: Establishes that neuropathy accrues after presentation.
  - reference: PMID:40687377
    reference_title: "Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients are unable to walk and do not develop verbal communication
      skills, requiring significant caregiver support for daily management.
    explanation: The functional endpoint the natural history converges on.
treatments:
- name: GS-100 (AAV9-mediated NGLY1 gene replacement)
  description: >-
    A recombinant single-stranded AAV9 vector delivering a functional copy of
    human NGLY1, given as a single intracerebroventricular dose. The route is
    the finding, not an implementation detail: in the Ngly1-null rat, ICV and
    IV+ICV administration improved behaviour while intravenous-only did not,
    and adding IV to ICV added nothing - which is the evidence that the CNS is
    the primary therapeutic target organ. Preclinical work showed dose-dependent
    CNS biodistribution, reduced CSF and brain GNA, and improved motor function,
    with CSF GNA reduction correlating with behavioural improvement. Safety
    studies in wild-type rats and non-human primates found no adverse effects at
    or near the clinical starting dose, supporting an FDA IND. This is an
    investigational therapy with no human efficacy data yet.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: NGLY1 N-glycanase deficiency
    treatment_effect: ACTIVATES
    description: >-
      Restores NGLY1 expression and enzymatic activity at the trigger node,
      rather than acting on any downstream consequence.
    evidence:
    - reference: PMID:34120625
      reference_title: "Reversibility of motor dysfunction in the rat model of NGLY1 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        restored NGLY1 expression in the brain and spinal cord, concomitant with
        increased enzymatic activity of NGLY1 in the brain
      explanation: Direct restoration of the deficient enzyme at the trigger node.
  - target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
    treatment_effect: INHIBITS
    description: >-
      Restoring the amidase removes the need for the ENGase bypass, and the GNA
      catabolite falls in CSF and brain.
    evidence:
    - reference: PMID:36320418
      reference_title: "AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        GS-100 delivered by ICV or IV+ICV significantly reduced levels of the
        substrate biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn or GNA)
        in CSF and brain tissue compared with untreated Ngly1-/- rats.
      explanation: Direct measurement of the biomarker response to treatment.
  evidence:
  - reference: PMID:40687377
    reference_title: "Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In pharmacology studies using Ngly1 -/- rats, intracerebroventricular
      (i.c.v.) administration of GS-100 showed dose-dependent biodistribution,
      increased hNGLY1 mRNA expression, reduced disease biomarker
      N-acetylglucosamine-asparagine (GNA), improved motor function, and
      prevented phenotype progression.
    explanation: The preclinical efficacy package supporting the IND.
  - reference: PMID:40687377
    reference_title: "Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These nonclinical data supported the Food and Drug Administration
      approval of an Investigational New Drug application for a first-in-human
      phase 1/2/3 dose-escalation clinical trial.
    explanation: Establishes the regulatory status - investigational, not approved.
  - reference: PMID:36320418
    reference_title: "AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      ICV and IV + ICV administration of GS-100 resulted in behavioral
      improvements in rotarod and rearing tests, whereas IV-only administration
      did not.
    explanation: >-
      The route-dependence result that makes intracerebroventricular delivery
      the chosen route.
- name: N-acetylglucosamine (GlcNAc) supplementation for alacrima
  description: >-
    An oral dietary supplement tested specifically against the tear-production
    deficit rather than against the disease as a whole, in a randomized
    double-blind placebo-controlled phase II study. Alacrima is the target
    because insufficient tear production causes progressive eye damage. No
    efficacy result is curated here; the trial record establishes only that the
    question was asked in a controlled design.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-acetylglucosamine
      term:
        id: CHEBI:59640
        label: N-acetylglucosamine
  evidence:
  - reference: clinicaltrials:NCT05402345
    reference_title: "A Phase II Randomized, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating Effect Of GlcNAc On Tear Production In Individuals With NGLY1-CDDG"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study is being done to see if the dietary supplement, GlcNAc,
      improves tear production in patients with NGLY1-CDDG.
