ALG3-congenital disorder of glycosylation

Mendelian MONDO:0010998 Pathograph 28 Show in embeddings browser congenital disorder of glycosylation autosomal recessive disease

ALG3-CDG (formerly CDG-Id) is a severe autosomal recessive congenital disorder of glycosylation caused by deficiency of the endoplasmic reticulum alpha-1,3-mannosyltransferase ALG3. The enzyme adds the sixth mannose to the growing lipid-linked oligosaccharide, so its loss truncates the precursor glycan at Man5GlcNAc2 and produces a characteristic N-glycan signature. Affected individuals have severe neurological involvement with epilepsy, microcephaly and hypotonia, together with ocular, skeletal, gastrointestinal, endocrine and renal involvement. Mortality is substantial and is recorded with its source under progression.

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1
Inheritance
7
Pathophys.
17
Phenotypes
2
Gaps
28
Pathograph
1
Genes
5
Medical Actions
10
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
ALG3-CDG is autosomal recessive, caused by biallelic ALG3 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:34090370 SUPPORT Human Clinical
"ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene."
Establishes autosomal recessive inheritance and the enzyme deficiency caused by ALG3 variants.
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Discussions and Knowledge Gaps

2
Is the severity of ALG3-CDG driven by the absence of mature glycan, or by the active transfer of a truncated Man5GlcNAc2 glycan that misfolds or mistargets its carrier proteins?
KNOWLEDGE GAP OPEN gap_alg3_truncated_versus_absent_glycan
Attached to
pathophysiology#Truncated Man5GlcNAc2 Lipid-Linked Precursor pathophysiology#Protein Hypoglycosylation
ALG3-CDG does not simply fail to glycosylate: it transfers a short, abnormal glycan, and the resulting N-glycan spectrum is disease characteristic. Patient fibroblasts now establish chronic UPR and ERAD activation, but do not distinguish toxicity of the truncated glycan from the consequences of missing mature glycans. That raises the possibility that the truncated glycan is actively harmful rather than merely insufficient, which would explain why a block partway along the assembly line is so severe. Distinguishing loss of function from gain of a bad glycan matters therapeutically, because the two imply opposite strategies: supplying the missing sugar versus preventing transfer of the truncated precursor.
Proposed experiments
Comparing truncated-glycan transfer against no-transfer in ALG3-deficient cells
exp_alg3_truncated_glycan_toxicity
In ALG3-deficient patient fibroblasts, compare glycoprotein folding, trafficking and ER stress between the native truncated-transfer state and a state where oligosaccharyltransferase-mediated transfer of the truncated precursor is blocked, to determine whether removing the abnormal glycan improves or worsens client protein handling.
Decision criterion
Improved client folding and reduced ER stress when truncated transfer is blocked would show the short glycan is actively harmful.
Supporting outcome
  • The truncated glycan is actively deleterious, favouring strategies that prevent its transfer
Refuting outcome
  • Blocking transfer worsens outcomes, confirming that any glycan is better than none and favouring substrate supplementation
Show evidence (1 reference)
PMID:38597022 SUPPORT In Vitro
"In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts"
Establishes the ER-stress phenotype motivating the question, but does not resolve whether truncated-glycan transfer or mature-glycan deficiency is causal.
Can the ALG3-specific N-glycan signature serve as a quantitative severity or treatment-response biomarker rather than only a diagnostic fingerprint?
KNOWLEDGE GAP OPEN gap_alg3_glycan_signature_as_biomarker
Attached to
pathophysiology#Truncated Man5GlcNAc2 Lipid-Linked Precursor pathophysiology#Multisystem Glycoprotein Dysfunction
The combined deficiency of hybrid glycans and of extension beyond Man5GlcNAc2 is described as unique to ALG3-CDG, which establishes it as a diagnostic fingerprint. What is not established is whether the magnitude of that deviation tracks clinical severity across the small published population, or whether it would move under any intervention. Without that, any future trial in this ultra-rare disorder has no surrogate endpoint and would have to rely on clinical outcomes in a population where about half die neonatally.
Proposed experiments
Correlating quantitative N-glycan deviation with clinical severity across the reported ALG3-CDG cohort
exp_alg3_glycan_severity_correlation
Assemble quantitative N-glycan profiles alongside standardized severity scoring and residual enzyme activity across available ALG3-CDG individuals and, where possible, serial samples, to test whether glycan deviation predicts severity and whether it varies within an individual over time.
Decision criterion
A monotonic relationship between glycan deviation and severity score, stable within individuals, would qualify it as a candidate surrogate endpoint.
Supporting outcome
  • Glycan deviation tracks severity and is a viable surrogate endpoint for trials
Refuting outcome
  • Glycan profile is invariant across severities, confining it to a purely diagnostic role
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"The degree of elevation of the mono/di oligo ratio of transferrin may correlate with severity and/or age, as seen in other CDGs, but we do not have enough power to definitively illustrate this."
The cohort raises the biomarker hypothesis but explicitly reports insufficient power to establish the correlation.
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Pathophysiology

7
ALG3 Alpha-1,3-Mannosyltransferase Deficiency
ALG3 is the endoplasmic reticulum alpha-1,3-mannosyltransferase (historically mannosyltransferase VI) that transfers the sixth mannose residue onto the growing lipid-linked oligosaccharide on the luminal face of the ER. Biallelic loss of function stalls assembly at that exact step, which is the organ-specific substitution this entry makes against the conserved CDG module: the module's generic assembly defect is here a single, positionally defined missing sugar.
ALG3 hgnc:23056 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG3 (hgnc:23056). hgnc:23056 is a gene from the HUGO Gene Nomenclature Committee.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
alpha-1,3-mannosyltransferase activity GO:0000033 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased alpha-1,3-mannosyltransferase activity (GO:0000033). GO:0000033 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Truncated Man5GlcNAc2 Lipid-Linked Precursor Blocking the sixth mannose transfer leaves the precursor arrested at Man5GlcNAc2.
Show evidence (1 reference)
PMID:10581255 SUPPORT Human Clinical
"Here we show that the molecular defect in the index patient is a missense mutation in the gene encoding the mannosyltransferase that transfers mannose from dolichyl-phosphate mannose on to the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-dolichol."
The foundational human molecular study identifies ALG3 as the mannosyltransferase acting on the Man5GlcNAc2 lipid-linked intermediate.
Truncated Man5GlcNAc2 Lipid-Linked Precursor
ALG3 deficiency causes Man5GlcNAc2-PP-dolichol to accumulate, while the leaky enzymatic defect permits some full-length precursor formation. Truncated oligosaccharides are transferred alongside full-length species, and later Golgi processing generates characteristic Man3-4 structures. The combined deficiency of hybrid glycans and extension beyond Man5GlcNAc2 is a disease-characteristic biochemical fingerprint.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Protein Hypoglycosylation Transfer of a truncated glycan onto nascent glycoproteins yields abnormally glycosylated mature protein.
Show evidence (4 references)
PMID:10581255 SUPPORT Human Clinical
"The defect results in the accumulation of the LLO intermediate and, due to its leaky nature, a residual formation of full-length LLOs."
Establishes both Man5-linked precursor accumulation and residual full-length precursor formation, avoiding an absolute assembly-block claim.
PMID:33583022 SUPPORT Human Clinical
"N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides."
Directly links the enzymatic block to the truncated precursor and the resulting N-glycan profile in patients.
PMID:33583022 SUPPORT Human Clinical
"This spectrum of N-glycan changes is unique to ALG3-CDG."
Establishes the diagnostic specificity of the glycan signature, which distinguishes ALG3-CDG from other CDG within the same module.
+ 1 more reference
Protein Hypoglycosylation
Nascent glycoproteins receive abnormal or absent N-glycans, detectable clinically as a type 1 transferrin isoelectric focusing pattern. From this node ALG3-CDG rejoins the conserved CDG pathway without substitution: the consequences are those of any hypoglycosylation state.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Constitutive IRE1-Mediated Unfolded Protein Response and ERAD Defective N-glycan extension chronically activates ER protein-quality control in patient-derived fibroblasts.
IGF-1 Axis Hypoglycosylation and Reduced Availability Hypoglycosylation affects proIGF-1 processing and IGF-1 receptor abundance in patient-derived fibroblasts.
Multisystem Glycoprotein Dysfunction Widespread glycoprotein dysfunction produces the multisystem clinical phenotype.
Show evidence (1 reference)
PMID:34090370 SUPPORT Human Clinical
"Transferrin isoelectric focusing revealed a type 1 pattern."
Documents the type 1 transferrin pattern that reports protein hypoglycosylation in an ALG3-CDG patient.
Constitutive IRE1-Mediated Unfolded Protein Response and ERAD
ALG3-CDG patient-derived skin fibroblasts have constitutively increased unfolded-protein-response and ER-associated-degradation activity, with the UPR mediated through the IRE1-alpha branch. This supplies a demonstrated cellular stress mechanism between abnormal N-glycans and tissue dysfunction.
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
IRE1-mediated unfolded protein response GO:0036498 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased IRE1-mediated unfolded protein response (GO:0036498). GO:0036498 is a biological process from the Gene Ontology. ↑ INCREASED ER-associated degradation GO:0036503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ER-associated degradation, annotated with ERAD pathway (GO:0036503). GO:0036503 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Multisystem Glycoprotein Dysfunction Chronic ER quality-control activation is a plausible contributor to organ dysfunction, but the tissue-specific intermediates remain unresolved.
Show evidence (1 reference)
PMID:38597022 SUPPORT In Vitro
"In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway."
Directly demonstrates increased UPR, ERAD and constitutive IRE1-alpha signaling in patient-derived cultured fibroblasts.
IGF-1 Axis Hypoglycosylation and Reduced Availability
In fibroblasts from two individuals with ALG3-CDG, proIGF-1 was hypoglycosylated, IGF-1 secretion and IGF-1 receptor abundance were reduced, and circulating IGF-1 was low. These observations identify an ALG3-relevant growth-factor axis, but the study explicitly leaves its contribution to growth failure and endocrine phenotypes unresolved.
dermal fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dermal fibroblast, annotated with skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
Downstream
Failure to thrive Reduced IGF-1 availability could contribute to impaired growth, but the study explicitly leaves this clinical consequence unresolved.
Show evidence (2 references)
PMID:35211808 SUPPORT In Vitro
"ALG3-CDG, ALG8-CDG, GMPPB-CDG and some PMM2-CDG fibroblasts showed hypoglycosylation of the proIGF-1Ea and lower IGF-1 secretion when compared with control (CTR)."
Supports proIGF-1 hypoglycosylation and reduced secretion in ALG3-CDG patient fibroblasts.
PMID:35211808 SUPPORT Human Clinical
"Lower IGF-1 serum concentration was observed in ALG3-CDG, ALG8-CDG and in some patients with PMM2-CDG, supporting our in vitro data."
Human serum measurements corroborate reduced IGF-1 availability, while not establishing its clinical consequences.
Multisystem Glycoprotein Dysfunction
The organism-level convergence: severe neurological involvement, ocular anomalies, dysmorphism, skeletal anomalies and feeding difficulties, with endocrine, renal, cardiac and immunological involvement recognized more recently. The breadth is what makes baseline multisystem evaluation at diagnosis the recommended approach rather than symptom-led referral.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Retinal Ganglion Cell Loss and Optic Nerve Involvement Among the affected systems, the eye shows a specifically neuroretinal degeneration rather than a purely structural anomaly.
Global developmental delay
Seizure
Microcephaly
Cerebellar vermis hypoplasia
Multiple joint contractures
Hypotonia
Feeding difficulties
Strabismus
Central hypothyroidism
Adrenal insufficiency
Nephrocalcinosis Renal involvement is part of the observed multisystem phenotype, although the intervening glycoproteins are unknown.
Recurrent infections Recurrent infections accompany multisystem dysfunction, but available immune testing does not establish a single causal pathway.
Aortic root dilatation Aortic root involvement is documented clinically without a resolved glycoprotein or connective-tissue mechanism.
Dilated cardiomyopathy
Show evidence (2 references)
PMID:33583022 SUPPORT Human Clinical
"Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties."
Enumerates the core multisystem phenotype across the largest reported series.
PMID:33583022 SUPPORT Human Clinical
"we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies"
Documents the newly recognized organ involvement that widened the surveillance recommendations.
Retinal Ganglion Cell Loss and Optic Nerve Involvement
The ocular phenotype is more than an incidental anomaly. Imaging in an ALG3-CDG patient showed profound retinal ganglion cell loss with inner retinal layer thinning alongside fundus hypopigmentation and optic disc pallor, so the visual impairment is a neuroretinal degeneration rather than a refractive or structural problem alone.
retinal ganglion cell CL:0000740 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal ganglion cell (CL:0000740). CL:0000740 is a cell type from the Cell Ontology.
Downstream
Optic atrophy
Optic nerve hypoplasia Optic nerve hypoplasia is co-located with the disease-specific ocular evidence, without asserting that retinal ganglion-cell loss causes the developmental anomaly.
Show evidence (2 references)
PMID:34090370 SUPPORT Human Clinical
"Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging."
Provides cell-level imaging evidence for the neuroretinal nature of the ocular phenotype.
PMID:34090370 SUPPORT Human Clinical
"Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia."
The disease-focused ophthalmic review identifies optic nerve hypoplasia as the most common reported substrate of visual impairment.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ALG3-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.
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Phenotypes

