MPDU1-congenital disorder of glycosylation

Mendelian MONDO:0012211 Pathograph 29 hereditary disease

MPDU1-congenital disorder of glycosylation is an ultra-rare autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in MPDU1. MPDU1 deficiency disrupts utilization of dolichol-phosphate-linked mannose and glucose donors in the endoplasmic reticulum, producing a CDG type I pattern with overlapping dystroglycanopathy-like manifestations.

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1
Inheritance
7
Pathophys.
16
Phenotypes
29
Pathograph
1
Genes
3
Treatments
4
Differentials
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
MPDU1-CDG is caused by biallelic pathogenic MPDU1 variants; reported cases include homozygous variants in consanguineous families and compound heterozygosity.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31741824 SUPPORT Human Clinical
"The two patients are brother and sister from Iraqi origin. They were the third and fourth child of consanguineous parents (first cousins), and had two healthy sisters (Figure 1A)."
The affected siblings from consanguineous parents support autosomal recessive inheritance in this MPDU1-CDG family.
PMID:11733564 SUPPORT Human Clinical
"Sequence analysis of the Lec35/MPDU1 gene, known to be involved in the use of dolichylphosphomannose and dolichylphosphoglucose, revealed mutations in all three patients."
This original case series identified MPDU1 variants in multiple affected patients with CDG-I.
⚙

Pathophysiology

7
MPDU1-dependent dolichol-linked donor utilization defect
MPDU1 loss impairs use of dolichol-phosphate-mannose and dolichol-phosphate-glucose donor substrates required for ER glycosylation reactions.
MPDU1 link
protein N-linked glycosylation link protein O-linked glycosylation via mannose link GPI anchor biosynthetic process link
endoplasmic reticulum link
Downstream
Truncated lipid-linked oligosaccharide accumulation Impaired donor utilization produces incomplete lipid-linked oligosaccharide precursors.
Show evidence (2 references)
PMID:11733556 SUPPORT In Vitro
"CDG-If is caused by a defect in the gene MPDU1, the human homologue of hamster Lec35, and is the first disorder to affect the use, rather than the biosynthesis, of donor substrates for lipid-linked oligosaccharides."
The original mechanistic report directly places MPDU1 upstream of dolichol-linked donor utilization rather than donor synthesis.
PMID:31741824 SUPPORT Human Clinical
"Mannose-phosphate-dolichol utilization defect 1 (MPDU1) plays a role in the utilization of DPM."
The later clinical report confirms the mechanistic role of MPDU1 in DPM utilization.
Truncated lipid-linked oligosaccharide accumulation
Patient cells accumulate incomplete lipid-linked oligosaccharides for N-linked glycosylation, leading to systemic protein hypoglycosylation.
fibroblast link
protein N-linked glycosylation link ↓ DECREASED
Downstream
Reduced alpha-dystroglycan O-mannosylation MPDU1-CDG can bridge CDG-I and dystroglycanopathy biology through impaired alpha-dystroglycan glycosylation.
Neurodevelopmental, feeding, and seizure involvement Systemic glycosylation failure is associated with severe psychomotor impairment, seizures, feeding failure, apnea, and respiratory decompensation.
Craniofacial, sensory, and skin involvement Multisystem glycosylation abnormalities are associated with facial dysmorphism, sensory involvement, and variable skin disease.
Hepatobiliary, renal, and hematologic involvement Severe MPDU1-CDG can include biliary-duct dilatation, renal cystic changes, thrombocytopenia, and coagulation abnormalities.
Show evidence (3 references)
PMID:11733564 SUPPORT In Vitro
"patients' fibroblasts accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation."
This abstract directly supports the biochemical intermediate node in patient fibroblasts.
PMID:31741824 SUPPORT Human Clinical
"These revealed reduced tetrasialotransferrin, with increased asialo‐ and disialotransferrin indicative of a CDG‐I (Figure 1D,E)."
The serum transferrin pattern supports systemic hypoglycosylation in a clinical patient sample.
PMID:31741824 SUPPORT In Vitro
"Increased levels of dolichol‐linked Man5GlcNAc2 and Man9GlcNAc2 accompanied by reduced amounts of Glc3Man9GlcNAc2 were detected (Figure 2A) which indicated shortage of DPM and DPG in the ER lumen."
Fibroblast LLO analysis directly supports accumulation of truncated dolichol-linked oligosaccharides.
Reduced alpha-dystroglycan O-mannosylation
MPDU1-CDG patient fibroblasts can show reduced functional alpha-dystroglycan glycosylation, explaining overlap with dystroglycanopathy features such as elevated creatine kinase, eye disease, and cardiomyopathy.
fibroblast link
protein O-linked glycosylation via mannose link ↓ DECREASED
Downstream
Dystroglycanopathy-overlap muscle, eye, and cardiac involvement Reduced alpha-dystroglycan O-mannosylation explains the overlap with dystroglycanopathy features including muscle injury, cardiomyopathy, and congenital eye disease.
Show evidence (2 references)
PMID:31741824 SUPPORT In Vitro
"Subsequently, we analyzed the O‐mannosylation of αDG in fibroblasts of patient P1 by IIH6 immunolabeling and a LO assay."
This describes direct testing of alpha-dystroglycan O-mannosylation in patient fibroblasts.
PMID:31741824 SUPPORT In Vitro
"We found that the signals for both IIH6 and LO were reduced in patient fibroblasts as compared to the signal of control fibroblasts (Figure 2C), suggesting reduced glycosylation of αDG."
Reduced IIH6 and laminin-overlay signals directly support reduced functional alpha-dystroglycan glycosylation.
Neurodevelopmental, feeding, and seizure involvement
Severe MPDU1-CDG causes profound neurodevelopmental impairment with seizures, failure to thrive, and seizure-associated apnea or respiratory insufficiency in the most severe infantile presentations.
Downstream
Global developmental delay Severe psychomotor impairment is a core neurologic manifestation of MPDU1-CDG.
Seizure Seizures are part of the severe neurologic MPDU1-CDG presentation.
Failure to thrive Feeding failure and poor growth occur in severe MPDU1-CDG.
Apnea Apnea is recurrent across reported patients and can occur in association with seizures.
Show evidence (2 references)
PMID:11733556 SUPPORT Human Clinical
"The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision."
The original MPDU1-CDG patient report supports severe psychomotor impairment, seizures, failure to thrive, skin disease, and visual involvement.
PMID:31741824 SUPPORT Human Clinical
"The clinical course was complicated by an increasing frequency and severity of seizures with epileptic apneas followed by respiratory insufficiency."
This severe case directly links seizures with epileptic apnea and respiratory insufficiency.
Dystroglycanopathy-overlap muscle, eye, and cardiac involvement
MPDU1-CDG can overlap with dystroglycanopathies through reduced alpha-dystroglycan O-mannosylation, producing hypotonia, elevated creatine kinase, cardiomyopathy, buphthalmos, and congenital glaucoma.
protein O-linked glycosylation via mannose link ↓ DECREASED
Downstream
Generalized hypotonia Hypotonia is reported as part of the MPDU1-CDG dystroglycanopathy-overlap phenotype.
Elevated circulating creatine kinase concentration Elevated CK reflects muscle involvement within the dystroglycanopathy overlap.
Cardiomyopathy Cardiomyopathy overlaps with the alpha-dystroglycan O-mannosylation disorder spectrum.
Buphthalmos Buphthalmos is part of the severe eye involvement overlapping with dystroglycanopathy phenotypes.
Glaucoma Congenital glaucoma is part of the MPDU1-CDG eye involvement overlapping with severe dystroglycanopathy phenotypes.
Show evidence (2 references)
PMID:31741824 SUPPORT Human Clinical
"Buphthalmos, glaucoma, DCM, and elevated CK are clinical features that overlap with the disease spectrum of the dystroglycanopathies."
The report explicitly groups these MPDU1-CDG findings with dystroglycanopathy-overlap features.
PMID:31741824 SUPPORT In Vitro
"In line with the clinical symptoms overlapping with dystroglycanopathies, we showed reduced O‐mannosylation of αDG in patient fibroblasts."
Patient fibroblast evidence connects the clinical overlap to reduced alpha-dystroglycan O-mannosylation.
Craniofacial, sensory, and skin involvement
MPDU1-CDG can include craniofacial dysmorphism, eye defects, hearing loss, and variable skin involvement such as ichthyosis or erythroderma.
Downstream
Abnormal facial shape Facial dysmorphism is recurrent in MPDU1-CDG.
Sensorineural hearing impairment Sensorineural hearing loss is reported in severe MPDU1-CDG.
Ichthyosis Skin abnormalities such as ichthyosis are reported across the MPDU1-CDG spectrum, although not in every case.
Show evidence (2 references)
PMID:31741824 SUPPORT Human Clinical
"So far, seven MPDU1‐CDG patients have been described. All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis."
This disease-specific summary supports recurrent facial, eye, apnea, and skin abnormalities in MPDU1-CDG.
PMID:31741824 SUPPORT Human Clinical
"A sensorineural hearing loss was identified with brainstem evoked response audiometry (BERA) evaluation."
This directly supports sensory involvement through sensorineural hearing loss.
Hepatobiliary, renal, and hematologic involvement
Severe MPDU1-CDG can present with intrahepatic biliary duct dilatation, renal cysts, thrombocytopenia, low antithrombin III, and related coagulation abnormalities.
liver link kidney link
Downstream
Biliary duct dilatation Intrahepatic biliary duct dilatation is a reported severe MPDU1-CDG manifestation.
Renal cyst Renal cysts are reported in the severe G73E MPDU1-CDG presentation.
Thrombocytopenia Congenital thrombocytopenia occurs with broader coagulation abnormalities in severe MPDU1-CDG.
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"The MPDU1‐CDG siblings shared the following abnormalities: massive dilatation of the intrahepatic biliary duct system, small renal cysts, buphthalmos with glaucoma, DCM, thrombocytopenia, elevated CK, and low ATIII."
This summary directly supports hepatobiliary, renal, hematologic, cardiac, ocular, and muscle-injury features in the affected siblings.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MPDU1-congenital disorder of glycosylation 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

