ALG6-congenital disorder of glycosylation

Mendelian MONDO:0011291 Pathograph 47 Show in embeddings browser congenital disorder of glycosylation type I disorder of protein N-glycosylation

ALG6-congenital disorder of glycosylation (ALG6-CDG, CDG-Ic) is an autosomal recessive defect of protein N-linked glycosylation caused by biallelic pathogenic ALG6 variants. Reduced ER alpha-1,3-glucosyltransferase function impairs addition of the first glucose to dolichol-linked Man9GlcNAc2, reducing efficient transfer of the glycan precursor to proteins. Developmental disability, axial hypotonia, epilepsy, ataxia, strabismus and feeding problems predominate; protein-losing enteropathy, endocrine and coagulation abnormalities, and cardiomyopathy occur in subsets. Severity and survival vary, and management is supportive and directed at the manifestations.

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MONDO

MONDO:0011291 ALG6-congenital disorder of glycosylation 1C

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Inheritance

Autosomal recessive inheritance HP:0000007

ALG6-CDG is caused by biallelic ALG6 variants; the founding mutation cosegregated with disease in a Mendelian recessive manner.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:10359825 SUPPORT PRIMARY RESULT Human Clinical

"The mutation cosegregated with the disease in a Mendelian recessive manner."

Segregation analysis in the original four patients establishes recessive transmission.

Discussions and Knowledge Gaps

Does the historical homozygous p.Tyr131His case establish ALG6-CDG?

KNOWLEDGE GAP RESOLVED resolved_alg6_y131his_reclassification

Attached to

pathophysiology#Biallelic Pathogenic ALG6 Variants

The 2020 primary report reclassified the woman described in the 2011 puberty paper as NR2F1-related BBSOAS and found normal glycosylation in fibroblasts and serum. Her attributed puberty, dysarthria and cortical visual findings are therefore not retained as ALG6 evidence without independent support. The original yeast assay used p.Tyr131His in cis with p.Ser308Arg and cannot establish the isolated common variant as causal. A normal adult transferrin result alone does not exclude every CDG.

Resolved 2026-09-21T05:04:09Z

Resolution: PMID:32407885 reclassified the historical patient as NR2F1-related BBSOAS and documented normal glycosylation. The isolated p.Tyr131His variant is not accepted here as a causal ALG6-CDG allele; independent ALG6 findings are retained with other sources.

Show evidence (2 references)

PMID:32407885 SUPPORT PRIMARY RESULT Human Clinical

"We report on a 31-year-old female initially diagnosed with ALG6-CDG based on glycosylation abnormalities on transferrin isoelectrofocusing and targeted genetic testing, and later diagnosed with BBSOAS by whole-exome sequencing (WES)."

Primary report of diagnostic revision.

PMID:32407885 SUPPORT PRIMARY RESULT Human Clinical

"Functional studies on cultured fibroblasts including Western blotting and RT-qPCR, as well as mass spectrometry of glycosylated transferrin and MALDI-TOF glycan analysis in serum, demonstrated normal glycosylation in this patient."

Functional and biochemical support for reassessment; no direct enzyme-activity assay is claimed.

Which hypoglycosylated protein is responsible for enterocyte heparan sulfate loss in ALG6-CDG protein-losing enteropathy?

KNOWLEDGE GAP OPEN gap_alg6_ple_causal_step

Attached to

pathophysiology#Enterocyte Heparan Sulfate Loss

The paired biopsy observation links enteropathy episodes with reduced heparan sulfate and syndecan-1 staining in one boy. Core-protein hypoglycosylation and impaired glycosylation of biosynthetic enzymes are alternative proposed explanations. Yeast growth-phase effects do not directly demonstrate enterocyte proliferation as the causal human intermediate. Neither a specific connecting protein nor rescue of human enteric leakage was established.

Proposed experiments

Site-occupancy glycoproteomics of patient enterocytes

exp_alg6_ple_glycoproteomics

Perform site-specific N-glycosylation occupancy measurement on intestinal biopsy material from ALG6-CDG patients during and after an enteropathy episode, comparing occupancy on heparan sulfate core proteins against occupancy on heparan sulfate biosynthetic enzymes.

Does p.Phe304Ser establish an ALG6-CDG severity modifier?

INTERPRETATION RESOLVED alg6_modifier_scope

The cited association compared severity groups in PMM2-CDG, not ALG6-CDG. It is retained as cross-disease context rather than an ALG6 structured modifier relationship. The later ALG6 cohort did not establish a clear genotype–phenotype correlation.

Resolved 2026-09-21T05:04:09Z

Resolution: Removed the PMM2-specific modifier association from the structured ALG6 genetic relationships; retained its scope in this interpretation discussion.

Show evidence (1 reference)

PMID:11875054 SUPPORT PRIMARY RESULT Human Clinical

"the F304S genotype frequency in 55 CDG-Ia patients classified as mild/moderate (n = 28), or severe (n = 27) was significantly higher in severely affected patients (0.41) than in mild/moderately affected patients (0.21)"

The quantitative basis for treating p.Phe304Ser as a severity modifier in PMM2-CDG.

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Pathophysiology

Biallelic Pathogenic ALG6 Variants

Recessive ALG6 variants impair the function required for the first glucose addition during ER lipid-linked oligosaccharide assembly. Different alleles require their own clinical and functional interpretation; the common p.Tyr131His variant is not treated as a proven cause.

ALG6 hgnc:23157

Downstream

ALG6 Alpha-1,3-Glucosyltransferase Deficiency The founding p.Ala333Val allele impairs heterologous complementation while retaining partial function.

Show evidence (1 reference)

PMID:10359825 SUPPORT PRIMARY RESULT Human Clinical

"The mutation cosegregated with the disease in a Mendelian recessive manner."

Segregation analysis in the original four patients establishes recessive transmission.

ALG6 Alpha-1,3-Glucosyltransferase Deficiency

Reduced ALG6 function impairs transfer of glucose from dolichyl-phosphate-glucose to dolichol-linked Man9GlcNAc2 in the ER. The founding human p.Ala333Val allele has residual function in yeast; neither a universal null mechanism nor a common quantitative activity threshold has been established for patient alleles.

ALG6 hgnc:23157

alpha-1,3-glucosyltransferase activity GO:0042281 ↓ DECREASED

endoplasmic reticulum GO:0005783

Experimental models

ALG6-deficient Saccharomyces cerevisiae complementation assay OTHER Heterologous complementation assesses functional capacity of the human construct in a yeast pathway.

Purified yeast ALG6 structural and glycosyltransferase assays OTHER Engineered catalytic-site substitutions interrogate the conserved first-glucose reaction.

Downstream

Incomplete Lipid-Linked Oligosaccharide Glucosylation Reduced first-glucose addition leaves increased unglucosylated Man9GlcNAc2 precursor.

Show evidence (2 references)

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

"By contrast, the mutant ALG6 cDNA of CDGS patients failed to revert the hypoglycosylation observed in alg6 yeasts, thereby proving a functional relationship between the alanine to valine substitution introduced by the C-->T transition and the CDGS phenotype."

The patient p.Ala333Val construct fails the CPY glycosylation-rescue readout; this is not a direct zero-activity measurement.

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

"However, the A333V mutation does not inactivate the glucosyltransferase as deduced from the partial growth restoration"

Partial growth rescue in the double-mutant yeast assay demonstrates residual function.

Incomplete Lipid-Linked Oligosaccharide Glucosylation

Patient fibroblasts accumulate dolichyl pyrophosphate-Man9GlcNAc2 lacking its normal glucose cap. This is an assembly defect upstream of transfer to protein; residual glucosylation is not excluded.

dolichol-linked oligosaccharide biosynthetic process GO:0006488 ↓ DECREASED

endoplasmic reticulum GO:0005783

Experimental models

ALG6-CDG patient fibroblast lipid-linked oligosaccharide profiling PRIMARY CELL CULTURE Patient-derived cells reproduce the disease biochemical substrate accumulation.

Downstream

Reduced Oligosaccharyltransferase-Mediated Glycan Transfer Incomplete donor glucosylation reduces efficient recognition and transfer by the oligosaccharyltransferase complex.

Show evidence (2 references)

PMID:10914684 SUPPORT PRIMARY RESULT In Vitro

"Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients."

Patient-derived cultured fibroblasts accumulate the unglucosylated substrate.

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

"The intensity of the RT-PCR signals obtained indicated similar expression levels"

The source compares ALG6/ALG5 RT-PCR signals in patient and control fibroblasts, rather than demonstrating transcript loss.

Reduced Oligosaccharyltransferase-Mediated Glycan Transfer

The incompletely glucosylated lipid-linked donor is transferred less efficiently to nascent proteins. This is an altered substrate effect, not a claim that ALG6-CDG is caused by an intrinsic oligosaccharyltransferase defect.

endoplasmic reticulum GO:0005783

Downstream

Protein Hypoglycosylation Inefficient transfer leaves some N-glycosylation sites unoccupied.

Show evidence (1 reference)

PMID:10359825 SUPPORT BACKGROUND Other

"A deficiency in glycosylation of the lipid-linked oligosaccharide results in the incomplete glycosylation of glycoprotein because of the decreased affinity of the oligosaccharyltransferase toward the incomplete substrate."

The conserved donor-recognition mechanism connects incomplete precursor glucosylation to reduced protein glycosylation.

Protein Hypoglycosylation

Reduced N-glycan occupancy affects serum and cellular glycoproteins. A type I transferrin profile provides a clinical readout. Growth-dependent worsening was measured in yeast assays and is not assumed for every patient tissue.

protein N-linked glycosylation GO:0006487 ↓ DECREASED

Downstream

Multisystem Glycoprotein Dysfunction Clinical organ effects accompany the glycosylation disorder; the particular substrate proteins and intervening tissue mechanisms remain incompletely resolved.

Enterocyte Heparan Sulfate Loss Hypoglycosylation of core proteins or biosynthetic machinery is a proposed contributor to the biopsy finding in a boy with episodic enteropathy.

Show evidence (1 reference)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"Carbohydrate deficient transferrin (Mayo Clinic) had a CDG type-I profile (abnormal mono-oligosaccharide/di-oligosaccharide transferrin and a-oligosaccharide/di-oligosaccharide transferrin ratios)."

A genetically diagnosed child had loss of transferrin glycan occupancy.

Enterocyte Heparan Sulfate Loss

One boy with ALG6-CDG had reduced basolateral heparan sulfate and syndecan-1 staining in small-intestinal enterocytes during gastroenteritis-associated protein-losing enteropathy, with improvement after the episode. This tissue observation does not establish the mechanism in all patients or prove that glycosaminoglycan sulfation is an N-linked glycosylation reaction.

enterocyte CL:0000584

Downstream

Intestinal Protein Loss Loss of basolateral HS is associated with episodic enteric protein leakage; causal necessity and rescue were not established.

Show evidence (1 reference)

PMID:11106564 SUPPORT PRIMARY RESULT Human Clinical

"Intestinal biopsy in a boy with gastroenteritis-induced protein-losing enteropathy (PLE) showed loss of heparan sulfate (HS) and syndecan-1 core protein from the basolateral surface of the enterocytes, which improved after PLE subsided."