17
Cardiovascular 2
Aortic root dilatation FREQUENT Aortic root aneurysm HP:0002616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic root dilatation, annotated with Aortic root aneurysm (HP:0002616). HP:0002616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Aortic root dilatation (Z score >2), with no other signs of connective tissue dysplasia, has been observed in four of our subjects"
Four observations in the ten-person cohort support a FREQUENT band and the need for cardiac baseline assessment.
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38917675 SUPPORT Human Clinical
"Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG"
Directly documents dilated cardiomyopathy in one molecularly confirmed ALG3-CDG participant.
Digestive 1
Feeding difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Gastrointestinal problems were observed in (8/10) including feeding difficulties (6/8) and failure to thrive (FTT) (4/8) (weight < second percentile) requiring tube feeding (3/8)."
Quantifies gastrointestinal involvement, feeding difficulty, failure to thrive and tube-feeding dependence in the cohort.
Endocrine 1
Adrenal insufficiency OCCASIONAL HP:0000846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal insufficiency (HP:0000846). HP:0000846 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Additionally, two of our newly reported individuals have panhypopituitarism (hypothyroidism, growth hormone deficiency, and adrenal insufficiency); both are on hormone replacement therapy."
Quantifies adrenal insufficiency within panhypopituitarism in two members of the ten-person cohort, supporting an OCCASIONAL band.
Eye 2
Optic atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34090370 SUPPORT Human Clinical
"Funduscopy showed hypopigmentation and optic disc pallor."
Documents the optic disc and fundus findings underpinning the optic neuropathy.
Strabismus FREQUENT HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Strabismus and optic atrophy were the most frequent ocular abnormalities."
Establishes strabismus as co-equal with optic atrophy among ocular findings.
Head and Neck 1
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"severe neurological involvement (epilepsy, microcephaly, and hypotonia)"
Lists microcephaly among the frequent core neurological features.
Immune 1
Recurrent infections FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33583022 SUPPORT Human Clinical
"we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies"
Establishes immune-system involvement while the more specific phenotype is grounded by the cohort's recurrent-infection count below.
PMID:33583022 SUPPORT Human Clinical
"In our cohort, recurrent infections have been observed in 6/8 (75%) individuals, but immunological studies were obtained in only two of them."
Quantifies recurrent infection at 6 of 8 individuals, supporting a FREQUENT band, while noting how few had formal immunological workup.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"severe neurological involvement (epilepsy, microcephaly, and hypotonia)"
Lists hypotonia alongside epilepsy and microcephaly as the frequent core neurological features.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23791010 SUPPORT Human Clinical
"They share similar clinical features with previously reported patients including facial dysmorphism, severe psychomotor retardation, microcephaly, seizures, and gastrointestinal symptoms."
Confirms severe psychomotor retardation as a shared feature across reported patients.
PMID:33583022 SUPPORT Human Clinical
"The degree of intellectual disability varied significantly within the cohort, with some individuals exhibiting profound developmental delays in all domains, while others achieved, as adults, neurocognitive abilities equivalent to an average age of 7 to 9 years."
Qualifies the severity: the cohort spans profound delay to a substantially milder neurocognitive outcome, so "severe" is not universal.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"severe neurological involvement (epilepsy, microcephaly, and hypotonia)"
Lists epilepsy among the frequent core neurological features.
Cerebellar vermis hypoplasia HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34090370 SUPPORT Human Clinical
"A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment."
Documents cerebellar vermis hypoplasia and cortical atrophy in a molecularly confirmed patient.
Growth 1
Failure to thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"failure to thrive (FTT) (4/8) (weight < second percentile) requiring tube feeding (3/8)"
Quantifies failure to thrive and the proportion requiring tube feeding.
Other 4
Multiple joint contractures FREQUENT HP:0002828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple joint contractures (HP:0002828). HP:0002828 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34090370 SUPPORT Human Clinical
"Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth."
Documents contractures and clubfeet present at birth.
PMID:33583022 SUPPORT Human Clinical
"Skeletal abnormalities were observed in eight of our cohort"
Quantifies skeletal involvement at 8 of 10 individuals, supporting a FREQUENT band.
Optic nerve hypoplasia HP:0000609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic nerve hypoplasia (HP:0000609). HP:0000609 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34090370 SUPPORT Human Clinical
"optic nerve atrophy/hypoplasia observed in 11 patients including the current study"
The review found the combined category of optic nerve atrophy or hypoplasia in 11 individuals. No frequency band is assigned to hypoplasia alone because the source does not disaggregate those findings.
Central hypothyroidism FREQUENT HP:0011787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Central hypothyroidism (HP:0011787). HP:0011787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Four of our subjects had central hypothyroidism with three requiring hormone replacement."
Quantifies central hypothyroidism in four members of the ten-person cohort, supporting a FREQUENT band.
Nephrocalcinosis OCCASIONAL HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Nephrocalcinosis has been seen in both P2 and P3; P3 has nephromegaly and cystic kidneys, while P6 had duplex kidney"
Documents the specific structural renal anomalies observed in the cohort.
🧬

Genetic Associations

1
ALG3 (Pathogenic Variants)
Gene: ALG3 hgnc:23056 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG3 (hgnc:23056). hgnc:23056 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:33583022 SUPPORT Human Clinical
"We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals."
Establishes the variant spectrum and the size of the reported world literature.
PMID:34090370 SUPPORT Human Clinical
"Thirty-three variants in 43 subjects with ALG3-CDG have been reported."
Updates the 2021 literature count and variant spectrum beyond the earlier 40-person cohort summary.
PMID:41089746 SUPPORT Human Clinical
"Whole exome sequencing confirmed a diagnosis of ALG3-CDG with compound heterozygous variants: c.165C > T (p.Gly55=) and c.1060C > T (p.Arg354Cys) in the ALG3 gene"
A 2025 molecularly confirmed case adds contemporary compound-heterozygous evidence to the allelic spectrum.
💊

Medical Actions

5
Antiseizure management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Seizures are typically intractable and non-febrile with variable semiology, and are managed with multiple antiseizure drugs. No pattern of drug efficacy could be discerned across the reported cases, so agent choice remains empiric. Ketogenic diet and cannabidiol are represented separately because their evidence and modalities differ from general pharmacotherapy.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33583022 SUPPORT Human Clinical
"Most of the reported patients had intractable nonfebrile seizures with different semiology despite treatment with multiple antiepileptic drugs (AEDs) in addition to a ketogenic diet"
Documents the intractability of the epilepsy and the multi-drug plus ketogenic-diet approach used.
PMID:33583022 SUPPORT Human Clinical
"A wide array of AEDs was utilized in a small number of individuals so, unfortunately, we are unable to discern a pattern of drug efficacy."
Records explicitly that no drug-efficacy pattern could be established, which is why no specific agent is recommended.
Ketogenic diet for intractable epilepsy
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
A ketogenic diet controlled or markedly reduced drug-resistant seizures in a pair of affected twins during ten months of follow-up. This is direct but very small case-series evidence, and hypoglycaemia risk requires caution.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32389449 SUPPORT Human Clinical
"Our patients were the first patients with ALG3-CDG whose intractable epilepsies were controlled by ketogenic diet."
Direct disease-specific twin case report supports seizure control with a ketogenic diet, without implying population-level efficacy.
PMID:32389449 SUPPORT Human Clinical
"However, CDG patients already have a tendency for hypoglycemia due to hyperinsulinism and it should be kept in mind that ketogenic diet may also potentiate this effect"
Qualifies the treatment with a disease-relevant safety concern.
Cannabidiol for ALG3-CDG with Lennox-Gastaut syndrome
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cannabidiol CHEBI:69478 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cannabidiol (CHEBI:69478). CHEBI:69478 is a therapeutic agent from Chemical Entities of Biological Interest.
In one 2025 case with concurrent ALG3-CDG and Lennox-Gastaut syndrome, cannabidiol plus dietary management produced seizure freedom for more than 13 months with EEG and developmental improvement. This is promising single-case evidence specific to the comorbid LGS context, not a general efficacy claim for ALG3-CDG epilepsy.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39831946 SUPPORT Human Clinical
"Cannabidiol therapy, combined with dietary management, led to seizure freedom for over 13 months, significant EEG improvement, and enhanced developmental outcomes."
Supports the reported outcome in a single ALG3-CDG/LGS case while the description preserves its limited scope.
Developmental therapies
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical, occupational and speech therapy are part of the recommended baseline management. All individuals with contractures who were still living received physical and occupational therapy, and none had required surgery.
Show evidence (2 references)
PMID:33583022 SUPPORT Human Clinical
"developmental assessment with initiation of physical, occupational, and speech therapies"
Part of the recommended baseline evaluation and management plan.
PMID:33583022 SUPPORT Human Clinical
"Of those with contractures and were still living, all received physical and occupational therapy, and none have yet undergone surgical treatment."
Documents that conservative therapy has so far been sufficient for the contractures in this cohort.
Baseline multisystem evaluation and monitoring
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. The management recommendation that emerged from the expanded phenotype is proactive rather than reactive: baseline endocrine, renal, cardiac and immunological evaluation at the time of diagnosis, with ongoing monitoring, because these systems are involved more often than the historical description suggested.
Show evidence (2 references)
PMID:33583022 SUPPORT Human Clinical
"These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring."
States the multisystem baseline evaluation and monitoring recommendation.
PMID:38917675 SUPPORT 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."
Adds a contemporary CDG natural-history recommendation for structured cardiac surveillance after documenting ALG3-CDG cardiomyopathy.
🔬

Biochemical Markers

3
Antithrombin III (DECREASED)
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"Low antithrombin III (43-59; RR: 86%-145%), decreased factor XI (44%-46%; RR 63%-142%), and prolonged APTT (37.2-58; RR 22-36 seconds) were the most common hematologic defects."
Gives the observed values and reference ranges for the coagulation abnormalities of ALG3-CDG.
Serum transaminases (INCREASED)
Show evidence (2 references)
PMID:33583022 SUPPORT Human Clinical
"Hepatopathy consisted of mild trans-aminitis (ALT 47-149"
Directly identifies hepatopathy as mild transaminitis and quantifies the reported ALT elevation.
PMID:33583022 SUPPORT Human Clinical
"6-40 IU/L, AST 55-128; RR 5-41IU/L)"
Separately quantifies the reported AST elevation without conflating it with the albumin abnormality.
Serum albumin (DECREASED)
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"6-40 IU/L, AST 55-128; RR 5-41IU/L) and hypoalbuminemia (2.6-3.7; RR 3.8-5.4 g/dL)."
Directly quantifies hypoalbuminaemia against the reported reference range.
🔬

Diagnosis

3
Transferrin isoelectric focusing
A type 1 transferrin isoelectric focusing pattern indicates a defect in the assembly or transfer of the lipid-linked oligosaccharide, placing the disorder in CDG type I and prompting targeted molecular or glycan analysis.
transferrin isoelectric focusing NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34090370 SUPPORT Human Clinical
"Transferrin isoelectric focusing revealed a type 1 pattern."
Documents the first-line biochemical screening result in ALG3-CDG.
N-glycan profiling
N-glycan analysis shows combined deficiency of hybrid glycans and of extension beyond Man5GlcNAc2, a pattern reported to be unique to ALG3-CDG. This makes glycan profiling potentially diagnostic rather than merely supportive within the CDG group. However, a 2024 study predicts that one processed ALG3-CDG glycan has the same molecular weight as a truncated MGAT2-CDG glycan, so mass alone may not distinguish every species.
N-glycan profiling NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:33583022 SUPPORT Human Clinical
"This spectrum of N-glycan changes is unique to ALG3-CDG."
Establishes the diagnostic specificity of the ALG3-CDG glycan signature.
PMID:41089746 SUPPORT Human Clinical
"This presented case highlights the importance of glycan profiling and genetic analysis in diagnosing congenital disorders of glycosylation, facilitating early intervention and management."
A 2025 case supports combined glycan profiling and genetic analysis in the contemporary diagnostic workflow.
PMID:38597022 SUPPORT In Vitro
"We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG."
Qualifies mass-based specificity because one predicted processed ALG3 glycan collides in molecular weight with a truncated MGAT2-CDG glycan.
Molecular genetic testing
Biallelic ALG3 variants confirm the diagnosis, and molecular testing is what distinguishes ALG3-CDG from the other CDG type I disorders that share the transferrin pattern.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33583022 SUPPORT Human Clinical
"We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing"
Documents combined molecular and biochemical testing as the diagnostic basis.
📈