16
Blood 1
Thrombocytopenia Thrombocytopenia (HP:0001873)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"There was a marked congenital thrombocytopenia (minimal 45 000 platelets/μL), a slightly decreased fibrinogen (minimal 96 mg/dL), and a nonmeasurable antithrombin III (ATIII, <20%)."
This directly supports thrombocytopenia and broader coagulation abnormalities in MPDU1-CDG.
Cardiovascular 1
Cardiomyopathy Cardiomyopathy (HP:0001638)
Show evidence (2 references)
PMID:31741824 SUPPORT Human Clinical
"Echocardiography detected a dilated aorta ascendens, a transient pulmonary hypertension, and a hypertrophic cardiomyopathy (HCM) at the age of 3 weeks, which developed in combination with an arterial hypertension."
This directly supports hypertrophic cardiomyopathy in one severe MPDU1-CDG patient.
PMID:31741824 SUPPORT Human Clinical
"At the age of 3 months, the patient evolved DCM with low output and a shortening fraction of at least 9%."
This directly supports dilated cardiomyopathy in the affected sister.
Ear 1
Sensorineural hearing impairment Sensorineural hearing impairment (HP:0000407)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"A sensorineural hearing loss was identified with brainstem evoked response audiometry (BERA) evaluation."
This supports hearing impairment identified by BERA in an MPDU1-CDG patient.
Genitourinary 1
Renal cyst Renal cyst (HP:0000107)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"However, at the age of 7 weeks, small renal cysts were suspected in an ultrasound scan."
This directly supports renal cysts in an affected MPDU1-CDG patient.
Head and Neck 1
Abnormal facial shape Abnormal facial shape (HP:0001999)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"Slight dysmorphic features were noted including a smooth philtrum, retrognathia, low‐set, posterior‐rotated ears, and hypertelorism with megalocorneae (Figure 1B)."
This directly supports facial dysmorphism in an affected MPDU1-CDG patient.
Integument 1
Ichthyosis Ichthyosis (HP:0008064)
Show evidence (1 reference)
PMID:31741824 PARTIAL Human Clinical
"All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis."
This supports ichthyosis or related skin abnormalities as common but not universal in MPDU1-CDG.
Metabolism 1
Elevated circulating creatine kinase concentration Elevated circulating creatine kinase concentration (HP:0003236)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"Blood CK levels were elevated up to 3090 U/L without substantial elevation of aspartate amino transferases (maximal 175 U/L) and alanine amino transferases (maximal 163 U/L), biochemical signs of cholestasis or icterus."
This directly supports elevated circulating creatine kinase in MPDU1-CDG.
Musculoskeletal 1
Generalized hypotonia Generalized hypotonia (HP:0001290)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"Here, we report two MPDU1-CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma."
This disease-specific case report directly lists hypotonia among MPDU1-CDG dystroglycanopathy-overlap features.
Nervous System 2
Global developmental delay Global developmental delay (HP:0001263)
Show evidence (2 references)
PMID:11733556 SUPPORT Human Clinical
"The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision."
The first CDG-If report directly describes severe psychomotor retardation.
PMID:31741824 SUPPORT Human Clinical
"So far, seven MPDU1‐CDG patients have been described. All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis."
This later report summarizes psychomotor retardation across all reported MPDU1-CDG patients at that time.
Seizure Seizure (HP:0001250)
Sequelae: Apnea Respiratory insufficiency
Show evidence (2 references)
PMID:11733556 SUPPORT Human Clinical
"The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision."
The original MPDU1-CDG report directly lists seizures.
PMID:31741824 SUPPORT Human Clinical
"At the age of 2 months, P1 showed tonic‐clonic seizures with multifocal sharp waves on electroencephalography (EEG)."
This case description supports early-onset seizures in MPDU1-CDG.
Respiratory 2
Respiratory insufficiency Respiratory insufficiency (HP:0002093)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"The clinical course was complicated by an increasing frequency and severity of seizures with epileptic apneas followed by respiratory insufficiency."
This directly supports respiratory insufficiency in severe MPDU1-CDG.
Apnea Apnea (HP:0002104)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis."
This directly supports apnea as a recurrent clinical feature of MPDU1-CDG.
Growth 1
Failure to thrive Failure to thrive (HP:0001508)
Show evidence (1 reference)
PMID:11733556 SUPPORT Human Clinical
"The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision."
Failure to thrive is directly reported in the original patient.
Other 3
Buphthalmos Buphthalmos (HP:0000557)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"The ophthalmological examination revealed a buphthalmos with slightly opaque corneae with a diameter of 11 mm and severe congenital glaucoma, requiring prompt trabeculectomy intervention."
This directly supports buphthalmos and severe congenital glaucoma in the second affected sibling.
Glaucoma Primary congenital glaucoma (HP:0008007)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"The megalocorneae possessed a diameter of 13 mm (normal in newborn = 9.5 mm). Further ophthalmologic examination revealed a buphthalmos with congenital glaucoma."
This directly supports congenital glaucoma in an affected MPDU1-CDG patient.
Biliary duct dilatation Abnormal biliary tract morphology (HP:0012440)
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"Abdominal sonography as well as magnetic resonance cholangiopancreatography showed a vast dilatation of the intrahepatic biliary ducts, especially within the left lobe of the liver (Figure 1C)."
This directly supports intrahepatic biliary duct dilatation in an MPDU1-CDG patient.
🧬

Genetic Associations

1
MPDU1 (Loss of function mutation)
Show evidence (2 references)
PMID:11733556 SUPPORT Human Clinical
"The patient has a homozygous point mutation (221T-->C, L74S) in a semiconserved amino acid of MPDU1."
This original report identified a homozygous MPDU1 variant in an affected patient.
PMID:31741824 SUPPORT Human Clinical
"Whole exome sequencing revealed a homozygous missense mutation Chr17(GRCh38): g.7585994G>A; NM_004870.3(MPDU1): c.218G>A; p.(G73E) in both patients."
This report supports MPDU1 as the causal gene and documents a recurrent homozygous missense variant in affected siblings.
💊

Treatments

3
Supportive multidisciplinary care
Action: supportive care MAXO:0000950
No disease-modifying therapy is established for MPDU1-CDG; reported management is supportive, including feeding, respiratory, neurologic, ophthalmologic, and cardiology care as indicated.
Target Phenotypes: Seizure ↗ Respiratory insufficiency ↗ Failure to thrive ↗ Apnea ↗
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"In her short life, the patient did not exhibit any psychomotor development, and had to be fed parenterally or by a gastric tube."
This supports supportive feeding management in a severe MPDU1-CDG case.
Cardiac surveillance
Action: supportive care MAXO:0000950
Because cardiomyopathy is an important CDG phenotype and MPDU1-CDG cases include cardiomyopathy, baseline and longitudinal cardiac surveillance is relevant to MPDU1-CDG care.
Target Phenotypes: Cardiomyopathy ↗
Show evidence (1 reference)
PMID:38917675 PARTIAL Human Clinical
"Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood."
This CDG cardiomyopathy recommendations paper supports cardiac surveillance for CDG patients; the evidence is general CDG guidance rather than MPDU1-specific prospective trial evidence.
Trabeculectomy for congenital glaucoma
Action: trabeculectomy MAXO:0001082
Ophthalmologic surgery may be required for severe congenital glaucoma in MPDU1-CDG.
Target Phenotypes: Primary congenital glaucoma ↗
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"The ophthalmological examination revealed a buphthalmos with slightly opaque corneae with a diameter of 11 mm and severe congenital glaucoma, requiring prompt trabeculectomy intervention."
This directly supports trabeculectomy as a reported ophthalmologic intervention for MPDU1-CDG-associated congenital glaucoma.
🔬

Biochemical Markers

2
CDG-I transferrin pattern (ABNORMAL)
Context: MPDU1-CDG produces a type I carbohydrate-deficient transferrin pattern.
Pathograph Readouts
Readout Of Truncated lipid-linked oligosaccharide accumulation Present Absent Diagnostic
The type I transferrin pattern reports impaired N-glycosylation downstream of incomplete lipid-linked oligosaccharide precursor formation.
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"These revealed reduced tetrasialotransferrin, with increased asialo‐ and disialotransferrin indicative of a CDG‐I (Figure 1D,E)."
This directly supports the abnormal transferrin glycosylation pattern.
Shortened lipid-linked oligosaccharides (ABNORMAL)
Context: Patient fibroblasts accumulate shortened dolichol-linked oligosaccharides, consistent with impaired MPDU1-dependent donor utilization.
Pathograph Readouts
Readout Of MPDU1-dependent dolichol-linked donor utilization defect Positive Diagnostic
Accumulated shortened dolichol-linked oligosaccharides report the MPDU1-dependent defect in donor use within the ER lumen.
Show evidence (2 references)
PMID:31741824 SUPPORT In Vitro
"Increased levels of dolichol‐linked Man5GlcNAc2 and Man9GlcNAc2 accompanied by reduced amounts of Glc3Man9GlcNAc2 were detected (Figure 2A) which indicated shortage of DPM and DPG in the ER lumen."
This directly supports shortened lipid-linked oligosaccharide accumulation in patient fibroblasts.
PMID:11733564 SUPPORT In Vitro
"Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of patients restored normal lipid-linked oligosaccharide biosynthesis."
Rescue by normal Lec35/MPDU1 supports causality of the MPDU1 defect for abnormal lipid-linked oligosaccharide biosynthesis.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from MPDU1-congenital disorder of glycosylation:

DK1-congenital disorder of glycosylation MONDO:0012556
Overlapping Features DOLK-CDG and other DPM synthesis or utilization disorders can overlap with MPDU1-CDG through combined CDG-I and dystroglycanopathy-like features.
Distinguishing Features
  • Molecular testing distinguishes MPDU1 variants from DOLK or DPM pathway defects.
DPM1-congenital disorder of glycosylation Not Yet Curated MONDO:0012123
Overlapping Features DPM1-CDG is a DPM-pathway CDG-I disorder that can overlap with MPDU1-CDG through reduced alpha-dystroglycan O-mannosylation and dystroglycanopathy features.
Distinguishing Features
  • Molecular testing distinguishes MPDU1 variants from DPM1 defects.
DPM2-congenital disorder of glycosylation Not Yet Curated MONDO:0014023
Overlapping Features DPM2-CDG shares the CDG-I and dystroglycanopathy-overlap differential space because DPM2 affects the same dolichol-phosphate-mannose pathway.
Distinguishing Features
  • Molecular testing distinguishes MPDU1 variants from DPM2 defects.
DPM3-congenital disorder of glycosylation Not Yet Curated MONDO:0013049
Overlapping Features DPM3-CDG is another DPM-pathway disorder with CDG-I and dystroglycanopathy-like overlap, including muscle and cardiac involvement.
Distinguishing Features
  • Molecular testing distinguishes MPDU1 variants from DPM3 defects.
{ }