    explanation: >-
      Establishes the intervention and its target symptom; supports the
      existence of the trial, not an efficacy claim.
diagnosis:
- name: Molecular genetic confirmation of biallelic NGLY1 variants
  description: >-
    NGLY1-CDDG is a molecular diagnosis. Identification of biallelic pathogenic
    NGLY1 variants in a proband with the clinical picture establishes it; no
    biochemical assay is diagnostic in its place.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Biallelic pathogenic NGLY1 variants in a proband establish the diagnosis.
  evidence:
  - reference: PMID:29419975
    reference_title: NGLY1-Related Congenital Disorder of Deglycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of NGLY1-CDDG is established in a proband by the
      identification of biallelic pathogenic variants in NGLY1 on molecular
      genetic testing.
    explanation: >-
      GeneReviews states the diagnostic criterion directly.
- name: Standard CDG serum screening does not detect NGLY1-CDDG
  description: >-
    A clinically critical negative. NGLY1-CDDG is a disorder of
    de-glycosylation, not of glycan synthesis, so the serum screens used to
    triage the congenital disorders of glycosylation are not informative here
    and a normal result does not exclude it. Screening an NGLY1-CDDG proband
    the way a CDG proband would be screened yields a false negative.
  diagnosis_term:
    preferred_term: serum transferrin glycoform screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  presence: Negative
  results: >-
    Serum transferrin glycoform analysis and N/O glycan profiling are
    unreliable for NGLY1-CDDG; proceed to molecular genetic testing.
  evidence:
  - reference: PMID:29419975
    reference_title: NGLY1-Related Congenital Disorder of Deglycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical serum screening tests for congenital disorders of glycosylation
      (i.e., analysis of serum transferrin glycoforms, N and O glycan
      profiling) will NOT reliably detect NGLY1-CDDG.
    explanation: >-
      GeneReviews states the negative screening result explicitly.
clinical_trials:
- name: NCT06199531
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    First-in-human, open-label, single-arm, dose-finding phase 1/2/3 study of a
    single intracerebroventricular dose of GS-100 in patients aged 2 to 18
    years. Registered as phase 3 on ClinicalTrials.gov although the protocol
    spans phases 1 through 3.
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: clinicaltrials:NCT06199531
    reference_title: "A Phase 1/2/3 Open-label, Single Arm, Dose-finding Study to Investigate Long-term Safety, Tolerability and Efficacy of GS-100, an Adeno-associated Virus Serotype 9 (AAV9) Vector-mediated Gene Transfer of Human NGLY1, in Patients With NGLY1 Deficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A non-randomized, open-label, Phase 1/2/3 study of a single
      intracerebroventricular (ICV) administration of a gene replacement therapy
      (GS-100) in participants who are 2 to 18 years old with NGLY1 Deficiency.
    explanation: The registered design of the first-in-human gene-therapy trial.
- name: NCT05402345
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Randomized, multicenter, double-blind, placebo-controlled phase II study of
    oral GlcNAc for tear production in NGLY1-CDDG.
  target_phenotypes:
  - preferred_term: Alacrima
    term:
      id: HP:0000522
      label: Alacrima
  evidence:
  - reference: clinicaltrials:NCT05402345
    reference_title: "A Phase II Randomized, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating Effect Of GlcNAc On Tear Production In Individuals With NGLY1-CDDG"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with NGLY1-CDDG, the disorder can lead to eye damage due to
      not being able to produce enough tears.
    explanation: Establishes the trial's rationale and target phenotype.