Paired biopsies in one affected boy associate basolateral HS/core-protein loss with an enteropathy episode.

Intestinal Protein Loss

Excess enteric protein loss in the subset with protein-losing enteropathy causes hypoalbuminemia and can require intensive nutritional and fluid support.

Downstream

Protein-losing enteropathy Excess enteric protein loss is the defining process of PLE.

Hypoalbuminemia Loss of albumin through the intestine contributes to low serum albumin.

Show evidence (1 reference)

url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf SUPPORT PRIMARY RESULT Human Clinical

"Patients with PLE had a more extensive workup, showing severe hypoalbuminemia"

The cohort reports severe hypoalbuminemia in the PLE subgroup.

Multisystem Glycoprotein Dysfunction

The clinical consequences of impaired glycoprotein processing are dominated by developmental and neurological dysfunction, with variable ocular, nutritional, endocrine, coagulation and cardiac involvement. This module-level hub does not specify unmeasured disease-specific ER-stress, neuronal-loss or receptor-signaling mechanisms.

Downstream

Neurodevelopmental delay Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Muscular hypotonia Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Seizure Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Strabismus Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Feeding difficulties Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Hyperinsulinemic hypoglycemia Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Myoclonic seizure Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Ataxia Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Proximal muscle weakness Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Failure to thrive Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Abnormality of coagulation Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Brachydactyly Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Autistic behavior Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Abnormal facial shape Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Nystagmus Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Hypoplasia of the corpus callosum Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Cerebellar atrophy Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Cerebral atrophy Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Microcephaly Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Delayed speech and language development Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Visual impairment Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Dilated cardiomyopathy Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Anemia Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Sleep disturbance Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Aggressive behavior Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Recurrent infections Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.

Show evidence (1 reference)

"We found abnormal development/ disability (n = 41) and hypotonia (n = 40) as the most common symptoms."

Primary clinical cohort documents the downstream neurological phenotype; it does not identify the responsible glycoproteins.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 2

Abnormality of coagulation HP:0001928

Show evidence (1 reference)

"Bleeding (increased bleeding time and easy bruising) was less common than expected ( n = 18) and were mainly subclinical."

The pooled finding supports a coagulation phenotype, not a clinical-bleeding frequency.

Anemia HP:0001903

Show evidence (1 reference)

"Seven patients also had anemia, most likely due to malab- sorption."

Observed anemia, with a proposed rather than demonstrated cause.

Cardiovascular 1

Dilated cardiomyopathy OCCASIONAL HP:0001644

Show evidence (2 references)

"Three patients had dilated cardiomyopathy"

Cohort-specific numerator for the cardiac manifestation.

PMID:20398363 SUPPORT PRIMARY RESULT Human Clinical

"These findings confirmed moderate cardiomyopathy of the dilated type."

The original case includes echocardiographic confirmation.

Digestive 2

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:14517965 SUPPORT BACKGROUND Human Clinical

"CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties."

Clinical description of ALG6-CDG; no feeding-specific denominator.

Protein-losing enteropathy OCCASIONAL HP:0002243

Show evidence (2 references)

"In 25 children, failure to thrive necessitated an increased caloric intake (special diet). Six patients had PLE."

Primary cohort numerator for enteropathy.

PMID:11106564 SUPPORT PRIMARY RESULT Human Clinical

Paired biopsies in one affected boy associate basolateral HS/core-protein loss with an enteropathy episode.

Endocrine 1

Hyperinsulinemic hypoglycemia HP:0000825

Show evidence (1 reference)

"Hyperinsulinism was found in two other patients with episodes of hypoglycemia."

Independent ALG6 cohort support, distinct from two patients with unspecified recurrent hypoglycemia.

Eye 3

Strabismus FREQUENT HP:0000486

Show evidence (1 reference)

"and strabismus (n = 25) in about half of the patients."

The counted ocular finding supports the frequency.

Nystagmus FREQUENT HP:0000639

Show evidence (1 reference)

"n y s t a g m u s(n =1 8 )"

The full text provides the nystagmus-specific count.

Visual impairment HP:0000505

Show evidence (1 reference)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"On physical examination at 18 months, she had a weak cry, no blink to threat, nor visual tracking."

Visual dysfunction in a confirmed case; the source does not establish cortical blindness.

Head and Neck 2

Abnormal facial shape FREQUENT HP:0001999

Coarse binding: variable spectrum

Show evidence (1 reference)

"Dysmorphic features in 15 patients were unspecific"

The full clinical narrative contradicts interpreting the abstract word rare as a quantified very-rare band.

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"She was born with congenital microcephaly (OFC 30.5 cm, <first percentile) and remained microcephalic with OFC of 43.2 cm (first percentile) at 18-month follow-up."

Single confirmed case, without a population frequency.

Immune 1

Recurrent infections HP:0002719

Show evidence (1 reference)

url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf SUPPORT PRIMARY RESULT Human Clinical

"Patients 4 and 5 had recurrent episodes of severe infections."

Primary observations from the five-person series, also included in the later cohort.

Limbs 1

Brachydactyly OCCASIONAL HP:0001156

Show evidence (1 reference)

PMID:27287710 SUPPORT PRIMARY RESULT Human Clinical

"Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly."

Seven of 41 patients, which is the counted basis for the OCCASIONAL band.

Metabolism 1

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

"Patients with PLE had a more extensive workup, showing severe hypoalbuminemia"

Observed in the selected enteropathy subgroup.

Musculoskeletal 2

Muscular hypotonia VERY_FREQUENT HP:0001252

Show evidence (1 reference)

"We found abnormal development/ disability (n = 41) and hypotonia (n = 40) as the most common symptoms."

Primary clinical cohort documents the downstream neurological phenotype; it does not identify the responsible glycoproteins.

Proximal muscle weakness HP:0003701

Show evidence (1 reference)

"Hypotonia was always axial and was associated with proximal muscle weakness."

Direct cohort description; no inferred universal weakness frequency.

Nervous System 11

Neurodevelopmental delay VERY_FREQUENT HP:0012758

Show evidence (1 reference)

"We found abnormal development/ disability (n = 41) and hypotonia (n = 40) as the most common symptoms."

Primary clinical cohort documents the downstream neurological phenotype; it does not identify the responsible glycoproteins.

Seizure FREQUENT HP:0001250

Show evidence (1 reference)

"Epilepsy was present in the majority of our patients ( n = 30)."

The narrative provides the seizure-specific numerator, rather than the abstract list of features.

Myoclonic seizure HP:0032794

Show evidence (1 reference)

"At onset, most children had myoclonic seizures or infantile spasms."

Subtype of epilepsy in the cohort, without a separate count.

Ataxia FREQUENT HP:0001251

Show evidence (1 reference)

"Additionally we found ataxia (n =2 0 )"

The full-text narrative provides the ataxia numerator.

Autistic behavior HP:0000729

Show evidence (1 reference)

"only five pa- tients were diagnosed with autism that showed classic di- agnostic features and regression in speech and development between the age of 3 and 4 years."

The cohort distinguishes diagnosed autism from broader behavioral features.

Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

"corpus callosum hypoplasia in one case"

Independent imaging observation supports the narrower finding.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

"Only six of the 20 patents with ataxia showed vermis hypoplasia and/or cerebellar atrophy"

Mixed imaging findings in a selected ataxic subgroup.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

"Other MRI findings included brain atrophy in several patients"

Primary clinical imaging observation.

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"Babbling was noted to occur by 5 months but remained nonverbal by 18 months."

Longitudinal language delay in a confirmed case.

Sleep disturbance OCCASIONAL HP:0002360

Show evidence (1 reference)

"Sleep disturbance requiring daily melatonin treatment was noted in seven."

Primary cohort observation.

Aggressive behavior OCCASIONAL HP:0000718

Show evidence (1 reference)

"Aggressive behavior, mostly around puberty, was present in five cases."

Primary cohort observation.

Growth 1

Failure to thrive FREQUENT HP:0001508

Show evidence (1 reference)

"In 25 children, failure to thrive necessitated an increased caloric intake (special diet)."

Feature-specific numerator supports the cohort-derived band.

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Genetic Associations

ALG6 pathogenic variants (Causative)

Gene: ALG6 hgnc:23157 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:14517965 SUPPORT BACKGROUND Human Clinical

"the most common disease-causing mutation, c998C>T (p. Ala333Val), which occurs in over half of all known CDG-Ic patients"

Historical 2003 frequency among then-known cases, not a current global allele frequency.

PMID:10914684 SUPPORT PRIMARY RESULT Human Clinical

"Haplotype analysis of CDG-Ic patients revealed a founder effect for the ALG6 allele bearing the A333 V mutation."

Founder origin of the common allele.

PMID:10914684 SUPPORT PRIMARY RESULT Human Clinical

"The genomic organization of the human ALG6 gene was determined, revealing 14 exons spread over 55 kb."

Gene structure relevant to variant ascertainment.

+ 1 more reference

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Medical Actions

Multidisciplinary supportive care

Action: Supportive Care NCIT:C15747

Platform: Other

No established disease-modifying treatment is documented in the reviewed ALG6 literature. Coordinate metabolic, neurological, nutritional, developmental and organ-specific care. Evidence for mannose in MPI-CDG does not establish benefit in ALG6-CDG.

Show evidence (1 reference)

PMID:25052310 SUPPORT BACKGROUND Human Clinical

"Treatment of ALG6-CDG is purely symptomatic."

ALG6-specific clinical utility guidance.

Individualized antiseizure treatment

Action: Anticonvulsant Therapy NCIT:C64172

Platform: Small molecule

Treat according to seizure type and response. The cohort used several agents, and some patients remain refractory. One child had initial electroclinical improvement with phenobarbital but subsequently had near-daily seizures despite multiple agents and ketogenic diet. Neither this observation nor isolated drug trials establish a preferred ALG6-specific regimen.

Mechanism Target:

MODULATES Seizure — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"After initiation of phenobarbital, there was a dramatic electroclinical improvement"

Initial response in one child, not durable disease-wide efficacy.

Target Phenotypes: Seizure HP:0001250

Show evidence (2 references)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"After initiation of phenobarbital, there was a dramatic electroclinical improvement"

Initial response in one child, not durable disease-wide efficacy.

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"Her epilepsy continued to be medically intractable."

The same case had persistent drug resistance.

Nutritional and feeding support

Action: Nutritional Support NCIT:C15433

Platform: Other

Assess growth, caloric requirements, oral motor function and swallowing safety. Use dietary support and enteral feeding when needed. Elemental feeds may help selected patients; no single formula is mandatory for all ALG6-CDG.

Mechanism Target:

MODULATES Failure to thrive — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

"In 25 children, failure to thrive necessitated an increased caloric intake (special diet)."

ALG6 cohort experience.

MODULATES Feeding difficulties — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve."

Historical broad N-linked CDG guidance, applied according to individual feeding needs.

Target Phenotypes: Failure to thrive HP:0001508 Feeding difficulties HP:0011968

Show evidence (2 references)

"In 25 children, failure to thrive necessitated an increased caloric intake (special diet)."

