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ALG12-congenital disorder of glycosylation

ALG12–Congenital Disorder of Glycosylation (ALG12‑CDG; historical CDG‑Ig) — Disease Characteristics Research Report

2026-05-10
Falcon MONDO:0011783 Model: Edison Scientific Literature 35 citations

ALG12–Congenital Disorder of Glycosylation (ALG12‑CDG; historical CDG‑Ig) — Disease Characteristics Research Report

Executive summary

ALG12‑CDG is a very rare autosomal recessive congenital disorder of glycosylation caused by deficiency of the ER luminal α1,6‑mannosyltransferase ALG12, which catalyzes addition of the 8th mannose during lipid‑linked oligosaccharide (LLO) assembly for protein N‑glycosylation. Biochemically it produces a type‑I carbohydrate‑deficient transferrin pattern and characteristic accumulation of truncated LLO/N‑glycans (notably Man7 intermediates and reduced Man8/Man9 species), with multisystem disease that often includes neurodevelopmental impairment, growth failure, dysmorphism, immunodeficiency (hypogammaglobulinemia), coagulation abnormalities, and variable severity up to early death. Recent (2023–2024) literature emphasizes accelerated CDG diagnosis via WES/WGS and emerging multi‑omics/proteomics tools, but also highlights the ongoing lack of targeted therapies for most CDGs, including ALG12‑CDG. (grubenmann2002alg12mannosyltransferasedefect pages 1-2, grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 1-1, monticelli2023congenitaldisordersof pages 1-2, pascoal2024revisitingtheimmunopathology pages 4-6)

Abbreviations

CDG: congenital disorder(s) of glycosylation; ER: endoplasmic reticulum; LLO: lipid‑linked oligosaccharide; Tf IEF: transferrin isoelectric focusing; MALDI‑TOF: matrix‑assisted laser desorption/ionization time‑of‑flight; MS: mass spectrometry; WES/WGS: whole‑exome/whole‑genome sequencing.

1. Disease information

1.1 What is the disease?

The first molecularly defined report described “a deficiency in the ALG12 ER α1,6‑mannosyltransferase resulting in a novel type of glycosylation disorder” and explicitly stated: “The ALG12 mannosyltransferase defect defines a new type of congenital disorder of glycosylation, designated CDG‑Ig.” (Grubenmann et al., 2002‑09; Human Molecular Genetics; DOI https://doi.org/10.1093/hmg/11.19.2331) (grubenmann2002alg12mannosyltransferasedefect pages 1-2)

A later case report defined the entity as: “Congenital disorder of glycosylation type Ig (ALG12‑CDG) is a rare inherited metabolic disease caused by a defect in alpha‑mannosyltransferase 8, encoded by the ALG12 gene (22q13.33).” (Ziburová et al., 2021‑09; American Journal of Medical Genetics A; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 1-1)

1.2 Key identifiers

  • MONDO: MONDO_0011783 (“ALG12‑congenital disorder of glycosylation”) (OpenTargets disease identifier) (OpenTargets Search: ALG12-congenital disorder of glycosylation-ALG12)
  • OMIM/MIM: Literature excerpts report #607143 (ziburova2021anovelhomozygous pages 2-2, sturiale2019alg12cdgnovelglycophenotype pages 1-2); one excerpt reported OMIM: 607144 (tahata2019complexphenotypesin pages 1-2). These inconsistencies indicate that a direct OMIM lookup is recommended for knowledge‑base normalization.
  • Orphanet / ICD‑10 / ICD‑11 / MeSH: Not present in the retrieved full texts; would require direct lookup in those databases (limitation of current tool‑retrieved corpus).

1.3 Synonyms / alternative names

1.4 Evidence sources

Most disease‑specific information is derived from individual patient case reports/series plus aggregated reviews of CDG (e.g., immunopathology and diagnostic evolution). (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, monticelli2023congenitaldisordersof pages 1-2, pascoal2024revisitingtheimmunopathology pages 4-6)

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): biallelic pathogenic variants in ALG12, encoding an ER mannosyltransferase involved in N‑glycan precursor assembly. (ziburova2021anovelhomozygous pages 2-2, grubenmann2002alg12mannosyltransferasedefect pages 1-2)

Mechanistic definition from a 2021 report: ALG12 encodes “the dolichyl‑P‑mannose Man‑7‑GlcNAc‑2‑PP‑dolichyl‑alpha‑6‑mannosyltransferase,” and “this enzyme transfers the eighth mannose residue from dolichyl‑P‑mannose to lipid‑linked oligosaccharides.” (Ziburová et al., 2021‑09; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 2-2)

2.2 Risk factors

  • Genetic risk factors (causal variants): autosomal‑recessive inheritance; risk elevated in families with carrier parents and potentially consanguinity (not directly documented in retrieved excerpts). (ziburova2021anovelhomozygous pages 2-2)
  • Environmental risk factors: none established for causation in current evidence; clinical complications (e.g., infections) are downstream consequences.