- name: NCT06122766
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Observational study characterizing the NGLY1 movement disorder and clinical
    features, motivated by the fact that the hyperkinetic movement disorder had
    only been described qualitatively.
  target_phenotypes:
  - preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: clinicaltrials:NCT06122766
    reference_title: "Investigation of NGLY1 Deficiency Movement Disorder & Clinical Features"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hyperkinetic movement disorder in NGLY1 Deficiency is highly complex
      and has been qualitatively described to include choreiform, athetoid,
      dystonic, myoclonic, action tremor, and dysmetric movements.
    explanation: >-
      Documents the movement-disorder phenomenology this observational study
      set out to quantify.
animal_models:
- name: Ngly1-/- rat (Sprague Dawley, CRISPR exon 11-12 deletion)
  species: Rat
  genotype: Ngly1 homozygous deletion of exons 11-12 and the 3' polyA region
  description: >-
    The workhorse model of the disease and the one the gene-therapy programme
    is built on. Unlike the mouse, it is viable, and it reproduces the human
    features that matter for an endpoint: motor and gait deficits, impaired
    spatial learning, peripheral axon loss, and elevated GNA in plasma and CSF.
    Longitudinal work out to 17-18 months added a progressive, lethal course -
    about half the animals dead or euthanized by 9-10 months, roughly 92%
    reduction in rotarod latency, widespread neuroinflammation, and loss of
    spinal motor neurons - which is what makes it a model of a progressive
    neurodegenerative disease rather than a static one.
  publication: PMID:41721346
  modeled_mechanisms:
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the neurological course including its progression and
      premature mortality.
    limitations: >-
      The rat's terminal course is not a documented feature of every human
      patient; the human median lifespan of about 13 years is cited from
      published clinical data rather than measured alongside the rodent. Ocular
      and hepatic components of the human phenotype are not the readouts this
      model is characterized on, so the RECAPITULATES claim rests on the
      neurological arm.
    readouts:
    - name: Rotarod latency
      target: Neurodevelopmental, ocular, and hepatic dysfunction
      direction: DECREASED
      interpretation: Motor performance decline with age in the null animals.
      evidence:
      - reference: PMID:41721346
        reference_title: "Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Surviving animals displayed phenotypes mirroring human NGLY1
          Deficiency disease progression, such as worsening motor deficits (~92%
          reduction in rotarod latency and ~82% reduction in rearing)
        explanation: Reports the motor measurements and their magnitude.
    - name: Survival
      target: Neurodevelopmental, ocular, and hepatic dysfunction
      direction: DECREASED
      interpretation: >-
        Premature mortality, the endpoint that distinguishes the aged rat from
        earlier young-adult characterizations.
      evidence:
      - reference: PMID:41721346
        reference_title: "Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          By 9-10 months of age, ~50% of the Ngly1⁻/⁻ rats had either died or met
          humane euthanasia criteria due to a severe decline in health.
        explanation: Reports the survival measurement directly.
    - name: Spinal motor neuron and peripheral axon counts
      target: Neurodevelopmental, ocular, and hepatic dysfunction
      direction: DECREASED
      interpretation: >-
        The neuropathological substrate of the motor decline, and the
        structural correlate of the human sensorimotor neuropathy.
      evidence:
      - reference: PMID:41721346
        reference_title: "Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          histopathological examination of Ngly1⁻/⁻ rats identified significant
          neuropathological abnormalities that were not present in the control
          cohorts, including loss of peripheral axons and spinal motor neurons
        explanation: Reports the histopathological measurement.
    evidence:
    - reference: PMID:41721346
      reference_title: "Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The findings reported here demonstrate that Ngly1⁻/⁻ rats recapitulate
        the severe, progressive course of NGLY1 Deficiency, including
        neurodegenerative deterioration, motor deficits, and premature
        mortality.
      explanation: >-
        The authors' own statement that the model is informative for the human
        disease course.
  - target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      The rat carries the same substrate biomarker as patients, in the same
      matrices, which is what allows a CSF endpoint to be carried from
      preclinical work into the trial.
    limitations: >-
      GNA is a readout of enzyme function, not of clinical benefit; the
      correlation between GNA reduction and behavioural improvement in this
      model is the basis for treating it as a surrogate, and that surrogacy is
      not yet established in humans.
    readouts:
    - name: CSF and brain GNA
      target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
      direction: INCREASED
      interpretation: >-
        Elevated in untreated null animals and reduced by gene transfer, which
        is what makes it a pharmacodynamic marker.
      evidence:
      - reference: PMID:40687377
        reference_title: "Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Reductions in GNA within central nervous system (CNS) tissues and
          cerebrospinal fluid (CSF) correlated significantly with improvements,
          suggesting that CSF GNA may serve as a clinical biomarker of
          therapeutic activity.
        explanation: Reports the biomarker measurement and its correlation with benefit.