ALG6 cohort experience.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve."

Historical broad N-linked CDG guidance, applied according to individual feeding needs.

Specialist management of protein-losing enteropathy

Platform: Other

Provide nutritional, albumin/fluid and electrolyte support according to severity. The cohort describes elemental diets and subcutaneous octreotide in selected patients. These are uncontrolled observations, with no demonstrated routine indication or standardized ALG6-specific regimen.

Mechanism Target:

MODULATES Protein-losing enteropathy — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

"Four PLE patients followed an elementary diet due PLE, and two received octreotide injections to decrease enteral protein loss."

Four received elemental diet and two received octreotide; overlap is unspecified. These are uncontrolled treatment observations.

Target Phenotypes: Protein-losing enteropathy HP:0002243

Show evidence (1 reference)

"Four PLE patients followed an elementary diet due PLE, and two received octreotide injections to decrease enteral protein loss."

Four received elemental diet and two received octreotide; overlap is unspecified. These are uncontrolled treatment observations.

Developmental rehabilitation and communication support

Action: Rehabilitation NCIT:C15315

Platform: Other

Provide physical, occupational and speech-language therapies, adaptive equipment, educational support and planning for adult assistance. Rehabilitation supports function and communication without evidence that it restores glycosylation or normalizes muscle tone.

Mechanism Target:

MODULATES Neurodevelopmental delay — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"Occupational therapy, physical therapy, and speech therapy should be instituted."

Historical N-linked CDG developmental-care guidance.

MODULATES Delayed speech and language development — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"Occupational therapy, physical therapy, and speech therapy should be instituted."

Historical N-linked CDG developmental-care guidance.

Target Phenotypes: Neurodevelopmental delay HP:0012758 Delayed speech and language development HP:0000750

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"Occupational therapy, physical therapy, and speech therapy should be instituted."

Historical N-linked CDG developmental-care guidance.

Ophthalmologic assessment and treatment

Action: Eye Examination NCIT:C38060

Platform: Other

Evaluate vision and strabismus, and use glasses, patching or surgery when clinically indicated. Poor visual responses warrant assessment rather than assuming a cortical origin.

Mechanism Target:

MODULATES Strabismus — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"therapies that preserve vision (glasses, patching, or surgery) can be instituted as needed."

Historical broad CDG ophthalmologic guidance.

Target Phenotypes: Strabismus HP:0000486

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"therapies that preserve vision (glasses, patching, or surgery) can be instituted as needed."

Historical broad CDG ophthalmologic guidance.

Coagulation assessment and perioperative planning

Platform: Other

Assess both procoagulant and anticoagulant factors and plan invasive procedures with hematology when abnormalities are present. Low factor levels can coexist with thrombosis risk; laboratory abnormalities do not mandate routine prophylactic replacement.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"Low levels of coagulation factors, both pro- and anticoagulant, rarely cause clinical problems in daily activities but must be addressed when an individual with CDG undergoes surgery."

Broad CDG perioperative guidance.

"Twelve patients underwent minor surgery (strabismus operation or tooth extraction) without compli- cations."

ALG6 cohort shows that abnormal tests are not equivalent to inevitable surgical bleeding.

Metabolic, endocrine, hepatic and cardiac surveillance

Platform: Other

Monitor growth, glycemia, liver function, thyroid/endocrine findings and coagulation in the clinical context. Documented cardiomyopathy supports cardiac assessment and follow-up; the mortality study proposes echocardiographic evaluation in N-linked CDG, without establishing an ALG6-specific interval or survival benefit. Treat confirmed abnormalities rather than isolated thyroid-binding changes.

Show evidence (2 references)

"regular screening of glycemia, coagulation, and endocrine and liver function."

ALG6 cohort recommendation after observed laboratory abnormalities.

PMID:20398363 SUPPORT PRIMARY RESULT Human Clinical

"The severity of the dilated cardiomyopathy in the present patient was moderate and required long-term cardiac treatment with captopril."

Clinical cardiac involvement merits assessment and specialist care.

Cardiomyopathy treatment

Platform: Other

Manage documented cardiac dysfunction with cardiology. In one reported boy, captopril was used for five years and withdrawn after stabilization; this single case does not establish comparative efficacy or a universal regimen.

Mechanism Target:

MODULATES Dilated cardiomyopathy — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

PMID:20398363 SUPPORT PRIMARY RESULT Human Clinical

"Captopril was just recently weaned off with stabilization of the cardiac function."

Longitudinal treatment observation in one patient.

Target Phenotypes: Dilated cardiomyopathy HP:0001644

Show evidence (1 reference)

PMID:20398363 SUPPORT PRIMARY RESULT Human Clinical

"Captopril was just recently weaned off with stabilization of the cardiac function."

Longitudinal treatment observation in one patient.

Behavioral, psychiatric and sleep care

Platform: Other

Assess mood, behavior, communication and sleep, and tailor treatment. Seven cohort participants used melatonin. A separate adolescent improved with escitalopram and risperidone but had dose-related extrapyramidal effects; that abstract-only case does not establish a standard combination for ALG6-CDG.

Mechanism Target:

MODULATES Sleep disturbance — Manifestation-directed care; this does not correct the ALG6 biochemical defect.

Show evidence (1 reference)

"Sleep disturbance requiring daily melatonin treatment was noted in seven."

Primary cohort treatment observation.

Target Phenotypes: Sleep disturbance HP:0002360

Show evidence (2 references)

"Sleep disturbance requiring daily melatonin treatment was noted in seven."

Primary cohort treatment observation.

PMID:39141102 SUPPORT PRIMARY RESULT Human Clinical

"The patient's symptoms improved with escitalopram and risperidone treatment. However, above a certain dosage, she was sensitive to extrapyramidal side effects."

Single adolescent case; individual response and adverse effects, not a comparative recommendation.

Genetic counseling and evaluation of relatives

Action: Genetic Counseling NCIT:C15240

Platform: Other

Confirm the familial causal variants, offer carrier and at-risk sibling testing, and discuss reproductive options. With two carrier parents, each pregnancy has the usual autosomal recessive 25% affected risk. Molecular prenatal or preimplantation testing can be considered after variant identification; fetal transferrin testing is unreliable.

Show evidence (3 references)

PMID:25052310 SUPPORT BACKGROUND Human Clinical

"The identiﬁcation of the pathogenic variant will permit heterozygote detection in the family, and prenatal diagnosis."

ALG6-specific family-testing guidance.

PMID:25052310 SUPPORT BACKGROUND Human Clinical

"Prenatal diagnosis should be performed by molecular analysis; fetal transferrin isoelectrofocusing leads to false results."

Molecular testing is preferred for an at-risk pregnancy.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT BACKGROUND Human Clinical

"It is appropriate to evaluate apparently asymptomatic older and younger sibs"

Broad CDG guidance supports early evaluation of at-risk siblings.

🔬

Biochemical Markers

Type I CDG serum transferrin isoelectric focusing pattern (Present)

Show evidence (1 reference)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"Carbohydrate deficient transferrin (Mayo Clinic) had a CDG type-I profile (abnormal mono-oligosaccharide/di-oligosaccharide transferrin and a-oligosaccharide/di-oligosaccharide transferrin ratios)."

A genetically diagnosed child had loss of transferrin glycan occupancy.

Dolichyl pyrophosphate-Man9GlcNAc2 accumulation in fibroblasts (Present)

Show evidence (1 reference)

PMID:10914684 SUPPORT PRIMARY RESULT In Vitro

"Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients."

The step-specific biochemical signature of ALG6 deficiency.

Low serum cholesterol and coagulation proteins (Variable)

Show evidence (1 reference)

PMID:25052310 SUPPORT BACKGROUND Human Clinical

"Striking biochemical abnormalities are unusually low levels of serum cholesterol, blood coagulation factor XI, and anticoagulation factors antithrombin, protein C, and protein S"

Clinical utility review summarizes biochemical findings, without universal penetrance.

🔬

Diagnosis

Transferrin glycoform analysis and molecular confirmation

Transferrin isoelectric focusing or mass spectrometry can identify a type I glycosylation pattern. ALG6-CDG is established by clinically interpreted biallelic pathogenic or likely pathogenic ALG6 variants, with segregation and biochemical/functional studies where needed. Exome or panel testing may precede transferrin testing in an infant with unexplained epilepsy. A VUS or benign variant alone is insufficient.

Show evidence (3 references)

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"Carbohydrate deficient transferrin (Mayo Clinic) had a CDG type-I profile (abnormal mono-oligosaccharide/di-oligosaccharide transferrin and a-oligosaccharide/di-oligosaccharide transferrin ratios)."

A genetically diagnosed child had loss of transferrin glycan occupancy.

PMID:36756224 SUPPORT PRIMARY RESULT Human Clinical

"Together, these tests confirmed the diagnosis of ALG6-CDG."

The child had compound heterozygous ALG6 variants plus repeated type I transferrin results.

PMID:32407885 SUPPORT PRIMARY RESULT Human Clinical

"This case is illustrative of the utility of whole exome sequencing in the diagnostic odyssey, and the potential pitfalls of relying on focused genetic testing results for diagnosis of conditions with complex overlapping phenotypes."

The reclassified patient illustrates why a targeted variant result requires phenotype and biochemical corroboration.

Fibroblast lipid-linked oligosaccharide analysis

Accumulation of Man9GlcNAc2 helps localize the defect. This specialized cultured-cell assay can be equivocal and is available in few centers; it is not required before every genomic diagnosis.

Show evidence (2 references)

PMID:10914684 SUPPORT PRIMARY RESULT In Vitro

"Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients."

Patient-derived cultured fibroblasts accumulate the unglucosylated substrate.

PMID:25052310 SUPPORT BACKGROUND Human Clinical

"the DLO analysis is cumbersome, produces sometimes equivocal results, and is only available in very few centers"

Limitations described in the clinical utility gene card.

Reassess discordant historical diagnoses

The woman reported with homozygous ALG6 p.Tyr131His in 2011 was later diagnosed with NR2F1-related Bosch-Boonstra-Schaaf optic atrophy syndrome. Normal glycosylation studies together with genomic reassessment supported reclassification; normal adult transferrin alone is not an absolute exclusion rule for all CDGs.

Show evidence (2 references)

PMID:32407885 SUPPORT PRIMARY RESULT Human Clinical

Primary report of diagnostic revision.

PMID:32407885 SUPPORT PRIMARY RESULT Human Clinical

Functional and biochemical support for reassessment; no direct enzyme-activity assay is claimed.

📈

Progression

Wide survival range with substantial diagnostic delay

Survival in ALG6-CDG spans a wide range. In a 37-patient CDG mortality cohort, the three ALG6-CDG patients survived to 12 months, 2 years and 21 years, the last being the oldest age of death in the whole cohort. Diagnosis was delayed to 16 years in one ALG6-CDG patient. Caution: this is a mortality cohort, so it is a description of the deceased, not a survival estimate for the disease.

Show evidence (3 references)

PMID:39923392 SUPPORT PRIMARY RESULT Human Clinical

"The three patients with ALG6-CDG had a wide age range and they survived to 12 months, 2 years and 21 years."