2.3 Protective factors

No validated protective genetic or environmental factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

Not specifically described for ALG12‑CDG in the retrieved evidence. In CDG more broadly, host glycan alterations may influence host–pathogen interactions, but ALG12‑specific GxE data were not retrieved. (pascoal2024revisitingtheimmunopathology pages 1-2)

3. Phenotypes (clinical features)

ALG12‑CDG presents as a multisystem disorder with marked inter‑individual variability.

3.1 Core phenotype spectrum (human evidence)

A 2021 synthesis of published cases reported frequent features including: “characteristic dysmorphism, psychomotor retardation, hypotonia, and/or skeletal abnormalities,” and also noted “feeding difficulties, respiratory distress, and frequent infections.” (Ziburová et al., 2021‑09; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 5-5)

3.2 Age of onset, severity, progression

  • Onset is typically congenital/neonatal or early infancy, consistent with CDG type I disorders; a 2021 report describes evaluation in a “newborn” with significant biochemical abnormalities. (ziburova2021anovelhomozygous pages 1-1)
  • Severity is variable, ranging from severe infantile lethal multisystem disease to milder presentations; a 2019 case series described three brothers including one who “died at 18 months” and two survivors with comparatively milder disease. (tahata2019complexphenotypesin pages 1-2)

3.3 Quality of life impact

Direct QoL instrument data specific to ALG12‑CDG were not captured in the retrieved texts. Real‑world impact is inferred from multisystem disability (developmental delay, recurrent infections, feeding problems).

3.4 Suggested HPO terms (examples)

(ontology suggestions; not exhaustive) * Developmental delay — HP:0001263 * Intellectual disability — HP:0001249 * Hypotonia — HP:0001252 * Growth delay / failure to thrive — HP:0001508 / HP:0001507 * Microcephaly — HP:0000252 (reported in some cases) (sturiale2019alg12cdgnovelglycophenotype pages 6-8) * Recurrent respiratory infections — HP:0002205 (supported by recurrent pneumonias/infections) (grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 5-5) * Hypogammaglobulinemia — HP:0004313 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6) * Abnormal coagulation / prolonged aPTT — HP:0011014 / HP:0030842 (sturiale2019alg12cdgnovelglycophenotype pages 6-8) * Cryptorchidism — HP:0000028; Micropenis — HP:0000054 (grubenmann2002alg12mannosyltransferasedefect pages 2-3)

4. Genetic / molecular information

4.1 Causal gene

  • ALG12 (approved symbol used in OpenTargets; Ensembl ENSG00000182858) (OpenTargets Search: ALG12-congenital disorder of glycosylation-ALG12)

4.2 Pathogenic variant classes (examples from primary reports)

Reported variants include missense, frameshift, and (in later literature) intronic splice‑altering variants; most evidence supports loss‑of‑function or hypomorphic loss‑of‑function. (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, ziburova2021anovelhomozygous pages 1-1)

Examples: * Compound heterozygous missense: T67M and R146Q in the first report. (grubenmann2002alg12mannosyltransferasedefect pages 1-2) * Frameshift: c.1001delA (p.N334TfsX15) reported in a family case series. (tahata2019complexphenotypesin pages 1-2) * Missense: c.1439T>C (p.Leu480Pro) reported as homozygous in a Slovak patient. (ziburova2021anovelhomozygous pages 1-1) * Compound heterozygous missense: c.367G>A (p.Gly123Arg) and c.1439T>C (p.Leu480Pro) in another patient. (sturiale2019alg12cdgnovelglycophenotype pages 6-8)

Population frequency note (limited): p.Leu480Pro was described as having a very low ExAC frequency (“8 × 10−6”). (sturiale2019alg12cdgnovelglycophenotype pages 6-8)

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No ALG12‑CDG‑specific modifier genes, epigenetic mechanisms, or recurrent chromosomal abnormalities were identified in the retrieved texts.

5. Environmental information

ALG12‑CDG is a Mendelian disorder primarily driven by biallelic ALG12 variants; no consistent non‑genetic causal environmental exposures were identified.