- name: Ngly1-null mouse (C57BL/6) and the Engase double knockout
  species: Mouse
  genotype: Ngly1 knockout on C57BL/6; Ngly1/Engase double knockout
  description: >-
    A negative and a genetic result rather than a phenotyping platform. The
    Ngly1-null mouse is embryonically lethal on a C57BL/6 background, which
    human NGLY1 deficiency is not, so on its own it fails as a model of the
    human disease. Its value is what rescues it: additionally deleting Engase
    partially rescues the lethality, and outcrossing to ICR partially rescues
    it too. Viable mixed-background animals then show a severe phenotype
    reminiscent of patients, and those defects are again suppressed by Engase
    deletion. This is the strongest genetic evidence that the damage in NGLY1
    deficiency is done by the diverted ENGase route rather than by the absence
    of deglycosylation as such.
  publication: PMID:28426790
  modeled_mechanisms:
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      On the C57BL/6 background the model dies in utero, so it cannot express
      the postnatal multisystem phenotype that defines the human disease.
    limitations: >-
      The failure is background-dependent, not absolute: a mixed C57BL/6-ICR
      background yields viable animals with a phenotype resembling patients. A
      strain-specific embryonic lethality with no human counterpart means any
      rescue measured against it is measured against the wrong endpoint, which
      is the core translational problem with this model.
    evidence:
    - reference: PMID:28426790
      reference_title: "Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we analyzed Ngly1-deficient mice and found that they are embryonic
        lethal in C57BL/6 background
      explanation: >-
        The embryonic lethality that human patients do not have, and which this
        model therefore fails to recapitulate.
  - target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Removing ENGase genetically removes the bypass route and rescues the
      phenotype, which is the causal test of that node.
    limitations: >-
      Germline deletion from conception is not the same intervention as
      pharmacological inhibition in a diagnosed patient, and the rescue is
      partial. No ENGase inhibitor has been tested in a human.
    readouts:
    - name: Survival of Ngly1-null animals
      target: ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
      direction: RESTORED
      interpretation: >-
        Partial restoration of viability on removing the bypass enzyme.
      evidence:
      - reference: PMID:28426790
        reference_title: "Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase
          (Engase), which is another de-N-glycosylating enzyme but leaves a single
          GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the
          lethality of the Ngly1-deficient mice
        explanation: Reports the rescue and its mechanism.
    evidence:
    - reference: PMID:28426790
      reference_title: "Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        cytoplasmic ENGase represents one of the potential therapeutic targets
        for this genetic disorder
      explanation: >-
        The authors' framing of the rescue as therapeutically informative for
        this node.
- name: Tamoxifen-inducible Ngly1-knockout (iNgly1) mouse
  species: Mouse
  genotype: Tamoxifen-inducible Ngly1 knockout on C57BL/6
  description: >-
    An inducible knockout that sidesteps the embryonic lethality of the
    constitutive C57BL/6 null and produces a postnatal phenotype - elevated
    GlcNAc-Asn, motor deficits, kyphosis, Purkinje cell loss, gait abnormality -
    in which systemic gene therapy can be tested. Systemic AAV.PHPeB delivery
    corrected multiple features at 8 weeks and near-completely normalized the
    neurological phenotype over a year.
  publication: PMID:39137042
  modeled_mechanisms:
  - target: Neurodevelopmental, ocular, and hepatic dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the motor, skeletal and cerebellar features of the human
      disease; the ocular and hepatic components are not among the reported
      readouts.
    limitations: >-
      Adult-inducible knockout does not model a congenital, developmental
      disease - the animal develops normally before the gene is removed, which
      is the opposite of the patient's situation. The therapeutic result also
      does not transfer as reported: AAV.PHPeB's CNS tropism is mouse-specific
      and, as the authors state, does not translate to primates.
