| domain | high-confidence finding | quantitative evidence | suggested ontology terms | evidence type |
|---|---|---|---|---|
| Disease identifiers | ALG1-congenital disorder of glycosylation is a rare N-glycosylation disorder; former name CDG-Ik; disease OMIM/MIM 608540; causal gene ALG1 MIM 605907 | Landmark cohort expanded known cases to 57 total by 2016 (39 new + 18 previously reported) (pqac-00000010, pqac-00000011) | MONDO: not confirmed here; OMIM: 608540; MeSH/ICD not confidently established from retrieved sources; synonym: ALG1-CDG, CDG-Ik | Human clinical cohort + disease literature |
| Gene / inheritance | Caused by biallelic pathogenic variants in ALG1; inheritance is autosomal recessive | 39 affected individuals from 32 unrelated families; 17 male / 22 female (pqac-00000009, pqac-00000010) | ALG1 (HGNC gene symbol); autosomal recessive inheritance | Human clinical genetics |
| Molecular function | ALG1 encodes an ER-localized beta-1,4 mannosyltransferase that adds the first mannose to the growing dolichol-linked oligosaccharide in N-glycosylation | First of 9 mannose residues in the DLO precursor (pqac-00000010, pqac-00000013) | GO: protein N-linked glycosylation; GO cellular component: endoplasmic reticulum; CHEBI labels: GDP-mannose, dolichol-PP-GlcNAc2 | Human + biochemical pathway literature |
| Pathomechanism | ALG1 deficiency causes incomplete lipid-linked oligosaccharide synthesis, under-occupied N-glycosylation sites, and transfer of truncated glycans to proteins; NeuAc-Gal-GlcNAc2 can form after Golgi processing of truncated GlcNAc2-bearing proteins | ~2–8% of purified serum transferrin carried the xeno-tetrasaccharide in prior biomarker studies cited by cohort authors; 27/27 tested ALG1-CDG patients in the 2016 cohort had the biomarker present (pqac-00000009, pqac-00000011) | GO: dolichol-linked oligosaccharide biosynthetic process; GO: protein glycosylation; UBERON: blood serum | Human biochemical + model-supported mechanism |
| Variant spectrum | Broad allelic heterogeneity with many novel missense/splice variants; p.Ser258Leu is the most recurrent severe allele in available cohort data | 31 potential variants identified; 26/31 (84%) novel; p.Ser258Leu present in 17/39 (44%) patients (pqac-00000006) | Sequence variant classes: missense, splice-site; ACMG labels when individually assessed in later case reports | Human clinical genetics |
| Core phenotype: developmental delay | Neurodevelopmental impairment is near-universal | Developmental delay 37/37 (100%) (pqac-00000009) | HPO: Developmental delay (HP:0001263) | Human clinical cohort |
| Core phenotype: hypotonia | Hypotonia is highly prevalent from infancy | Hypotonia 37/39 (95%) (pqac-00000009) | HPO: Hypotonia (HP:0001252) | Human clinical cohort |
| Core phenotype: seizures/epilepsy | Seizures or epilepsy are highly prevalent | Seizures/epilepsy 36/38 (95%) (pqac-00000009) | HPO: Seizure (HP:0001250); Epilepsy (HP:0001250/label) | Human clinical cohort |
| Core phenotype: microcephaly | Microcephaly is common | Microcephaly 27/37 (73%) (pqac-00000009) | HPO: Microcephaly (HP:0000252) | Human clinical cohort |
| Core phenotype: intellectual disability | Intellectual disability is frequent among evaluable survivors | Intellectual disability 21/22 (95%) evaluable (pqac-00000009) | HPO: Intellectual disability (HP:0001249) | Human clinical cohort |
| Neuroimaging phenotype | Abnormal brain imaging is common, chiefly cerebral/cerebellar atrophy | Abnormal brain imaging 25/37 (68%); cerebral or cerebellar atrophy 11/25 (44% of abnormal scans) (pqac-00000009) | HPO: Abnormality of brain imaging; Cerebral atrophy (HP:0002059); Cerebellar atrophy (HP:0001272); UBERON: cerebrum, cerebellum | Human clinical cohort |