6. Mechanism / pathophysiology

6.1 Causal chain (from gene defect to biochemical signature)

  1. ALG12 enzymatic defect in ER N‑glycan precursor assembly: ALG12 adds the 8th mannose residue during LLO synthesis. (ziburova2021anovelhomozygous pages 2-2, pascoal2024revisitingtheimmunopathology pages 4-6)
  2. Truncated LLO accumulation: patient fibroblasts showed accumulation of DolPP‑GlcNAc2Man7 and absence of mature DolPP‑GlcNAc2Man9Glc3. (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
  3. Transfer of truncated glycans to proteins → hypoglycosylation: serum transferrin IEF shows a type‑I CDG pattern (decreased tetrasialotransferrin with increased disialo/asialo forms). (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
  4. Systemic multisystem disease due to widespread hypoglycosylation affecting secreted and membrane proteins (neurodevelopment, immunity, coagulation, endocrine axes). (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6)

6.2 Biochemical abnormalities in serum glycomics

A 2021 report found MS evidence of impaired ALG12 activity: “analysis of neutral serum N‑glycans by mass spectrometry revealed the accumulation of GlcNAc2Man5–7 and decreased levels of GlcNAc2Man8–9.” (ziburova2021anovelhomozygous pages 1-1)

6.3 Immune involvement (expert synthesis)

A 2024 immunopathology review classifies ALG12‑CDG among “predominantly antibody deficiencies” characterized by “hypogammaglobulinemia and low IgG.” (Pascoal et al., 2024‑03; Frontiers in Immunology; DOI https://doi.org/10.3389/fimmu.2024.1350101) (pascoal2024revisitingtheimmunopathology pages 3-4, pascoal2024revisitingtheimmunopathology pages 4-6)

Mechanistic framing in the same review: defective glycosylation can lead to “defective antibody glycosylation,” reducing stability and Fc receptor binding, likely contributing to antibody deficiency and infection susceptibility. (pascoal2024revisitingtheimmunopathology pages 4-6)

6.4 Suggested GO / CL / pathway terms (examples)

  • GO Biological Process: protein N‑linked glycosylation; dolichol‑linked oligosaccharide biosynthetic process.
  • GO Cellular Component: endoplasmic reticulum membrane; ER lumen.
  • Cell Ontology (CL): B cell (CL:0000236), plasma cell (CL:0000786), hepatocyte (CL:0000182), neuron (CL:0000540) — reflecting immune, liver/coagulation, and neurodevelopmental involvement.
  • Reactome/KEGG pathway concept: N‑glycan precursor (LLO) biosynthesis in ER (ALG3/ALG9/ALG12 steps referenced in CDG literature). (pascoal2024revisitingtheimmunopathology pages 4-6)

7. Anatomical structures affected

Based on reported phenotypes and biochemical effects: * Central nervous system (neurodevelopmental delay, hypotonia) (UBERON:0000955 — brain) * Immune system (hypogammaglobulinemia, infections) (UBERON:0002405 — immune system) * Liver / plasma protein production (coagulation factors, antithrombin, transaminases) (UBERON:0002107 — liver) (grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 5-5) * Male reproductive system (micropenis, cryptorchidism) (UBERON:0000079 — male reproductive system) (grubenmann2002alg12mannosyltransferasedefect pages 2-3)

Subcellular localization relevant to mechanism: endoplasmic reticulum (GO:0005783) consistent with ER mannosyltransferase role and LLO assembly. (grubenmann2002alg12mannosyltransferasedefect pages 1-2, ziburova2021anovelhomozygous pages 2-2)

8. Temporal development

No formal staging system specific to ALG12‑CDG was identified.

9. Inheritance and population

9.1 Inheritance

Autosomal recessive, supported by homozygous and compound heterozygous cases. (ziburova2021anovelhomozygous pages 2-2, sturiale2019alg12cdgnovelglycophenotype pages 6-8)

9.2 Epidemiology

Robust incidence/prevalence estimates for ALG12‑CDG were not found in the retrieved evidence. However, multiple primary sources emphasize extreme rarity: * “To date, only 15 patients have been diagnosed with ALG12‑CDG globally.” (Ziburová et al., 2021‑09; DOI https://doi.org/10.1002/ajmg.a.62474) (ziburova2021anovelhomozygous pages 1-1) * Another excerpt states the Slovak case “brings the total number of published cases of this subtype to 16.” (ziburova2021anovelhomozygous pages 5-5)

10. Diagnostics

10.1 Clinical biochemical tests

Transferrin isoelectric focusing / carbohydrate‑deficient transferrin * Index case evidence: transferrin IEF demonstrated decreased tetrasialotransferrin with increased disialo/asialotransferrin (type‑I CDG pattern). (grubenmann2002alg12mannosyltransferasedefect pages 2-3)