Progression

1
Neonatal and early mortality
Almost half of reported individuals die before or during the neonatal period. Survival is nevertheless variable, including survival into adulthood. All nine reported individuals homozygous for p.Arg171Gln died very early, a possible genotype association; outside that cluster the largest cohort found no clear genotype-phenotype correlation.
Show evidence (2 references)
PMID:34090370 SUPPORT Human Clinical
"almost half of them die before or during the neonatal period"
Source for the mortality statement, which previously appeared only as an unevidenced sentence in the entry description.
PMID:33583022 SUPPORT Human Clinical
"All of these nine cases with this genotype passed away very early in life"
Supports the observed p.Arg171Gln homozygote mortality cluster, classified as PARTIAL because the authors call the correlation possible and found no broader clear genotype-phenotype relationship.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Forty-three individuals had been reported by the June 2021 ophthalmic review. New disease-specific cases appeared in 2025, so 43 is a dated lower bound rather than a current total. Population prevalence remains unknown; later mechanistic cohorts may overlap prior cases and are not summed here.
Show evidence (2 references)
PMID:34090370 SUPPORT Human Clinical
"Thirty-three variants in 43 subjects with ALG3-CDG have been reported."
Anchors the last explicitly enumerated literature count while avoiding its conversion to population prevalence.
PMID:39831946 SUPPORT Human Clinical
"This study presents the first reported case of a Korean patient with Alpha-1,3-Mannosyltransferase-Congenital Disorder of Glycosylation (ALG3-CDG)"
Demonstrates that additional disease-specific cases were published after the 43-person review, making that count a lower bound.
{ }