    readouts:
    - name: Neurological phenotype after systemic gene transfer
      target: Neurodevelopmental, ocular, and hepatic dysfunction
      direction: RESTORED
      interpretation: >-
        Durable near-complete normalization over a year, the strongest efficacy
        result in any NGLY1 model.
      evidence:
      - reference: PMID:39137042
        reference_title: "Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          another cohort of AAV.PHPeB-treated iNgly1 mice were monitored over a
          year and showed near-complete normalization of the neurological
          aspects of the disease phenotype, demonstrating the durability of gene
          therapy
        explanation: Reports the treatment response and its durability.
    evidence:
    - reference: PMID:39137042
      reference_title: "Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we first characterized a tamoxifen-inducible Ngly1-knockout (iNgly1)
        C57BL/6J mouse model, which exhibited symptoms recapitulating human
        disease, including elevation of the biomarker GlcNAc-Asn, motor
        deficits, kyphosis, Purkinje cell loss, and gait abnormalities
      explanation: The model's characterized phenotype.
discussions:
- discussion_id: gap_ngly1_which_substrate_explains_the_phenotype
  prompt: >-
    Which NGLY1 substrate or function accounts for the clinical phenotype -
    alacrima, the hyperkinetic movement disorder, the neuropathy - and is ERAD
    involvement even part of the answer?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired cytosolic deglycosylation of ERAD substrates
  - pathophysiology#Failed NFE2L1 sequence editing and proteasome bounce-back failure
  - pathophysiology#ENGase-mediated alternative deglycosylation and GlcNAc-Asn accumulation
  rationale: >-
    The textbook account - NGLY1 deglycosylates ERAD substrates, so its loss
    breaks ERAD - is under direct challenge. Work on the Drosophila model
    states plainly that loss of NGLY1 has little effect on ERAD and does not
    prevent degradation of misfolded proteins, and that the physiological
    significance of NGLY1 in ERAD is not understood. Meanwhile the best
    characterized substrate, NFE2L1/Nrf1, is not an ERAD client being disposed
    of but a transcription factor being activated, and NGLY1 has further
    reported substrates and functions - NKCC1, BMP signaling, AMPK signaling,
    and a non-enzymatic role in aquaporin transcription - none of which has
    been tied to a specific clinical feature. Nothing in the literature
    connects any single substrate to alacrima, to the movement disorder, or to
    the length-dependent neuropathy. This entry therefore keeps every edge from
    a molecular node to the clinical consequence typed as
    INDIRECT_UNKNOWN_INTERMEDIATES, and curates the ERAD node as a perturbation
    rather than as a demonstrated degradative failure.
  evidence:
  - reference: PMID:40773511
    reference_title: "Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Despite this, the physiological significance of NGLY1 in ERAD is not
      understood.
    explanation: >-
      States the gap in the ERAD account directly, from a group working on the
      pathway.
  - reference: PMID:39137042
    reference_title: "Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiological basis of NGLY1 deficiency may be associated with
      the absence of various enzymatic and nonenzymatic roles of NGLY1
    explanation: >-
      An independent statement that the causal function is unresolved and may
      not be the enzymatic one at all.
  proposed_experiments:
  - experiment_id: exp_ngly1_substrate_specific_rescue
    name: Substrate-specific rescue in a viable NGLY1-deficient model
    description: >-
      In the Ngly1-null rat or the inducible mouse, restore individual
      candidate outputs one at a time - constitutively edited Nrf1, corrected
      NKCC1, ENGase suppression - without restoring NGLY1 itself, and score
      tear production, motor phenotype, and nerve conduction separately. A
      feature that a single-substrate rescue corrects is a feature that
      substrate explains. Note the constraint the Nrf1 work supplies: mutants
      mimicking constitutive activation are cytotoxic, so the Nrf1 arm needs a
      conditional design.