Lipid‑linked oligosaccharide analysis (patient fibroblasts) * Demonstrated accumulation of truncated DolPP‑GlcNAc2Man7 and loss of mature DolPP‑GlcNAc2Man9Glc3. (grubenmann2002alg12mannosyltransferasedefect pages 2-3)

Serum N‑glycan profiling by MS * “Accumulation of GlcNAc2Man5–7 and decreased levels of GlcNAc2Man8–9” in neutral serum N‑glycans. (ziburova2021anovelhomozygous pages 1-1)

10.2 Genetic testing

Exome/genome sequencing is widely used for CDG diagnosis broadly. A 2023 review states: “CDG diagnosis has been at a rapid pace since the introduction of whole‑exome/whole‑genome sequencing as a diagnostic tool.” (Monticelli et al., 2023‑08; Orphanet J Rare Dis; DOI https://doi.org/10.1186/s13023-023-02852-w) (monticelli2023congenitaldisordersof pages 1-2)

The same review also emphasizes: “genetic analysis is the most reliable diagnostic.” (monticelli2023congenitaldisordersof pages 14-15)

10.3 Differential diagnosis

A comprehensive differential diagnosis list specific to ALG12‑CDG was not present in the retrieved texts. Practically, it overlaps with other CDG type I (LLO assembly/transfer) disorders, where transferrin IEF abnormalities prompt gene‑panel/WES/WGS confirmation.

11. Outcome / prognosis

Evidence indicates variable prognosis: * Severe early‑fatal multisystem disease is reported (e.g., infant death in a sibling group; fatal neonatal/infant outcomes in some cases). (tahata2019complexphenotypesin pages 1-2, ziburova2021anovelhomozygous pages 5-5) * Survivors can have chronic neurodevelopmental disability and recurrent infections. (tahata2019complexphenotypesin pages 1-2, grubenmann2002alg12mannosyltransferasedefect pages 2-3)

Quantitative survival curves or life expectancy estimates specific to ALG12‑CDG were not found in retrieved texts.

12. Treatment

12.1 Disease‑modifying therapy

No ALG12‑CDG‑specific disease‑modifying therapy was identified in the retrieved evidence.

12.2 Supportive and rehabilitative care (real‑world implementation)

  • Immunoglobulin replacement has been used in cases with hypogammaglobulinemia; the index case received “regular immunoglobulin infusions.” (grubenmann2002alg12mannosyltransferasedefect pages 2-3)
  • However, the 2024 immunopathology review notes that Ig infusion “attempts” in some ALG12‑CDG patients showed “apparent lack of success” (case‑dependent; limited published evidence). (pascoal2024revisitingtheimmunopathology pages 4-6)
  • Additional supportive management is implied by disease manifestations (infection management, nutritional support, coagulation monitoring).

Suggested MAXO terms (examples) * Immunoglobulin replacement therapy (MAXO term for IVIG/SCIG) * Anti‑infective therapy / infection prophylaxis * Nutritional support / enteral feeding * Coagulation factor replacement / management of coagulopathy * Physical therapy / occupational therapy / speech therapy for developmental impairment

12.3 Clinical trials

No interventional trials specific to ALG12‑CDG were found. A key real‑world research infrastructure is an observational CDG natural history study: * NCT04199000 (ClinicalTrials.gov; first posted 2019; recruiting): observational case‑only study with “genetically, enzymatically, or molecularly confirmed diagnosis of CDG or NGLY1 deficiency,” enrollment target 500; includes questionnaires, clinical exams, Nijmegen progression scale and PROMIS measures; allows biospecimen collection for biomarker/DNA studies. ALG12 is listed among keywords. URL: https://clinicaltrials.gov/study/NCT04199000 (NCT04199000 chunk 1, NCT04199000 chunk 2)

13. Prevention

No primary prevention exists for Mendelian ALG12‑CDG beyond reproductive and carrier testing strategies: * Carrier testing in at‑risk families (based on known familial variants) * Prenatal diagnosis / preimplantation genetic testing where appropriate

These approaches were not detailed in the retrieved corpus but follow standard practice for autosomal recessive disorders.

14. Other species / natural disease

No naturally occurring veterinary disease analogs for ALG12‑CDG were identified in the retrieved evidence.

15. Model organisms / experimental systems

Direct ALG12‑CDG functional modeling evidence in the retrieved corpus is limited but includes: * Yeast complementation/ortholog modeling: The original report used yeast functional complementation to show that ALG12 patient mutations fail to rescue an alg12 yeast mutant, supporting pathogenicity. (grubenmann2002alg12mannosyltransferasedefect pages 1-2)

No detailed mammalian or zebrafish ALG12‑specific in vivo phenotype data were retrieved in this tool run; therefore, this section should be revisited with dedicated model‑organism database searches (MGI/ZFIN/IMPC) if required.