Source YAML

click to show 
name: MPDU1-congenital disorder of glycosylation
creation_date: "2026-05-11T14:53:11Z"
updated_date: "2026-05-18T06:43:07Z"
description: >-
  MPDU1-congenital disorder of glycosylation is an ultra-rare autosomal
  recessive congenital disorder of glycosylation caused by biallelic pathogenic
  variants in MPDU1. MPDU1 deficiency disrupts utilization of
  dolichol-phosphate-linked mannose and glucose donors in the endoplasmic
  reticulum, producing a CDG type I pattern with overlapping
  dystroglycanopathy-like manifestations.
category: Mendelian
parents:
- hereditary disease
synonyms:
- CDG-If
- MPDU1-CDG
- congenital disorder of glycosylation type If
- mannose-P-dolichol utilization defect 1
disease_term:
  preferred_term: MPDU1-congenital disorder of glycosylation
  term:
    id: MONDO:0012211
    label: MPDU1-congenital disorder of glycosylation
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    MPDU1-CDG is caused by biallelic pathogenic MPDU1 variants; reported cases
    include homozygous variants in consanguineous families and compound
    heterozygosity.
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two patients are brother and sister from Iraqi origin. They were the third and fourth child of consanguineous parents (first cousins), and had two healthy sisters (Figure 1A).
    explanation: >-
      The affected siblings from consanguineous parents support autosomal
      recessive inheritance in this MPDU1-CDG family.
  - reference: PMID:11733564
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the Lec35/MPDU1 gene, known to be involved in the use of dolichylphosphomannose and dolichylphosphoglucose, revealed mutations in all three patients.
    explanation: >-
      This original case series identified MPDU1 variants in multiple affected
      patients with CDG-I.
pathophysiology:
- name: MPDU1-dependent dolichol-linked donor utilization defect
  description: >-
    MPDU1 loss impairs use of dolichol-phosphate-mannose and
    dolichol-phosphate-glucose donor substrates required for ER glycosylation
    reactions.
  genes:
  - preferred_term: MPDU1
    term:
      id: hgnc:7207
      label: MPDU1
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation via mannose
    term:
      id: GO:0035269
      label: protein O-linked glycosylation via mannose
  - preferred_term: GPI anchor biosynthetic process
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
  locations:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  chemical_entities:
  - preferred_term: dolichol phosphate mannose
    modifier: ABNORMAL
    term:
      id: CHEBI:17624
      label: dolichyl beta-D-mannosyl phosphate
  - preferred_term: dolichol phosphate glucose
    modifier: ABNORMAL
    term:
      id: CHEBI:15812
      label: dolichyl beta-D-glucosyl phosphate
  evidence:
  - reference: PMID:11733556
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CDG-If is caused by a defect in the gene MPDU1, the human homologue of hamster Lec35, and is the first disorder to affect the use, rather than the biosynthesis, of donor substrates for lipid-linked oligosaccharides.
    explanation: >-
      The original mechanistic report directly places MPDU1 upstream of
      dolichol-linked donor utilization rather than donor synthesis.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mannose-phosphate-dolichol utilization defect 1 (MPDU1) plays a role in the utilization of DPM.
    explanation: >-
      The later clinical report confirms the mechanistic role of MPDU1 in DPM
      utilization.
  downstream:
  - target: Truncated lipid-linked oligosaccharide accumulation
    description: >-
      Impaired donor utilization produces incomplete lipid-linked
      oligosaccharide precursors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11733556
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This leads to the synthesis of incomplete and poorly transferred precursor oligosaccharides lacking both mannose and glucose residues.
      explanation: >-
        The defining MPDU1-CDG report directly links impaired donor utilization
        to synthesis of incomplete lipid-linked oligosaccharide precursors.
- name: Truncated lipid-linked oligosaccharide accumulation
  description: >-
    Patient cells accumulate incomplete lipid-linked oligosaccharides for
    N-linked glycosylation, leading to systemic protein hypoglycosylation.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: N-glycan precursor
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  evidence:
  - reference: PMID:11733564
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      patients' fibroblasts accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation.
    explanation: >-
      This abstract directly supports the biochemical intermediate node in
      patient fibroblasts.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These revealed reduced tetrasialotransferrin, with increased asialo‐ and disialotransferrin indicative of a CDG‐I (Figure 1D,E).
    explanation: >-
      The serum transferrin pattern supports systemic hypoglycosylation in a
      clinical patient sample.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Increased levels of dolichol‐linked Man5GlcNAc2 and Man9GlcNAc2 accompanied by reduced amounts of Glc3Man9GlcNAc2 were detected (Figure 2A) which indicated shortage of DPM and DPG in the ER lumen.
    explanation: >-
      Fibroblast LLO analysis directly supports accumulation of truncated
      dolichol-linked oligosaccharides.
  downstream:
  - target: Reduced alpha-dystroglycan O-mannosylation
    description: >-
      MPDU1-CDG can bridge CDG-I and dystroglycanopathy biology through
      impaired alpha-dystroglycan glycosylation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - shortage of dolichol-phosphate-mannose in the endoplasmic reticulum
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        analyses in fibroblasts showed shortened lipid linked oligosaccharides and DPM, and reduced O-mannosylation of αDG.
      explanation: >-
        Patient fibroblast analyses jointly support shortened lipid-linked
        oligosaccharides, abnormal DPM handling, and reduced alpha-dystroglycan
        O-mannosylation.
  - target: Neurodevelopmental, feeding, and seizure involvement
    description: >-
      Systemic glycosylation failure is associated with severe psychomotor
      impairment, seizures, feeding failure, apnea, and respiratory
      decompensation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:11733556
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision.
      explanation: >-
        The original patient report connects MPDU1-CDG to neurologic,
        feeding/growth, skin, and visual manifestations.
  - target: Craniofacial, sensory, and skin involvement
    description: >-
      Multisystem glycosylation abnormalities are associated with facial
      dysmorphism, sensory involvement, and variable skin disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        So far, seven MPDU1‐CDG patients have been described. All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
      explanation: >-
        The disease-specific report summarizes recurrent craniofacial, eye,
        apnea, and skin findings across known MPDU1-CDG patients.
  - target: Hepatobiliary, renal, and hematologic involvement
    description: >-
      Severe MPDU1-CDG can include biliary-duct dilatation, renal cystic
      changes, thrombocytopenia, and coagulation abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The MPDU1‐CDG siblings shared the following abnormalities: massive dilatation of the intrahepatic biliary duct system, small renal cysts, buphthalmos with glaucoma, DCM, thrombocytopenia, elevated CK, and low ATIII.
      explanation: >-
        This disease-specific summary supports a shared hepatobiliary, renal,
        hematologic, ocular, cardiac, and muscle-injury phenotype in the
        affected siblings.
- name: Reduced alpha-dystroglycan O-mannosylation
  description: >-
    MPDU1-CDG patient fibroblasts can show reduced functional
    alpha-dystroglycan glycosylation, explaining overlap with
    dystroglycanopathy features such as elevated creatine kinase, eye disease,
    and cardiomyopathy.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: protein O-linked glycosylation via mannose
    term:
      id: GO:0035269
      label: protein O-linked glycosylation via mannose
    modifier: DECREASED
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subsequently, we analyzed the O‐mannosylation of αDG in fibroblasts of patient P1 by IIH6 immunolabeling and a LO assay.
    explanation: >-
      This describes direct testing of alpha-dystroglycan O-mannosylation in
      patient fibroblasts.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that the signals for both IIH6 and LO were reduced in patient fibroblasts as compared to the signal of control fibroblasts (Figure 2C), suggesting reduced glycosylation of αDG.
    explanation: >-
      Reduced IIH6 and laminin-overlay signals directly support reduced
      functional alpha-dystroglycan glycosylation.
  downstream:
  - target: Dystroglycanopathy-overlap muscle, eye, and cardiac involvement
    description: >-
      Reduced alpha-dystroglycan O-mannosylation explains the overlap with
      dystroglycanopathy features including muscle injury, cardiomyopathy, and
      congenital eye disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal alpha-dystroglycan glycosylation
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we report two MPDU1-CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma.
      explanation: >-
        The clinical report explicitly frames the muscle, cardiac, and eye
        findings as dystroglycanopathy-overlap features in MPDU1-CDG.
- name: Neurodevelopmental, feeding, and seizure involvement
  description: >-
    Severe MPDU1-CDG causes profound neurodevelopmental impairment with
    seizures, failure to thrive, and seizure-associated apnea or respiratory
    insufficiency in the most severe infantile presentations.
  evidence:
  - reference: PMID:11733556
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision.
    explanation: >-
      The original MPDU1-CDG patient report supports severe psychomotor
      impairment, seizures, failure to thrive, skin disease, and visual
      involvement.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course was complicated by an increasing frequency and severity of seizures with epileptic apneas followed by respiratory insufficiency.
    explanation: >-
      This severe case directly links seizures with epileptic apnea and
      respiratory insufficiency.
  downstream:
  - target: Global developmental delay
    description: >-
      Severe psychomotor impairment is a core neurologic manifestation of
      MPDU1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        So far, seven MPDU1‐CDG patients have been described. All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
      explanation: >-
        Psychomotor retardation in all known patients supports developmental
        delay as a downstream neurologic manifestation.
  - target: Seizure
    description: >-
      Seizures are part of the severe neurologic MPDU1-CDG presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At the age of 2 months, P1 showed tonic‐clonic seizures with multifocal sharp waves on electroencephalography (EEG).
      explanation: >-
        The case report directly supports seizures in MPDU1-CDG.
  - target: Failure to thrive
    description: >-
      Feeding failure and poor growth occur in severe MPDU1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:11733556
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision.
      explanation: >-
        The original report directly lists failure to thrive.
  - target: Apnea
    description: >-
      Apnea is recurrent across reported patients and can occur in association
      with seizures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
      explanation: >-
        This summary supports apnea as a recurrent MPDU1-CDG feature.
- name: Dystroglycanopathy-overlap muscle, eye, and cardiac involvement
  description: >-
    MPDU1-CDG can overlap with dystroglycanopathies through reduced
    alpha-dystroglycan O-mannosylation, producing hypotonia, elevated creatine
    kinase, cardiomyopathy, buphthalmos, and congenital glaucoma.
  biological_processes:
  - preferred_term: protein O-linked glycosylation via mannose
    term:
      id: GO:0035269
      label: protein O-linked glycosylation via mannose
    modifier: DECREASED
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Buphthalmos, glaucoma, DCM, and elevated CK are clinical features that overlap with the disease spectrum of the dystroglycanopathies.
    explanation: >-
      The report explicitly groups these MPDU1-CDG findings with
      dystroglycanopathy-overlap features.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In line with the clinical symptoms overlapping with dystroglycanopathies, we showed reduced O‐mannosylation of αDG in patient fibroblasts.
    explanation: >-
      Patient fibroblast evidence connects the clinical overlap to reduced
      alpha-dystroglycan O-mannosylation.
  downstream:
  - target: Generalized hypotonia
    description: >-
      Hypotonia is reported as part of the MPDU1-CDG dystroglycanopathy-overlap
      phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we report two MPDU1-CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma.
      explanation: >-
        The report directly lists hypotonia among the dystroglycanopathy-overlap
        findings.
  - target: Elevated circulating creatine kinase concentration
    description: >-
      Elevated CK reflects muscle involvement within the dystroglycanopathy
      overlap.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Blood CK levels were elevated up to 3090 U/L without substantial elevation of aspartate amino transferases (maximal 175 U/L) and alanine amino transferases (maximal 163 U/L), biochemical signs of cholestasis or icterus.
      explanation: >-
        This directly supports elevated CK in an affected MPDU1-CDG patient.
  - target: Cardiomyopathy
    description: >-
      Cardiomyopathy overlaps with the alpha-dystroglycan O-mannosylation
      disorder spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal alpha-dystroglycan O-mannosylation
    evidence:
    - reference: PMID:31741824
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hence, the cardiac pathomechanism in MPDU1‐CDG patient 1 could be related to abnormal O‐mannosylation, although studies in heart biopsies are warranted to study this.
      explanation: >-
        The authors propose abnormal O-mannosylation as the likely cardiac
        mechanism while appropriately noting that direct heart-tissue evidence
        remains unavailable.
  - target: Buphthalmos
    description: >-
      Buphthalmos is part of the severe eye involvement overlapping with
      dystroglycanopathy phenotypes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ophthalmological examination revealed a buphthalmos with slightly opaque corneae with a diameter of 11 mm and severe congenital glaucoma, requiring prompt trabeculectomy intervention.
      explanation: >-
        This directly supports buphthalmos with severe congenital glaucoma in
        an affected MPDU1-CDG sibling.
  - target: Glaucoma
    description: >-
      Congenital glaucoma is part of the MPDU1-CDG eye involvement overlapping
      with severe dystroglycanopathy phenotypes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ophthalmological examination revealed a buphthalmos with slightly opaque corneae with a diameter of 11 mm and severe congenital glaucoma, requiring prompt trabeculectomy intervention.
      explanation: >-
        This directly supports severe congenital glaucoma in an affected
        MPDU1-CDG sibling.
- name: Craniofacial, sensory, and skin involvement
  description: >-
    MPDU1-CDG can include craniofacial dysmorphism, eye defects, hearing loss,
    and variable skin involvement such as ichthyosis or erythroderma.
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, seven MPDU1‐CDG patients have been described. All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
    explanation: >-
      This disease-specific summary supports recurrent facial, eye, apnea, and
      skin abnormalities in MPDU1-CDG.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sensorineural hearing loss was identified with brainstem evoked response audiometry (BERA) evaluation.
    explanation: >-
      This directly supports sensory involvement through sensorineural hearing
      loss.
  downstream:
  - target: Abnormal facial shape
    description: >-
      Facial dysmorphism is recurrent in MPDU1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Slight dysmorphic features were noted including a smooth philtrum, retrognathia, low‐set, posterior‐rotated ears, and hypertelorism with megalocorneae (Figure 1B).
      explanation: >-
        This directly supports abnormal facial shape in an affected patient.
  - target: Sensorineural hearing impairment
    description: >-
      Sensorineural hearing loss is reported in severe MPDU1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A sensorineural hearing loss was identified with brainstem evoked response audiometry (BERA) evaluation.
      explanation: >-
        This directly supports hearing impairment in an affected patient.
  - target: Ichthyosis
    description: >-
      Skin abnormalities such as ichthyosis are reported across the MPDU1-CDG
      spectrum, although not in every case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
      explanation: >-
        This supports ichthyosis as a common but variable MPDU1-CDG skin
        feature.
- name: Hepatobiliary, renal, and hematologic involvement
  description: >-
    Severe MPDU1-CDG can present with intrahepatic biliary duct dilatation,
    renal cysts, thrombocytopenia, low antithrombin III, and related coagulation
    abnormalities.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MPDU1‐CDG siblings shared the following abnormalities: massive dilatation of the intrahepatic biliary duct system, small renal cysts, buphthalmos with glaucoma, DCM, thrombocytopenia, elevated CK, and low ATIII.
    explanation: >-
      This summary directly supports hepatobiliary, renal, hematologic,
      cardiac, ocular, and muscle-injury features in the affected siblings.
  downstream:
  - target: Biliary duct dilatation
    description: >-
      Intrahepatic biliary duct dilatation is a reported severe MPDU1-CDG
      manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Abdominal sonography as well as magnetic resonance cholangiopancreatography showed a vast dilatation of the intrahepatic biliary ducts, especially within the left lobe of the liver (Figure 1C).
      explanation: >-
        Imaging directly supports intrahepatic biliary duct dilatation.
  - target: Renal cyst
    description: >-
      Renal cysts are reported in the severe G73E MPDU1-CDG presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, at the age of 7 weeks, small renal cysts were suspected in an ultrasound scan.