| Ocular phenotype | Ocular abnormalities are frequent | Ocular abnormalities 27/36 (75%); strabismus 10/27 (37%); nystagmus 6/27 (22%) (pqac-00000009) | HPO: Strabismus (HP:0000486); Nystagmus (HP:0000639); UBERON: eye | Human clinical cohort |
| Dysmorphism | Dysmorphic facial features are common | 24/39 (62%) (pqac-00000009) | HPO: Facial dysmorphism (label) | Human clinical cohort |
| Hematologic involvement | Hematologic defects are common but heterogeneous | 18/34 (53%) (pqac-00000009) | HPO: Hematologic abnormality (label); UBERON: blood | Human clinical cohort |
| Gastrointestinal involvement | GI disease is common and may include chronic diarrhea and protein-losing enteropathy | GI problems 20/38 (53%); among those with GI manifestations, chronic diarrhea 7/20 and PLE 5/20 (pqac-00000009) | HPO: Chronic diarrhea (HP:0002028); Protein-losing enteropathy (HP:0002242); UBERON: intestine | Human clinical cohort |
| Skeletal involvement | Skeletal abnormalities occur in about one-third | 13/39 (33%); scoliosis 5/13; kyphosis 2/13; joint contractures 3/13 (pqac-00000009) | HPO: Scoliosis (HP:0002650); Kyphosis (HP:0002808); Joint contracture (HP:0001371) | Human clinical cohort |
| Hypoalbuminemia / renal-enteric severity marker | Hypoalbuminemia marks severe multisystem disease and may reflect enteric or renal protein loss | Hypoalbuminemia 12/39 (31%); all 12 died, mean age at death 6.75 months; within this group PLE documented in 2 and renal disease in 3 (pqac-00000009) | HPO: Hypoalbuminemia (HP:0003073); Proteinuria/renal disease labels | Human clinical cohort |
| Prognosis / mortality | Mortality is high, especially in infancy and in specific genotypes | Premature death 17/39 (44%); deaths before 12 months 11/17 (65%); clinical range spans mild ID to death in first weeks/2 years (pqac-00000009, pqac-00000010) | HPO: Early death (label) | Human clinical cohort |
| Genotype-phenotype correlation | Homozygous p.Ser258Leu and compound heterozygous p.Gln50Arg are associated with particularly poor survival | All 6 homozygous p.Ser258Leu patients died within first 5 months; 4/5 with p.Gln50Arg compound heterozygosity died at 5–28 months (pqac-00000009, pqac-00000006) | Sequence variant labels; prognostic genotype annotation | Human clinical cohort |
| Diagnostic screening | Abnormal carbohydrate-deficient transferrin testing is a consistent screening clue in the major cohort, though normal transferrin can occur in some CDG and at least one later ALG1 case | 39/39 in Ng cohort had at least one abnormal CDT result; methods included ESI-MS and IEF. A later long-term series reported one ALG1-CDG patient with normal transferrin IEF (pqac-00000009, pqac-00000010, pqac-00000014) | LOINC/HPO labels: abnormal transferrin glycosylation; UBERON: serum | Human clinical cohort + longitudinal center experience |
| Diagnostic biomarker | Xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a high-value ALG1-associated biomarker useful to confirm diagnosis | Detected in all 27/27 tested ALG1-CDG patients in the 2016 cohort; present on either serum or fibroblast glycoproteins; prior studies detected it on ~2–8% of purified serum transferrin (pqac-00000010, pqac-00000011) | CHEBI labels: N-acetylglucosamine, galactose, sialic acid; biomarker label: NeuAc-Gal-GlcNAc2 | Human biochemical biomarker |
| Functional confirmation | Variant pathogenicity can be supported by yeast complementation rather than severity prediction | Human wild-type vs missense ALG1 constructs tested in temperature-sensitive alg1-deficient yeast for growth and CPY glycosylation rescue; authors caution assay does not rank clinical severity (pqac-00000010, pqac-00000009, pqac-00000013) | GO: carboxypeptidase Y glycosylation assay label; model: Saccharomyces cerevisiae | Functional model assay |