Recent developments and latest research (prioritizing 2023–2024)

Diagnostic acceleration and unmet needs

A 2023 Orphanet Journal of Rare Diseases review (patent‑focused) summarizes the state of the field: * CDG comprises “more than 160” defects. (monticelli2023congenitaldisordersof pages 1-2) * “CDG diagnosis has been at a rapid pace since the introduction of whole‑exome/whole‑genome sequencing as a diagnostic tool.” (monticelli2023congenitaldisordersof pages 1-2) * Despite progress, “diagnostic tools, drugs, and biomarkers are still urgently needed.” (monticelli2023congenitaldisordersof pages 1-2)

Immune phenotype synthesis for ALG12‑CDG

A 2024 Frontiers in Immunology review places ALG12‑CDG into an inborn‑errors‑of‑immunity framing as predominantly antibody deficiency and discusses how glycosylation defects can compromise antibody properties and infection defense. (pascoal2024revisitingtheimmunopathology pages 3-4, pascoal2024revisitingtheimmunopathology pages 4-6)

Emerging translational methods

A 2024 targeted proteomics paper describes an MRM assay to quantify low‑abundance ER glycosyltransferases in CDG patient fibroblasts and explicitly situates ALG12 among the ER enzymes in the pathway context (“ALG3, ALG9, ALG12…”). This represents a real‑world implementation of quantitative proteomics for CDG mechanism and potentially diagnostics/biomarker development. (Lin et al., 2024‑01; Int J Mol Sci; DOI https://doi.org/10.3390/ijms25021191) (lin2024targetedproteomicsreveals pages 1-2)

Key statistics and data points (from retrieved studies)

Evidence organization artifact

The following table summarizes key facts for knowledge‑base ingestion:

Table (click to expand)
Category Key findings (concise) Evidence type Primary citations (include PMID if available; otherwise DOI/URL)
Disease definition ALG12-congenital disorder of glycosylation (ALG12-CDG), historically CDG-Ig, is a rare type I CDG caused by deficiency of ALG12 ER α1,6-mannosyltransferase; severe multisystem disease with hypoglycosylation. OMIM/MIM reported in literature as #607143; one excerpt also cites OMIM:607144. Human case report, review Grubenmann et al., 2002, Hum Mol Genet, DOI: https://doi.org/10.1093/hmg/11.19.2331; Ziburová et al., 2021, AJMG A, DOI: https://doi.org/10.1002/ajmg.a.62474; Tahata et al., 2019, Mol Genet Metab, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, ziburova2021anovelhomozygous pages 2-2, tahata2019complexphenotypesin pages 1-2)
Gene/enzyme function ALG12 encodes dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase / α-mannosyltransferase 8, which adds the 8th mannose to the lipid-linked oligosaccharide precursor during N-glycan biosynthesis in the ER. Human case report, review Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Pascoal et al., 2024, Front Immunol, DOI: https://doi.org/10.3389/fimmu.2024.1350101 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, ziburova2021anovelhomozygous pages 2-2, pascoal2024revisitingtheimmunopathology pages 4-6)
Inheritance Autosomal recessive; reported in homozygous and compound heterozygous states. Human case report/series Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2 (ziburova2021anovelhomozygous pages 2-2, tahata2019complexphenotypesin pages 1-2, sturiale2019alg12cdgnovelglycophenotype pages 6-8)
Core phenotypes Commonly reported: psychomotor/intellectual delay, hypotonia, growth retardation/failure to thrive, microcephaly, dysmorphic facial features, recurrent infections, feeding difficulties, respiratory distress, skeletal abnormalities; variable severity including neonatal/infantile fatal cases and milder presentations. Human case report/series, review Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; de la Morena-Barrio et al., 2020, DOI: https://doi.org/10.1002/mgg3.1304 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, ziburova2021anovelhomozygous pages 5-5)
Immune involvement Predominantly antibody deficiency phenotype: hypogammaglobulinemia/low IgG, recurrent severe bacterial or sinopulmonary infections, altered lymphocyte counts/dysfunction. 2024 review groups ALG12-CDG with predominantly antibody deficiencies. Human case report, review Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Pascoal et al., 2024, DOI: https://doi.org/10.3389/fimmu.2024.1350101; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6, ziburova2021anovelhomozygous pages 6-7)
Coagulation/endocrine Reported coagulation abnormalities include low antithrombin III, prolonged APTT, decreased coagulation factors; endocrine/metabolic findings include undetectable IGF-1/IGF-BP3, hypoglycemia, low cholesterol, elevated transaminases, and male genital anomalies (micropenis/cryptorchidism). Human case report/series Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, sturiale2019alg12cdgnovelglycophenotype pages 6-8, ziburova2021anovelhomozygous pages 5-5, tahata2019complexphenotypesin pages 1-2)
Diagnostics (transferrin IEF, LLO, serum N-glycan MS) Serum transferrin IEF shows a type I CDG pattern with decreased tetrasialotransferrin and increased disialo-/asialotransferrin. Patient fibroblasts can show truncated LLO with accumulation of DolPP-GlcNAc2Man7 and absence/reduction of mature DolPP-GlcNAc2Man9Glc3. Serum N-glycan MS/MALDI-TOF shows accumulation of GlcNAc2Man5-7 with decreased GlcNAc2Man8-9; transferrin/total serum glycomics can reveal mono-glycosylated transferrin and increased high-mannose/hybrid glycans. Human case report/series Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, ziburova2021anovelhomozygous pages 1-1, sturiale2019alg12cdgnovelglycophenotype pages 6-8)
Variant examples Reported pathogenic/likely pathogenic examples include compound heterozygous p.T67M and p.R146Q; c.1001delA (p.N334Tfs*15) with c.671C>T (p.T224M, reported as VUS in one series); c.367G>A (p.Gly123Arg) and c.1439T>C (p.Leu480Pro); homozygous c.1439T>C (p.Leu480Pro); novel p.Val26Asp. 2025 report (outside requested priority window) adds an intronic splice variant upstream of exon 2. Human case report/series Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Tahata et al., 2019, DOI: https://doi.org/10.1016/j.ymgme.2019.08.007; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2; Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474 (grubenmann2002alg12mannosyltransferasedefect pages 1-2, tahata2019complexphenotypesin pages 1-2, sturiale2019alg12cdgnovelglycophenotype pages 6-8, ziburova2021anovelhomozygous pages 1-1)
Epidemiology/patient counts Extremely rare. Literature excerpts report “only 15 patients” worldwide by 2021 and “16 published cases” after the Slovak case; no robust prevalence/incidence estimate identified in available context. Human case report, review Ziburová et al., 2021, DOI: https://doi.org/10.1002/ajmg.a.62474; Piedade et al., 2022, J Rare Dis, DOI: https://doi.org/10.1007/s44162-022-00003-6 (ziburova2021anovelhomozygous pages 1-1, ziburova2021anovelhomozygous pages 5-5)
Management/supportive care No disease-specific curative therapy identified in available context. Supportive care includes immunoglobulin replacement/IVIG in patients with hypogammaglobulinemia, management of infections, nutritional/supportive multidisciplinary care, and monitoring of coagulation/endocrine issues. Reported response to Ig infusion may be variable or limited in some ALG12-CDG cases. Human case report, review Grubenmann et al., 2002, DOI: https://doi.org/10.1093/hmg/11.19.2331; Pascoal et al., 2024, DOI: https://doi.org/10.3389/fimmu.2024.1350101 (grubenmann2002alg12mannosyltransferasedefect pages 2-3, pascoal2024revisitingtheimmunopathology pages 4-6)
Research/real-world implementations Real-world diagnosis increasingly uses WES/WGS for CDG discovery/confirmation; MS-based glycomics (MALDI-MS/UHPLC-ESI-MS) refines subtype-specific glycophenotypes; targeted proteomics/MRM assays for ER glycosyltransferases were introduced in 2024 and include the ALG12 pathway, supporting translational diagnostics/research. Patent review notes CDG diagnosis accelerated with WES/WGS and that diagnostic tools, drugs, and biomarkers remain urgently needed. Review, translational research Monticelli et al., 2023, DOI: https://doi.org/10.1186/s13023-023-02852-w; Sturiale et al., 2019, DOI: https://doi.org/10.1007/s10719-019-09890-2; Lin et al., 2024, DOI: https://doi.org/10.3390/ijms25021191 (monticelli2023congenitaldisordersof pages 1-2, sturiale2019alg12cdgnovelglycophenotype pages 1-2, lin2024targetedproteomicsreveals pages 1-2)
Clinical trial registry (NCT04199000) Ongoing observational natural-history study: “Clinical and Basic Investigations Into Congenital Disorders of Glycosylation” (NCT04199000), recruiting, case-only, target enrollment 500, includes genetically/enzymatically/molecularly confirmed CDG or NGLY1 deficiency; outcomes include disease severity/progression measures and biomarker collection. ALG12 is listed among keywords, making the registry relevant to ALG12-CDG. Trial registry ClinicalTrials.gov NCT04199000: https://clinicaltrials.gov/study/NCT04199000 (NCT04199000 chunk 1, NCT04199000 chunk 2)

Table: This table summarizes key disease facts, clinical and molecular findings, diagnostics, management, and current research implementations for ALG12-CDG using only evidence available in the conversation context. It is designed for rapid knowledge-base ingestion with source-linked citations.