      explanation: >-
        This directly supports renal cysts in an affected patient.
  - target: Thrombocytopenia
    description: >-
      Congenital thrombocytopenia occurs with broader coagulation abnormalities
      in severe MPDU1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There was a marked congenital thrombocytopenia (minimal 45 000 platelets/μL), a slightly decreased fibrinogen (minimal 96 mg/dL), and a nonmeasurable antithrombin III (ATIII, <20%).
      explanation: >-
        This directly supports thrombocytopenia and coagulation abnormalities
        in MPDU1-CDG.
phenotypes:
- name: Global developmental delay
  category: Neurologic
  description: >-
    Severe psychomotor and global developmental impairment is a core feature of
    MPDU1-CDG.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:11733556
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision.
    explanation: >-
      The first CDG-If report directly describes severe psychomotor
      retardation.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, seven MPDU1‐CDG patients have been described. All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
    explanation: >-
      This later report summarizes psychomotor retardation across all reported
      MPDU1-CDG patients at that time.
- name: Generalized hypotonia
  category: Neurologic
  description: >-
    Hypotonia is a frequent early neurologic and neuromuscular manifestation.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report two MPDU1-CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma.
    explanation: >-
      This disease-specific case report directly lists hypotonia among
      MPDU1-CDG dystroglycanopathy-overlap features.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures occur in severe MPDU1-CDG and may be associated with apnea and
    respiratory decompensation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:11733556
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision.
    explanation: >-
      The original MPDU1-CDG report directly lists seizures.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 2 months, P1 showed tonic‐clonic seizures with multifocal sharp waves on electroencephalography (EEG).
    explanation: >-
      This case description supports early-onset seizures in MPDU1-CDG.
  sequelae:
  - target: Apnea
    description: >-
      Severe seizures can be accompanied by epileptic apneas in MPDU1-CDG.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - epileptic apnea
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The clinical course was complicated by an increasing frequency and severity of seizures with epileptic apneas followed by respiratory insufficiency.
      explanation: >-
        This directly supports seizure-associated epileptic apneas in a severe
        MPDU1-CDG case.
  - target: Respiratory insufficiency
    description: >-
      Epileptic apneas can be followed by respiratory insufficiency in severe
      MPDU1-CDG.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - epileptic apnea
    evidence:
    - reference: PMID:31741824
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The clinical course was complicated by an increasing frequency and severity of seizures with epileptic apneas followed by respiratory insufficiency.
      explanation: >-
        This directly links worsening seizures, epileptic apneas, and
        respiratory insufficiency.
- name: Failure to thrive
  category: Growth
  description: >-
    Failure to thrive and feeding difficulty can occur in MPDU1-CDG.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:11733556
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision.
    explanation: >-
      Failure to thrive is directly reported in the original patient.
- name: Ichthyosis
  category: Dermatologic
  description: >-
    Dry, scaling skin or ichthyosis is reported in some MPDU1-CDG patients but
    can be absent in the severe siblings described in 2019.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:31741824
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
    explanation: >-
      This supports ichthyosis or related skin abnormalities as common but not
      universal in MPDU1-CDG.
- name: Buphthalmos
  category: Ophthalmologic
  description: >-
    Buphthalmos with congenital glaucoma has been reported in severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Buphthalmos
    term:
      id: HP:0000557
      label: Buphthalmos
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ophthalmological examination revealed a buphthalmos with slightly opaque corneae with a diameter of 11 mm and severe congenital glaucoma, requiring prompt trabeculectomy intervention.
    explanation: >-
      This directly supports buphthalmos and severe congenital glaucoma in the
      second affected sibling.
- name: Glaucoma
  category: Ophthalmologic
  description: >-
    Congenital glaucoma can accompany buphthalmos in MPDU1-CDG.
  phenotype_term:
    preferred_term: Primary congenital glaucoma
    term:
      id: HP:0008007
      label: Primary congenital glaucoma
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The megalocorneae possessed a diameter of 13 mm (normal in newborn = 9.5 mm). Further ophthalmologic examination revealed a buphthalmos with congenital glaucoma.
    explanation: >-
      This directly supports congenital glaucoma in an affected MPDU1-CDG
      patient.
- name: Abnormal facial shape
  category: Craniofacial
  description: >-
    Facial dysmorphism, including smooth philtrum, retrognathia,
    low-set/posterior-rotated ears, and hypertelorism, has been reported in
    severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Slight dysmorphic features were noted including a smooth philtrum, retrognathia, low‐set, posterior‐rotated ears, and hypertelorism with megalocorneae (Figure 1B).
    explanation: >-
      This directly supports facial dysmorphism in an affected MPDU1-CDG
      patient.
- name: Sensorineural hearing impairment
  category: Audiologic
  description: >-
    Sensorineural hearing loss has been reported in severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sensorineural hearing loss was identified with brainstem evoked response audiometry (BERA) evaluation.
    explanation: >-
      This supports hearing impairment identified by BERA in an MPDU1-CDG
      patient.
- name: Cardiomyopathy
  category: Cardiovascular
  description: >-
    MPDU1-CDG can include cardiomyopathy, with dilated cardiomyopathy and
    hypertrophic cardiomyopathy both reported in severe siblings.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Echocardiography detected a dilated aorta ascendens, a transient pulmonary hypertension, and a hypertrophic cardiomyopathy (HCM) at the age of 3 weeks, which developed in combination with an arterial hypertension.
    explanation: >-
      This directly supports hypertrophic cardiomyopathy in one severe
      MPDU1-CDG patient.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 3 months, the patient evolved DCM with low output and a shortening fraction of at least 9%.
    explanation: >-
      This directly supports dilated cardiomyopathy in the affected sister.
- name: Elevated circulating creatine kinase concentration
  category: Musculoskeletal
  description: >-
    Elevated creatine kinase is part of the dystroglycanopathy-overlap phenotype.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Blood CK levels were elevated up to 3090 U/L without substantial elevation of aspartate amino transferases (maximal 175 U/L) and alanine amino transferases (maximal 163 U/L), biochemical signs of cholestasis or icterus.
    explanation: >-
      This directly supports elevated circulating creatine kinase in
      MPDU1-CDG.
- name: Biliary duct dilatation
  category: Gastrointestinal
  description: >-
    Massive intrahepatic biliary duct dilatation has been reported in severe
    MPDU1-CDG.
  phenotype_term:
    preferred_term: Biliary duct dilatation
    term:
      id: HP:0012440
      label: Abnormal biliary tract morphology
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abdominal sonography as well as magnetic resonance cholangiopancreatography showed a vast dilatation of the intrahepatic biliary ducts, especially within the left lobe of the liver (Figure 1C).
    explanation: >-
      This directly supports intrahepatic biliary duct dilatation in an
      MPDU1-CDG patient.
- name: Renal cyst
  category: Renal
  description: >-
    Small renal cysts have been reported in severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, at the age of 7 weeks, small renal cysts were suspected in an ultrasound scan.
    explanation: >-
      This directly supports renal cysts in an affected MPDU1-CDG patient.
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Congenital thrombocytopenia and coagulation abnormalities have been reported
    in severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a marked congenital thrombocytopenia (minimal 45 000 platelets/μL), a slightly decreased fibrinogen (minimal 96 mg/dL), and a nonmeasurable antithrombin III (ATIII, <20%).
    explanation: >-
      This directly supports thrombocytopenia and broader coagulation
      abnormalities in MPDU1-CDG.
- name: Respiratory insufficiency
  category: Respiratory
  description: >-
    Severe apnea and respiratory insufficiency can occur in severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course was complicated by an increasing frequency and severity of seizures with epileptic apneas followed by respiratory insufficiency.
    explanation: >-
      This directly supports respiratory insufficiency in severe MPDU1-CDG.
- name: Apnea
  category: Respiratory
  description: >-
    Apnea is a recurrent respiratory feature and can occur with seizures in
    severe MPDU1-CDG.
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed psychomotor retardation and most patients had hypotonia, facial dysmorphism, eye defects, apnea, and skin abnormalities such as ichthyosis.
    explanation: >-
      This directly supports apnea as a recurrent clinical feature of
      MPDU1-CDG.
genetic:
- name: MPDU1
  association: Loss of function mutation
  gene_term:
    preferred_term: MPDU1
    term:
      id: hgnc:7207
      label: MPDU1
  evidence:
  - reference: PMID:11733556
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has a homozygous point mutation (221T-->C, L74S) in a semiconserved amino acid of MPDU1.
    explanation: >-
      This original report identified a homozygous MPDU1 variant in an affected
      patient.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed a homozygous missense mutation Chr17(GRCh38): g.7585994G>A; NM_004870.3(MPDU1): c.218G>A; p.(G73E) in both patients.
    explanation: >-
      This report supports MPDU1 as the causal gene and documents a recurrent
      homozygous missense variant in affected siblings.
diagnosis:
- name: Transferrin isoform analysis
  description: >-
    Serum transferrin isoelectric focusing or mass spectrometry detects a CDG-I
    pattern with reduced tetrasialotransferrin and increased asialo- and
    disialotransferrin.
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: MAXO:0000006
      label: clinical laboratory procedure
  results: CDG-I transferrin pattern.
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These revealed reduced tetrasialotransferrin, with increased asialo‐ and disialotransferrin indicative of a CDG‐I (Figure 1D,E).
    explanation: >-
      This directly supports transferrin isoform analysis as a diagnostic
      screen for MPDU1-CDG.
  - reference: PMID:28122681
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of transferrin isoforms is applied as a screening test for CDG type I (CDG-I) and type II (CDG-II).
    explanation: >-
      This CDG cohort paper supports transferrin isoform analysis as a general
      CDG screening method.
- name: MPDU1 molecular genetic testing
  description: >-
    Molecular diagnosis is confirmed by identifying biallelic pathogenic MPDU1
    variants using single-gene testing, CDG panels, or exome sequencing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: MPDU1
        term:
          id: hgnc:7207
          label: MPDU1
  results: Biallelic pathogenic MPDU1 variants.
  evidence:
  - reference: PMID:28122681
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all patients, molecular diagnosis was confirmed either by single gene testing, targeted next generation sequencing for CDG genes, or by whole exome sequencing.
    explanation: >-
      This supports molecular confirmation of CDG subtypes, including the
      MPDU1-CDG patient in this non-PMM2 cohort.
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES was also performed of the patients' healthy sisters and parents and confirmed parental segregation of the mutation (Figure 1A).
    explanation: >-
      This supports exome sequencing and segregation analysis for MPDU1-CDG
      diagnosis.
biochemical:
- name: CDG-I transferrin pattern
  presence: ABNORMAL
  context: >-
    MPDU1-CDG produces a type I carbohydrate-deficient transferrin pattern.
  biomarker_term:
    preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
  readouts:
  - target: Truncated lipid-linked oligosaccharide accumulation
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The type I transferrin pattern reports impaired N-glycosylation downstream
      of incomplete lipid-linked oligosaccharide precursor formation.
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These revealed reduced tetrasialotransferrin, with increased asialo‐ and disialotransferrin indicative of a CDG‐I (Figure 1D,E).
    explanation: >-
      This directly supports the abnormal transferrin glycosylation pattern.
- name: Shortened lipid-linked oligosaccharides
  presence: ABNORMAL
  context: >-
    Patient fibroblasts accumulate shortened dolichol-linked oligosaccharides,
    consistent with impaired MPDU1-dependent donor utilization.
  biomarker_term:
    preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
  readouts:
  - target: MPDU1-dependent dolichol-linked donor utilization defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Accumulated shortened dolichol-linked oligosaccharides report the
      MPDU1-dependent defect in donor use within the ER lumen.
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Increased levels of dolichol‐linked Man5GlcNAc2 and Man9GlcNAc2 accompanied by reduced amounts of Glc3Man9GlcNAc2 were detected (Figure 2A) which indicated shortage of DPM and DPG in the ER lumen.
    explanation: >-
      This directly supports shortened lipid-linked oligosaccharide accumulation
      in patient fibroblasts.
  - reference: PMID:11733564
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of patients restored normal lipid-linked oligosaccharide biosynthesis.
    explanation: >-
      Rescue by normal Lec35/MPDU1 supports causality of the MPDU1 defect for
      abnormal lipid-linked oligosaccharide biosynthesis.
treatments:
- name: Supportive multidisciplinary care
  description: >-
    No disease-modifying therapy is established for MPDU1-CDG; reported
    management is supportive, including feeding, respiratory, neurologic,
    ophthalmologic, and cardiology care as indicated.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  - preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In her short life, the patient did not exhibit any psychomotor development, and had to be fed parenterally or by a gastric tube.
    explanation: >-
      This supports supportive feeding management in a severe MPDU1-CDG case.
- name: Cardiac surveillance
  description: >-
    Because cardiomyopathy is an important CDG phenotype and MPDU1-CDG cases
    include cardiomyopathy, baseline and longitudinal cardiac surveillance is
    relevant to MPDU1-CDG care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:38917675
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood.
    explanation: >-
      This CDG cardiomyopathy recommendations paper supports cardiac
      surveillance for CDG patients; the evidence is general CDG guidance rather
      than MPDU1-specific prospective trial evidence.
- name: Trabeculectomy for congenital glaucoma
  description: >-
    Ophthalmologic surgery may be required for severe congenital glaucoma in
    MPDU1-CDG.
  treatment_term:
    preferred_term: trabeculectomy
    term:
      id: MAXO:0001082
      label: trabeculectomy
  target_phenotypes:
  - preferred_term: Primary congenital glaucoma
    term:
      id: HP:0008007
      label: Primary congenital glaucoma
  evidence:
  - reference: PMID:31741824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ophthalmological examination revealed a buphthalmos with slightly opaque corneae with a diameter of 11 mm and severe congenital glaucoma, requiring prompt trabeculectomy intervention.
    explanation: >-
      This directly supports trabeculectomy as a reported ophthalmologic
      intervention for MPDU1-CDG-associated congenital glaucoma.
differential_diagnoses:
- name: DK1-congenital disorder of glycosylation
  disease_term:
    preferred_term: DK1-congenital disorder of glycosylation
    term:
      id: MONDO:0012556
      label: DK1-congenital disorder of glycosylation
  description: >-
    DOLK-CDG and other DPM synthesis or utilization disorders can overlap with
    MPDU1-CDG through combined CDG-I and dystroglycanopathy-like features.
  distinguishing_features:
  - Molecular testing distinguishes MPDU1 variants from DOLK or DPM pathway defects.
- name: DPM1-congenital disorder of glycosylation
  disease_term:
    preferred_term: DPM1-congenital disorder of glycosylation
    term:
      id: MONDO:0012123
      label: congenital disorder of glycosylation type 1E
  description: >-
    DPM1-CDG is a DPM-pathway CDG-I disorder that can overlap with MPDU1-CDG
    through reduced alpha-dystroglycan O-mannosylation and dystroglycanopathy
    features.
  distinguishing_features:
  - Molecular testing distinguishes MPDU1 variants from DPM1 defects.
- name: DPM2-congenital disorder of glycosylation
  disease_term:
    preferred_term: DPM2-congenital disorder of glycosylation
    term:
      id: MONDO:0014023
      label: congenital muscular dystrophy with intellectual disability and severe epilepsy
  description: >-
    DPM2-CDG shares the CDG-I and dystroglycanopathy-overlap differential space
    because DPM2 affects the same dolichol-phosphate-mannose pathway.
  distinguishing_features:
  - Molecular testing distinguishes MPDU1 variants from DPM2 defects.
- name: DPM3-congenital disorder of glycosylation
  disease_term:
    preferred_term: DPM3-congenital disorder of glycosylation
    term:
      id: MONDO:0013049
      label: DPM3-congenital disorder of glycosylation
  description: >-
    DPM3-CDG is another DPM-pathway disorder with CDG-I and
    dystroglycanopathy-like overlap, including muscle and cardiac involvement.
  distinguishing_features:
  - Molecular testing distinguishes MPDU1 variants from DPM3 defects.
clinical_trials: []
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 29 citations 2026-05-11T11:20:39.224732