  - experiment_id: exp_ngly1_lacrimal_gland_mechanism
    name: Why the lacrimal gland
    description: >-
      Alacrima is near-pathognomonic and among the earliest features, yet no
      mechanism links NGLY1 to tear production. Profile lacrimal gland tissue
      from a viable model for NGLY1-dependent substrates, testing in particular
      the reported non-enzymatic role in aquaporin transcription, which is the
      only proposed route with an obvious connection to secretion.
- discussion_id: mismatch_ngly1_mouse_rat_human_severity
  prompt: >-
    Ngly1-null mice die in utero, Ngly1-null rats live to adulthood and then
    degenerate, and human patients survive to a median of about 13 years. Which
    of these is the right model of human NGLY1 deficiency, and what does the
    disagreement mean?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#NGLY1 N-glycanase deficiency
  - pathophysiology#Neurodevelopmental, ocular, and hepatic dysfunction
  rationale: >-
    The species spread is not a nuisance but a finding. Complete loss of the
    same enzyme is embryonically lethal in one rodent and compatible with
    adult life in another, and the mouse lethality is itself
    strain-dependent - outcrossing C57BL/6 to ICR partially rescues it, as does
    deleting Engase. Whatever makes the difference is a modifier of severity
    that is not NGLY1, and the same logic likely applies to the phenotypic
    heterogeneity seen between human patients with identical NGLY1 genotypes.
    The practical consequence is that a therapeutic rescue measured against
    mouse embryonic lethality is measured against an endpoint no patient has,
    while the rat's progressive adult decline is a closer match to the human
    course but was only characterized out to 17-18 months in 2026. Curating
    either rodent result as though it were a human result would overstate it.
  evidence:
  - reference: PMID:28426790
    reference_title: "Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a change in the genetic background of C57BL/6 mice, produced by crossing
      the mice with an outbred mouse strain (ICR) could partially rescue the
      embryonic lethality of Ngly1-deficient mice
    explanation: >-
      Shows severity in the mouse is set by background modifiers rather than by
      Ngly1 genotype alone.
  - reference: PMID:41721346
    reference_title: "Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, Ngly1⁻/⁻ mice (C57BL/6) are embryonically lethal, and prior
      characterization of Ngly1⁻/⁻ rats was restricted to young adult rat (~7
      months old), leaving late-onset phenotypes and potential lifespan
      reduction unexplored.
    explanation: >-
      States the species discrepancy and the gap in rat characterization that
      the study was designed to close.
  - reference: PMID:42361657
    reference_title: "Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients carried homozygous variants, and no clear
      genotype-phenotype correlation was observed.
    explanation: >-
      The human counterpart of the modifier problem: severity is not read off
      the NGLY1 genotype in patients either.
  proposed_experiments:
  - experiment_id: exp_ngly1_modifier_mapping_across_backgrounds
    name: Map the background modifiers of Ngly1-null severity
    description: >-
      Cross the Ngly1 null onto a panel of inbred backgrounds and map the loci
      that convert embryonic lethality into viability. Candidate modifiers with
      human orthologs - SEL1L is already one such candidate from the Drosophila
      screen - can then be tested against severity in the patient cohort, where
      genotype currently predicts nothing.
- discussion_id: gap_ngly1_gene_therapy_partial_rescue
  prompt: >-
    AAV9-delivered NGLY1 suppressed convulsions in Ngly1-null rats without
    correcting EEG abnormality or sleep fragmentation. What does the
    dissociation mean for what gene therapy can be expected to achieve?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#GS-100 (AAV9-mediated NGLY1 gene replacement)
  - pathophysiology#Neurodevelopmental, ocular, and hepatic dysfunction
  rationale: >-
    The gene-therapy programme has a strong preclinical package on motor
    endpoints and on the GNA biomarker, and it is easy to read that as
    disease-wide correction. A separate group, dosing AAV9-hNGLY1 into the same
    rat model, found the opposite for two other endpoints: NGLY1 protein was
    robustly expressed and deglycosylation activity partially restored, and
    non-epileptic convulsions fell, but EEG abnormalities and sleep disruption
    did not improve. Only partial restoration of enzymatic activity was
    achieved, so the dissociation may reflect dose rather than a ceiling on
    what restoration can fix; the alternative - that some features are already
    developmentally fixed by the time of dosing, or depend on a function the
    vector does not restore - has different implications for patient selection
    and for the age at which treatment is worth giving. The trial's co-primary
    endpoints are CSF GNA and motor function, neither of which would detect
    this gap.