Limitations of this report (from available tool‑retrieved corpus)

  1. PMIDs were not available in the retrieved text snippets for several primary papers (DOIs/URLs were available); therefore, PMID‑level citation could not be consistently provided.
  2. Orphanet/ICD/MeSH identifiers were not present in the retrieved full texts; normalization would require direct database queries.
  3. Quantitative phenotype frequencies (percentages across cohorts) are largely unavailable because ALG12‑CDG literature is dominated by small case reports/series.
  4. Animal model phenotype data specific to ALG12 were not retrieved beyond yeast complementation.

Source URLs and publication dates (high‑priority items)

References

  1. (grubenmann2002alg12mannosyltransferasedefect pages 1-2): C. Grubenmann, C. Frank, S. Kjaergaard, E. Berger, M. Aebi, and T. Hennet. Alg12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Human molecular genetics, 11 19:2331-9, Sep 2002. URL: https://doi.org/10.1093/hmg/11.19.2331, doi:10.1093/hmg/11.19.2331. This article has 103 citations and is from a domain leading peer-reviewed journal.

  2. (grubenmann2002alg12mannosyltransferasedefect pages 2-3): C. Grubenmann, C. Frank, S. Kjaergaard, E. Berger, M. Aebi, and T. Hennet. Alg12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Human molecular genetics, 11 19:2331-9, Sep 2002. URL: https://doi.org/10.1093/hmg/11.19.2331, doi:10.1093/hmg/11.19.2331. This article has 103 citations and is from a domain leading peer-reviewed journal.

  3. (ziburova2021anovelhomozygous pages 1-1): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.

  4. (monticelli2023congenitaldisordersof pages 1-2): Maria Monticelli, Tania D’Onofrio, Jaak Jaeken, Eva Morava, Giuseppina Andreotti, and Maria Vittoria Cubellis. Congenital disorders of glycosylation: narration of a story through its patents. Orphanet Journal of Rare Diseases, Aug 2023. URL: https://doi.org/10.1186/s13023-023-02852-w, doi:10.1186/s13023-023-02852-w. This article has 19 citations and is from a peer-reviewed journal.

  5. (pascoal2024revisitingtheimmunopathology pages 4-6): Carlota Pascoal, Rita Francisco, Patrícia Mexia, Beatriz Luís Pereira, Pedro Granjo, Helena Coelho, Mariana Barbosa, Vanessa dos Reis Ferreira, and Paula Alexandra Videira. Revisiting the immunopathology of congenital disorders of glycosylation: an updated review. Frontiers in Immunology, Mar 2024. URL: https://doi.org/10.3389/fimmu.2024.1350101, doi:10.3389/fimmu.2024.1350101. This article has 15 citations and is from a peer-reviewed journal.

  6. (OpenTargets Search: ALG12-congenital disorder of glycosylation-ALG12): Open Targets Query (ALG12-congenital disorder of glycosylation-ALG12, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  7. (ziburova2021anovelhomozygous pages 2-2): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.

  8. (sturiale2019alg12cdgnovelglycophenotype pages 1-2): Luisa Sturiale, Sebastiano Bianca, Domenico Garozzo, Alessandra Terracciano, Emanuele Agolini, Angela Messina, Angelo Palmigiano, Francesca Esposito, Chiara Barone, Antonio Novelli, Agata Fiumara, Jaak Jaeken, and Rita Barone. Alg12-cdg: novel glycophenotype insights endorse the molecular defect. Glycoconjugate Journal, 36:461-472, Sep 2019. URL: https://doi.org/10.1007/s10719-019-09890-2, doi:10.1007/s10719-019-09890-2. This article has 22 citations and is from a peer-reviewed journal.

  9. (tahata2019complexphenotypesin pages 1-2): Shawn Tahata, Lauren B. Gunderson, Brendan Lanpher, and E. Morava. Complex phenotypes in alg12-congenital disorder of glycosylation (alg12-cdg): case series and review of the literature. Molecular genetics and metabolism, 128:409-414, Dec 2019. URL: https://doi.org/10.1016/j.ymgme.2019.08.007, doi:10.1016/j.ymgme.2019.08.007. This article has 25 citations and is from a peer-reviewed journal.