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: MPDU1-congenital disorder of glycosylation
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on MPDU1-congenital disorder of glycosylation covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

MPDU1-congenital disorder of glycosylation (MPDU1-CDG; historical CDG-If): comprehensive disease characteristics report

Executive summary

MPDU1-congenital disorder of glycosylation is an ultra-rare, autosomal recessive disorder of endoplasmic-reticulum (ER) glycosylation caused by biallelic pathogenic variants in MPDU1 (mannose-P-dolichol utilization defect 1). The central defect is impaired utilization/bioavailability of dolichol-phosphate–linked sugar donors (Dol-P-Man and Dol-P-Glc) required for N-glycosylation, with secondary disruption of other glycosylation-dependent pathways (including α-dystroglycan O-mannosylation and GPI-anchor maturation), producing a multisystem phenotype (neurodevelopmental delay, seizures, hypotonia, skin and ocular disease, hepatic/biliary disease, cardiomyopathy, and hematologic/coagulation abnormalities). Core diagnostic evidence includes a CDG type I transferrin pattern and a characteristic lipid-linked oligosaccharide (LLO) profile with accumulation of truncated intermediates (Man5GlcNAc2 and Man9GlcNAc2). (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8, schenk2003mpdu1mutationsunderlie pages 6-8)

Key identifiers and nomenclature (disease information)

Disease name: MPDU1-congenital disorder of glycosylation (OpenTargets Search: MPDU1-congenital disorder of glycosylation,congenital disorder of glycosylation-MPDU1)

Key identifiers (available from tool-supported sources in this report): - MONDO: MONDO:0012211 (“MPDU1-congenital disorder of glycosylation”) (OpenTargets Search: MPDU1-congenital disorder of glycosylation,congenital disorder of glycosylation-MPDU1)

Historical/alternative names and synonyms (from primary/review literature): - CDG-If / CDG-1f (older CDG nomenclature) (tol2019amutationin pages 6-8, schenk2003mpdu1mutationsunderlie pages 1-2) - mannose-P-dolichol utilization defect 1; MPDU1 is also referred to as the human homolog of hamster Lec35 (haeuptle2009congenitaldisordersof pages 9-10, kranz2001amutationin pages 1-2)

Evidence origin: Most MPDU1-CDG disease knowledge is derived from individual case reports/series and small institutional cohorts rather than large EHR-derived datasets or population registries (tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 10-14).

Important limitation: OMIM/Orphanet/ICD identifiers were not directly retrievable using the available tools in this run; therefore, they are not asserted here.

1) Key concepts and definitions (current understanding)

Congenital disorders of glycosylation (CDG) and “CDG type I pattern”

MPDU1-CDG is classified among disorders of N-glycan assembly/ER glycosylation that typically produce a CDG type I serum transferrin pattern (reflecting under-occupancy of N-glycosylation sites). In the MPDU1 cases described, transferrin analysis showed reduced fully sialylated transferrin and increased asialo-/disialotransferrin. (tol2019amutationin pages 5-6, schenk2003mpdu1mutationsunderlie pages 5-6)

MPDU1 function and the dolichol-linked donor concept

MPDU1 encodes an ER membrane protein required for efficient utilization (bioavailability/presentation) of the lipid-linked monosaccharide donors dolichol-P-mannose (Dol-P-Man) and dolichol-P-glucose (Dol-P-Glc) in the ER. Evidence from patient cells and complementation experiments supports a role in lateral distribution/chaperoning of dolichol-linked donors rather than a simple “flippase” that translocates them across the ER membrane. (schenk2003mpdu1mutationsunderlie pages 6-8, kranz2001amutationin pages 5-7, kranz2001amutationin pages 1-2)

2) Etiology (causal factors, risk/protective factors, GxE)

Disease causal factors

  • Genetic etiology: biallelic pathogenic variants in MPDU1 cause MPDU1-CDG. The earliest definitive causal demonstrations used patient fibroblasts showing abnormal LLO profiles and functional rescue after expression of wild-type MPDU1/Lec35 cDNA. (schenk2003mpdu1mutationsunderlie pages 6-8, schenk2003mpdu1mutationsunderlie pages 1-2)

Inheritance and risk factors

  • Autosomal recessive inheritance is supported by homozygous affected individuals with heterozygous parents, and by compound heterozygosity in some reported families. (kranz2001amutationin pages 5-7, schenk2003mpdu1mutationsunderlie pages 5-6)
  • Consanguinity is reported in at least one family with homozygous p.G73E. (tol2019amutationin pages 1-2)

Protective factors and gene–environment interactions

No validated protective genetic variants, environmental protective factors, or gene–environment interactions specific to MPDU1-CDG were identified in the retrieved evidence. Given the Mendelian mechanism, environmental modifiers are plausible but currently undocumented for MPDU1-CDG in the sources available here.

3) Phenotypes (clinical spectrum; HPO suggestions; frequency where available)

Overview of clinical phenotype

Across reported MPDU1-CDG patients, commonly described features include neurodevelopmental impairment and seizures, hypotonia, dermatologic abnormalities (ichthyosis/scaling; variably present), ocular anomalies (including congenital glaucoma/buphthalmos), hepatic/biliary involvement (including massive biliary duct dilatation in some), cardiomyopathy, thrombocytopenia/coagulation abnormalities, and elevated creatine kinase. (tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 10-14)

A notable 2019 report explicitly highlights overlap with dystroglycanopathy. Direct abstract quote: “Here, we report two MPDU1‐CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma.” (van Tol et al., 2019; published Sep 2019; https://doi.org/10.1002/jmd2.12060) (tol2019amutationin pages 1-2)

Phenotype-by-phenotype with ontology suggestions

Below are representative phenotype categories; reported frequencies are limited because case counts are small.

1) Neurodevelopmental delay / psychomotor retardation - Type: symptom/clinical sign - Onset: typically infancy/early childhood in reported cases - Suggested HPO: HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability) - Evidence: psychomotor retardation/delay repeatedly noted in early and later case descriptions. (haeuptle2009congenitaldisordersof pages 9-10, kranz2001amutationin pages 1-2)

2) Seizures / epilepsy; apnea with seizures - Type: symptom - Suggested HPO: HP:0001250 (Seizures), HP:0002104 (Apnea) - Course: can be severe; seizure-induced apnea contributed to death in at least one early case. (haeuptle2009congenitaldisordersof pages 9-10, kranz2001amutationin pages 1-2)

3) Hypotonia and neuromuscular involvement - Type: clinical sign - Suggested HPO: HP:0001252 (Hypotonia) - Evidence: hypotonia is common; dystroglycanopathy overlap suggests muscle involvement in some cases. (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8)

4) Skin involvement (ichthyosis/scaling/erythroderma/desquamation) - Type: physical manifestation - Suggested HPO: HP:0008064 (Ichthyosis), HP:0000964 (Eczema) (if applicable), HP:0000988 (Skin rash) - Variability: may be absent in some MPDU1-CDG patients. (tol2019amutationin pages 1-2, teneiji2017phenotypicandgenotypic pages 10-14, kranz2001amutationin pages 1-2)

5) Ocular disease (buphthalmos, congenital glaucoma, corneal clouding, visual impairment/amaurosis) - Type: physical manifestation - Suggested HPO: HP:0007721 (Congenital glaucoma), HP:0000613 (Buphthalmos), HP:0000518 (Visual impairment) - Clinical importance: severe congenital glaucoma may require urgent intervention (trabeculectomy noted in compiled case summaries). (tol2019amutationin pages 6-8)

6) Cardiac involvement (cardiomyopathy) - Type: clinical sign - Suggested HPO: HP:0001638 (Cardiomyopathy), HP:0001644 (Dilated cardiomyopathy), HP:0001639 (Hypertrophic cardiomyopathy) - Evidence: cardiomyopathy present in multiple MPDU1-CDG cases; MPDU1 is also listed among CDG genes associated with cardiomyopathy in 2024 screening recommendations. (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, zemet2024cardiomyopathyanuncommon pages 3-5)

7) Hepatic/biliary involvement - Type: clinical sign / imaging abnormality - Suggested HPO: HP:0001392 (Hepatomegaly) (if present), HP:0003270 (Abnormality of the biliary tract), HP:0002240 (Hepatic dysfunction) - Evidence: hepatocellular/synthetic dysfunction noted in a cohort case; biliary duct dilatation emphasized in the 2019 siblings. (tol2019amutationin pages 1-2, teneiji2017phenotypicandgenotypic pages 10-14)

8) Hematologic/coagulation abnormalities - Type: laboratory abnormality - Suggested HPO: HP:0001873 (Thrombocytopenia), HP:0001928 (Coagulopathy) - Evidence: thrombocytopenia and low antithrombin III reported. (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8)

Quality-of-life impact

No MPDU1-CDG–specific quality-of-life instruments (e.g., EQ-5D/SF-36) were found in the retrieved evidence. However, severe neurodevelopmental impairment, feeding dependence, seizures, visual disability, and cardiomyopathy imply substantial functional limitation. (tol2019amutationin pages 5-6, kranz2001amutationin pages 1-2)

4) Genetic and molecular information

Causal gene

  • Gene: MPDU1 (mannose-P-dolichol utilization defect 1) (haeuptle2009congenitaldisordersof pages 9-10)
  • Protein features (as summarized in reviewed evidence): ER membrane protein; reviews describe multiple transmembrane domains and ER localization. (haeuptle2009congenitaldisordersof pages 9-10)

Pathogenic variants (examples explicitly captured in the retrieved evidence)

  • c.218G>A (p.G73E) (recurrent; associated with severe early-lethal disease in multiple reported cases) (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, schenk2003mpdu1mutationsunderlie pages 5-6)
  • 221T>C (p.L74S) (homozygous in the initial 2001 JCI patient; parental heterozygosity shown) (kranz2001amutationin pages 5-7, kranz2001amutationin pages 1-2)
  • c.356T>C (p.L119P) (homozygous in one of the 2003 JCI patients) (schenk2003mpdu1mutationsunderlie pages 5-6)
  • 2T>C (p.M1T) and c.511delC (frameshift) (compound heterozygosity in one 2003 JCI patient) (schenk2003mpdu1mutationsunderlie pages 5-6)
  • Additional missense variants reported in an Arab molecularly characterized summary: p.Gly104Ser and p.Gln126Pro (bastaki2018single‐centerexperienceof pages 8-10)

Variant types observed: primarily missense; at least one frameshift (c.511delC) and start-loss (p.M1T) are reported. (schenk2003mpdu1mutationsunderlie pages 5-6)

Allele frequencies in population databases: not available in the retrieved evidence; therefore not asserted.