  evidence:
  - reference: PMID:41176936
    reference_title: "AAV9-mediated NGLY1 gene replacement suppresses non-epileptic convulsions in Ngly1(-/-) rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      While NGLY1 protein was robustly expressed in the brain with partial
      restoration of enzymatic deglycosylation activity, AAV9-hNGLY1-treated
      Ngly1-/- rats showed no significant improvement in EEG abnormalities or
      sleep disruption.
    explanation: The negative result at the heart of this gap.
  - reference: PMID:41176936
    reference_title: "AAV9-mediated NGLY1 gene replacement suppresses non-epileptic convulsions in Ngly1(-/-) rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      persistent EEG seizures and sleep disturbances indicate only a partial
      therapeutic benefit, underscoring the need for further refinement of gene
      therapy strategies, as well as additional therapeutic options, for NGLY1
      deficiency
    explanation: >-
      The authors' own reading, which is more cautious than the programme-level
      preclinical summaries.
  proposed_experiments:
  - experiment_id: exp_ngly1_dose_response_across_endpoint_classes
    name: Dose-response across endpoint classes in the Ngly1-null rat
    description: >-
      Dose AAV9-NGLY1 across a range spanning the reported partial-restoration
      level, and score motor function, GNA, EEG, and sleep architecture in the
      same animals. If EEG and sleep respond at higher restored activity, the
      dissociation is a dose effect; if they remain refractory at full
      restoration, they identify features that gene replacement cannot address.
  - experiment_id: exp_ngly1_treatment_age_window
    name: Does the age at dosing determine which features respond
    description: >-
      Compare dosing at weaning against dosing after the phenotype is
      established in the Ngly1-null rat, using the same endpoint panel. A
      window effect would bear directly on the 2-to-18-year enrolment range of
      the first-in-human trial.
datasets:
- accession: geo:GSE301626
  title: NGLY1-dependent conversion of N-glycosylated N to D is essential for transcription of proteasome genes
  description: >-
    Transcriptomic profiling of HeLa cells expressing glycan-less Nrf1 mutants
    (9NA and 9ND) in which all nine putative N-glycosylation sites were
    replaced, isolating the sequence-editing-specific contribution to Nrf1
    function. This is the primary dataset behind the NFE2L1 sequence-editing
    node in this entry.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 9
  publication: PMID:41468431
  notes: >-
    Found by GEO DataSets search and verified against NCBI E-utilities on
    2026-08-20; title, sample count, and organism are GEO's own values. DIRECT
    relevance - the series is the deposited data of the cited NGLY1 paper, not
    a gene-name match.
- accession: geo:GSE295078
  title: Single-nucleus transcriptomics of inducible Ngly1-/- cerebellum
  description: >-
    Single-nucleus RNA sequencing of cerebella from Ngly1fl/fl, iNgly1-/- and
    iNgly1-/-Sting1-/- mice, examining cell-type-specific effects of NGLY1
    deficiency and the contribution of the STING pathway. The Sting1 double
    knockout arm is what makes the series informative rather than descriptive:
    it tests whether an inflammatory pathway mediates the neurodegeneration.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 6
  publication: PMID:40644312
  notes: >-
    Found by GEO DataSets search and verified against NCBI E-utilities on
    2026-08-20. DIRECT relevance - an Ngly1 knockout series in the inducible
    mouse model this entry curates. The associated publication
    (PMID:40644312, STING-driven noninflammatory neurodegeneration) is not yet
    curated as evidence in this entry; the dataset is recorded here without
    inheriting any claim from it.
📚

References & Deep Research

References

1
PMID:29419975
NGLY1-Related Congenital Disorder of Deglycosylation.
No top-level findings curated for this source.