Source YAML

click to show 
name: ALG3-congenital disorder of glycosylation
creation_date: "2026-08-01T05:14:29Z"
description: >-
  ALG3-CDG (formerly CDG-Id) is a severe autosomal recessive congenital disorder
  of glycosylation caused by deficiency of the endoplasmic reticulum
  alpha-1,3-mannosyltransferase ALG3. The enzyme adds the sixth mannose to the
  growing lipid-linked oligosaccharide, so its loss truncates the precursor
  glycan at Man5GlcNAc2 and produces a characteristic N-glycan signature.
  Affected individuals have severe neurological involvement with
  epilepsy, microcephaly and hypotonia, together with ocular, skeletal,
  gastrointestinal, endocrine and renal involvement. Mortality is substantial
  and is recorded with its source under progression.
category: Mendelian
parents:
- congenital disorder of glycosylation
- autosomal recessive disease
synonyms:
- ALG3-CDG
- CDG-Id
- CDG Id
- congenital disorder of glycosylation type Id
disease_term:
  preferred_term: ALG3-congenital disorder of glycosylation
  term:
    id: MONDO:0010998
    label: ALG3-congenital disorder of glycosylation
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    ALG3-CDG is autosomal recessive, caused by biallelic ALG3 variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene."
    explanation: >-
      Establishes autosomal recessive inheritance and the enzyme deficiency
      caused by ALG3 variants.
pathophysiology:
- name: ALG3 Alpha-1,3-Mannosyltransferase Deficiency
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  description: >-
    ALG3 is the endoplasmic reticulum alpha-1,3-mannosyltransferase (historically
    mannosyltransferase VI) that transfers the sixth mannose residue onto the
    growing lipid-linked oligosaccharide on the luminal face of the ER. Biallelic
    loss of function stalls assembly at that exact step, which is the
    organ-specific substitution this entry makes against the conserved CDG
    module: the module's generic assembly defect is here a single, positionally
    defined missing sugar.
  genes:
  - preferred_term: ALG3
    term:
      id: hgnc:23056
      label: ALG3
  molecular_functions:
  - preferred_term: alpha-1,3-mannosyltransferase activity
    term:
      id: GO:0000033
      label: alpha-1,3-mannosyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:10581255
    reference_title: "Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that the molecular defect in the index patient is a missense mutation in the gene encoding the mannosyltransferase that transfers mannose from dolichyl-phosphate mannose on to the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-dolichol."
    explanation: >-
      The foundational human molecular study identifies ALG3 as the
      mannosyltransferase acting on the Man5GlcNAc2 lipid-linked intermediate.
  downstream:
  - target: Truncated Man5GlcNAc2 Lipid-Linked Precursor
    description: >-
      Blocking the sixth mannose transfer leaves the precursor arrested at
      Man5GlcNAc2.
- name: Truncated Man5GlcNAc2 Lipid-Linked Precursor
  biological_scale: MOLECULAR
  description: >-
    ALG3 deficiency causes Man5GlcNAc2-PP-dolichol to accumulate, while the
    leaky enzymatic defect permits some full-length precursor formation.
    Truncated oligosaccharides are transferred alongside full-length species,
    and later Golgi processing generates characteristic Man3-4 structures. The
    combined deficiency of hybrid glycans and extension beyond Man5GlcNAc2 is a
    disease-characteristic biochemical fingerprint.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:10581255
    reference_title: "Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The defect results in the accumulation of the LLO intermediate and, due to its leaky nature, a residual formation of full-length LLOs."
    explanation: >-
      Establishes both Man5-linked precursor accumulation and residual
      full-length precursor formation, avoiding an absolute assembly-block claim.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides."
    explanation: >-
      Directly links the enzymatic block to the truncated precursor and the
      resulting N-glycan profile in patients.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This spectrum of N-glycan changes is unique to ALG3-CDG."
    explanation: >-
      Establishes the diagnostic specificity of the glycan signature, which
      distinguishes ALG3-CDG from other CDG within the same module.
  - reference: PMID:41089746
    reference_title: "Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results revealed an abnormal N-glycan profile, characterized by an increased relative abundance of truncated mannosylated structures (Hex3HexNAc2 and Hex4HexNAc2) and a decreased presence of higher-order mannose structures (Hex6-8HexNAc2)."
    explanation: >-
      A 2025 case independently confirms increased truncated Man3-4 structures
      and depletion of higher-mannose glycans.
  downstream:
  - target: Protein Hypoglycosylation
    description: >-
      Transfer of a truncated glycan onto nascent glycoproteins yields
      abnormally glycosylated mature protein.
- name: Protein Hypoglycosylation
  biological_scale: CELLULAR
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  description: >-
    Nascent glycoproteins receive abnormal or absent N-glycans, detectable
    clinically as a type 1 transferrin isoelectric focusing pattern. From this
    node ALG3-CDG rejoins the conserved CDG pathway without substitution: the
    consequences are those of any hypoglycosylation state.
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transferrin isoelectric focusing revealed a type 1 pattern."
    explanation: >-
      Documents the type 1 transferrin pattern that reports protein
      hypoglycosylation in an ALG3-CDG patient.
  downstream:
  - target: Constitutive IRE1-Mediated Unfolded Protein Response and ERAD
    causal_link_type: DIRECT
    description: >-
      Defective N-glycan extension chronically activates ER protein-quality
      control in patient-derived fibroblasts.
  - target: IGF-1 Axis Hypoglycosylation and Reduced Availability
    causal_link_type: DIRECT
    description: >-
      Hypoglycosylation affects proIGF-1 processing and IGF-1 receptor abundance
      in patient-derived fibroblasts.
  - target: Multisystem Glycoprotein Dysfunction
    description: >-
      Widespread glycoprotein dysfunction produces the multisystem clinical
      phenotype.
- name: Constitutive IRE1-Mediated Unfolded Protein Response and ERAD
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    ALG3-CDG patient-derived skin fibroblasts have constitutively increased
    unfolded-protein-response and ER-associated-degradation activity, with the
    UPR mediated through the IRE1-alpha branch. This supplies a demonstrated
    cellular stress mechanism between abnormal N-glycans and tissue dysfunction.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: IRE1-mediated unfolded protein response
    term:
      id: GO:0036498
      label: IRE1-mediated unfolded protein response
    modifier: INCREASED
  - preferred_term: ER-associated degradation
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:38597022
    reference_title: Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway."
    explanation: >-
      Directly demonstrates increased UPR, ERAD and constitutive IRE1-alpha
      signaling in patient-derived cultured fibroblasts.
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic ER quality-control activation is a plausible contributor to organ
      dysfunction, but the tissue-specific intermediates remain unresolved.
- name: IGF-1 Axis Hypoglycosylation and Reduced Availability
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In fibroblasts from two individuals with ALG3-CDG, proIGF-1 was
    hypoglycosylated, IGF-1 secretion and IGF-1 receptor abundance were reduced,
    and circulating IGF-1 was low. These observations identify an ALG3-relevant
    growth-factor axis, but the study explicitly leaves its contribution to
    growth failure and endocrine phenotypes unresolved.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  evidence:
  - reference: PMID:35211808
    reference_title: Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ALG3-CDG, ALG8-CDG, GMPPB-CDG and some PMM2-CDG fibroblasts showed hypoglycosylation of the proIGF-1Ea and lower IGF-1 secretion when compared with control (CTR)."
    explanation: >-
      Supports proIGF-1 hypoglycosylation and reduced secretion in ALG3-CDG
      patient fibroblasts.
  - reference: PMID:35211808
    reference_title: Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower IGF-1 serum concentration was observed in ALG3-CDG, ALG8-CDG and in some patients with PMM2-CDG, supporting our in vitro data."
    explanation: >-
      Human serum measurements corroborate reduced IGF-1 availability, while
      not establishing its clinical consequences.
  downstream:
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced IGF-1 availability could contribute to impaired growth, but the
      study explicitly leaves this clinical consequence unresolved.
- name: Multisystem Glycoprotein Dysfunction
  biological_scale: ORGANISM
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: ABNORMAL
  description: >-
    The organism-level convergence: severe neurological involvement, ocular
    anomalies, dysmorphism, skeletal anomalies and feeding difficulties, with
    endocrine, renal, cardiac and immunological involvement recognized more
    recently. The breadth is what makes baseline multisystem evaluation at
    diagnosis the recommended approach rather than symptom-led referral.
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties."
    explanation: >-
      Enumerates the core multisystem phenotype across the largest reported
      series.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies"
    explanation: >-
      Documents the newly recognized organ involvement that widened the
      surveillance recommendations.
  downstream:
  - target: Retinal Ganglion Cell Loss and Optic Nerve Involvement
    description: >-
      Among the affected systems, the eye shows a specifically neuroretinal
      degeneration rather than a purely structural anomaly.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar vermis hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Multiple joint contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Central hypothyroidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Adrenal insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nephrocalcinosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Renal involvement is part of the observed multisystem phenotype, although
      the intervening glycoproteins are unknown.
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recurrent infections accompany multisystem dysfunction, but available
      immune testing does not establish a single causal pathway.
  - target: Aortic root dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Aortic root involvement is documented clinically without a resolved
      glycoprotein or connective-tissue mechanism.
  - target: Dilated cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Retinal Ganglion Cell Loss and Optic Nerve Involvement
  biological_scale: TISSUE
  description: >-
    The ocular phenotype is more than an incidental anomaly. Imaging in an
    ALG3-CDG patient showed profound retinal ganglion cell loss with inner
    retinal layer thinning alongside fundus hypopigmentation and optic disc
    pallor, so the visual impairment is a neuroretinal degeneration rather than a
    refractive or structural problem alone.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging."
    explanation: >-
      Provides cell-level imaging evidence for the neuroretinal nature of the
      ocular phenotype.
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia."
    explanation: >-
      The disease-focused ophthalmic review identifies optic nerve hypoplasia as
      the most common reported substrate of visual impairment.
  downstream:
  - target: Optic atrophy
    causal_link_type: DIRECT
  - target: Optic nerve hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Optic nerve hypoplasia is co-located with the disease-specific ocular
      evidence, without asserting that retinal ganglion-cell loss causes the
      developmental anomaly.
phenotypes:
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay dominates the clinical picture, but its degree varies
    widely: some individuals have profound delay across all domains, while
    others reach adult neurocognitive abilities equivalent to an average age of
    seven to nine years. No frequency band is assigned because the cited cohort
    describes severity variation without a disorder-wide denominator for
    developmental delay.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:23791010
    reference_title: "ALG3-CDG (CDG-Id): clinical, biochemical and molecular findings in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They share similar clinical features with previously reported patients including facial dysmorphism, severe psychomotor retardation, microcephaly, seizures, and gastrointestinal symptoms."
    explanation: >-
      Confirms severe psychomotor retardation as a shared feature across reported
      patients.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of intellectual disability varied significantly within the cohort, with some individuals exhibiting profound developmental delays in all domains, while others achieved, as adults, neurocognitive abilities equivalent to an average age of 7 to 9 years."
    explanation: >-
      Qualifies the severity: the cohort spans profound delay to a substantially
      milder neurocognitive outcome, so "severe" is not universal.
- name: Seizure
  category: Neurologic
  description: >-
    Epilepsy is a core neurological manifestation and a major contributor to
    morbidity.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement (epilepsy, microcephaly, and hypotonia)"
    explanation: >-
      Lists epilepsy among the frequent core neurological features.
- name: Microcephaly
  category: Neurologic
  description: >-
    Microcephaly accompanies the developmental delay and, with cortical atrophy
    and cerebellar vermis hypoplasia, reflects a structural brain phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement (epilepsy, microcephaly, and hypotonia)"
    explanation: >-
      Lists microcephaly among the frequent core neurological features.
- name: Cerebellar vermis hypoplasia
  category: Neurologic
  description: >-
    Cerebellar vermis hypoplasia with cortical atrophy, part of the structural
    brain involvement and a recurrent CDG neuroimaging theme.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment."
    explanation: >-
      Documents cerebellar vermis hypoplasia and cortical atrophy in a
      molecularly confirmed patient.
- name: Multiple joint contractures
  category: Skeletal
  description: >-
    Joint contractures and clubfeet may be present from birth, part of a broad
    skeletal phenotype that also includes arthrogryposis, scoliosis, hip
    dysplasia, camptodactyly and overlapping digits, seen in eight of the ten
    cohort individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Multiple joint contractures
    term:
      id: HP:0002828
      label: Multiple joint contractures
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth."
    explanation: >-
      Documents contractures and clubfeet present at birth.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities were observed in eight of our cohort"
    explanation: >-
      Quantifies skeletal involvement at 8 of 10 individuals, supporting a
      FREQUENT band.
- name: Optic atrophy
  category: Ophthalmologic
  description: >-
    Optic disc pallor with fundus hypopigmentation and optic nerve hypoplasia,
    accompanied by retinal ganglion cell loss on optical coherence tomography.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Funduscopy showed hypopigmentation and optic disc pallor."
    explanation: >-
      Documents the optic disc and fundus findings underpinning the optic
      neuropathy.
- name: Optic nerve hypoplasia
  category: Ophthalmologic
  description: >-
    Optic nerve hypoplasia is the most commonly identified cause of visual
    impairment in the published ophthalmic review, and may coexist with retinal
    ganglion-cell loss and optic-disc pallor.
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "optic nerve atrophy/hypoplasia observed in 11 patients including the current study"
    explanation: >-
      The review found the combined category of optic nerve atrophy or
      hypoplasia in 11 individuals. No frequency band is assigned to hypoplasia
      alone because the source does not disaggregate those findings.
- name: Hypotonia
  category: Neurologic
  description: >-
    Hypotonia completes the core neurological triad with epilepsy and
    microcephaly in the source's own framing of the frequent features.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement (epilepsy, microcephaly, and hypotonia)"
    explanation: >-
      Lists hypotonia alongside epilepsy and microcephaly as the frequent core
      neurological features.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Gastrointestinal problems affect most of the cohort, with feeding
    difficulties in six of eight and failure to thrive in four of eight,
    three of whom required tube feeding. This is the practical reason nutrition
    assessment is part of the recommended baseline evaluation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal problems were observed in (8/10) including feeding difficulties (6/8) and failure to thrive (FTT) (4/8) (weight < second percentile) requiring tube feeding (3/8)."
    explanation: >-
      Quantifies gastrointestinal involvement, feeding difficulty, failure to
      thrive and tube-feeding dependence in the cohort.
- name: Failure to thrive
  category: Growth
  description: >-
    Failure to thrive with weight below the second percentile, requiring tube
    feeding in a subset.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive (FTT) (4/8) (weight < second percentile) requiring tube feeding (3/8)"
    explanation: >-
      Quantifies failure to thrive and the proportion requiring tube feeding.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus is, with optic atrophy, one of the two most frequent ocular
    abnormalities.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strabismus and optic atrophy were the most frequent ocular abnormalities."
    explanation: >-
      Establishes strabismus as co-equal with optic atrophy among ocular
      findings.
- name: Central hypothyroidism
  category: Endocrine
  description: >-
    Endocrine involvement was previously unreported in ALG3-CDG and was present
    in more than half the cohort, including central hypothyroidism, central
    adrenal insufficiency and growth hormone deficiency with consequent
    hypoglycaemia. This is the finding that drives the baseline endocrine
    evaluation recommendation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Central hypothyroidism
    term:
      id: HP:0011787
      label: Central hypothyroidism
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four of our subjects had central hypothyroidism with three requiring hormone replacement."
    explanation: >-
      Quantifies central hypothyroidism in four members of the ten-person
      cohort, supporting a FREQUENT band.
- name: Adrenal insufficiency
  category: Endocrine
  description: >-
    Central adrenal insufficiency, part of the pituitary-axis involvement that
    in two individuals amounted to panhypopituitarism.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, two of our newly reported individuals have panhypopituitarism (hypothyroidism, growth hormone deficiency, and adrenal insufficiency); both are on hormone replacement therapy."
    explanation: >-
      Quantifies adrenal insufficiency within panhypopituitarism in two members
      of the ten-person cohort, supporting an OCCASIONAL band.
- name: Nephrocalcinosis
  category: Genitourinary
  description: >-
    Structural renal involvement is newly recognized in ALG3-CDG and includes
    nephrocalcinosis, nephromegaly, cystic kidneys and duplex kidney, which is
    why baseline renal evaluation is recommended.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrocalcinosis has been seen in both P2 and P3; P3 has nephromegaly and cystic kidneys, while P6 had duplex kidney"
    explanation: >-
      Documents the specific structural renal anomalies observed in the cohort.
- name: Recurrent infections
  category: Immunologic
  description: >-
    Recurrent infection, predominantly upper and lower respiratory, affects three
    quarters of the cohort, and is one of the reasons baseline immunological
    evaluation is now recommended at diagnosis. Only one evaluated individual
    had a specific antibody deficiency; another similarly affected individual
    had recurrent infections despite a normal immunological workup. The
    computable phenotype is therefore recurrent infection rather than a
    generalized immunodeficiency assertion.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies"
    explanation: >-
      Establishes immune-system involvement while the more specific phenotype
      is grounded by the cohort's recurrent-infection count below.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, recurrent infections have been observed in 6/8 (75%) individuals, but immunological studies were obtained in only two of them."
    explanation: >-
      Quantifies recurrent infection at 6 of 8 individuals, supporting a
      FREQUENT band, while noting how few had formal immunological workup.
- name: Aortic root dilatation
  category: Cardiovascular
  description: >-
    Mild aortic-root dilatation was newly observed in four members of the 2021
    cohort without other signs of connective-tissue dysplasia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Aortic root dilatation
    term:
      id: HP:0002616
      label: Aortic root aneurysm
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aortic root dilatation (Z score >2), with no other signs of connective tissue dysplasia, has been observed in four of our subjects"
    explanation: >-
      Four observations in the ten-person cohort support a FREQUENT band and
      the need for cardiac baseline assessment.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Dilated cardiomyopathy has been documented in one ALG3-CDG participant in a
    305-person CDG natural-history cohort. It is retained as a rare but serious
    manifestation without a frequency band.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:38917675
    reference_title: "Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG"
    explanation: >-
      Directly documents dilated cardiomyopathy in one molecularly confirmed
      ALG3-CDG participant.
biochemical:
- name: Antithrombin III
  presence: DECREASED
  notes: >-
    Low antithrombin III is the most common haematologic defect, alongside
    decreased factor XI and a prolonged activated partial thromboplastin time.
    Coagulopathy is a classic congenital-disorder-of-glycosylation readout,
    since several coagulation factors are themselves N-glycoproteins.
    Reported at 43-59% of normal against a reference range of 86-145%.
    A structured reference_ranges block with a LOINC binding is a natural
    follow-up; the LOINC codes were not verified during this curation, so the
    interval is recorded here as source-quoted text rather than as a
    machine-readable range.
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low antithrombin III (43-59; RR: 86%-145%), decreased factor XI (44%-46%; RR 63%-142%), and prolonged APTT (37.2-58; RR 22-36 seconds) were the most common hematologic defects."
    explanation: >-
      Gives the observed values and reference ranges for the coagulation
      abnormalities of ALG3-CDG.
- name: Serum transaminases
  presence: INCREASED
  notes: >-
    Mild transaminitis constitutes hepatic involvement, which is milder here
    than in some other CDG types.
    ALT 47-149 IU/L (reference range 6-40) and AST 55-128 IU/L (reference range
    5-41).
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatopathy consisted of mild trans-aminitis (ALT 47-149"
    explanation: >-
      Directly identifies hepatopathy as mild transaminitis and quantifies the
      reported ALT elevation.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "6-40 IU/L, AST 55-128; RR 5-41IU/L)"
    explanation: >-
      Separately quantifies the reported AST elevation without conflating it
      with the albumin abnormality.
- name: Serum albumin
  presence: DECREASED
  notes: >-
    Hypoalbuminaemia was reported at 2.6-3.7 g/dL against a reference range of
    3.8-5.4 g/dL.
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "6-40 IU/L, AST 55-128; RR 5-41IU/L) and hypoalbuminemia (2.6-3.7; RR 3.8-5.4 g/dL)."
    explanation: >-
      Directly quantifies hypoalbuminaemia against the reported reference range.
genetic:
- name: ALG3
  gene_term:
    preferred_term: ALG3
    term:
      id: hgnc:23056
      label: ALG3
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    Encodes the ER alpha-1,3-mannosyltransferase that adds the sixth mannose to
    the lipid-linked oligosaccharide. A 2021 ophthalmic review counted 33
    pathogenic or likely pathogenic variants among 43 individuals, and later
    disease-specific reports continue to expand the allelic spectrum.
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals."
    explanation: >-
      Establishes the variant spectrum and the size of the reported world
      literature.
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-three variants in 43 subjects with ALG3-CDG have been reported."
    explanation: >-
      Updates the 2021 literature count and variant spectrum beyond the earlier
      40-person cohort summary.
  - reference: PMID:41089746
    reference_title: "Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing confirmed a diagnosis of ALG3-CDG with compound heterozygous variants: c.165C > T (p.Gly55=) and c.1060C > T (p.Arg354Cys) in the ALG3 gene"
    explanation: >-
      A 2025 molecularly confirmed case adds contemporary compound-heterozygous
      evidence to the allelic spectrum.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Forty-three individuals had been reported by the June 2021 ophthalmic
    review. New disease-specific cases appeared in 2025, so 43 is a dated lower
    bound rather than a current total. Population prevalence remains unknown;
    later mechanistic cohorts may overlap prior cases and are not summed here.
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-three variants in 43 subjects with ALG3-CDG have been reported."
    explanation: >-
      Anchors the last explicitly enumerated literature count while avoiding its
      conversion to population prevalence.
  - reference: PMID:39831946
    reference_title: First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study presents the first reported case of a Korean patient with Alpha-1,3-Mannosyltransferase-Congenital Disorder of Glycosylation (ALG3-CDG)"
    explanation: >-
      Demonstrates that additional disease-specific cases were published after
      the 43-person review, making that count a lower bound.
progression:
- phase: Neonatal and early mortality
  notes: >-
    Almost half of reported individuals die before or during the neonatal
    period. Survival is nevertheless variable, including survival into
    adulthood. All nine reported individuals homozygous for p.Arg171Gln died
    very early, a possible genotype association; outside that cluster the
    largest cohort found no clear genotype-phenotype correlation.
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "almost half of them die before or during the neonatal period"
    explanation: >-
      Source for the mortality statement, which previously appeared only as an
      unevidenced sentence in the entry description.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of these nine cases with this genotype passed away very early in life"
    explanation: >-
      Supports the observed p.Arg171Gln homozygote mortality cluster, classified
      as PARTIAL because the authors call the correlation possible and found no
      broader clear genotype-phenotype relationship.
diagnosis:
- name: Transferrin isoelectric focusing
  description: >-
    A type 1 transferrin isoelectric focusing pattern indicates a defect in the
    assembly or transfer of the lipid-linked oligosaccharide, placing the
    disorder in CDG type I and prompting targeted molecular or glycan analysis.
  diagnosis_term:
    preferred_term: transferrin isoelectric focusing
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:34090370
    reference_title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transferrin isoelectric focusing revealed a type 1 pattern."
    explanation: >-
      Documents the first-line biochemical screening result in ALG3-CDG.
- name: N-glycan profiling
  description: >-
    N-glycan analysis shows combined deficiency of hybrid glycans and of
    extension beyond Man5GlcNAc2, a pattern reported to be unique to ALG3-CDG.
    This makes glycan profiling potentially diagnostic rather than merely
    supportive within the CDG group. However, a 2024 study predicts that one
    processed ALG3-CDG glycan has the same molecular weight as a truncated
    MGAT2-CDG glycan, so mass alone may not distinguish every species.
  diagnosis_term:
    preferred_term: N-glycan profiling
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This spectrum of N-glycan changes is unique to ALG3-CDG."
    explanation: >-
      Establishes the diagnostic specificity of the ALG3-CDG glycan signature.
  - reference: PMID:41089746
    reference_title: "Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This presented case highlights the importance of glycan profiling and genetic analysis in diagnosing congenital disorders of glycosylation, facilitating early intervention and management."
    explanation: >-
      A 2025 case supports combined glycan profiling and genetic analysis in the
      contemporary diagnostic workflow.
  - reference: PMID:38597022
    reference_title: Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG."
    explanation: >-
      Qualifies mass-based specificity because one predicted processed ALG3
      glycan collides in molecular weight with a truncated MGAT2-CDG glycan.
- name: Molecular genetic testing
  description: >-
    Biallelic ALG3 variants confirm the diagnosis, and molecular testing is what
    distinguishes ALG3-CDG from the other CDG type I disorders that share the
    transferrin pattern.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing"
    explanation: >-
      Documents combined molecular and biochemical testing as the diagnostic
      basis.
treatments:
- name: Antiseizure management
  description: >-
    Seizures are typically intractable and non-febrile with variable semiology,
    and are managed with multiple antiseizure drugs. No pattern of drug efficacy
    could be discerned across the reported cases, so agent choice remains
    empiric. Ketogenic diet and cannabidiol are represented separately because
    their evidence and modalities differ from general pharmacotherapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the reported patients had intractable nonfebrile seizures with different semiology despite treatment with multiple antiepileptic drugs (AEDs) in addition to a ketogenic diet"
    explanation: >-
      Documents the intractability of the epilepsy and the multi-drug plus
      ketogenic-diet approach used.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A wide array of AEDs was utilized in a small number of individuals so, unfortunately, we are unable to discern a pattern of drug efficacy."
    explanation: >-
      Records explicitly that no drug-efficacy pattern could be established,
      which is why no specific agent is recommended.
- name: Ketogenic diet for intractable epilepsy
  description: >-
    A ketogenic diet controlled or markedly reduced drug-resistant seizures in
    a pair of affected twins during ten months of follow-up. This is direct but
    very small case-series evidence, and hypoglycaemia risk requires caution.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32389449
    reference_title: Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patients were the first patients with ALG3-CDG whose intractable epilepsies were controlled by ketogenic diet."
    explanation: >-
      Direct disease-specific twin case report supports seizure control with a
      ketogenic diet, without implying population-level efficacy.
  - reference: PMID:32389449
    reference_title: Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, CDG patients already have a tendency for hypoglycemia due to hyperinsulinism and it should be kept in mind that ketogenic diet may also potentiate this effect"
    explanation: >-
      Qualifies the treatment with a disease-relevant safety concern.
- name: Cannabidiol for ALG3-CDG with Lennox-Gastaut syndrome
  description: >-
    In one 2025 case with concurrent ALG3-CDG and Lennox-Gastaut syndrome,
    cannabidiol plus dietary management produced seizure freedom for more than
    13 months with EEG and developmental improvement. This is promising
    single-case evidence specific to the comorbid LGS context, not a general
    efficacy claim for ALG3-CDG epilepsy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cannabidiol
      term:
        id: CHEBI:69478
        label: cannabidiol
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39831946
    reference_title: First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cannabidiol therapy, combined with dietary management, led to seizure freedom for over 13 months, significant EEG improvement, and enhanced developmental outcomes."
    explanation: >-
      Supports the reported outcome in a single ALG3-CDG/LGS case while the
      description preserves its limited scope.
- name: Developmental therapies
  description: >-
    Physical, occupational and speech therapy are part of the recommended
    baseline management. All individuals with contractures who were still living
    received physical and occupational therapy, and none had required surgery.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental assessment with initiation of physical, occupational, and speech therapies"
    explanation: >-
      Part of the recommended baseline evaluation and management plan.
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of those with contractures and were still living, all received physical and occupational therapy, and none have yet undergone surgical treatment."
    explanation: >-
      Documents that conservative therapy has so far been sufficient for the
      contractures in this cohort.
- name: Baseline multisystem evaluation and monitoring
  description: >-
    No disease-modifying therapy exists. The management recommendation that
    emerged from the expanded phenotype is proactive rather than reactive:
    baseline endocrine, renal, cardiac and immunological evaluation at the time
    of diagnosis, with ongoing monitoring, because these systems are involved
    more often than the historical description suggested.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring."
    explanation: >-
      States the multisystem baseline evaluation and monitoring recommendation.
  - reference: PMID:38917675
    reference_title: "Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation."
    supports: SUPPORT
    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: >-
      Adds a contemporary CDG natural-history recommendation for structured
      cardiac surveillance after documenting ALG3-CDG cardiomyopathy.
discussions:
- discussion_id: gap_alg3_truncated_versus_absent_glycan
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the severity of ALG3-CDG driven by the absence of mature glycan, or by the
    active transfer of a truncated Man5GlcNAc2 glycan that misfolds or mistargets
    its carrier proteins?
  attaches_to:
  - pathophysiology#Truncated Man5GlcNAc2 Lipid-Linked Precursor
  - pathophysiology#Protein Hypoglycosylation
  rationale: >-
    ALG3-CDG does not simply fail to glycosylate: it transfers a short,
    abnormal glycan, and the resulting N-glycan spectrum is disease
    characteristic. Patient fibroblasts now establish chronic UPR and ERAD
    activation, but do not distinguish toxicity of the truncated glycan from
    the consequences of missing mature glycans. That raises the possibility
    that the truncated glycan is actively harmful rather than merely
    insufficient, which would explain why a block partway along the assembly
    line is so severe. Distinguishing loss of function from gain of a bad glycan
    matters therapeutically, because the two imply opposite strategies:
    supplying the missing sugar versus preventing transfer of the truncated
    precursor.
  evidence:
  - reference: PMID:38597022
    reference_title: Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts"
    explanation: >-
      Establishes the ER-stress phenotype motivating the question, but does not
      resolve whether truncated-glycan transfer or mature-glycan deficiency is
      causal.
  proposed_experiments:
  - experiment_id: exp_alg3_truncated_glycan_toxicity
    name: Comparing truncated-glycan transfer against no-transfer in ALG3-deficient cells
    description: >-
      In ALG3-deficient patient fibroblasts, compare glycoprotein folding,
      trafficking and ER stress between the native truncated-transfer state and a
      state where oligosaccharyltransferase-mediated transfer of the truncated
      precursor is blocked, to determine whether removing the abnormal glycan
      improves or worsens client protein handling.
    decision_criterion: >-
      Improved client folding and reduced ER stress when truncated transfer is
      blocked would show the short glycan is actively harmful.
    supporting_outcome:
    - The truncated glycan is actively deleterious, favouring strategies that prevent its transfer
    refuting_outcome:
    - Blocking transfer worsens outcomes, confirming that any glycan is better than none and favouring substrate supplementation
- discussion_id: gap_alg3_glycan_signature_as_biomarker
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Can the ALG3-specific N-glycan signature serve as a quantitative severity or
    treatment-response biomarker rather than only a diagnostic fingerprint?
  attaches_to:
  - pathophysiology#Truncated Man5GlcNAc2 Lipid-Linked Precursor
  - pathophysiology#Multisystem Glycoprotein Dysfunction
  rationale: >-
    The combined deficiency of hybrid glycans and of extension beyond Man5GlcNAc2
    is described as unique to ALG3-CDG, which establishes it as a diagnostic
    fingerprint. What is not established is whether the magnitude of that
    deviation tracks clinical severity across the small published population,
    or whether it would move under any intervention. Without that,
    any future trial in this ultra-rare disorder has no surrogate endpoint and
    would have to rely on clinical outcomes in a population where about half die
    neonatally.
  evidence:
  - reference: PMID:33583022
    reference_title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of elevation of the mono/di oligo ratio of transferrin may correlate with severity and/or age, as seen in other CDGs, but we do not have enough power to definitively illustrate this."
    explanation: >-
      The cohort raises the biomarker hypothesis but explicitly reports
      insufficient power to establish the correlation.
  proposed_experiments:
  - experiment_id: exp_alg3_glycan_severity_correlation
    name: Correlating quantitative N-glycan deviation with clinical severity across the reported ALG3-CDG cohort
    description: >-
      Assemble quantitative N-glycan profiles alongside standardized severity
      scoring and residual enzyme activity across available ALG3-CDG individuals
      and, where possible, serial samples, to test whether glycan deviation
      predicts severity and whether it varies within an individual over time.
    decision_criterion: >-
      A monotonic relationship between glycan deviation and severity score, stable
      within individuals, would qualify it as a candidate surrogate endpoint.
    supporting_outcome:
    - Glycan deviation tracks severity and is a viable surrogate endpoint for trials
    refuting_outcome:
    - Glycan profile is invariant across severities, confining it to a purely diagnostic role
references:
- reference: PMID:10581255
  title: "Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase"
- reference: PMID:23791010
  title: "ALG3-CDG (CDG-Id): clinical, biochemical and molecular findings in two siblings"
- reference: PMID:32389449
  title: Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG
- reference: PMID:33583022
  title: "Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG"
- reference: PMID:34090370
  title: "ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings"
- reference: PMID:35211808
  title: Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation
- reference: PMID:38597022
  title: Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG
- reference: PMID:38917675
  title: "Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation"
- reference: PMID:39831946
  title: First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome
- reference: PMID:41089746
  title: "Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis"
📚