| Recent 2024 development | Targeted MRM proteomics in patient fibroblasts showed selective reduction of ALG1 protein abundance without broad compensatory changes in other ER glycosyltransferases | 3 ALG1-CDG fibroblast lines, all homozygous c.773C>T p.S258L, showed substantial reduction of ALG1 protein; other GT transcript/protein levels remained largely unchanged (pqac-00000016, pqac-00000017) | GO: proteomics; CL: fibroblast; protein abundance label | Human primary-cell proteomics (2024) |
| Epidemiology | Direct observed prevalence is not established; modeled birth prevalence is very low and varies by ancestry | Estimated prevalence from gnomAD/ClinVar model: NFE 1:881,984; AFR 1:329,069; AMR 1:2,981,452; EAS 1:2,543,998; SAS 1:1,559,334; ASJ 1:47,656; FIN 1:4,775,806; EST 1:3,882,716 (pqac-00000015) | Epidemiology label; autosomal recessive rare disease | Computational population estimate |
| Treatment status | No ALG1-specific approved disease-modifying therapy was identified in retrieved evidence; management is supportive and complication-directed | No relevant ALG1-specific interventional trial or supplementation efficacy study was retrieved; supportive care inferred from multisystem complications such as epilepsy, feeding/GI, infection, renal/respiratory failure (pqac-00000009, pqac-00000003) | MAXO labels: antiseizure therapy, nutritional support, infection management, respiratory support, rehabilitation (labels only) | Evidence gap + real-world supportive care inference |
| Prevention / family planning | Prevention is genetic rather than environmental: recurrence-risk counseling and reproductive testing are relevant | Later case literature documents prenatal diagnosis in an ALG1 family leading to a healthy subsequent pregnancy (pqac-00000003) | Genetic counseling; prenatal diagnosis; carrier testing | Human case report |
| Environmental factors | No disease-specific environmental or infectious cause established; this is a Mendelian disorder | No validated environmental triggers/protective factors found in retrieved ALG1-specific evidence | Not applicable / no confident ontology term | Evidence gap |
| Anatomical systems affected | Multisystem disease with primary nervous system involvement and frequent eye, GI, hematologic, skeletal, renal, and respiratory complications | Quantitative system involvement summarized above; causes of death included respiratory failure, renal failure, and infections leading to sepsis (pqac-00000009) | UBERON: brain, eye, intestine, kidney, blood, skeletal system; CL labels as needed | Human clinical cohort |
| Other species / natural disease | No naturally occurring veterinary ALG1-CDG identified in retrieved evidence | No specific animal natural-disease reports found | NCBI Taxon: not established | Evidence gap |
| Models / evidence gaps | Available disease-relevant models are yeast and patient fibroblasts; no validated ALG1-specific vertebrate model, single-cell, spatial transcriptomic, or disease-specific multi-omics atlas was identified in retrieved evidence | Yeast temperature-sensitive alg1 model and patient fibroblasts available; no relevant ALG1 clinical trials found; no single-cell/spatial studies identified (pqac-00000010, pqac-00000011, pqac-00000016, pqac-00000017) | Model system labels: Saccharomyces cerevisiae, fibroblast | Model organism / in vitro + evidence gap |


*Table: This table compiles high-confidence, disease-specific findings for ALG1-CDG across identifiers, genetics, phenotypes, mechanism, biomarkers, prognosis, epidemiology, and current evidence gaps. It is designed as a compact knowledge-base artifact with quantitative evidence and ontology-oriented annotations.*