Functional consequences

Collectively, patient-cell studies indicate the molecular defect leads to impaired use of Dol-P-Man and Dol-P-Glc, causing truncated LLO assembly and downstream protein hypoglycosylation; a 2003 mechanistic proposal is that MPDU1 acts as a dolichol-sugar “chaperone” supporting lateral distribution of dolichol-linked donors in the ER membrane. (schenk2003mpdu1mutationsunderlie pages 6-8, kranz2001amutationin pages 1-2)

Modifier genes

No MPDU1-CDG–specific modifier genes were identified in the retrieved evidence. One broader glycosylation modifier discussion exists in other contexts (e.g., ALG6 F304S modifying DHDDS-related disease), but this is not specific to MPDU1-CDG pathogenesis. (hamzan2023epidemiologyandprevalence pages 5-7)

5) Environmental information

No environmental toxins, lifestyle exposures, or infectious triggers are established contributors to MPDU1-CDG in the retrieved evidence (consistent with a primary Mendelian etiology).

6) Mechanism / pathophysiology

Causal chain (from gene to clinical phenotype)

1) Biallelic MPDU1 variants → MPDU1 loss/dysfunction in the ER membrane (kranz2001amutationin pages 5-7, schenk2003mpdu1mutationsunderlie pages 5-6) 2) Impaired utilization/bioavailability of Dol-P-Man and Dol-P-Glc needed by ER mannosyl-/glucosyltransferases (schenk2003mpdu1mutationsunderlie pages 6-8, kranz2001amutationin pages 1-2) 3) Characteristic LLO assembly defect with accumulation of truncated dolichol-PP-linked intermediates (notably Man5GlcNAc2 and Man9GlcNAc2) and reduced/aberrant mature Glc3Man9GlcNAc2; incomplete oligosaccharides can be transferred to proteins (schenk2003mpdu1mutationsunderlie pages 6-8, schenk2003mpdu1mutationsunderlie pages 1-2, tol2019amutationin media 2abc4e54) 4) Systemic glycoprotein hypoglycosylation, detectable via serum transferrin isoform analysis (CDG-I pattern) (schenk2003mpdu1mutationsunderlie pages 5-6, tol2019amutationin media 2abc4e54) 5) Multi-pathway downstream effects, including reduced O-mannosylation of α-dystroglycan (explaining dystroglycanopathy overlap) and impaired GPI-anchor maturation (reduced surface CD59) (tol2019amutationin pages 6-8, schenk2003mpdu1mutationsunderlie pages 6-8) 6) Organ dysfunction (neurodevelopmental delay/seizures, ocular disease, skin barrier defects/ichthyosis in many, cardiac and hepatobiliary manifestations) (tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 10-14)

Molecular pathways/processes and ontology suggestions

  • N-linked glycosylation (ER LLO assembly and transfer)
  • Suggested GO Biological Process: GO:0006487 (protein N-linked glycosylation)
  • Suggested GO Cellular Component: GO:0005783 (endoplasmic reticulum)

  • Evidence: truncated LLO intermediates and hypoglycosylated serum transferrin; rescue by wild-type MPDU1. (schenk2003mpdu1mutationsunderlie pages 6-8, schenk2003mpdu1mutationsunderlie pages 1-2)

  • Dolichol-linked monosaccharide utilization

  • Suggested GO BP (closest plausible): GO:0019673 (dolichol-linked oligosaccharide biosynthetic process) / GO:0019358 (dolichol biosynthetic process) (note: MPDU1 affects utilization rather than synthesis)

  • Evidence: Dol-P-Man/Dol-P-Glc present but not efficiently used; proposed lateral distribution mechanism. (schenk2003mpdu1mutationsunderlie pages 6-8)

  • O-mannosylation of α-dystroglycan (dystroglycanopathy overlap)

  • Suggested GO BP: GO:0035269 (protein O-linked mannosylation)

  • Evidence: reduced IIH6/laminin overlay binding indicating reduced functional glycosylation of α-dystroglycan. (tol2019amutationin pages 6-8)

  • GPI-anchor biosynthesis (secondary)

  • Suggested GO BP: GO:0006506 (GPI anchor biosynthetic process)
  • Evidence: reduced cell-surface GPI-anchored CD59 in patient cells. (schenk2003mpdu1mutationsunderlie pages 6-8)

Cell types (CL suggestions)

Direct cell-type-specific pathology is not well established in the retrieved evidence. However, based on organ involvement: - Suggested CL: CL:0000540 (neuron), CL:0000746 (cardiomyocyte), CL:0000548 (hepatocyte), CL:0000333 (fibroblast) (the main experimental patient cell type used). (tol2019amutationin pages 5-6, schenk2003mpdu1mutationsunderlie pages 6-8)

7) Anatomical structures affected (UBERON suggestions)

Evidence supports multisystem involvement: - Nervous system: UBERON:0001016 (nervous system) (seizures, neurodevelopmental delay) (kranz2001amutationin pages 1-2) - Eye: UBERON:0000970 (eye) (congenital glaucoma, buphthalmos, visual impairment) (tol2019amutationin pages 6-8) - Skin: UBERON:0002097 (skin of body) (ichthyosis/scaling) (teneiji2017phenotypicandgenotypic pages 10-14, kranz2001amutationin pages 1-2) - Heart: UBERON:0000948 (heart) (cardiomyopathy) (tol2019amutationin pages 5-6) - Liver/biliary system: UBERON:0002107 (liver); UBERON:0000059 (bile duct) (liver dysfunction; biliary duct dilatation) (tol2019amutationin pages 1-2, teneiji2017phenotypicandgenotypic pages 10-14)

Subcellular localization emphasized in mechanism: - Endoplasmic reticulum membrane (GO CC: ER membrane; MPDU1 is an ER membrane protein). (haeuptle2009congenitaldisordersof pages 9-10, kranz2001amutationin pages 1-2)

8) Temporal development

  • Typical onset: congenital/infantile presentation is most consistent with reported cases (severe multisystem disease in infancy; early deaths in severe genotypes). (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8)
  • Progression/course: variable; p.G73E has been repeatedly associated with very severe early-lethal disease, while other alleles show mild-to-moderate disease in earlier series. (tol2019amutationin pages 6-8, haeuptle2009congenitaldisordersof pages 9-10)

9) Inheritance and population

Inheritance

Autosomal recessive inheritance is supported by segregation in families and by homozygous/compound heterozygous genotypes in affected individuals. (tol2019amutationin pages 5-6, kranz2001amutationin pages 5-7, schenk2003mpdu1mutationsunderlie pages 5-6)

Epidemiology

No MPDU1-specific population prevalence/incidence estimate was identified in the retrieved evidence (typical for ultra-rare CDGs). For contextual, country-level CDG screening prevalence: - A 2018–2022 Malaysian national reference-lab dataset identified 2 confirmed CDG diagnoses among 548 suspected cases, yielding a calculated birth prevalence of 0.22 per 100,000 live births for CDG overall (not MPDU1-specific), and 0.85 per 100,000 for combined abnormal transferrin patterns. (Hamzan 2023; published Apr 2023; https://doi.org/10.37231/ajmb.2023.7.1.601) (hamzan2023epidemiologyandprevalence pages 1-3, hamzan2023epidemiologyandprevalence pages 3-5) - Direct abstract quote: “Overall, the prevalence of CDG in Malaysia was low and may be underestimated yet consistent with other reported in other countries.” (hamzan2023epidemiologyandprevalence pages 1-3)

Population/variant observations

  • Recurrent p.G73E (c.218G>A) appears in multiple unrelated MPDU1-CDG patients and is repeatedly associated with severe early-lethal disease, suggesting either a recurrent mutational hotspot or possible population recurrence; detailed founder analysis was not available in retrieved evidence. (tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 33-37)
  • Consanguinity is reported in at least one affected family with p.G73E. (tol2019amutationin pages 1-2)

10) Diagnostics

Clinical suspicion

Patients may present with a CDG-like multisystem phenotype (neurodevelopmental delay, seizures, hypotonia, failure to thrive, skin/eye disease, hepatic/biliary abnormalities) and/or dystroglycanopathy features (myopathy, elevated CK, cardiomyopathy), prompting biochemical and genetic testing. (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8)

Biochemical testing (real-world implementation)

1) Serum transferrin isoform analysis - Methods used: transferrin isoelectric focusing (TIEF/IEF), sometimes quantified by HPLC-based approaches; CDG-I pattern reported in MPDU1-CDG including increased disialotransferrin and reduced tetrasialotransferrin. (tol2019amutationin pages 5-6, teneiji2017phenotypicandgenotypic pages 10-14, teneiji2017phenotypicandgenotypic pages 6-10) - Figure-based evidence: TIEF pattern is shown in van Tol et al. 2019 (Figure 1D). (tol2019amutationin media 2abc4e54)

2) Lipid-linked oligosaccharide (LLO) profiling in patient fibroblasts - Methods: HPLC analysis of LLOs; thin-layer chromatography (TLC) for hydrophobic extracts including Dol-P-Man/Dol-P-Glc-related measures. (tol2019amutationin pages 5-6, tol2019amutationin pages 1-2) - Figure-based evidence: LLO HPLC profile is shown in van Tol et al. 2019 (Figure 2A). (tol2019amutationin media 2abc4e54)

3) Functional glycosylation of α-dystroglycan - Methods: IIH6 immunolabeling and laminin overlay assays in fibroblasts to show reduced O-mannosylation/functional glycosylation of α-dystroglycan. (tol2019amutationin pages 6-8)

Genetic testing

  • Approaches in published cohorts/cases include single-gene testing, targeted next-generation sequencing panels for CDG genes, and whole-exome sequencing (WES) with segregation analysis. (tol2019amutationin pages 5-6, teneiji2017phenotypicandgenotypic pages 6-10)

Differential diagnosis

MPDU1-CDG can overlap clinically and biochemically with other CDG type I conditions and with dystroglycanopathies due to DPM synthesis/utilization defects (e.g., DOLK-, DPM1/2/3-related disorders). (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8)

Screening

There is no evidence in retrieved sources that MPDU1-CDG is included in routine newborn screening panels. Population screening for CDG more broadly often uses transferrin isoform analysis (IEF/CZE/HPLC), but sensitivity varies by subtype; genetic testing is increasingly used for definitive diagnosis. (teneiji2017phenotypicandgenotypic pages 6-10, hamzan2023epidemiologyandprevalence pages 3-5)

11) Outcome / prognosis

Prognosis is highly variable. Severe disease with early infant death has been repeatedly described in p.G73E homozygous patients (deaths reported within the first year of life in some cases). (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8)

A review of dolichol-linked oligosaccharide disorders notes variable severity and reports one patient dying in early childhood following seizure-induced apnea, while others had milder disease. (haeuptle2009congenitaldisordersof pages 9-10)

12) Treatment and management

Disease-modifying therapy

No established disease-specific or pathway-targeted therapy for MPDU1-CDG was identified in the retrieved evidence; management is therefore primarily supportive. (tol2019amutationin pages 6-8)

Supportive and multidisciplinary care (current real-world implementations)

Care is typically individualized and may include: - Neurology: antiseizure management; monitoring for apnea/respiratory complications (MAXO suggestions: antiseizure therapy; respiratory support). (tol2019amutationin pages 5-6, kranz2001amutationin pages 1-2) - Nutrition/feeding: feeding support including tube feeding when required (MAXO: enteral nutrition). (tol2019amutationin pages 5-6) - Ophthalmology: early evaluation and management of congenital glaucoma (e.g., surgical intervention reported in compiled cases) (MAXO: glaucoma surgery; vision rehabilitation). (tol2019amutationin pages 6-8) - Cardiology: surveillance and management of cardiomyopathy/heart failure where present (MAXO: cardiac monitoring; heart failure pharmacotherapy). (tol2019amutationin pages 5-6, zemet2024cardiomyopathyanuncommon pages 3-5) - Hepatology/Gastroenterology: evaluation of hepatocellular dysfunction and biliary tract abnormalities. (tol2019amutationin pages 1-2, teneiji2017phenotypicandgenotypic pages 10-14) - Hematology: monitoring thrombocytopenia and coagulation factors such as antithrombin III. (tol2019amutationin pages 5-6)

2024 expert recommendations relevant to MPDU1-CDG (cardiac screening)

A 2024 expert recommendations paper on cardiomyopathy in CDG lists MPDU1 among CDG genes associated with cardiomyopathy and proposes baseline and longitudinal cardiac surveillance for CDG patients: echocardiogram and ECG at diagnosis, annual follow-up for the first 5 years, then every 2–3 years until adulthood if stable, and approximately every 5 years thereafter. (Zemet et al., Aug 2024; https://doi.org/10.1016/j.ymgme.2024.108513) (zemet2024cardiomyopathyanuncommon pages 3-5, zemet2024cardiomyopathyanuncommon pages 1-3)

13) Prevention

Primary prevention of MPDU1-CDG is not currently feasible outside genetic strategies. Secondary/tertiary prevention focuses on early diagnosis and proactive management of organ complications.