ALG6-CDG-specific survival ages from the mortality cohort.

PMID:39923392 SUPPORT PRIMARY RESULT Human Clinical

"The youngest age of mortality in this cohort is 1 month for two patients with SLC35A3-CDG and PIGA-CDG, the oldest age was 21 years for a patient with ALG6-CDG."

Places the ALG6-CDG maximum at the top of the whole CDG mortality cohort.

PMID:39923392 SUPPORT PRIMARY RESULT Human Clinical

"However, CDG diagnosis was delayed to the age of 17 years for a patient with ALG3-CDG, 16 years for a patient with ALG6-CDG"

Documents diagnostic delay of 16 years in an ALG6-CDG patient.

Early childhood mortality with long-lived survivors

The 2016 paper reports eleven early childhood deaths and adult survivors, with PLE, sepsis and seizures among the causes. Internal table/narrative discrepancies in ages and cohort counts preclude a reconstructed survival curve. This selected retrospective cohort and the separate deceased-only series are not population mortality estimates.

Show evidence (2 references)

PMID:27287710 SUPPORT PRIMARY RESULT Human Clinical

"Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures."

Counted early-childhood mortality with named causes, from the largest cohort.

PMID:27287710 SUPPORT PRIMARY RESULT Human Clinical

"The oldest patient was a 40 year-old Dutch woman."

The upper end of the survival range, and longer than the 21 years reported in the smaller mortality cohort.

📊

Prevalence

Published ALG6-CDG literature through 2016

Cases In Literature

The 2016 review reported 89 published patients. This historical count and contemporary ranking among CDGs do not estimate current population prevalence. The clinical utility gene card states that incidence and prevalence are unknown.

Show evidence (2 references)

PMID:27287710 SUPPORT BACKGROUND Human Clinical

"ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG."

Historical literature count, not a current population estimate.

PMID:25052310 SUPPORT BACKGROUND Human Clinical

"The frequency and the prevalence of the disease are not known."

No measured population frequency is available in this clinical utility review.

🔬

Clinical Trials

NCT04199000 NOT_APPLICABLE

Observational consortium study of the natural history, causes and treatments of CDG, including ALG6-CDG. The mortality paper cites this protocol, but also includes retrospective deceased cases outside prospective enrollment. The generated registry summary does not establish a current recruitment status.

Show evidence (2 references)

PMID:39923392 SUPPORT PRIMARY RESULT Human Clinical

"This NH protocol was approved by the NIH and the Mayo Institutional Review Board (IRB) that served as the central IRB with local context review at each FCDGC NH site (NCT04199000)."

Registers the natural history study identifier that produced the survival data cited in this entry.

clinicaltrials:NCT04199000 SUPPORT BACKGROUND Other

"The purpose of this research is to study the natural history of congenital disorders of glycosylation and its causes and treatments."

Registry purpose, not a demonstrated treatment effect.

🧫

Experimental Models

ALG6-deficient Saccharomyces cerevisiae complementation assay OTHER

Human wild-type or p.Ala333Val ALG6 was expressed in Saccharomyces cerevisiae alg6 mutants. CPY glycoform rescue and synthetic growth rescue in alg6 wbp1-2 double mutants are distinct readouts. These assays support impaired but residual activity of the founding allele; they did not test every human variant.

Publication

PMID:10359825

Pathograph links

ALG6 Alpha-1,3-Glucosyltransferase Deficiency partially recapitulates fidelity: moderate Heterologous complementation assesses functional capacity of the human construct in a yeast pathway.

Limitations: Growth and CPY glycosylation depend on yeast background, expression and assay conditions. Failure of one rescue readout is not a quantitative zero-activity measurement or proof of human organ pathology.

Readouts

Failure of mutant CPY glycosylation rescue

Direction: INCREASED

Interpretation: Compared with the partially rescuing wild-type human construct, p.Ala333Val leaves CPY hypoglycosylation uncorrected in this assay.

Show evidence (1 reference)

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

The patient p.Ala333Val construct fails the CPY glycosylation-rescue readout; this is not a direct zero-activity measurement.

Growth rescue in alg6 wbp1-2 yeast

Direction: DECREASED

Interpretation: The p.Ala333Val construct partially restores growth, supporting residual function.

Show evidence (1 reference)

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

"However, the A333V mutation does not inactivate the glucosyltransferase as deduced from the partial growth restoration"

Partial growth rescue in the double-mutant yeast assay demonstrates residual function.

Show evidence (1 reference)

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

"Expression of the human ALG5 and ALG6 cDNA could partially complement the respective S. cerevisiae alg5 and alg6 deficiency."

Establishes that human ALG6 functionally substitutes in the yeast system, which is what makes the assay informative for human alleles.

ALG6-CDG patient fibroblast lipid-linked oligosaccharide profiling PRIMARY_CELL_CULTURE

Cultured patient fibroblasts show accumulation of the unglucosylated ALG6 substrate. The original p.Ala333Val study also found similar ALG6 RT-PCR signals in patient and control fibroblasts, so reduced transcript abundance is not asserted as that allele mechanism.

Publication

PMID:10914684

Pathograph links

Incomplete Lipid-Linked Oligosaccharide Glucosylation recapitulates fidelity: high Patient-derived cells reproduce the disease biochemical substrate accumulation.

Limitations: Fibroblasts do not model organ-specific developmental, neurological or enterocyte dysfunction.

Readouts

Dolichyl pyrophosphate-Man9GlcNAc2 accumulation

Direction: INCREASED

Interpretation: Accumulated unglucosylated precursor localizes the assembly block.

Show evidence (2 references)

PMID:10914684 SUPPORT PRIMARY RESULT In Vitro

"Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients."

Patient-derived cultured fibroblasts accumulate the unglucosylated substrate.

+ 1 more reference

Show evidence (2 references)

PMID:10914684 SUPPORT PRIMARY RESULT In Vitro

"Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients."

Patient-derived cultured fibroblasts accumulate the unglucosylated substrate.

PMID:10359825 SUPPORT PRIMARY RESULT In Vitro

"The intensity of the RT-PCR signals obtained indicated similar expression levels"

The source compares ALG6/ALG5 RT-PCR signals in patient and control fibroblasts, rather than demonstrating transcript loss.

Purified yeast ALG6 structural and glycosyltransferase assays OTHER

Saccharomyces cerevisiae ALG6 expressed through an Sf9/baculovirus system was purified for cryo-EM and synthetic-substrate assays. The apo nanodisc structure is 3.0 Å and donor-bound detergent structure 3.9 Å. Patient positions were mapped onto the yeast structure; they were not functionally tested as a clinical allele series. The acceptor groove, donor-glucose geometry and binding order remain incompletely resolved.

Publication

PMID:32103179

Pathograph links

ALG6 Alpha-1,3-Glucosyltransferase Deficiency perturbs fidelity: moderate Engineered catalytic-site substitutions interrogate the conserved first-glucose reaction.

Limitations: Asp69/Asp99/His378 substitutions are engineered yeast variants, not patient alleles. Endpoint incubation times differ between wild type and mutants; most assays were conducted once. The STT3-coupled readout is distinct from ALG6 catalysis. No patient residual-activity threshold, clinical rescue or human tissue mechanism is established.

Readouts

Engineered Asp69 substitution reduces transfer

Direction: INCREASED

Interpretation: Asp69Ala abolishes and Asp69Asn reduces the measured transfer reaction.

Show evidence (1 reference)

PMID:32103179 SUPPORT PRIMARY RESULT In Vitro

"Finally, mutating Asp69 to an alanine abolished ALG6 function, and mutating it to an asparagine strongly reduced activity."

Engineered active-site perturbation in purified yeast enzyme.

Show evidence (2 references)

PMID:32103179 SUPPORT PRIMARY RESULT In Vitro

"The specificity of ALG6 can be demonstrated in vitro, where only glucose, but not mannose, is transferred from a Dol25-P carrier"

Purified yeast enzyme with synthetic short-chain donor/acceptor substrates, not human patient cells.

PMID:32103179 SUPPORT PRIMARY RESULT In Vitro

"Purified ALG6 indeed retains activity in the presence of EDTA"

Direct biochemical evidence for metal-independent transfer.