References & Deep Research

References

10
PMID:10581255
Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase
No top-level findings curated for this source.
PMID:23791010
ALG3-CDG (CDG-Id): clinical, biochemical and molecular findings in two siblings
No top-level findings curated for this source.
PMID:32389449
Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG
No top-level findings curated for this source.
PMID:33583022
Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG
No top-level findings curated for this source.
PMID:34090370
ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings
No top-level findings curated for this source.
PMID:35211808
Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation
No top-level findings curated for this source.
PMID:38597022
Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG
No top-level findings curated for this source.
PMID:38917675
Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation
No top-level findings curated for this source.
PMID:39831946
First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome
No top-level findings curated for this source.
PMID:41089746
Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 12 citations 2026-08-01T12:51:28.156705

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: ALG3-congenital disorder of glycosylation
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on ALG3-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 NCIT (NCI Thesaurus) clinical-intervention 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, NCIT, 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 (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

ALG3-congenital disorder of glycosylation: comprehensive disease-characteristics report

Executive summary

ALG3-congenital disorder of glycosylation (ALG3-CDG) is an ultra-rare, autosomal-recessive disorder of endoplasmic-reticulum N-linked glycosylation caused by biallelic pathogenic variants in ALG3. Deficient ALG3 α-1,3-mannosyltransferase activity prevents normal extension of the dolichol-linked oligosaccharide beyond Man5GlcNAc2, producing truncated lipid-linked oligosaccharides, protein hypoglycosylation, and severe congenital multisystem disease. Neurologic, ocular, skeletal, feeding, growth, endocrine, immune, renal, cardiac, and coagulation abnormalities have all been documented. Approximately 40 affected individuals had been reported by the largest 2021 cohort, so frequency, survival, penetrance, and genotype–phenotype estimates remain imprecise. No disease-modifying treatment or ALG3-CDG-specific clinical trial was identified; management is supportive and surveillance-based. (alsharhan2021expandingthephenotype pages 3-5, alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 1-3)

The following table summarizes the most actionable knowledge-base annotations.