  • Genetic counseling (primary prevention at family level): because inheritance is autosomal recessive, carrier testing in parents and at-risk relatives, reproductive counseling, and options such as prenatal diagnosis or preimplantation genetic testing are conceptually applicable (not directly evidenced in retrieved texts, but consistent with AR inheritance demonstrated in primary reports). (kranz2001amutationin pages 5-7)

14) Other species / natural disease

No naturally occurring animal disease analogs were identified in the retrieved evidence.

15) Model organisms and experimental systems

Although whole-animal disease models were not retrieved here, multiple experimental systems directly support MPDU1 biology: - Hamster CHO cell (Lec35) complementation system: MPDU1 is orthologous to hamster Lec35; patient alleles show impaired correction of the Lec35 phenotype compared with wild-type MPDU1, supporting functional impact of human variants. (kranz2001amutationin pages 5-7, kranz2001amutationin pages 1-2) - Patient fibroblast rescue experiments: expression of normal Lec35/MPDU1 cDNA restored normal LLO biosynthesis in patient fibroblasts, providing strong functional causality evidence. (schenk2003mpdu1mutationsunderlie pages 6-8)

Recent developments and “latest research” emphasis (2023–2024)

Because MPDU1-CDG is extremely rare, MPDU1-specific 2023–2024 primary case reports were not retrievable within the available tool outputs in this run. However, important 2023–2024 developments relevant to MPDU1-CDG clinical practice include: 1) 2024 cardiomyopathy surveillance recommendations in CDG (gene list includes MPDU1; provides longitudinal screening schedule). (zemet2024cardiomyopathyanuncommon pages 3-5, zemet2024cardiomyopathyanuncommon pages 1-3) 2) ClinicalTrials.gov natural history infrastructure (NCT04199000) explicitly includes MPDU1 in the targeted CDG spectrum and collects standardized clinical severity measures and biospecimens for biomarker research. (Study posted 2019; recruiting; https://clinicaltrials.gov/study/NCT04199000) (NCT04199000 chunk 1) 3) 2023 national reference-lab epidemiology data illustrating how transferrin-based screening is implemented at scale and how prevalence estimates may be derived (though not MPDU1-specific). (hamzan2023epidemiologyandprevalence pages 1-3, hamzan2023epidemiologyandprevalence pages 3-5)

Key statistics and data points (from retrieved evidence)

  • In a CDG natural history cohort (FCDGC) of 305 molecularly confirmed CDG patients (as of June 2023), 17 (5.6%) had cardiomyopathy; MPDU1-CDG was not among the cardiomyopathy genotypes identified in that cohort subset, but MPDU1 is included among CDG genes reported with cardiomyopathy in the literature. (zemet2024cardiomyopathyanuncommon pages 5-6, zemet2024cardiomyopathyanuncommon pages 3-5)
  • Malaysian screening-based birth prevalence estimates for CDG overall: 0.22 per 100,000 live births (CDG overall) and 0.85 per 100,000 live births (abnormal transferrin patterns), based on 2018–2022 reference-lab data. (hamzan2023epidemiologyandprevalence pages 1-3, hamzan2023epidemiologyandprevalence pages 3-5)

Curated quick-reference table (variants/phenotypes/diagnostics/management)

Category Summary
Disease / names MPDU1-congenital disorder of glycosylation; historical names: CDG-If, MPDU1-CDG, mannose-P-dolichol utilization defect 1; MONDO: MONDO:0012211 (Open Targets disease association) (OpenTargets Search: MPDU1-congenital disorder of glycosylation,congenital disorder of glycosylation-MPDU1, haeuptle2009congenitaldisordersof pages 9-10, schenk2003mpdu1mutationsunderlie pages 1-2)
Evidence base Ultra-rare, disease-level knowledge is derived primarily from individual case reports/series and small CDG cohorts rather than large epidemiologic datasets (tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 10-14, hamzan2023epidemiologyandprevalence pages 1-3)
Inheritance Autosomal recessive; homozygous and compound-heterozygous MPDU1 variants reported, with parental heterozygosity/segregation shown in key families (tol2019amutationin pages 5-6, kranz2001amutationin pages 5-7, schenk2003mpdu1mutationsunderlie pages 5-6)
Causal gene MPDU1 encodes an ER membrane protein required for efficient utilization/lateral distribution of dolichol-P-mannose (Dol-P-Man) and dolichol-P-glucose (Dol-P-Glc) during glycosylation; orthologous to hamster Lec35 (haeuptle2009congenitaldisordersof pages 9-10, schenk2003mpdu1mutationsunderlie pages 6-8, kranz2001amutationin pages 1-2)
Key reported variants c.218G>A (p.G73E) recurrent severe variant; 221T>C (p.L74S); c.356T>C (p.L119P); 2T>C (p.M1T); c.511delC frameshift; additional reported missense variants p.Gly104Ser and p.Gln126Pro in Arab summary literature (tol2019amutationin pages 5-6, teneiji2017phenotypicandgenotypic pages 33-37, kranz2001amutationin pages 5-7, schenk2003mpdu1mutationsunderlie pages 5-6, bastaki2018single‐centerexperienceof pages 8-10)
Core neurologic features Psychomotor/neurodevelopmental delay or retardation, severe hypotonia, seizures/epilepsy, failure to thrive, apnea/respiratory compromise in severe cases (tol2019amutationin pages 6-8, haeuptle2009congenitaldisordersof pages 9-10, kranz2001amutationin pages 1-2)
Skin features Ichthyosis, dry skin with scaling/erythroderma, patchy desquamation; skin involvement is variable and may be absent in some newer cases (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 10-14, schenk2003mpdu1mutationsunderlie pages 5-6, kranz2001amutationin pages 1-2)
Eye features Visual impairment/amaurosis, enlarged cloudy corneae, buphthalmos, congenital glaucoma, other eye defects; glaucoma may require urgent ophthalmologic intervention (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, haeuptle2009congenitaldisordersof pages 9-10)
Cardiac features Cardiomyopathy reported, including dilated cardiomyopathy and hypertrophic cardiomyopathy; MPDU1 is listed among CDG genes associated with cardiomyopathy in recent cardiac review/guidance (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, zemet2024cardiomyopathyanuncommon pages 3-5)
Hepatic / biliary features Hepatocellular/synthetic liver dysfunction, increased liver echogenicity, and striking biliary duct dilatation in some cases (tol2019amutationin pages 1-2, teneiji2017phenotypicandgenotypic pages 10-14)
Hematologic / coagulation features Thrombocytopenia, low antithrombin III, and coagulation abnormalities have been documented (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8)
Additional organ involvement Gastrointestinal problems, feeding dependence, small renal cysts, facial dysmorphism, elevated CK, pulmonary hypertension, VSD in some patients (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 10-14, haeuptle2009congenitaldisordersof pages 9-10)
Biochemical hallmark: transferrin CDG-I transferrin pattern with hypoglycosylated serum transferrin; increased asialo-/disialotransferrin and reduced tetrasialotransferrin reported by TIEF/IEF and confirmed by ESI-MS in some patients (tol2019amutationin pages 5-6, teneiji2017phenotypicandgenotypic pages 10-14, schenk2003mpdu1mutationsunderlie pages 1-2, schenk2003mpdu1mutationsunderlie pages 5-6, tol2019amutationin media 2abc4e54)
Biochemical hallmark: LLO profile Accumulation of truncated lipid-linked oligosaccharides (LLOs), especially Man5GlcNAc2 and Man9GlcNAc2; mature Glc3Man9GlcNAc2 reduced/abnormal; incomplete oligosaccharides can be transferred to protein (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, haeuptle2009congenitaldisordersof pages 9-10, schenk2003mpdu1mutationsunderlie pages 6-8, schenk2003mpdu1mutationsunderlie pages 1-2, tol2019amutationin media 2abc4e54)
Functional defect Impaired utilization rather than synthesis of Dol-P-Man and Dol-P-Glc; MPDU1 is proposed to act as a dolichol-sugar chaperone/lateral distributor in the ER rather than a simple flippase (haeuptle2009congenitaldisordersof pages 9-10, schenk2003mpdu1mutationsunderlie pages 6-8, kranz2001amutationin pages 5-7, kranz2001amutationin pages 1-2)
Other pathway effects Reduced O-mannosylation of α-dystroglycan (dystroglycanopathy overlap) and reduced cell-surface GPI-anchored CD59 have been shown in patient cells (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8, schenk2003mpdu1mutationsunderlie pages 6-8)
Diagnostic modalities Serum TIEF/IEF ± HPLC/CZE screening; ESI-MS transferrin analysis; fibroblast LLO HPLC/TLC; WES or targeted NGS; segregation analysis; functional complementation in fibroblasts/CHO cells; IIH6 immunolabeling/laminin overlay for α-dystroglycan (tol2019amutationin pages 5-6, tol2019amutationin pages 1-2, tol2019amutationin pages 6-8, teneiji2017phenotypicandgenotypic pages 33-37, kranz2001amutationin pages 5-7, tol2019amutationin media 2abc4e54, hamzan2023epidemiologyandprevalence pages 3-5)
Differential diagnostic context Overlaps biochemically with other CDG-I defects and clinically with dystroglycanopathies, especially disorders affecting DPM synthesis/utilization (e.g., DOLK/DPM pathway disorders) (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8)
Outcomes / prognosis Prognosis is variable but often severe; recurrent p.G73E is associated with particularly severe disease and early infant death (reported deaths before ~11 months in some cases); one earlier patient died in early childhood following seizure-induced apnea (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8, haeuptle2009congenitaldisordersof pages 9-10)
Management No disease-modifying therapy established; current care is supportive and multidisciplinary: nutritional/feeding support, seizure management, ophthalmologic care, cardiology, hepatology, and coagulation monitoring as indicated (tol2019amutationin pages 5-6, tol2019amutationin pages 6-8)
Cardiac surveillance suggestion Because MPDU1 is among CDG types linked to cardiomyopathy, recent CDG guidance recommends baseline ECG + echocardiogram at diagnosis, annual cardiac follow-up for the first 5 years, then every 2–3 years until adulthood if stable, and about every 5 years thereafter; ongoing cardiology care if cardiomyopathy is present (zemet2024cardiomyopathyanuncommon pages 3-5, zemet2024cardiomyopathyanuncommon pages 1-3)
Current research / implementation MPDU1-CDG is included within the Frontiers in CDG Consortium natural history infrastructure and the observational study NCT04199000, which collects longitudinal clinical data and biospecimens across molecularly confirmed CDG subtypes (NCT04199000 chunk 1, zemet2024cardiomyopathyanuncommon pages 3-5, zemet2024cardiomyopathyanuncommon pages 1-3)

Table: This table condenses the main disease-defining, molecular, clinical, biochemical, diagnostic, prognostic, and management facts for MPDU1-congenital disorder of glycosylation. It is designed as a quick-reference artifact for knowledge-base curation and evidence tracing.