{ }

Source YAML

click to show

name: ALG6-congenital disorder of glycosylation
creation_date: '2026-08-24T13:45:00Z'
description: ALG6-congenital disorder of glycosylation (ALG6-CDG, CDG-Ic) is an autosomal recessive defect of protein N-linked glycosylation caused by biallelic pathogenic ALG6 variants. Reduced ER alpha-1,3-glucosyltransferase function impairs addition of the first glucose to dolichol-linked Man9GlcNAc2, reducing efficient transfer of the glycan precursor to proteins. Developmental disability, axial hypotonia, epilepsy, ataxia, strabismus and feeding problems predominate; protein-losing enteropathy, endocrine and coagulation abnormalities, and cardiomyopathy occur in subsets. Severity and survival vary, and management is supportive and directed at the manifestations.
synonyms:
- ALG6-CDG
- CDG-Ic
- CDG1C
- congenital disorder of glycosylation type Ic
- carbohydrate-deficient glycoprotein syndrome type Ic
- ALG6 deficiency
- glucosyltransferase 1 deficiency
- alpha-1,3-glucosyltransferase deficiency
category: Mendelian
disease_term:
  preferred_term: ALG6-congenital disorder of glycosylation
  term:
    id: MONDO:0011291
    label: ALG6-congenital disorder of glycosylation 1C
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011291
      label: ALG6-congenital disorder of glycosylation 1C
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: ALG6-CDG is caused by biallelic ALG6 variants; the founding mutation cosegregated with disease in a Mendelian recessive manner.
  evidence:
  - reference: PMID:10359825
    reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mutation cosegregated with the disease in a Mendelian recessive manner.
    explanation: Segregation analysis in the original four patients establishes recessive transmission.
    quote_role: PRIMARY_RESULT
prevalence:
- population: Published ALG6-CDG literature through 2016
  measure_type: CASES_IN_LITERATURE
  notes: The 2016 review reported 89 published patients. This historical count and contemporary ranking among CDGs do not estimate current population prevalence. The clinical utility gene card states that incidence and prevalence are unknown.
  evidence:
  - reference: PMID:27287710
    reference_title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG.
    explanation: Historical literature count, not a current population estimate.
  - reference: PMID:25052310
    reference_title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: The frequency and the prevalence of the disease are not known.
    explanation: No measured population frequency is available in this clinical utility review.
pathophysiology:
- name: Biallelic Pathogenic ALG6 Variants
  biological_scale: MOLECULAR
  description: Recessive ALG6 variants impair the function required for the first glucose addition during ER lipid-linked oligosaccharide assembly. Different alleles require their own clinical and functional interpretation; the common p.Tyr131His variant is not treated as a proven cause.
  evidence:
  - reference: PMID:10359825
    reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mutation cosegregated with the disease in a Mendelian recessive manner.
    explanation: Segregation analysis in the original four patients establishes recessive transmission.
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: ALG6
    term:
      id: hgnc:23157
      label: ALG6
  downstream:
  - target: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
    description: The founding p.Ala333Val allele impairs heterologous complementation while retaining partial function.
    causal_link_type: DIRECT
    evidence: &id001
    - &id011
      reference: PMID:10359825
      reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: By contrast, the mutant ALG6 cDNA of CDGS patients failed to revert the hypoglycosylation observed in alg6 yeasts, thereby proving a functional relationship between the alanine to valine substitution introduced by the C-->T transition and the CDGS phenotype.
      explanation: The patient p.Ala333Val construct fails the CPY glycosylation-rescue readout; this is not a direct zero-activity measurement.
    - &id012
      reference: PMID:10359825
      reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: However, the A333V mutation does not inactivate the glucosyltransferase as deduced from the partial growth restoration
      explanation: Partial growth rescue in the double-mutant yeast assay demonstrates residual function.
- name: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
  conforms_to: congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect
  biological_scale: MOLECULAR
  description: Reduced ALG6 function impairs transfer of glucose from dolichyl-phosphate-glucose to dolichol-linked Man9GlcNAc2 in the ER. The founding human p.Ala333Val allele has residual function in yeast; neither a universal null mechanism nor a common quantitative activity threshold has been established for patient alleles.
  genes:
  - preferred_term: ALG6
    term:
      id: hgnc:23157
      label: ALG6
  molecular_functions:
  - preferred_term: alpha-1,3-glucosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0042281
      label: dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence: *id001
  downstream:
  - target: Incomplete Lipid-Linked Oligosaccharide Glucosylation
    description: Reduced first-glucose addition leaves increased unglucosylated Man9GlcNAc2 precursor.
    causal_link_type: DIRECT
    evidence: &id002
    - &id010
      reference: PMID:10914684
      reference_title: Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients.
      explanation: Patient-derived cultured fibroblasts accumulate the unglucosylated substrate.
    - reference: PMID:10359825
      reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The intensity of the RT-PCR signals obtained indicated similar expression levels
      explanation: The source compares ALG6/ALG5 RT-PCR signals in patient and control fibroblasts, rather than demonstrating transcript loss.
- name: Incomplete Lipid-Linked Oligosaccharide Glucosylation
  biological_scale: MOLECULAR
  description: Patient fibroblasts accumulate dolichyl pyrophosphate-Man9GlcNAc2 lacking its normal glucose cap. This is an assembly defect upstream of transfer to protein; residual glucosylation is not excluded.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence: *id002
  downstream:
  - target: Reduced Oligosaccharyltransferase-Mediated Glycan Transfer
    description: Incomplete donor glucosylation reduces efficient recognition and transfer by the oligosaccharyltransferase complex.
    causal_link_type: DIRECT
    evidence: &id003
    - reference: PMID:10359825
      reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: A deficiency in glycosylation of the lipid-linked oligosaccharide results in the incomplete glycosylation of glycoprotein because of the decreased affinity of the oligosaccharyltransferase toward the incomplete substrate.
      explanation: The conserved donor-recognition mechanism connects incomplete precursor glucosylation to reduced protein glycosylation.
- name: Reduced Oligosaccharyltransferase-Mediated Glycan Transfer
  biological_scale: MOLECULAR
  description: The incompletely glucosylated lipid-linked donor is transferred less efficiently to nascent proteins. This is an altered substrate effect, not a claim that ALG6-CDG is caused by an intrinsic oligosaccharyltransferase defect.
  evidence: *id003
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  downstream:
  - target: Protein Hypoglycosylation
    description: Inefficient transfer leaves some N-glycosylation sites unoccupied.
    causal_link_type: DIRECT
    evidence: *id003
- name: Protein Hypoglycosylation
  conforms_to: congenital_disorder_of_glycosylation#Protein Hypoglycosylation
  biological_scale: CELLULAR
  description: Reduced N-glycan occupancy affects serum and cellular glycoproteins. A type I transferrin profile provides a clinical readout. Growth-dependent worsening was measured in yeast assays and is not assumed for every patient tissue.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence: &id008
  - &id009
    reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Carbohydrate deficient transferrin (Mayo Clinic) had a CDG type-I profile (abnormal mono-oligosaccharide/di-oligosaccharide transferrin and a-oligosaccharide/di-oligosaccharide transferrin ratios).
    explanation: A genetically diagnosed child had loss of transferrin glycan occupancy.
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
    description: Clinical organ effects accompany the glycosylation disorder; the particular substrate proteins and intervening tissue mechanisms remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: &id006
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We found abnormal development/ disability (n = 41) and hypotonia (n = 40) as the most common symptoms.
      explanation: Primary clinical cohort documents the downstream neurological phenotype; it does not identify the responsible glycoproteins.
      directness: INDIRECT
  - target: Enterocyte Heparan Sulfate Loss
    description: Hypoglycosylation of core proteins or biosynthetic machinery is a proposed contributor to the biopsy finding in a boy with episodic enteropathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: &id004
    - reference: PMID:11106564
      reference_title: Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: Incomplete N:-linked glycosylation of an HS core protein and/or other biosynthetic enzymes may explain the selective localized loss of HS and PLE.
      explanation: The authors propose alternative connecting mechanisms; neither a specific defective glycoprotein nor causal rescue is demonstrated.
      directness: INDIRECT
- name: Enterocyte Heparan Sulfate Loss
  biological_scale: TISSUE
  description: One boy with ALG6-CDG had reduced basolateral heparan sulfate and syndecan-1 staining in small-intestinal enterocytes during gastroenteritis-associated protein-losing enteropathy, with improvement after the episode. This tissue observation does not establish the mechanism in all patients or prove that glycosaminoglycan sulfation is an N-linked glycosylation reaction.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  evidence: &id005
  - &id007
    reference: PMID:11106564
    reference_title: Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Intestinal biopsy in a boy with gastroenteritis-induced protein-losing enteropathy (PLE) showed loss of heparan sulfate (HS) and syndecan-1 core protein from the basolateral surface of the enterocytes, which improved after PLE subsided.
    explanation: Paired biopsies in one affected boy associate basolateral HS/core-protein loss with an enteropathy episode.
  downstream:
  - target: Intestinal Protein Loss
    description: Loss of basolateral HS is associated with episodic enteric protein leakage; causal necessity and rescue were not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *id004
- name: Intestinal Protein Loss
  biological_scale: TISSUE
  description: Excess enteric protein loss in the subset with protein-losing enteropathy causes hypoalbuminemia and can require intensive nutritional and fluid support.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patients with PLE had a more extensive workup, showing severe hypoalbuminemia
    explanation: The cohort reports severe hypoalbuminemia in the PLE subgroup.
  downstream:
  - target: Protein-losing enteropathy
    description: Excess enteric protein loss is the defining process of PLE.
    causal_link_type: DIRECT
    evidence: *id005
  - target: Hypoalbuminemia
    description: Loss of albumin through the intestine contributes to low serum albumin.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patients with PLE had a more extensive workup, showing severe hypoalbuminemia
      explanation: Observed association in the PLE subgroup; other albumin determinants may also contribute.
- name: Multisystem Glycoprotein Dysfunction
  conforms_to: congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction
  biological_scale: ORGANISM
  description: The clinical consequences of impaired glycoprotein processing are dominated by developmental and neurological dysfunction, with variable ocular, nutritional, endocrine, coagulation and cardiac involvement. This module-level hub does not specify unmeasured disease-specific ER-stress, neuronal-loss or receptor-signaling mechanisms.
  evidence: *id006
  downstream:
  - target: Neurodevelopmental delay
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We found abnormal development/ disability (n = 41) and hypotonia (n = 40) as the most common symptoms.
      explanation: Primary clinical cohort documents the downstream neurological phenotype; it does not identify the responsible glycoproteins.
      directness: INDIRECT
  - target: Muscular hypotonia
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We found abnormal development/ disability (n = 41) and hypotonia (n = 40) as the most common symptoms.
      explanation: Primary clinical cohort documents the downstream neurological phenotype; it does not identify the responsible glycoproteins.
      directness: INDIRECT
  - target: Seizure
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Epilepsy was present in the majority of our patients ( n = 30).
      explanation: The narrative provides the seizure-specific numerator, rather than the abstract list of features.
      directness: INDIRECT
  - target: Strabismus
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: and strabismus (n = 25) in about half of the patients.
      explanation: The counted ocular finding supports the frequency.
      directness: INDIRECT
  - target: Feeding difficulties
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:14517965
      reference_title: Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties.
      explanation: Clinical description of ALG6-CDG; no feeding-specific denominator.
      directness: INDIRECT
  - target: Hyperinsulinemic hypoglycemia
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hyperinsulinism was found in two other patients with episodes of hypoglycemia.
      explanation: Independent ALG6 cohort support, distinct from two patients with unspecified recurrent hypoglycemia.
      directness: INDIRECT
  - target: Myoclonic seizure
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: At onset, most children had myoclonic seizures or infantile spasms.
      explanation: Subtype of epilepsy in the cohort, without a separate count.
      directness: INDIRECT
  - target: Ataxia
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Additionally we found ataxia (n =2 0 )
      explanation: The full-text narrative provides the ataxia numerator.
      directness: INDIRECT
  - target: Proximal muscle weakness
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hypotonia was always axial and was associated with proximal muscle weakness.
      explanation: Direct cohort description; no inferred universal weakness frequency.
      directness: INDIRECT
  - target: Failure to thrive
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: In 25 children, failure to thrive necessitated an increased caloric intake (special diet).
      explanation: Feature-specific numerator supports the cohort-derived band.
      directness: INDIRECT
  - target: Abnormality of coagulation