Domain Knowledge-base finding Quantitative evidence Suggested ontology terms Evidence type/source
Disease identifiers Rare Mendelian CDG caused by ALG3 deficiency; also called ALG3-CDG, CDG-Id, CDGS-IV/CDBS-IV; MONDO disease-target association available ~40 reported individuals by 2021; first reported in 1995 (alsharhan2021expandingthephenotype pages 3-5, alsharhan2021expandingthephenotype pages 6-8, himmelreich2019novelvariantsand pages 1-2, OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3) MONDO:0010998; congenital disorder of glycosylation; autosomal recessive inheritance (HP:0000007) Human cohort/review + Open Targets disease record (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2, OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3)
Inheritance / etiology Primary cause is biallelic germline pathogenic variants in ALG3 encoding ER alpha-1,3-mannosyltransferase 11 novel variants in 10 new individuals in 2021 cohort; 4 additional biochemically confirmed variants in 2019 cohort (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2) ALG3; protein N-linked glycosylation (GO:0006487); endoplasmic reticulum membrane Human molecular genetics (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2)
Hallmark neurologic phenotype Severe multisystem disease with prominent neurologic involvement including epilepsy, microcephaly, hypotonia, developmental delay/intellectual disability Nijmegen scores averaged 31 in 8 evaluated individuals; seizures often intractable (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6) Seizure (HP:0001250); Microcephaly (HP:0000252); Hypotonia (HP:0001252); Global developmental delay (HP:0001263); Intellectual disability (HP:0001249) Human cohort/case series (alsharhan2021expandingthephenotype pages 3-5, alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6)
Ocular phenotype Frequent ophthalmic disease including strabismus/optic atrophy; severe cases may include retinal ganglion cell loss, optic nerve hypoplasia, cataracts, chorioretinal dystrophy Ocular findings described as among most frequent in cohort; optic nerve hypoplasia highlighted in literature review (alsharhan2021expandingthephenotype pages 5-6, farolfi2021alg3cdgapatient pages 4-5) Strabismus (HP:0000486); Optic atrophy (HP:0000648); Optic nerve hypoplasia (HP:0000609); Congenital cataract (HP:0000519); Nystagmus (HP:0000639) Human case series/case report (alsharhan2021expandingthephenotype pages 5-6, farolfi2021alg3cdgapatient pages 4-5)
Skeletal / congenital anomalies Skeletal anomalies and contractures are common; clubfeet, scoliosis, arthrogryposis, hip dysplasia reported Skeletal abnormalities in 8/10 in 2021 cohort (alsharhan2021expandingthephenotype pages 5-6) Arthrogryposis multiplex congenita (HP:0002804); Talipes equinovarus (HP:0001762); Scoliosis (HP:0002650); Joint contracture (HP:0001371) Human cohort (alsharhan2021expandingthephenotype pages 5-6)
Feeding / GI / growth Feeding difficulties and failure to thrive are common; some require tube feeding GI problems in 8/10; feeding difficulties 6/8; failure to thrive 4/8; tube feeding 3/8 (alsharhan2021expandingthephenotype pages 5-6) Feeding difficulties (HP:0011968); Failure to thrive (HP:0001508) Human cohort (alsharhan2021expandingthephenotype pages 5-6)
Expanded phenotype Endocrine, immunologic, renal, cardiac, and neural tube defect features broaden current disease understanding Endocrine abnormalities in >50%; recurrent infections/immunodeficiency in 75% (6/8); mild aortic root dilatation in 4 subjects; renal anomalies reported (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 1-3) Hypothyroidism (HP:0000821); Adrenal insufficiency (HP:0000846); Immunodeficiency (HP:0002721); Recurrent infections (HP:0002719); Aortic root dilatation (HP:0002616); Renal cyst (HP:0000107) Human cohort (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 1-3)
Biochemical mechanism Loss of ALG3 function blocks addition of mannose to Man5GlcNAc2-PP-dolichol in ER, causing substrate accumulation and truncated LLOs with deficient N-glycan extension Accumulation of Man5GlcNAc2-PP-dolichol; reduced mature Glc3Man9GlcNAc2-PP-dolichol; reduced Man9GlcNAc2 and increased Man0-4GlcNAc2 in plasma (himmelreich2019novelvariantsand pages 1-2, himmelreich2019novelvariantsand pages 6-7, alsharhan2021expandingthephenotype pages 5-6) Protein N-linked glycosylation (GO:0006487); dolichol-linked oligosaccharide biosynthetic process; endoplasmic reticulum (GO:0005783) Human biochemical/molecular studies (himmelreich2019novelvariantsand pages 1-2, himmelreich2019novelvariantsand pages 6-7, alsharhan2021expandingthephenotype pages 5-6)
Diagnostic biomarkers Type I carbohydrate-deficient transferrin profile is a key screen; plasma N-glycan profiling shows a pattern considered distinctive for ALG3-CDG Elevated disialotransferrin 24.12 ± 0.41% (normal 5.0-13.5%) and reduced tetrasialotransferrin 26.9 ± 1.24% (normal 30.0-55.0%) in 2019 cohort; increased mono:di-glycosylated ratio in 2021 cohort (himmelreich2019novelvariantsand pages 6-7, alsharhan2021expandingthephenotype pages 5-6) Abnormal transferrin glycosylation; carbohydrate-deficient transferrin; N-glycan biosynthetic defect Human clinical biochemistry (himmelreich2019novelvariantsand pages 6-7, alsharhan2021expandingthephenotype pages 5-6, alsharhan2021expandingthephenotype pages 1-3)
Diagnostic methods Diagnosis is established by molecular testing plus biochemical confirmation; useful methods include serum transferrin IEF/capillary electrophoresis, plasma protein N-glycan MS, and LLO analysis Diagnostic delay of 4-33 years in 50% of cases in one cohort (alsharhan2021expandingthephenotype pages 5-6) Whole exome sequencing; gene panel testing; serum transferrin isoelectric focusing Human clinical diagnostics (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2, alsharhan2021expandingthephenotype pages 5-6, alsharhan2021expandingthephenotype pages 10-11)
Management No curative disease-specific therapy established; care is supportive and multidisciplinary with recommended baseline endocrine, renal, cardiac, and immunologic evaluation Hormone replacement used in 2 subjects; PT/OT used for contractures; seizures often refractory to multiple AEDs; ketogenic diet noted as successful in affected twins in cited literature (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6, alsharhan2021expandingthephenotype pages 10-11) Supportive care; physical therapy; occupational therapy; antiepileptic therapy Human cohort/case-based management evidence (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6, alsharhan2021expandingthephenotype pages 10-11)
Prognosis / mortality Course is congenital and often severe, but survival into adulthood is possible with variable neurodevelopment; early lethality occurs in a subset 3 deaths reported among 10 newly described individuals in 2021 article context (stillbirth, neonatal death, death at 1 year from multiorgan failure); one review/case paper states almost half die before or during neonatal period (alsharhan2021expandingthephenotype pages 3-5, farolfi2021alg3cdgapatient pages 4-5) Multisystem disorder; developmental disability Human cohort/case report (alsharhan2021expandingthephenotype pages 3-5, farolfi2021alg3cdgapatient pages 4-5)
Recent developments (2023-2024) Broader CDG field emphasizes multi-omics and unmet need for targeted therapies; 2024 sources suggest cardiac screening relevance and preclinical glycosylation-directed therapy, but not validated ALG3-specific treatment 2023 review: 163 CDG genetic defects / 193 phenotypes; no ALG3-specific interventional trial retrieved; one 2024 cardiomyopathy paper included a patient with ALG3-CDG (search results) (OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3) Multi-omics; natural history; cardiomyopathy screening Authoritative review/Open Targets + targeted literature search (OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3)
Evidence gaps No established environmental or infectious causes, no confirmed protective factors, no robust penetrance estimates, no validated natural-history registry specific to ALG3-CDG, and no clearly established animal model/natural disease in other species retrieved here Clinical trials search returned no relevant ALG3-specific interventional trials; model-organism evidence in retrieved set was indirect/general rather than validated ALG3-specific disease model Not available / not established Explicit gap from targeted searches and available evidence set (OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3)

Table: This table condenses the most actionable knowledge-base facts for ALG3-congenital disorder of glycosylation, including identifiers, core phenotypes, molecular mechanism, diagnostics, management, prognosis, and key evidence gaps. It is designed to support structured disease annotation while keeping direct human evidence separate from broader CDG context.

Evidence framework and limitations

Claims below are labeled by evidence type: human clinical, human biochemical, cellular/in vitro, or general CDG evidence. The strongest disease-specific evidence comes from small case series published in 2019 and 2021. The most recent ALG3-specific mechanistic paper found in the search was a 2024 study of deficient glycan extension and ER stress, but its full text was unavailable to the evidence extractor; it is therefore identified as an emerging source rather than used for unsupported quantitative claims. No robust population cohort, randomized trial, validated ALG3-specific quality-of-life instrument, or disease-specific natural-history registry analysis was retrieved.

1. Disease information

Definition

ALG3-CDG is a monogenic congenital disorder of N-glycosylation. The disease results from loss of ALG3-dependent addition of mannose to the dolichol-linked Man5GlcNAc2 precursor in the ER. The resulting generalized protein hypoglycosylation produces a predominantly neurodevelopmental but broadly multisystem phenotype. (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2)

Identifiers and names

  • MONDO: MONDO:0010998.
  • OMIM phenotype: 601110, reported in the ALG3-CDG literature. This should not be confused with the separate gene-entry identifier used by some databases. (alsharhan2021expandingthephenotype pages 3-5)
  • Gene: ALG3, Ensembl ENSG00000214160; approved name “ALG3 alpha-1,3-mannosyltransferase.” Open Targets associates this single target with MONDO:0010998. (OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3)
  • Common names: ALG3-CDG; congenital disorder of glycosylation type Id; CDG-Id; CDGS-IV; carbohydrate-deficient glycoprotein syndrome type IV; CDBS-IV. (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2)
  • Orphanet, MeSH, ICD-10/ICD-11: a disease-specific code was not verified in the retrieved evidence. In clinical coding, it may fall under broader congenital glycosylation/metabolic-disorder categories; a database implementation should not assign an unverified specific code.

The evidence is aggregated disease-level literature, supplemented by individual case and family reports. It is not derived from a population-scale EHR dataset.

Key abstract quotation

The largest disease-specific series states: “Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties.” Alsharhan et al., Journal of Inherited Metabolic Disease, published March 2021, DOI: https://doi.org/10.1002/jimd.12367. (alsharhan2021expandingthephenotype pages 1-3)

2. Etiology

Causal factor

The primary cause is biallelic germline pathogenic or likely pathogenic ALG3 variants, producing autosomal-recessive deficiency of ER α-1,3-mannosyltransferase. Variant classes include missense, nonsense, frameshift, and splice-region variants. Reported pathogenic changes are enriched in predicted transmembrane regions, consistent with disruption of an integral ER membrane enzyme. (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2)

Illustrative biochemically confirmed variants include c.350G>C (p.Arg117Pro), c.1263G>A (p.Trp421Ter), c.1037A>G (p.Asn346Ser), c.296+4A>G, and c.160_196del. Another patient carried variants in trans, c.116del p.(Pro39Argfs*40) and c.1060C>T p.(Arg354Cys), classified as pathogenic under ACMG criteria in that report. (himmelreich2019novelvariantsand pages 1-2, farolfi2021alg3cdgapatient pages 4-5)

Risk factors

  • Established genetic risk: two disease-causing ALG3 alleles; parental consanguinity increases the probability of homozygosity in autosomal-recessive families.
  • Family history: affected siblings or known carrier parents confer the expected Mendelian recurrence risk.
  • Environmental, lifestyle, occupational, infectious, age, or sex risk factors: none established. These factors do not cause the inherited enzymatic defect.
  • Modifier genes: none validated.
  • Somatic causation: not supported; the reported disease alleles are constitutional/germline.

Protective factors and gene–environment interaction

No protective allele, diet, exposure, or reproducible gene–environment interaction has been established. Supportive nutrition may reduce secondary malnutrition but does not correct the primary glycosylation defect. Environmental modifiers of seizure burden, infection frequency, or nutritional status may affect morbidity, but these are not proven disease-specific interactions.

3. Phenotypes

Phenotype estimates are vulnerable to ascertainment bias and small denominators. Onset is generally prenatal, neonatal, or early infantile, although diagnosis may be delayed into adulthood.

Neurologic and developmental

  • Global developmental delay/intellectual disability—usually severe but variable; some adults in one cohort had neurocognitive abilities corresponding approximately to ages 7–9 years. Suggested terms: HP:0001263, HP:0001249.
  • Epilepsy, often nonfebrile and drug-resistant; multiple antiseizure medications and sometimes ketogenic diet have been used. HP:0001250.
  • Hypotonia, sometimes with later hypertonia. HP:0001252; hypertonia HP:0001276.
  • Microcephaly. HP:0000252.
  • Brain abnormalities: cortical atrophy, cerebellar vermis hypoplasia, and neural-tube defects have been reported. Suggested terms: cerebral cortical atrophy HP:0002120; cerebellar vermis hypoplasia HP:0001320; neural-tube defect HP:0045005.

The mean Nijmegen CDG severity score was 31, in the severe range, among eight assessed individuals in the 2021 cohort. (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6)

Ophthalmic

Strabismus and optic atrophy are prominent. Optic-nerve hypoplasia, retinal ganglion-cell loss, inner-retinal thinning, nystagmus, congenital cataracts, corneal opacity, chorioretinal dystrophy, and severe visual impairment have also been described. Suggested HPO terms include HP:0000486 (strabismus), HP:0000648 (optic atrophy), HP:0000609 (optic-nerve hypoplasia), HP:0000519 (congenital cataract), and HP:0000639 (nystagmus). (alsharhan2021expandingthephenotype pages 5-6, farolfi2021alg3cdgapatient pages 4-5)

Musculoskeletal and congenital anomalies

Skeletal abnormalities occurred in 8/10 members of the 2021 cohort. Findings include arthrogryposis, joint contractures, clubfeet/talipes, scoliosis, and hip dysplasia. Suggested terms: HP:0002804, HP:0001371, HP:0001762, HP:0002650, and HP:0001385. These manifestations may be congenital and can materially limit mobility and activities of daily living. (alsharhan2021expandingthephenotype pages 5-6)

Feeding, gastrointestinal, and growth

Gastrointestinal or feeding problems affected 8/10; among eight with detailed data, 6/8 had feeding difficulty, 4/8 failure to thrive, and 3/8 required tube feeding. Suggested terms: feeding difficulty HP:0011968, failure to thrive HP:0001508, and tube feeding dependence where applicable. (alsharhan2021expandingthephenotype pages 5-6)

Endocrine, immune, renal, cardiac, and hematologic

  • Endocrine abnormalities occurred in more than half of the 2021 cohort and included central hypothyroidism, adrenal insufficiency, growth-hormone deficiency, panhypopituitarism, and hypoglycemia. Suggested terms: HP:0000821, HP:0000846, HP:0000824, and HP:0001943. Hormone replacement was required in affected individuals. (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6)
  • Recurrent infections or immunodeficiency occurred in 6/8 (75%) of sufficiently characterized subjects. Suggested terms: HP:0002719 and HP:0002721. (alsharhan2021expandingthephenotype pages 6-8)
  • Renal findings include nephromegaly, cystic kidneys, and duplex kidney. Suggested terms include nephromegaly HP:0000105, renal cyst HP:0000107, and duplex collecting system where applicable. (alsharhan2021expandingthephenotype pages 6-8)
  • Mild aortic-root dilatation was reported in four subjects; cardiomyopathy and vascular-anatomy abnormalities have also been reported. Suggested term: HP:0002616. (alsharhan2021expandingthephenotype pages 6-8, himmelreich2019novelvariantsand pages 1-2)
  • Coagulation abnormalities include low antithrombin III, reduced factor XI, prolonged activated partial thromboplastin time, and other glycoprotein-related abnormalities. (alsharhan2021expandingthephenotype pages 5-6)

Quality of life

No ALG3-CDG-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was retrieved. Nevertheless, severe developmental disability, refractory epilepsy, visual impairment, feeding-tube dependence, contractures, recurrent infections, and multispecialty surveillance imply major effects on independence, education, mobility, communication, family caregiving, and health-care utilization.