Figure/table evidence extracted from primary literature

  • Transferrin IEF and LLO profiling figures and a multi-patient clinical feature table are available in the van Tol et al. 2019 report, supporting key biochemical hallmarks and clinical comparisons. (tol2019amutationin media 2abc4e54, tol2019amutationin media 23fb2f88, tol2019amutationin media 7782a19e, tol2019amutationin media 364fb774)

References (URLs and publication dates where available)

  • Kranz C, et al. The Journal of Clinical Investigation (Dec 2001). https://doi.org/10.1172/jci13635 (kranz2001amutationin pages 1-2, kranz2001amutationin pages 5-7)
  • Schenk B, et al. Journal of Clinical Investigation (Mar 2003). https://doi.org/10.1172/jci200113419c (schenk2003mpdu1mutationsunderlie pages 1-2, schenk2003mpdu1mutationsunderlie pages 5-6, schenk2003mpdu1mutationsunderlie pages 6-8)
  • van Tol W, et al. JIMD Reports (Sep 2019). https://doi.org/10.1002/jmd2.12060 (tol2019amutationin pages 1-2, tol2019amutationin pages 6-8)
  • Hamzan NI. Asian Journal of Medicine and Biomedicine (Apr 2023). https://doi.org/10.37231/ajmb.2023.7.1.601 (hamzan2023epidemiologyandprevalence pages 1-3)
  • Zemet R, et al. Molecular Genetics and Metabolism (Aug 2024). https://doi.org/10.1016/j.ymgme.2024.108513 (zemet2024cardiomyopathyanuncommon pages 3-5)
  • ClinicalTrials.gov: NCT04199000 (posted 2019; recruiting as retrieved). https://clinicaltrials.gov/study/NCT04199000 (NCT04199000 chunk 1)

References

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  2. (tol2019amutationin pages 6-8): Walinka van Tol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type i and dystroglycanopathy. JIMD Reports, 50:31-39, Sep 2019. URL: https://doi.org/10.1002/jmd2.12060, doi:10.1002/jmd2.12060. This article has 17 citations and is from a peer-reviewed journal.

  3. (schenk2003mpdu1mutationsunderlie pages 6-8): B. Schenk, T. Imbach, C. Frank, C. Grubenmann, G. Raymond, H. Hurvitz, I. Korn‐Lubetzki, S. Revel-Vik, A. Raas-Rotschild, A. Luder, J. Jaeken, E. Berger, G. Matthijs, T. Hennet, and M. Aebi. Mpdu1 mutations underlie a novel human congenital disorder of glycosylation, designated type if. Journal of Clinical Investigation, 111:925-a-925, Mar 2003. URL: https://doi.org/10.1172/jci200113419c, doi:10.1172/jci200113419c. This article has 186 citations and is from a highest quality peer-reviewed journal.

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  6. (haeuptle2009congenitaldisordersof pages 9-10): Micha A. Haeuptle and Thierry Hennet. Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol‐linked oligosaccharides. Human Mutation, 30:1628-1641, Dec 2009. URL: https://doi.org/10.1002/humu.21126, doi:10.1002/humu.21126. This article has 233 citations and is from a domain leading peer-reviewed journal.

  7. (kranz2001amutationin pages 1-2): Christian Kranz, Jonas Denecke, Mark A. Lehrman, Sutapa Ray, Petra Kienz, Gunilla Kreissel, Dijana Sagi, Jasna Peter-Katalinic, Hudson H. Freeze, Thomas Schmid, Sabine Jackowski-Dohrmann, Erik Harms, and Thorsten Marquardt. A mutation in the human mpdu1 gene causes congenital disorder of glycosylation type if (cdg-if). The Journal of clinical investigation, 108 11:1613-9, Dec 2001. URL: https://doi.org/10.1172/jci13635, doi:10.1172/jci13635. This article has 160 citations.

  8. (teneiji2017phenotypicandgenotypic pages 10-14): Amal Al Teneiji, Theodora U.J. Bruun, Sarah Sidky, Dawn Cordeiro, Ronald D Cohn, Roberto Mendoza-Londono, Mahendranath Moharir, Julian Raiman, Komudi Siriwardena, Lianna Kyriakopoulou, and Saadet Mercimek-Mahmutoglu. Phenotypic and genotypic spectrum of congenital disorders of glycosylation type i and type ii. Molecular genetics and metabolism, 120 3:235-242, Mar 2017. URL: https://doi.org/10.1016/j.ymgme.2016.12.014, doi:10.1016/j.ymgme.2016.12.014. This article has 80 citations and is from a peer-reviewed journal.

  9. (tol2019amutationin pages 5-6): Walinka van Tol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type i and dystroglycanopathy. JIMD Reports, 50:31-39, Sep 2019. URL: https://doi.org/10.1002/jmd2.12060, doi:10.1002/jmd2.12060. This article has 17 citations and is from a peer-reviewed journal.

  10. (schenk2003mpdu1mutationsunderlie pages 5-6): B. Schenk, T. Imbach, C. Frank, C. Grubenmann, G. Raymond, H. Hurvitz, I. Korn‐Lubetzki, S. Revel-Vik, A. Raas-Rotschild, A. Luder, J. Jaeken, E. Berger, G. Matthijs, T. Hennet, and M. Aebi. Mpdu1 mutations underlie a novel human congenital disorder of glycosylation, designated type if. Journal of Clinical Investigation, 111:925-a-925, Mar 2003. URL: https://doi.org/10.1172/jci200113419c, doi:10.1172/jci200113419c. This article has 186 citations and is from a highest quality peer-reviewed journal.

  11. (kranz2001amutationin pages 5-7): Christian Kranz, Jonas Denecke, Mark A. Lehrman, Sutapa Ray, Petra Kienz, Gunilla Kreissel, Dijana Sagi, Jasna Peter-Katalinic, Hudson H. Freeze, Thomas Schmid, Sabine Jackowski-Dohrmann, Erik Harms, and Thorsten Marquardt. A mutation in the human mpdu1 gene causes congenital disorder of glycosylation type if (cdg-if). The Journal of clinical investigation, 108 11:1613-9, Dec 2001. URL: https://doi.org/10.1172/jci13635, doi:10.1172/jci13635. This article has 160 citations.

  12. (zemet2024cardiomyopathyanuncommon pages 3-5): Roni Zemet, Kyle D. Hope, Andrew C. Edmondson, Rameen Shah, Maria Patino, Abigail M. Yesso, Justin H. Berger, Kyriakie Sarafoglou, Austin Larson, Christina Lam, Eva Morava, and Fernando Scaglia. Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: recommendations for baseline screening and follow-up evaluation. Molecular Genetics and Metabolism, 142:108513, Aug 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108513, doi:10.1016/j.ymgme.2024.108513. This article has 14 citations and is from a peer-reviewed journal.

  13. (bastaki2018single‐centerexperienceof pages 8-10): Fatma Bastaki, Sami Bizzari, Sana Hamici, Pratibha Nair, Madiha Mohamed, Fatima Saif, Ethar Mustafa Malik, Mahmoud Taleb Al‐Ali, and Abdul Rezzak Hamzeh. Single‐center experience of n‐linked congenital disorders of glycosylation with a summary of molecularly characterized cases in arabs. Annals of Human Genetics, 82:35-47, Jan 2018. URL: https://doi.org/10.1111/ahg.12220, doi:10.1111/ahg.12220. This article has 33 citations and is from a peer-reviewed journal.

  14. (hamzan2023epidemiologyandprevalence pages 5-7): Nurul Izzati Hamzan. Epidemiology and prevalence of patients with congenital disorders of glycosylation in malaysia. Asian Journal of Medicine and Biomedicine, 7:56-64, Apr 2023. URL: https://doi.org/10.37231/ajmb.2023.7.1.601, doi:10.37231/ajmb.2023.7.1.601. This article has 1 citations.

  15. (tol2019amutationin media 2abc4e54): Walinka van Tol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type i and dystroglycanopathy. JIMD Reports, 50:31-39, Sep 2019. URL: https://doi.org/10.1002/jmd2.12060, doi:10.1002/jmd2.12060. This article has 17 citations and is from a peer-reviewed journal.

  16. (hamzan2023epidemiologyandprevalence pages 1-3): Nurul Izzati Hamzan. Epidemiology and prevalence of patients with congenital disorders of glycosylation in malaysia. Asian Journal of Medicine and Biomedicine, 7:56-64, Apr 2023. URL: https://doi.org/10.37231/ajmb.2023.7.1.601, doi:10.37231/ajmb.2023.7.1.601. This article has 1 citations.

  17. (hamzan2023epidemiologyandprevalence pages 3-5): Nurul Izzati Hamzan. Epidemiology and prevalence of patients with congenital disorders of glycosylation in malaysia. Asian Journal of Medicine and Biomedicine, 7:56-64, Apr 2023. URL: https://doi.org/10.37231/ajmb.2023.7.1.601, doi:10.37231/ajmb.2023.7.1.601. This article has 1 citations.

  18. (teneiji2017phenotypicandgenotypic pages 33-37): Amal Al Teneiji, Theodora U.J. Bruun, Sarah Sidky, Dawn Cordeiro, Ronald D Cohn, Roberto Mendoza-Londono, Mahendranath Moharir, Julian Raiman, Komudi Siriwardena, Lianna Kyriakopoulou, and Saadet Mercimek-Mahmutoglu. Phenotypic and genotypic spectrum of congenital disorders of glycosylation type i and type ii. Molecular genetics and metabolism, 120 3:235-242, Mar 2017. URL: https://doi.org/10.1016/j.ymgme.2016.12.014, doi:10.1016/j.ymgme.2016.12.014. This article has 80 citations and is from a peer-reviewed journal.

  19. (teneiji2017phenotypicandgenotypic pages 6-10): Amal Al Teneiji, Theodora U.J. Bruun, Sarah Sidky, Dawn Cordeiro, Ronald D Cohn, Roberto Mendoza-Londono, Mahendranath Moharir, Julian Raiman, Komudi Siriwardena, Lianna Kyriakopoulou, and Saadet Mercimek-Mahmutoglu. Phenotypic and genotypic spectrum of congenital disorders of glycosylation type i and type ii. Molecular genetics and metabolism, 120 3:235-242, Mar 2017. URL: https://doi.org/10.1016/j.ymgme.2016.12.014, doi:10.1016/j.ymgme.2016.12.014. This article has 80 citations and is from a peer-reviewed journal.

  20. (zemet2024cardiomyopathyanuncommon pages 1-3): Roni Zemet, Kyle D. Hope, Andrew C. Edmondson, Rameen Shah, Maria Patino, Abigail M. Yesso, Justin H. Berger, Kyriakie Sarafoglou, Austin Larson, Christina Lam, Eva Morava, and Fernando Scaglia. Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: recommendations for baseline screening and follow-up evaluation. Molecular Genetics and Metabolism, 142:108513, Aug 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108513, doi:10.1016/j.ymgme.2024.108513. This article has 14 citations and is from a peer-reviewed journal.

  21. (NCT04199000 chunk 1): Eva Morava-Kozicz. Clinical and Basic Investigations Into Congenital Disorders of Glycosylation. Icahn School of Medicine at Mount Sinai. 2019. ClinicalTrials.gov Identifier: NCT04199000

  22. (zemet2024cardiomyopathyanuncommon pages 5-6): Roni Zemet, Kyle D. Hope, Andrew C. Edmondson, Rameen Shah, Maria Patino, Abigail M. Yesso, Justin H. Berger, Kyriakie Sarafoglou, Austin Larson, Christina Lam, Eva Morava, and Fernando Scaglia. Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: recommendations for baseline screening and follow-up evaluation. Molecular Genetics and Metabolism, 142:108513, Aug 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108513, doi:10.1016/j.ymgme.2024.108513. This article has 14 citations and is from a peer-reviewed journal.

  23. (tol2019amutationin media 23fb2f88): Walinka van Tol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type i and dystroglycanopathy. JIMD Reports, 50:31-39, Sep 2019. URL: https://doi.org/10.1002/jmd2.12060, doi:10.1002/jmd2.12060. This article has 17 citations and is from a peer-reviewed journal.

  24. (tol2019amutationin media 7782a19e): Walinka van Tol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type i and dystroglycanopathy. JIMD Reports, 50:31-39, Sep 2019. URL: https://doi.org/10.1002/jmd2.12060, doi:10.1002/jmd2.12060. This article has 17 citations and is from a peer-reviewed journal.

  25. (tol2019amutationin media 364fb774): Walinka van Tol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type i and dystroglycanopathy. JIMD Reports, 50:31-39, Sep 2019. URL: https://doi.org/10.1002/jmd2.12060, doi:10.1002/jmd2.12060. This article has 17 citations and is from a peer-reviewed journal.