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Bleeding (increased bleeding time and easy bruising) was less common than expected ( n = 18) and were mainly subclinical.
      explanation: The pooled finding supports a coagulation phenotype, not a clinical-bleeding frequency.
      directness: INDIRECT
  - target: Brachydactyly
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27287710
      reference_title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly.
      explanation: Seven of 41 patients, which is the counted basis for the OCCASIONAL band.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Autistic behavior
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: only five pa- tients were diagnosed with autism that showed classic di- agnostic features and regression in speech and development between the age of 3 and 4 years.
      explanation: The cohort distinguishes diagnosed autism from broader behavioral features.
      directness: INDIRECT
  - target: Abnormal facial shape
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Dysmorphic features in 15 patients were unspecific
      explanation: The full clinical narrative contradicts interpreting the abstract word rare as a quantified very-rare band.
      directness: INDIRECT
  - target: Nystagmus
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: n y s t a g m u s(n =1 8 )
      explanation: The full text provides the nystagmus-specific count.
      directness: INDIRECT
  - target: Hypoplasia of the corpus callosum
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: corpus callosum hypoplasia in one case
      explanation: Independent imaging observation supports the narrower finding.
      directness: INDIRECT
  - target: Cerebellar atrophy
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Only six of the 20 patents with ataxia showed vermis hypoplasia and/or cerebellar atrophy
      explanation: Mixed imaging findings in a selected ataxic subgroup.
      directness: INDIRECT
  - target: Cerebral atrophy
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Other MRI findings included brain atrophy in several patients
      explanation: Primary clinical imaging observation.
      directness: INDIRECT
  - target: Microcephaly
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36756224
      reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: She was born with congenital microcephaly (OFC 30.5 cm, <first percentile) and remained microcephalic with OFC of 43.2 cm (first percentile) at 18-month follow-up.
      explanation: Single confirmed case, without a population frequency.
      directness: INDIRECT
  - target: Delayed speech and language development
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36756224
      reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Babbling was noted to occur by 5 months but remained nonverbal by 18 months.
      explanation: Longitudinal language delay in a confirmed case.
      directness: INDIRECT
  - target: Visual impairment
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36756224
      reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: On physical examination at 18 months, she had a weak cry, no blink to threat, nor visual tracking.
      explanation: Visual dysfunction in a confirmed case; the source does not establish cortical blindness.
      directness: INDIRECT
  - target: Dilated cardiomyopathy
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Three patients had dilated cardiomyopathy
      explanation: Cohort-specific numerator for the cardiac manifestation.
      directness: INDIRECT
  - target: Anemia
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Seven patients also had anemia, most likely due to malab- sorption.
      explanation: Observed anemia, with a proposed rather than demonstrated cause.
      directness: INDIRECT
  - target: Sleep disturbance
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Sleep disturbance requiring daily melatonin treatment was noted in seven.
      explanation: Primary cohort observation.
      directness: INDIRECT
  - target: Aggressive behavior
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Aggressive behavior, mostly around puberty, was present in five cases.
      explanation: Primary cohort observation.
      directness: INDIRECT
  - target: Recurrent infections
    description: Clinical manifestation associated with ALG6-CDG; the responsible glycoprotein and tissue sequence are not individually resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patients 4 and 5 had recurrent episodes of severe infections.
      explanation: Primary observations from the five-person series, also included in the later cohort.
      directness: INDIRECT
phenotypes:
- name: Neurodevelopmental delay
  category: Neurologic
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  description: Developmental impairment was reported in all 41 clinical-cohort participants, across a wide age range. The broader binding avoids asserting that every assessment documented global delay in a child under five.
  evidence: *id006
  frequency: VERY_FREQUENT
- name: Muscular hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: Usually axial, often with proximal weakness. The full 2016 narrative reports 40/41, although the abstract says all.
  evidence: *id006
  frequency: VERY_FREQUENT
- name: Seizure
  category: Neurologic
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: Epilepsy occurred in 30/41 patients in the 2016 narrative; nine had intractable seizures. Onset and response vary, and severe epileptic encephalopathy is a subset.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Epilepsy was present in the majority of our patients ( n = 30).
    explanation: The narrative provides the seizure-specific numerator, rather than the abstract list of features.
  frequency: FREQUENT
- name: Strabismus
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  description: Reported in 25/41 patients in the retrospective cohort.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: and strabismus (n = 25) in about half of the patients.
    explanation: The counted ocular finding supports the frequency.
  frequency: FREQUENT
- name: Feeding difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  description: Feeding problems may require calorie supplementation or tube feeding; they are not synonymous with protein-losing enteropathy.
  evidence:
  - reference: PMID:14517965
    reference_title: Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties.
    explanation: Clinical description of ALG6-CDG; no feeding-specific denominator.
- name: Protein-losing enteropathy
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  description: Reported in six of 41 cohort patients. Severe episodic disease during gastroenteritis was studied in one boy; that course is not required in every affected individual.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In 25 children, failure to thrive necessitated an increased caloric intake (special diet). Six patients had PLE.
    explanation: Primary cohort numerator for enteropathy.
  - *id007
  frequency: OCCASIONAL
- name: Hyperinsulinemic hypoglycemia
  category: Endocrine
  phenotype_term:
    preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
  description: The 2016 cohort independently documents two patients with hyperinsulinism and hypoglycemia. Laboratory screening was incomplete, so no frequency is assigned. This evidence replaces the reclassified NR2F1 case.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hyperinsulinism was found in two other patients with episodes of hypoglycemia.
    explanation: Independent ALG6 cohort support, distinct from two patients with unspecified recurrent hypoglycemia.
- name: Myoclonic seizure
  category: Neurologic
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  description: Myoclonic seizures and infantile spasms are documented seizure presentations. This replaces nonspecific myoclonus attributed to the reclassified patient.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At onset, most children had myoclonic seizures or infantile spasms.
    explanation: Subtype of epilepsy in the cohort, without a separate count.
- name: Ataxia
  category: Neurologic
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  description: Reported in 20/41 cohort patients, not universally. Cerebellar MRI findings were present only in a subset.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Additionally we found ataxia (n =2 0 )
    explanation: The full-text narrative provides the ataxia numerator.
  frequency: FREQUENT
- name: Proximal muscle weakness
  category: Neurologic
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  description: The cohort associates axial hypotonia with proximal weakness, without a separately tabulated weakness denominator.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hypotonia was always axial and was associated with proximal muscle weakness.
    explanation: Direct cohort description; no inferred universal weakness frequency.
- name: Failure to thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  description: Increased caloric intake was required in 25 of 41 children in the cohort.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In 25 children, failure to thrive necessitated an increased caloric intake (special diet).
    explanation: Feature-specific numerator supports the cohort-derived band.
  frequency: FREQUENT
- name: Abnormality of coagulation
  category: Hematologic
  phenotype_term:
    preferred_term: Abnormality of coagulation
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  description: Prolonged bleeding time, easy bruising and deficient pro- or anticoagulant factors occur. The cohort grouped increased bleeding time and bruising in 18 patients, mostly subclinical; that is not a denominator for overt hemorrhage. Thrombosis was reported in one patient.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Bleeding (increased bleeding time and easy bruising) was less common than expected ( n = 18) and were mainly subclinical.
    explanation: The pooled finding supports a coagulation phenotype, not a clinical-bleeding frequency.
- name: Brachydactyly
  description: Shortened digits with missing or uncalcified phalanges, part of the limb anomalies the cohort paper names in its title.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:27287710
    reference_title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly.
    explanation: Seven of 41 patients, which is the counted basis for the OCCASIONAL band.
    quote_role: PRIMARY_RESULT
- name: Autistic behavior
  category: Neurologic
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  description: Autistic features occurred among the 14 participants with behavioral or mood problems; only five were diagnosed with autism. The combined behavioral denominator is not assigned to autism.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: only five pa- tients were diagnosed with autism that showed classic di- agnostic features and regression in speech and development between the age of 3 and 4 years.
    explanation: The cohort distinguishes diagnosed autism from broader behavioral features.
- name: Abnormal facial shape
  category: Craniofacial
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: VARIABLE_SPECTRUM
  description: Nonspecific facial differences were reported in 15/41 patients in the full text, including deep-set eyes, bitemporal narrowing, broad nasal bridge, short philtrum and hypertelorism. They are neither obligatory nor a reliable negative discriminator.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Dysmorphic features in 15 patients were unspecific
    explanation: The full clinical narrative contradicts interpreting the abstract word rare as a quantified very-rare band.
  frequency: FREQUENT
- name: Nystagmus
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  description: Reported in 18/41 patients in the cohort.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: n y s t a g m u s(n =1 8 )
    explanation: The full text provides the nystagmus-specific count.
  frequency: FREQUENT
- name: Hypoplasia of the corpus callosum
  category: Neurologic
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  description: The cohort reports one case independently of the historical p.Tyr131His patient. This is hypoplasia, not established partial agenesis.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: corpus callosum hypoplasia in one case
    explanation: Independent imaging observation supports the narrower finding.
- name: Cerebellar atrophy
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  description: Vermis hypoplasia and/or cerebellar atrophy occurred in six of 20 patients with ataxia; the combined count does not establish an atrophy-specific frequency.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Only six of the 20 patents with ataxia showed vermis hypoplasia and/or cerebellar atrophy
    explanation: Mixed imaging findings in a selected ataxic subgroup.
- name: Cerebral atrophy
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  description: Brain atrophy is documented in several cohort patients and in the child with explosive infantile epilepsy.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Other MRI findings included brain atrophy in several patients
    explanation: Primary clinical imaging observation.
- name: Microcephaly
  category: Neurologic
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  description: Present in some severe cases; congenital microcephaly persisted in a child with genetically and biochemically confirmed ALG6-CDG.
  evidence:
  - reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She was born with congenital microcephaly (OFC 30.5 cm, <first percentile) and remained microcephalic with OFC of 43.2 cm (first percentile) at 18-month follow-up.
    explanation: Single confirmed case, without a population frequency.
- name: Delayed speech and language development
  category: Neurologic
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  description: Speech disability was common among cohort participants old enough to assess; several remained nonverbal. The paper does not supply an unambiguous speech-specific denominator.
  evidence:
  - reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Babbling was noted to occur by 5 months but remained nonverbal by 18 months.
    explanation: Longitudinal language delay in a confirmed case.
- name: Visual impairment
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  description: Visual loss or poor tracking is reported in confirmed cases, but a central visual origin is not assumed from the reclassified 2011 case.
  evidence:
  - reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: On physical examination at 18 months, she had a weak cry, no blink to threat, nor visual tracking.
    explanation: Visual dysfunction in a confirmed case; the source does not establish cortical blindness.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  description: Reported in three of 41 cohort patients. The original Saudi case is included in that cohort and should not be counted again.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Three patients had dilated cardiomyopathy
    explanation: Cohort-specific numerator for the cardiac manifestation.
  - reference: PMID:20398363