4. Genetic and molecular information

ALG3 encodes a 438-amino-acid, approximately 50.1-kDa, integral ER membrane α-1,3-mannosyltransferase. It is the first dolichol-phosphate-mannose-dependent mannosyltransferase acting on the luminal phase of N-glycan precursor assembly. (himmelreich2019novelvariantsand pages 1-2)

Reported disease alleles include missense, nonsense, frameshift, deletion, and splice-region variants. Functional consequences are predominantly loss of function or marked reduction in enzymatic competence, although measured ALG3 protein abundance can vary and protein quantity alone does not establish normal catalytic function. In the 2019 study, patient-specific protein abundance ranged from 14.3% to 122.4% of control, illustrating that pathogenicity may reflect abnormal structure or catalytic activity rather than simple absence. (himmelreich2019novelvariantsand pages 6-7)

The 2021 cohort added 11 novel variants in 10 individuals, and the 2019 study added four biochemically confirmed variants. Population allele frequencies were not available in the extracted evidence; disease-causing alleles are expected to be rare, but each variant should be checked directly in the current gnomAD release before knowledge-base ingestion. (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2)

No validated modifier gene, disease-specific methylation signature, recurrent pathogenic chromosomal rearrangement, anticipation mechanism, or repeat expansion has been established. Large deletions involving ALG3 could theoretically cause disease if biallelic or paired with a pathogenic sequence variant, but this was not demonstrated in the retrieved cohort evidence.

5. Environmental information

ALG3-CDG is not caused by toxins, radiation, pollution, occupation, smoking, alcohol, diet, or infection. No infectious trigger or zoonotic transmission exists. Diet and medical exposures can alter secondary complications—for example nutritional status or seizure control—but do not create or reverse the congenital enzymatic lesion. Thus, environmental and lifestyle fields should be annotated “not established as etiologic”, not “absent in every patient.”

6. Mechanism and pathophysiology

Upstream causal chain

  1. Biallelic ALG3 dysfunction reduces ER α-1,3-mannosyltransferase activity.
  2. ALG3 fails to transfer mannose from dolichol-phosphate-mannose to Man5GlcNAc2-PP-dolichol.
  3. Man5GlcNAc2-PP-dolichol accumulates, while mature Glc3Man9GlcNAc2-PP-dolichol falls.
  4. The oligosaccharyltransferase system receives an undersized precursor, resulting in inefficient site occupancy and transfer of truncated glycans.
  5. Plasma and cellular glycoproteins show hypoglycosylation and deficient extension beyond Man5GlcNAc2.
  6. Dysfunction of many glycoproteins across developing brain, eye, endocrine organs, skeleton, immune system, liver/coagulation system, kidney, and heart produces the multisystem phenotype. (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2, himmelreich2019novelvariantsand pages 6-7)

No normal pathway can extend the ALG3-deficient precursor to Man8GlcNAc2 or Man9GlcNAc2 without the missing ALG3 reaction. Plasma studies accordingly show reduced Man9GlcNAc2 and altered small high-mannose species. (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6)

Downstream cellular processes

The best-supported processes are defective protein N-linked glycosylation, impaired glycoprotein folding/trafficking, and altered glycoprotein stability or function. A 2024 study titled Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG identifies ER stress as an active recent research direction, but quantitative findings were not available in the retrieved full-text evidence and should not yet be converted into patient-level frequency claims.

Suggested GO annotations include:

  • GO:0006487—protein N-linked glycosylation;
  • GO:0005783—endoplasmic reticulum;
  • ER membrane and dolichol-linked oligosaccharide biosynthetic process;
  • protein folding and ER quality-control processes, where supported experimentally.

Relevant cell types are broad rather than a uniquely targeted lineage. Suggested CL labels include neuron, retinal ganglion cell, skeletal muscle cell/myocyte, chondrocyte, hepatocyte, endocrine cell, renal epithelial cell, cardiomyocyte, and immune lymphoid/myeloid cells. These are mechanistic annotation suggestions based on affected tissues; direct single-cell validation is lacking.

Molecular profiling and advanced technology

Plasma N-glycomics is the strongest disease-specific molecular-profile evidence: increased small high-mannose species, reduced Man9GlcNAc2, and combined deficiency of hybrid glycans/glycan extension beyond Man5GlcNAc2 were described as distinctive for ALG3-CDG. No disease-specific single-cell RNA sequencing, spatial transcriptomics, lipidomics, integrated multi-omics, organoid, or CRISPR-screen dataset was retrieved. (alsharhan2021expandingthephenotype pages 1-3, alsharhan2021expandingthephenotype pages 5-6)

7. Anatomical structures affected

Organ and system level

  • Central nervous system: cerebral cortex, cerebellar vermis, and broader developing brain.
  • Eye and visual pathways: retina, retinal ganglion cells, optic nerve/anterior optic pathways, lens, cornea, and ocular motor apparatus.
  • Musculoskeletal system: joints, spine, feet, hips, skeletal muscle, and connective tissues.
  • Endocrine system: hypothalamic-pituitary axes, thyroid, adrenal, and growth-regulatory pathways.
  • Gastrointestinal/nutritional system: oropharyngeal feeding function and growth.
  • Immune/hematologic system: immunoglobulin/immune function and glycosylated coagulation proteins.
  • Kidney and urinary tract: renal parenchyma and collecting-system development.
  • Cardiovascular system: aortic root, myocardium, and vascular anatomy. (alsharhan2021expandingthephenotype pages 6-8, himmelreich2019novelvariantsand pages 1-2, farolfi2021alg3cdgapatient pages 4-5)

Suggested UBERON labels include brain (UBERON:0000955), cerebral cortex (UBERON:0000956), cerebellum (UBERON:0002037), eye (UBERON:0000970), retina (UBERON:0000966), optic nerve (UBERON:0000941), kidney (UBERON:0002113), heart (UBERON:0000948), and pituitary gland (UBERON:0000007).

Subcellular localization

The primary compartment is the endoplasmic-reticulum membrane; the affected substrate is a dolichol-linked oligosaccharide assembled on the ER membrane. Lateralization is generally bilateral/systemic rather than intrinsically unilateral.

8. Temporal development

ALG3-CDG is congenital, with pathogenic glycosylation impairment present from embryonic development. Prenatal or neonatal manifestations may include neural-tube defects, congenital contractures, clubfeet, dysmorphism, ocular abnormalities, growth problems, or neonatal multisystem failure. Neurologic and feeding abnormalities usually become apparent in infancy or early childhood.

The course is chronic and lifelong among survivors. Developmental impairment may remain severe; epilepsy can be persistent and refractory; orthopedic contractures and scoliosis may progress; endocrine, immune, renal, and cardiac abnormalities may be detected later through surveillance. Diagnosis was delayed by 4–33 years in 50% of one cohort, demonstrating that congenital onset does not ensure early recognition. (alsharhan2021expandingthephenotype pages 5-6)

No validated disease stages, remission pattern, or quantitative progression model exists. The prenatal and early postnatal periods are critical because glycosylation is essential to organogenesis, while early childhood offers a practical window for seizure treatment, nutritional support, hormone replacement, visual assessment, and prevention of orthopedic complications.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous carrier parents, each pregnancy has the standard 25% affected, 50% carrier, and 25% unaffected/non-carrier probabilities, assuming both variants are fully disease-causing.

By 2021, the literature contained approximately 40 reported individuals; a separate ophthalmic review counted 43 subjects and 33 variants, likely reflecting differences in publication timing or inclusion criteria. This is a case count, not prevalence. Reliable incidence, prevalence per 100,000, carrier frequency, sex ratio, penetrance, or life-table estimates are unavailable. (alsharhan2021expandingthephenotype pages 6-8, farolfi2021alg3cdgapatient pages 4-5)

Affected individuals have been reported across multiple geographic and ancestral backgrounds, including European, Middle Eastern, Asian, Caribbean, and other families. No single founder allele or population-specific founder effect was established in the retrieved evidence. Consanguinity can enrich homozygous alleles but is not necessary; compound heterozygous disease is well documented. (farolfi2021alg3cdgapatient pages 4-5)

Penetrance is presumed high for clearly deleterious biallelic alleles, but formal estimates are absent. Expressivity is variable. Anticipation is not expected. Germline mosaicism has not been established but remains a general residual counseling consideration after an apparently de novo event.

10. Diagnostics

Recommended workflow

  1. Clinical suspicion: congenital or early-onset multisystem disease with severe developmental delay, epilepsy, microcephaly/hypotonia, ocular disease, contractures/clubfeet, feeding failure, endocrine abnormalities, recurrent infections, renal anomalies, or cardiac disease.
  2. Biochemical screening: serum transferrin isoelectric focusing, capillary electrophoresis, or mass-spectrometric transferrin glycoform analysis. ALG3-CDG usually gives a type-I pattern, indicating deficient glycan-site occupancy/assembly.
  3. Molecular testing: a CDG/multisystem disease panel, exome sequencing, or genome sequencing demonstrating two pathogenic/likely pathogenic ALG3 variants in trans.
  4. Biochemical confirmation: plasma protein N-glycan profiling by mass spectrometry and, where available, fibroblast lipid-linked oligosaccharide analysis.
  5. Family testing: parental segregation and cascade testing. (alsharhan2021expandingthephenotype pages 3-5, himmelreich2019novelvariantsand pages 1-2, himmelreich2019novelvariantsand pages 6-7)

In the 2019 cohort, disialotransferrin was 24.12 ± 0.41% versus a reference interval of 5.0–13.5%, and tetrasialotransferrin was 26.9 ± 1.24% versus 30.0–55.0%. Fibroblast phosphomannomutase activity was normal, helping distinguish ALG3-CDG from PMM2-CDG. LLO analysis showed Man5GlcNAc2-PP-dolichol accumulation. (himmelreich2019novelvariantsand pages 6-7)

Genetic-test utility

  • Panel or WES: appropriate first-line molecular approaches when the phenotype is recognizable or broadly multisystem.
  • WGS: useful after negative panel/WES, especially for noncoding, structural, complex, or poorly captured variants.
  • Single-gene sequencing: appropriate when biochemical profiling strongly points to ALG3.
  • Deletion/duplication analysis: consider if only one pathogenic allele is identified.
  • CMA, karyotype, FISH, mitochondrial DNA, and repeat-expansion testing: not primary tests for isolated suspected ALG3-CDG, although CMA may be appropriate for an unresolved syndromic phenotype.
  • RNA studies: potentially useful for splice variants or variants of uncertain significance; not a routine validated disease-specific diagnostic.

Imaging and organ assessment

Brain MRI, ophthalmologic examination with optical coherence tomography when feasible, EEG, echocardiography, renal ultrasound, endocrine testing, immunologic assessment, coagulation studies, growth/nutritional evaluation, and orthopedic assessment are guided by the phenotype. The 2021 authors specifically recommend baseline and ongoing endocrine, renal, cardiac, and immunologic evaluation. (alsharhan2021expandingthephenotype pages 1-3)

Differential diagnosis

Important differentials include PMM2-CDG, ALG1-CDG, ALG2-CDG, ALG6-CDG, ALG8-CDG, ALG9-CDG, ALG12-CDG, DPAGT1-CDG, DPM-pathway disorders, and other congenital syndromes featuring arthrogryposis, optic-nerve hypoplasia, epilepsy, or abnormal transferrin glycosylation. The ALG3-associated LLO and plasma N-glycan signature provides discrimination from many type-I CDGs.

Screening

ALG3-CDG is not part of routine population newborn screening. Targeted familial carrier testing, cascade testing, prenatal molecular diagnosis, and preimplantation genetic testing are feasible after familial variants are established.

11. Outcome and prognosis

Prognosis is highly variable but often serious. Survival into adulthood—up to 37 years in the 2021 series—is documented, while stillbirth, neonatal death, and death at one year from multiorgan failure also occurred. One ophthalmic review stated that almost half of reported subjects died before or during the neonatal period, but this estimate is strongly susceptible to small-sample and publication bias and should not be treated as a population survival rate. (alsharhan2021expandingthephenotype pages 3-5, farolfi2021alg3cdgapatient pages 4-5)

No valid 5- or 10-year survival estimates, life expectancy, mortality rate, or standardized disability-adjusted-life-year data exist. Major morbidity arises from severe neurodevelopmental disability, refractory epilepsy, visual impairment, feeding and growth failure, contractures, endocrine deficiency, recurrent infections, coagulation abnormalities, renal disease, and cardiac complications.

Potentially adverse prognostic indicators—based on clinical reasoning rather than validated models—include prenatal structural anomalies, neonatal multisystem failure, severe brain malformations, refractory seizures, profound feeding failure, major cardiomyopathy, adrenal insufficiency, immunodeficiency, and recurrent serious infection. No validated molecular prognostic biomarker or genotype-based survival model exists.

12. Treatment

Current standard: supportive multidisciplinary care

There is no approved curative or disease-modifying therapy. Treatment should be individualized and may include:

  • antiseizure medications; ketogenic diet may be considered for drug-resistant epilepsy under specialist supervision, although response is inconsistent and evidence in ALG3-CDG is case-based;
  • enteral nutritional support, feeding therapy, and management of aspiration or growth failure;
  • thyroid, glucocorticoid, growth-hormone, or other endocrine replacement when deficiency is documented;
  • physical and occupational therapy, stretching, orthoses, and orthopedic surgery when indicated for contractures, clubfeet, hip disease, or scoliosis;
  • visual habilitation and management of cataract or other treatable ocular disease;
  • treatment and prevention of infections based on immunologic assessment;
  • cardiology, nephrology, hematology, and coagulation management based on organ findings. (alsharhan2021expandingthephenotype pages 6-8, alsharhan2021expandingthephenotype pages 5-6, alsharhan2021expandingthephenotype pages 10-11)

Suggested NCIt intervention concepts include Supportive Care, Anticonvulsant Therapy, Ketogenic Diet, Enteral Nutrition, Hormone Replacement Therapy, Physical Therapy, Occupational Therapy, Orthopedic Surgery, and Genetic Counseling. Exact NCIt identifiers should be resolved against the current NCIt release.

