| 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 (pqac-00000001, pqac-00000002, pqac-00000003, pqac-00000000) | MONDO:0010998; congenital disorder of glycosylation; autosomal recessive inheritance (HP:0000007) | Human cohort/review + Open Targets disease record (pqac-00000001, pqac-00000003, pqac-00000000) |
| 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 (pqac-00000001, pqac-00000003) | ALG3; protein N-linked glycosylation (GO:0006487); endoplasmic reticulum membrane | Human molecular genetics (pqac-00000001, pqac-00000003) |
| 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 (pqac-00000002, pqac-00000009) | Seizure (HP:0001250); Microcephaly (HP:0000252); Hypotonia (HP:0001252); Global developmental delay (HP:0001263); Intellectual disability (HP:0001249) | Human cohort/case series (pqac-00000001, pqac-00000002, pqac-00000009) |
| 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 (pqac-00000004, pqac-00000007) | Strabismus (HP:0000486); Optic atrophy (HP:0000648); Optic nerve hypoplasia (HP:0000609); Congenital cataract (HP:0000519); Nystagmus (HP:0000639) | Human case series/case report (pqac-00000004, pqac-00000007) |
| Skeletal / congenital anomalies | Skeletal anomalies and contractures are common; clubfeet, scoliosis, arthrogryposis, hip dysplasia reported | Skeletal abnormalities in 8/10 in 2021 cohort (pqac-00000004) | Arthrogryposis multiplex congenita (HP:0002804); Talipes equinovarus (HP:0001762); Scoliosis (HP:0002650); Joint contracture (HP:0001371) | Human cohort (pqac-00000004) |
| 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 (pqac-00000004, pqac-00000009) | Feeding difficulties (HP:0011968); Failure to thrive (HP:0001508) | Human cohort (pqac-00000004, pqac-00000009) |
| 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 (pqac-00000002, pqac-00000005) | 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 (pqac-00000002, pqac-00000005) |
| 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 (pqac-00000003, pqac-00000006, pqac-00000009) | Protein N-linked glycosylation (GO:0006487); dolichol-linked oligosaccharide biosynthetic process; endoplasmic reticulum (GO:0005783) | Human biochemical/molecular studies (pqac-00000003, pqac-00000006, pqac-00000009) |
| 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 (pqac-00000006, pqac-00000009) | Abnormal transferrin glycosylation; carbohydrate-deficient transferrin; N-glycan biosynthetic defect | Human clinical biochemistry (pqac-00000006, pqac-00000009, pqac-00000010) |
| 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 (pqac-00000004, pqac-00000009) | Whole exome sequencing; gene panel testing; serum transferrin isoelectric focusing | Human clinical diagnostics (pqac-00000001, pqac-00000003, pqac-00000004, pqac-00000008) |
| 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 (pqac-00000002, pqac-00000004, pqac-00000008) | Supportive care; physical therapy; occupational therapy; antiepileptic therapy | Human cohort/case-based management evidence (pqac-00000002, pqac-00000004, pqac-00000008) |
| 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 (pqac-00000001, pqac-00000007) | Multisystem disorder; developmental disability | Human cohort/case report (pqac-00000001, pqac-00000007) |
| 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) (pqac-00000000) | Multi-omics; natural history; cardiomyopathy screening | Authoritative review/Open Targets + targeted literature search (pqac-00000000) |
| 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 (pqac-00000000) |


*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.*