    reference_title: 'A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: These findings confirmed moderate cardiomyopathy of the dilated type.
    explanation: The original case includes echocardiographic confirmation.
  frequency: OCCASIONAL
- name: Hypoalbuminemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  description: Severe hypoalbuminemia is particularly associated with protein-losing enteropathy.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patients with PLE had a more extensive workup, showing severe hypoalbuminemia
    explanation: Observed in the selected enteropathy subgroup.
- name: Anemia
  category: Hematologic
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  description: Seven cohort patients had anemia, which the authors attributed provisionally to malabsorption.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Seven patients also had anemia, most likely due to malab- sorption.
    explanation: Observed anemia, with a proposed rather than demonstrated cause.
- name: Sleep disturbance
  category: Neurologic
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  description: Seven patients required melatonin for sleep disturbance.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Sleep disturbance requiring daily melatonin treatment was noted in seven.
    explanation: Primary cohort observation.
  frequency: OCCASIONAL
- name: Aggressive behavior
  category: Behavioral
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  description: Aggressive behavior was reported in five patients, mostly around puberty.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Aggressive behavior, mostly around puberty, was present in five cases.
    explanation: Primary cohort observation.
  frequency: OCCASIONAL
- name: Recurrent infections
  category: Immunologic
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  description: Recurrent infections occurred in the South African neurological subgroup. They do not by themselves establish a primary immunodeficiency.
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patients 4 and 5 had recurrent episodes of severe infections.
    explanation: Primary observations from the five-person series, also included in the later cohort.
biochemical:
- name: Type I CDG serum transferrin isoelectric focusing pattern
  presence: Present
  specificity: Diagnostic support
  notes: A type I pattern reflects missing N-glycan chains and supports an assembly/transfer defect; it does not identify ALG6 specifically. The historical p.Tyr131His patient with normal glycosylation was reclassified as NR2F1-related BBSOAS and is not evidence for a confirmed ALG6 exception.
  evidence: *id008
- name: Dolichyl pyrophosphate-Man9GlcNAc2 accumulation in fibroblasts
  presence: Present
  specificity: Diagnostic support
  notes: Lipid-linked oligosaccharide analysis in cultured fibroblasts shows accumulation of the ALG6 substrate, localising the defect to the glucosylation step rather than to earlier mannosylation.
  evidence:
  - reference: PMID:10914684
    reference_title: Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Analysis of lipid-linked oligosaccharides in fibroblasts confirmed the accumulation of dolichyl pyrophosphate-Man9GlcNAc2 in the CDG-Ic patients.
    explanation: The step-specific biochemical signature of ALG6 deficiency.
    quote_role: PRIMARY_RESULT
- name: Low serum cholesterol and coagulation proteins
  presence: Variable
  specificity: Supportive, not specific
  notes: Low cholesterol, factor XI and anticoagulant factors are reported; concentrations and clinical coagulation consequences vary.
  evidence:
  - reference: PMID:25052310
    reference_title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Striking biochemical abnormalities are unusually low levels of serum cholesterol, blood coagulation factor XI, and anticoagulation factors antithrombin, protein C, and protein S
    explanation: Clinical utility review summarizes biochemical findings, without universal penetrance.
progression:
- phase: Wide survival range with substantial diagnostic delay
  notes: 'Survival in ALG6-CDG spans a wide range. In a 37-patient CDG mortality cohort, the three ALG6-CDG patients survived to 12 months, 2 years and 21 years, the last being the oldest age of death in the whole cohort. Diagnosis was delayed to 16 years in one ALG6-CDG patient. Caution: this is a mortality cohort, so it is a description of the deceased, not a survival estimate for the disease.'
  evidence:
  - reference: PMID:39923392
    reference_title: Causes of mortality in the congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The three patients with ALG6-CDG had a wide age range and they survived to 12 months, 2 years and 21 years.
    explanation: ALG6-CDG-specific survival ages from the mortality cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39923392
    reference_title: Causes of mortality in the congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The youngest age of mortality in this cohort is 1 month for two patients with SLC35A3-CDG and PIGA-CDG, the oldest age was 21 years for a patient with ALG6-CDG.
    explanation: Places the ALG6-CDG maximum at the top of the whole CDG mortality cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39923392
    reference_title: Causes of mortality in the congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, CDG diagnosis was delayed to the age of 17 years for a patient with ALG3-CDG, 16 years for a patient with ALG6-CDG
    explanation: Documents diagnostic delay of 16 years in an ALG6-CDG patient.
    quote_role: PRIMARY_RESULT
- phase: Early childhood mortality with long-lived survivors
  notes: The 2016 paper reports eleven early childhood deaths and adult survivors, with PLE, sepsis and seizures among the causes. Internal table/narrative discrepancies in ages and cohort counts preclude a reconstructed survival curve. This selected retrospective cohort and the separate deceased-only series are not population mortality estimates.
  evidence:
  - reference: PMID:27287710
    reference_title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures.
    explanation: Counted early-childhood mortality with named causes, from the largest cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27287710
    reference_title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The oldest patient was a 40 year-old Dutch woman.
    explanation: The upper end of the survival range, and longer than the 21 years reported in the smaller mortality cohort.
    quote_role: PRIMARY_RESULT
clinical_trials:
- name: NCT04199000
  phase: NOT_APPLICABLE
  description: Observational consortium study of the natural history, causes and treatments of CDG, including ALG6-CDG. The mortality paper cites this protocol, but also includes retrospective deceased cases outside prospective enrollment. The generated registry summary does not establish a current recruitment status.
  evidence:
  - reference: PMID:39923392
    reference_title: Causes of mortality in the congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This NH protocol was approved by the NIH and the Mayo Institutional Review Board (IRB) that served as the central IRB with local context review at each FCDGC NH site (NCT04199000).
    explanation: Registers the natural history study identifier that produced the survival data cited in this entry.
    quote_role: PRIMARY_RESULT
  - reference: clinicaltrials:NCT04199000
    reference_title: Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: The purpose of this research is to study the natural history of congenital disorders of glycosylation and its causes and treatments.
    explanation: Registry purpose, not a demonstrated treatment effect.
genetic:
- name: ALG6 pathogenic variants
  gene_term:
    preferred_term: ALG6
    term:
      id: hgnc:23157
      label: ALG6
  association: Causative
  relationship_type: CAUSATIVE
  notes: Biallelic pathogenic ALG6 variants cause the disease. p.Ala333Val was common in historical cohorts and has a founder haplotype; p.Ile299del and splice variants also recur. The 2016 clinical cohort did not establish a clear genotype–phenotype correlation. Heterologous complementation was performed for selected alleles, not every subsequently reported variant. p.Tyr131His is not treated as causative; the historical homozygous patient was reclassified.
  evidence:
  - reference: PMID:14517965
    reference_title: Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most common disease-causing mutation, c998C>T (p. Ala333Val), which occurs in over half of all known CDG-Ic patients
    explanation: Historical 2003 frequency among then-known cases, not a current global allele frequency.
    quote_role: BACKGROUND
  - reference: PMID:10914684
    reference_title: Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Haplotype analysis of CDG-Ic patients revealed a founder effect for the ALG6 allele bearing the A333 V mutation.
    explanation: Founder origin of the common allele.
    quote_role: PRIMARY_RESULT
  - reference: PMID:10914684
    reference_title: Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The genomic organization of the human ALG6 gene was determined, revealing 14 exons spread over 55 kb.
    explanation: Gene structure relevant to variant ascertainment.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27287710
    reference_title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation.
    explanation: Names the two commonest alleles across 41 patients and records the absence of a genotype-phenotype correlation, which is why this entry curates no allele-stratified phenotype claims.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Transferrin glycoform analysis and molecular confirmation
  description: Transferrin isoelectric focusing or mass spectrometry can identify a type I glycosylation pattern. ALG6-CDG is established by clinically interpreted biallelic pathogenic or likely pathogenic ALG6 variants, with segregation and biochemical/functional studies where needed. Exome or panel testing may precede transferrin testing in an infant with unexplained epilepsy. A VUS or benign variant alone is insufficient.
  evidence:
  - *id009
  - reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Together, these tests confirmed the diagnosis of ALG6-CDG.
    explanation: The child had compound heterozygous ALG6 variants plus repeated type I transferrin results.
  - reference: PMID:32407885
    reference_title: 'Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: This case is illustrative of the utility of whole exome sequencing in the diagnostic odyssey, and the potential pitfalls of relying on focused genetic testing results for diagnosis of conditions with complex overlapping phenotypes.
    explanation: The reclassified patient illustrates why a targeted variant result requires phenotype and biochemical corroboration.
- name: Fibroblast lipid-linked oligosaccharide analysis
  description: Accumulation of Man9GlcNAc2 helps localize the defect. This specialized cultured-cell assay can be equivocal and is available in few centers; it is not required before every genomic diagnosis.
  evidence:
  - *id010
  - reference: PMID:25052310
    reference_title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: the DLO analysis is cumbersome, produces sometimes equivocal results, and is only available in very few centers
    explanation: Limitations described in the clinical utility gene card.
- name: Reassess discordant historical diagnoses
  description: The woman reported with homozygous ALG6 p.Tyr131His in 2011 was later diagnosed with NR2F1-related Bosch-Boonstra-Schaaf optic atrophy syndrome. Normal glycosylation studies together with genomic reassessment supported reclassification; normal adult transferrin alone is not an absolute exclusion rule for all CDGs.
  evidence: &id013
  - reference: PMID:32407885
    reference_title: 'Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We report on a 31-year-old female initially diagnosed with ALG6-CDG based on glycosylation abnormalities on transferrin isoelectrofocusing and targeted genetic testing, and later diagnosed with BBSOAS by whole-exome sequencing (WES).
    explanation: Primary report of diagnostic revision.
  - reference: PMID:32407885
    reference_title: 'Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Functional studies on cultured fibroblasts including Western blotting and RT-qPCR, as well as mass spectrometry of glycosylated transferrin and MALDI-TOF glycan analysis in serum, demonstrated normal glycosylation in this patient.
    explanation: Functional and biochemical support for reassessment; no direct enzyme-activity assay is claimed.
treatments:
- name: Multidisciplinary supportive care
  description: No established disease-modifying treatment is documented in the reviewed ALG6 literature. Coordinate metabolic, neurological, nutritional, developmental and organ-specific care. Evidence for mannose in MPI-CDG does not establish benefit in ALG6-CDG.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:25052310
    reference_title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Treatment of ALG6-CDG is purely symptomatic.
    explanation: ALG6-specific clinical utility guidance.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Individualized antiseizure treatment
  description: Treat according to seizure type and response. The cohort used several agents, and some patients remain refractory. One child had initial electroclinical improvement with phenobarbital but subsequently had near-daily seizures despite multiple agents and ketogenic diet. Neither this observation nor isolated drug trials establish a preferred ALG6-specific regimen.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: After initiation of phenobarbital, there was a dramatic electroclinical improvement
    explanation: Initial response in one child, not durable disease-wide efficacy.
  - reference: PMID:36756224
    reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her epilepsy continued to be medically intractable.
    explanation: The same case had persistent drug resistance.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Seizure
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: PMID:36756224
      reference_title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: After initiation of phenobarbital, there was a dramatic electroclinical improvement
      explanation: Initial response in one child, not durable disease-wide efficacy.
- name: Nutritional and feeding support
  description: Assess growth, caloric requirements, oral motor function and swallowing safety. Use dietary support and enteral feeding when needed. Elemental feeds may help selected patients; no single formula is mandatory for all ALG6-CDG.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In 25 children, failure to thrive necessitated an increased caloric intake (special diet).
    explanation: ALG6 cohort experience.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve.
    explanation: Historical broad N-linked CDG guidance, applied according to individual feeding needs.
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  target_mechanisms:
  - target: Failure to thrive
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: In 25 children, failure to thrive necessitated an increased caloric intake (special diet).
      explanation: ALG6 cohort experience.
  - target: Feeding difficulties