Experimental therapies and recent research

No ALG3-CDG-specific interventional trial or NCT identifier was retrieved. No gene replacement, CRISPR editing, RNA therapy, enzyme replacement, or cell therapy has reached established clinical use.

A 2024 preclinical study reported that liposome-encapsulated mannose-1-phosphate improved global N-glycosylation across selected CDG cellular systems, but this should not be interpreted as clinical efficacy for ALG3-CDG; ALG3 acts downstream of mannose-1-phosphate supply, and disease-specific benefit requires direct experimental confirmation. Likewise, the 2024 ER-stress study may reveal downstream therapeutic targets, but it does not establish an approved treatment.

No response rate, comparative effectiveness estimate, or ALG3-specific pharmacogenomic recommendation exists.

13. Prevention

Primary prevention through lifestyle change or vaccination is not applicable to a constitutive autosomal-recessive disorder. Reproductive prevention options include genetic counseling, carrier testing of relatives, partner testing, preimplantation genetic testing, chorionic-villus sampling, amniocentesis, or appropriately validated noninvasive approaches after familial variants are known.

Secondary prevention consists of earlier recognition through transferrin glycoform testing and molecular diagnosis in symptomatic children or at-risk relatives. Tertiary prevention includes seizure control, adequate nutrition, aspiration precautions, contracture management, endocrine replacement, vaccination and infection planning, and surveillance of renal, cardiac, immune, visual, and coagulation complications. (alsharhan2021expandingthephenotype pages 1-3)

No disease-specific population screening, vaccine, chemoprophylaxis, or environmental intervention is established.

14. Other species and natural disease

No naturally occurring ALG3-CDG-equivalent disease in companion animals, livestock, or wildlife was identified in the retrieved literature. Consequently, no breed-specific VBO annotation or veterinary prevalence can be assigned. The disorder is not infectious and has no zoonotic or cross-species transmission potential.

ALG3 orthologs and the dolichol-linked oligosaccharide pathway are evolutionarily conserved in eukaryotes, especially yeast and mammals. This conservation supports mechanistic comparison, but orthology should not be conflated with naturally occurring veterinary disease. Species-specific NCBI Gene and Taxon identifiers should be pulled directly from current NCBI records during database ingestion.

15. Model organisms and experimental systems

Available systems

  • Patient fibroblasts: the most disease-proximal experimental system used to measure LLO accumulation, glycosylation, phosphomannomutase activity, and ALG3 protein abundance. (himmelreich2019novelvariantsand pages 1-2, himmelreich2019novelvariantsand pages 6-7)
  • Yeast ALG-pathway models: Saccharomyces cerevisiae ALG mutants are historically important for dissecting dolichol-linked oligosaccharide assembly and testing functional complementation. Their strengths are pathway conservation and tractable genetics; limitations include lack of human neurodevelopment, endocrine organs, and complex tissue phenotypes.
  • Engineered cellular models: suitable for variant complementation, glycoproteomic analysis, ER-stress assays, and therapeutic screening.

No well-validated ALG3-CDG mouse, rat, zebrafish, Drosophila, C. elegans, organoid, or patient-derived iPSC model that recapitulates the full human phenotype was established in the retrieved evidence. Model-database searches should therefore treat any ALG3 knockout phenotype as pathway evidence until disease-specific phenotypic concordance is demonstrated.

Research applications and limitations

Cellular and yeast models can define residual enzyme activity, LLO composition, N-glycan extension, ER stress, and variant pathogenicity. They cannot directly model intellectual disability, epilepsy, visual behavior, pituitary dysfunction, or survival. Future priorities include conditional mammalian models, patient-derived neural/retinal organoids, and isogenic CRISPR-corrected iPSC pairs.

Recent developments and expert interpretation

A 2023 state-of-the-art review characterized CDG as a rapidly expanding field in which multi-omics has accelerated gene discovery and mechanistic resolution, while targeted therapy remains the central unmet need. It reported 163 known CDG genetic defects encompassing 193 phenotypes, underscoring how exceptionally sparse the subtype-specific ALG3 evidence remains. Francisco et al., Orphanet Journal of Rare Diseases, published October 2023, DOI: https://doi.org/10.1186/s13023-023-02879-z.

The most authoritative ALG3-specific management opinion remains the 2021 recommendation for baseline and ongoing endocrine, renal, cardiac, and immunologic evaluation. This is biologically plausible and directly derived from newly recognized organ involvement, but it remains expert cohort-based guidance rather than a randomized or consensus-guideline-tested schedule. (alsharhan2021expandingthephenotype pages 1-3)

The disease’s most useful emerging biomarker is not merely a generic type-I transferrin profile but the more specific plasma N-glycan combination of truncated extension beyond Man5GlcNAc2 and deficient hybrid glycans. The authors’ abstract describes this spectrum as “unique to ALG3-CDG,” making it a valuable orthogonal confirmation tool for variant interpretation. (alsharhan2021expandingthephenotype pages 1-3)

Priority knowledge gaps

  1. Population prevalence, incidence, carrier frequency, and unbiased survival estimates.
  2. Prospective natural history and standardized patient-reported outcomes.
  3. Variant-level residual activity and robust genotype–phenotype relationships.
  4. Validated surveillance intervals and evidence-based treatment pathways.
  5. Disease-specific animal, iPSC, neural, and retinal models.
  6. Clinical translation of glycan-directed, ER-stress-modifying, gene, or RNA therapies.
  7. Systematic single-cell, spatial, proteomic, metabolomic, and glycoproteomic profiling.

Overall, the evidence supports ALG3-CDG as a congenital, autosomal-recessive ER glycosylation disorder with a recognizable biochemical signature and severe but variable multisystem phenotype. The strongest immediate real-world application is combined biochemical–genomic diagnosis followed by proactive multidisciplinary surveillance; disease-modifying therapy remains an unmet research objective.

References

  1. (alsharhan2021expandingthephenotype pages 3-5): Hind Alsharhan, Bobby G. Ng, Earnest James Paul Daniel, Jennifer Friedman, Eniko K. Pivnick, Amal Al‐Hashem, Eissa Ali Faqeih, Pengfei Liu, Nicole M. Engelhardt, Kierstin N. Keller, Jie Chen, Pamela A. Mazzeo, Jill A. Rosenfeld, Michael J. Bamshad, Deborah A. Nickerson, Kimiyo M. Raymond, Hudson H. Freeze, Miao He, Andrew C. Edmondson, and Christina Lam. Expanding the phenotype, genotype and biochemical knowledge of alg3‐cdg. Journal of Inherited Metabolic Disease, 44:987-1000, Mar 2021. URL: https://doi.org/10.1002/jimd.12367, doi:10.1002/jimd.12367. This article has 24 citations and is from a peer-reviewed journal.

  2. (alsharhan2021expandingthephenotype pages 6-8): Hind Alsharhan, Bobby G. Ng, Earnest James Paul Daniel, Jennifer Friedman, Eniko K. Pivnick, Amal Al‐Hashem, Eissa Ali Faqeih, Pengfei Liu, Nicole M. Engelhardt, Kierstin N. Keller, Jie Chen, Pamela A. Mazzeo, Jill A. Rosenfeld, Michael J. Bamshad, Deborah A. Nickerson, Kimiyo M. Raymond, Hudson H. Freeze, Miao He, Andrew C. Edmondson, and Christina Lam. Expanding the phenotype, genotype and biochemical knowledge of alg3‐cdg. Journal of Inherited Metabolic Disease, 44:987-1000, Mar 2021. URL: https://doi.org/10.1002/jimd.12367, doi:10.1002/jimd.12367. This article has 24 citations and is from a peer-reviewed journal.

  3. (alsharhan2021expandingthephenotype pages 1-3): Hind Alsharhan, Bobby G. Ng, Earnest James Paul Daniel, Jennifer Friedman, Eniko K. Pivnick, Amal Al‐Hashem, Eissa Ali Faqeih, Pengfei Liu, Nicole M. Engelhardt, Kierstin N. Keller, Jie Chen, Pamela A. Mazzeo, Jill A. Rosenfeld, Michael J. Bamshad, Deborah A. Nickerson, Kimiyo M. Raymond, Hudson H. Freeze, Miao He, Andrew C. Edmondson, and Christina Lam. Expanding the phenotype, genotype and biochemical knowledge of alg3‐cdg. Journal of Inherited Metabolic Disease, 44:987-1000, Mar 2021. URL: https://doi.org/10.1002/jimd.12367, doi:10.1002/jimd.12367. This article has 24 citations and is from a peer-reviewed journal.

  4. (himmelreich2019novelvariantsand pages 1-2): Nastassja Himmelreich, Bianca Dimitrov, Virginia Geiger, Matthias Zielonka, Anna‐Marlen Hutter, Lars Beedgen, Andreas Hüllen, Maximilian Breuer, Verena Peters, Kai‐Christian Thiemann, Georg F. Hoffmann, Irmgard Sinning, Thierry Dupré, Sandrine Vuillaumier‐Barrot, Catherine Barrey, Jonas Denecke, Wolfgang Kölfen, Gesche Düker, Rainer Ganschow, Michael J. Lentze, Stuart Moore, Nathalie Seta, Andreas Ziegler, and Christian Thiel. Novel variants and clinical symptoms in four new alg3‐cdg patients, review of the literature, and identification of aagrp‐alg3 as a novel alg3 variant with alanine and glycine‐rich n‐terminus. Human Mutation, 40:938-951, May 2019. URL: https://doi.org/10.1002/humu.23764, doi:10.1002/humu.23764. This article has 28 citations and is from a domain leading peer-reviewed journal.

  5. (OpenTargets Search: ALG3-congenital disorder of glycosylation-ALG3): Open Targets Query (ALG3-congenital disorder of glycosylation-ALG3, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  6. (alsharhan2021expandingthephenotype pages 5-6): Hind Alsharhan, Bobby G. Ng, Earnest James Paul Daniel, Jennifer Friedman, Eniko K. Pivnick, Amal Al‐Hashem, Eissa Ali Faqeih, Pengfei Liu, Nicole M. Engelhardt, Kierstin N. Keller, Jie Chen, Pamela A. Mazzeo, Jill A. Rosenfeld, Michael J. Bamshad, Deborah A. Nickerson, Kimiyo M. Raymond, Hudson H. Freeze, Miao He, Andrew C. Edmondson, and Christina Lam. Expanding the phenotype, genotype and biochemical knowledge of alg3‐cdg. Journal of Inherited Metabolic Disease, 44:987-1000, Mar 2021. URL: https://doi.org/10.1002/jimd.12367, doi:10.1002/jimd.12367. This article has 24 citations and is from a peer-reviewed journal.

  7. (farolfi2021alg3cdgapatient pages 4-5): Martina Farolfi, Anna Cechova, Nina Ondruskova, Jana Zidkova, Bohdan Kousal, Hana Hansikova, Tomas Honzik, and Petra Liskova. Alg3-cdg: a patient with novel variants and review of the genetic and ophthalmic findings. BMC Ophthalmology, Jun 2021. URL: https://doi.org/10.1186/s12886-021-02013-2, doi:10.1186/s12886-021-02013-2. This article has 14 citations and is from a peer-reviewed journal.

  8. (himmelreich2019novelvariantsand pages 6-7): Nastassja Himmelreich, Bianca Dimitrov, Virginia Geiger, Matthias Zielonka, Anna‐Marlen Hutter, Lars Beedgen, Andreas Hüllen, Maximilian Breuer, Verena Peters, Kai‐Christian Thiemann, Georg F. Hoffmann, Irmgard Sinning, Thierry Dupré, Sandrine Vuillaumier‐Barrot, Catherine Barrey, Jonas Denecke, Wolfgang Kölfen, Gesche Düker, Rainer Ganschow, Michael J. Lentze, Stuart Moore, Nathalie Seta, Andreas Ziegler, and Christian Thiel. Novel variants and clinical symptoms in four new alg3‐cdg patients, review of the literature, and identification of aagrp‐alg3 as a novel alg3 variant with alanine and glycine‐rich n‐terminus. Human Mutation, 40:938-951, May 2019. URL: https://doi.org/10.1002/humu.23764, doi:10.1002/humu.23764. This article has 28 citations and is from a domain leading peer-reviewed journal.

  9. (alsharhan2021expandingthephenotype pages 10-11): Hind Alsharhan, Bobby G. Ng, Earnest James Paul Daniel, Jennifer Friedman, Eniko K. Pivnick, Amal Al‐Hashem, Eissa Ali Faqeih, Pengfei Liu, Nicole M. Engelhardt, Kierstin N. Keller, Jie Chen, Pamela A. Mazzeo, Jill A. Rosenfeld, Michael J. Bamshad, Deborah A. Nickerson, Kimiyo M. Raymond, Hudson H. Freeze, Miao He, Andrew C. Edmondson, and Christina Lam. Expanding the phenotype, genotype and biochemical knowledge of alg3‐cdg. Journal of Inherited Metabolic Disease, 44:987-1000, Mar 2021. URL: https://doi.org/10.1002/jimd.12367, doi:10.1002/jimd.12367. This article has 24 citations and is from a peer-reviewed journal.

Artifacts