  10. (ziburova2021anovelhomozygous pages 7-8): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.

  11. (pascoal2024revisitingtheimmunopathology pages 1-2): Carlota Pascoal, Rita Francisco, Patrícia Mexia, Beatriz Luís Pereira, Pedro Granjo, Helena Coelho, Mariana Barbosa, Vanessa dos Reis Ferreira, and Paula Alexandra Videira. Revisiting the immunopathology of congenital disorders of glycosylation: an updated review. Frontiers in Immunology, Mar 2024. URL: https://doi.org/10.3389/fimmu.2024.1350101, doi:10.3389/fimmu.2024.1350101. This article has 15 citations and is from a peer-reviewed journal.

  12. (ziburova2021anovelhomozygous pages 5-5): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.

  13. (sturiale2019alg12cdgnovelglycophenotype pages 6-8): Luisa Sturiale, Sebastiano Bianca, Domenico Garozzo, Alessandra Terracciano, Emanuele Agolini, Angela Messina, Angelo Palmigiano, Francesca Esposito, Chiara Barone, Antonio Novelli, Agata Fiumara, Jaak Jaeken, and Rita Barone. Alg12-cdg: novel glycophenotype insights endorse the molecular defect. Glycoconjugate Journal, 36:461-472, Sep 2019. URL: https://doi.org/10.1007/s10719-019-09890-2, doi:10.1007/s10719-019-09890-2. This article has 22 citations and is from a peer-reviewed journal.

  14. (pascoal2024revisitingtheimmunopathology pages 3-4): Carlota Pascoal, Rita Francisco, Patrícia Mexia, Beatriz Luís Pereira, Pedro Granjo, Helena Coelho, Mariana Barbosa, Vanessa dos Reis Ferreira, and Paula Alexandra Videira. Revisiting the immunopathology of congenital disorders of glycosylation: an updated review. Frontiers in Immunology, Mar 2024. URL: https://doi.org/10.3389/fimmu.2024.1350101, doi:10.3389/fimmu.2024.1350101. This article has 15 citations and is from a peer-reviewed journal.

  15. (monticelli2023congenitaldisordersof pages 14-15): Maria Monticelli, Tania D’Onofrio, Jaak Jaeken, Eva Morava, Giuseppina Andreotti, and Maria Vittoria Cubellis. Congenital disorders of glycosylation: narration of a story through its patents. Orphanet Journal of Rare Diseases, Aug 2023. URL: https://doi.org/10.1186/s13023-023-02852-w, doi:10.1186/s13023-023-02852-w. This article has 19 citations and is from a peer-reviewed journal.

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

  17. (NCT04199000 chunk 2): Eva Morava-Kozicz. Clinical and Basic Investigations Into Congenital Disorders of Glycosylation. Icahn School of Medicine at Mount Sinai. 2019. ClinicalTrials.gov Identifier: NCT04199000

  18. (lin2024targetedproteomicsreveals pages 1-2): Qingsong Lin, Lei Zhou, Chuen Lam, Roman Sakson, Lars Beedgen, Patrick Bernhard, K. M. Alp, Nicole Lübbehusen, R. Röth, Beate Niesler, Marcin Luzarowski, Olga Shevchuk, Matthias P. Mayer, Christian Thiel, and Thomas Ruppert. Targeted proteomics reveals quantitative differences in low-abundance glycosyltransferases of patients with congenital disorders of glycosylation. International Journal of Molecular Sciences, 25:1191, Jan 2024. URL: https://doi.org/10.3390/ijms25021191, doi:10.3390/ijms25021191. This article has 5 citations.

  19. (ziburova2021anovelhomozygous pages 6-7): Jana Ziburová, Marek Nemčovič, Sergej Šesták, Jana Bellová, Zuzana Pakanová, Barbara Siváková, Anna Šalingová, Claudia Šebová, Mária Ostrožlíková, Dimitra‐Evanthia Lekka, Jana Brucknerová, Ingrid Brucknerová, Martina Skokňová, Alexandra Mc Cullough, Gabriela Hrčková, Anna Hlavatá, Vladimír Bzdúch, Ján Mucha, and Peter Baráth. A novel homozygous mutation in the human alg12 gene results in an aberrant profile of oligomannose n‐glycans in patient's serum. American Journal of Medical Genetics. Part a, 185:3494-3501, Sep 2021. URL: https://doi.org/10.1002/ajmg.a.62474, doi:10.1002/ajmg.a.62474. This article has 17 citations and is from a peer-reviewed journal.