NGLY1-congenital disorder of deglycosylation

Mendelian MONDO:0800044 Pathograph 4 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. NGLY1 deficiency blocks this deglycosylation step, disrupts ER-associated degradation and proteasomal processing of glycoproteins, and produces a multisystem neurodevelopmental disorder with developmental delay, hypotonia, hyperkinetic movement disorder, alacrima, elevated liver transaminases, microcephaly, seizures, and peripheral neuropathy.

Ask OpenScientist

Ask a research question about NGLY1-congenital disorder of deglycosylation. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
3
Pathophys.
9
Phenotypes
4
Pathograph
1
Genes
1
References
🏷

Classifications

👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
NGLY1-CDDG is caused by biallelic pathogenic variants in NGLY1.
Autosomal recessive inheritance
Show evidence (1 reference)
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.
⚙

Pathophysiology

3
NGLY1 N-glycanase deficiency
Biallelic NGLY1 variants abolish or markedly reduce N-glycanase 1 protein and enzymatic activity.
NGLY1 hgnc:17646
protein deglycosylation GO:0006517 ↓ DECREASED
peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity GO:0000224 ↓ 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 ⚠ ABNORMAL protein deglycosylation GO:0006517 ↓ DECREASED
Downstream
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.
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.
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.
⬡

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.
●

Phenotypes

9
Eye 2
Optic atrophy Optic atrophy HP:0000648
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 Retinal dystrophy HP:0000556
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.
Limbs 1
Short foot Short foot HP:0001773
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 1
Elevated liver transaminases Elevated circulating hepatic transaminase concentration HP:0002910
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"elevated liver transaminases (6/7)"
The clinical series reports elevated liver transaminases.
Musculoskeletal 1
Hypotonia OBLIGATE Hypotonia HP:0001252
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.
Nervous System 3
Global developmental delay Global developmental delay HP:0001263
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
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 Peripheral neuropathy HP:0009830
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"abnormal nerve conduction (3/3)."
Abnormal nerve conduction supports peripheral neuropathy.
Other 1
Alacrima Alacrima HP:0000522
Show evidence (1 reference)
PMID:24651605 SUPPORT Human Clinical
"hypolacrima or alacrima (7/8)"
The clinical series reports hypolacrima or alacrima in most patients.
🧬

Genetic Associations

1
NGLY1 (Biallelic loss-of-function variants)
Gene: NGLY1 hgnc:17646 relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:25900930 SUPPORT Human Clinical
"We identified nine cases with mutations in NGLY1."
The biochemical study identifies NGLY1 mutations in affected individuals.
🔬

Biochemical Markers

1
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.
{ }

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. NGLY1 deficiency blocks this deglycosylation step,
  disrupts ER-associated degradation and proteasomal processing of
  glycoproteins, and produces a multisystem neurodevelopmental disorder with
  developmental delay, hypotonia, hyperkinetic movement disorder, alacrima,
  elevated liver transaminases, microcephaly, seizures, and peripheral
  neuropathy.
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.
pathophysiology:
- name: NGLY1 N-glycanase 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
  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: 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: Neurodevelopmental, ocular, and hepatic 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
  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.
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.
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.
📚

References & Deep Research

References

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