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
      reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve.
      explanation: Historical broad N-linked CDG guidance, applied according to individual feeding needs.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: Specialist management of protein-losing enteropathy
  description: Provide nutritional, albumin/fluid and electrolyte support according to severity. The cohort describes elemental diets and subcutaneous octreotide in selected patients. These are uncontrolled observations, with no demonstrated routine indication or standardized ALG6-specific regimen.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Four PLE patients followed an elementary diet due PLE, and two received octreotide injections to decrease enteral protein loss.
    explanation: Four received elemental diet and two received octreotide; overlap is unspecified. These are uncontrolled treatment observations.
  target_phenotypes:
  - preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  target_mechanisms:
  - target: Protein-losing enteropathy
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Four PLE patients followed an elementary diet due PLE, and two received octreotide injections to decrease enteral protein loss.
      explanation: Four received elemental diet and two received octreotide; overlap is unspecified. These are uncontrolled treatment observations.
- name: Developmental rehabilitation and communication support
  description: Provide physical, occupational and speech-language therapies, adaptive equipment, educational support and planning for adult assistance. Rehabilitation supports function and communication without evidence that it restores glycosylation or normalizes muscle tone.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Occupational therapy, physical therapy, and speech therapy should be instituted.
    explanation: Historical N-linked CDG developmental-care guidance.
  target_phenotypes:
  - preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  target_mechanisms:
  - target: Neurodevelopmental delay
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
      reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: Occupational therapy, physical therapy, and speech therapy should be instituted.
      explanation: Historical N-linked CDG developmental-care guidance.
  - target: Delayed speech and language development
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
      reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: Occupational therapy, physical therapy, and speech therapy should be instituted.
      explanation: Historical N-linked CDG developmental-care guidance.
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
- name: Ophthalmologic assessment and treatment
  description: Evaluate vision and strabismus, and use glasses, patching or surgery when clinically indicated. Poor visual responses warrant assessment rather than assuming a cortical origin.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: therapies that preserve vision (glasses, patching, or surgery) can be instituted as needed.
    explanation: Historical broad CDG ophthalmologic guidance.
  target_phenotypes:
  - preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  target_mechanisms:
  - target: Strabismus
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
      reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: therapies that preserve vision (glasses, patching, or surgery) can be instituted as needed.
      explanation: Historical broad CDG ophthalmologic guidance.
  treatment_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
- name: Coagulation assessment and perioperative planning
  description: Assess both procoagulant and anticoagulant factors and plan invasive procedures with hematology when abnormalities are present. Low factor levels can coexist with thrombosis risk; laboratory abnormalities do not mandate routine prophylactic replacement.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Low levels of coagulation factors, both pro- and anticoagulant, rarely cause clinical problems in daily activities but must be addressed when an individual with CDG undergoes surgery.
    explanation: Broad CDG perioperative guidance.
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Twelve patients underwent minor surgery (strabismus operation or tooth extraction) without compli- cations.
    explanation: ALG6 cohort shows that abnormal tests are not equivalent to inevitable surgical bleeding.
- name: Metabolic, endocrine, hepatic and cardiac surveillance
  description: Monitor growth, glycemia, liver function, thyroid/endocrine findings and coagulation in the clinical context. Documented cardiomyopathy supports cardiac assessment and follow-up; the mortality study proposes echocardiographic evaluation in N-linked CDG, without establishing an ALG6-specific interval or survival benefit. Treat confirmed abnormalities rather than isolated thyroid-binding changes.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: regular screening of glycemia, coagulation, and endocrine and liver function.
    explanation: ALG6 cohort recommendation after observed laboratory abnormalities.
  - reference: PMID:20398363
    reference_title: 'A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The severity of the dilated cardiomyopathy in the present patient was moderate and required long-term cardiac treatment with captopril.
    explanation: Clinical cardiac involvement merits assessment and specialist care.
- name: Cardiomyopathy treatment
  description: Manage documented cardiac dysfunction with cardiology. In one reported boy, captopril was used for five years and withdrawn after stabilization; this single case does not establish comparative efficacy or a universal regimen.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:20398363
    reference_title: 'A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Captopril was just recently weaned off with stabilization of the cardiac function.
    explanation: Longitudinal treatment observation in one patient.
  target_phenotypes:
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  target_mechanisms:
  - target: Dilated cardiomyopathy
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: PMID:20398363
      reference_title: 'A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Captopril was just recently weaned off with stabilization of the cardiac function.
      explanation: Longitudinal treatment observation in one patient.
- name: Behavioral, psychiatric and sleep care
  description: Assess mood, behavior, communication and sleep, and tailor treatment. Seven cohort participants used melatonin. A separate adolescent improved with escitalopram and risperidone but had dose-related extrapyramidal effects; that abstract-only case does not establish a standard combination for ALG6-CDG.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Sleep disturbance requiring daily melatonin treatment was noted in seven.
    explanation: Primary cohort treatment observation.
  - reference: PMID:39141102
    reference_title: 'Psychiatric assessment and therapy in an adolescent with ALG6-CDG: a six-month follow-up case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient's symptoms improved with escitalopram and risperidone treatment. However, above a certain dosage, she was sensitive to extrapyramidal side effects.
    explanation: Single adolescent case; individual response and adverse effects, not a comparative recommendation.
  target_phenotypes:
  - preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  target_mechanisms:
  - target: Sleep disturbance
    treatment_effect: MODULATES
    description: Manifestation-directed care; this does not correct the ALG6 biochemical defect.
    evidence:
    - reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      reference_title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Sleep disturbance requiring daily melatonin treatment was noted in seven.
      explanation: Primary cohort treatment observation.
- name: Genetic counseling and evaluation of relatives
  description: Confirm the familial causal variants, offer carrier and at-risk sibling testing, and discuss reproductive options. With two carrier parents, each pregnancy has the usual autosomal recessive 25% affected risk. Molecular prenatal or preimplantation testing can be considered after variant identification; fetal transferrin testing is unreliable.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:25052310
    reference_title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: The identiﬁcation of the pathogenic variant will permit heterozygote detection in the family, and prenatal diagnosis.
    explanation: ALG6-specific family-testing guidance.
  - reference: PMID:25052310
    reference_title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Prenatal diagnosis should be performed by molecular analysis; fetal transferrin isoelectrofocusing leads to false results.
    explanation: Molecular testing is preferred for an at-risk pregnancy.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: It is appropriate to evaluate apparently asymptomatic older and younger sibs
    explanation: Broad CDG guidance supports early evaluation of at-risk siblings.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
experimental_models:
- name: ALG6-deficient Saccharomyces cerevisiae complementation assay
  experimental_model_type: OTHER
  description: Human wild-type or p.Ala333Val ALG6 was expressed in Saccharomyces cerevisiae alg6 mutants. CPY glycoform rescue and synthetic growth rescue in alg6 wbp1-2 double mutants are distinct readouts. These assays support impaired but residual activity of the founding allele; they did not test every human variant.
  publication: PMID:10359825
  modeled_mechanisms:
  - target: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Heterologous complementation assesses functional capacity of the human construct in a yeast pathway.
    limitations: Growth and CPY glycosylation depend on yeast background, expression and assay conditions. Failure of one rescue readout is not a quantitative zero-activity measurement or proof of human organ pathology.
    readouts:
    - name: Failure of mutant CPY glycosylation rescue
      target: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
      direction: INCREASED
      interpretation: Compared with the partially rescuing wild-type human construct, p.Ala333Val leaves CPY hypoglycosylation uncorrected in this assay.
      evidence:
      - *id011
    - name: Growth rescue in alg6 wbp1-2 yeast
      target: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
      direction: DECREASED
      interpretation: The p.Ala333Val construct partially restores growth, supporting residual function.
      evidence:
      - *id012
  evidence:
  - reference: PMID:10359825
    reference_title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Expression of the human ALG5 and ALG6 cDNA could partially complement the respective S. cerevisiae alg5 and alg6 deficiency.
    explanation: Establishes that human ALG6 functionally substitutes in the yeast system, which is what makes the assay informative for human alleles.
    quote_role: PRIMARY_RESULT
- name: ALG6-CDG patient fibroblast lipid-linked oligosaccharide profiling
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Cultured patient fibroblasts show accumulation of the unglucosylated ALG6 substrate. The original p.Ala333Val study also found similar ALG6 RT-PCR signals in patient and control fibroblasts, so reduced transcript abundance is not asserted as that allele mechanism.
  publication: PMID:10914684
  evidence: *id002
  modeled_mechanisms:
  - target: Incomplete Lipid-Linked Oligosaccharide Glucosylation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Patient-derived cells reproduce the disease biochemical substrate accumulation.
    limitations: Fibroblasts do not model organ-specific developmental, neurological or enterocyte dysfunction.
    readouts:
    - name: Dolichyl pyrophosphate-Man9GlcNAc2 accumulation
      target: Incomplete Lipid-Linked Oligosaccharide Glucosylation
      direction: INCREASED
      interpretation: Accumulated unglucosylated precursor localizes the assembly block.
      evidence: *id002
- name: Purified yeast ALG6 structural and glycosyltransferase assays
  experimental_model_type: OTHER
  description: Saccharomyces cerevisiae ALG6 expressed through an Sf9/baculovirus system was purified for cryo-EM and synthetic-substrate assays. The apo nanodisc structure is 3.0 Å and donor-bound detergent structure 3.9 Å. Patient positions were mapped onto the yeast structure; they were not functionally tested as a clinical allele series. The acceptor groove, donor-glucose geometry and binding order remain incompletely resolved.
  publication: PMID:32103179
  evidence:
  - reference: PMID:32103179
    reference_title: Structure and mechanism of the ER-based glucosyltransferase ALG6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The specificity of ALG6 can be demonstrated in vitro, where only glucose, but not mannose, is transferred from a Dol25-P carrier
    explanation: Purified yeast enzyme with synthetic short-chain donor/acceptor substrates, not human patient cells.
  - reference: PMID:32103179
    reference_title: Structure and mechanism of the ER-based glucosyltransferase ALG6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Purified ALG6 indeed retains activity in the presence of EDTA
    explanation: Direct biochemical evidence for metal-independent transfer.
  modeled_mechanisms:
  - target: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
    relationship: PERTURBS
    fidelity: MODERATE
    description: Engineered catalytic-site substitutions interrogate the conserved first-glucose reaction.
    limitations: Asp69/Asp99/His378 substitutions are engineered yeast variants, not patient alleles. Endpoint incubation times differ between wild type and mutants; most assays were conducted once. The STT3-coupled readout is distinct from ALG6 catalysis. No patient residual-activity threshold, clinical rescue or human tissue mechanism is established.
    readouts:
    - name: Engineered Asp69 substitution reduces transfer
      target: ALG6 Alpha-1,3-Glucosyltransferase Deficiency
      direction: INCREASED
      interpretation: Asp69Ala abolishes and Asp69Asn reduces the measured transfer reaction.
      evidence:
      - reference: PMID:32103179
        reference_title: Structure and mechanism of the ER-based glucosyltransferase ALG6.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Finally, mutating Asp69 to an alanine abolished ALG6 function, and mutating it to an asparagine strongly reduced activity.
        explanation: Engineered active-site perturbation in purified yeast enzyme.
discussions:
- discussion_id: resolved_alg6_y131his_reclassification
  kind: KNOWLEDGE_GAP
  status: RESOLVED
  prompt: Does the historical homozygous p.Tyr131His case establish ALG6-CDG?
  attaches_to:
  - pathophysiology#Biallelic Pathogenic ALG6 Variants
  rationale: The 2020 primary report reclassified the woman described in the 2011 puberty paper as NR2F1-related BBSOAS and found normal glycosylation in fibroblasts and serum. Her attributed puberty, dysarthria and cortical visual findings are therefore not retained as ALG6 evidence without independent support. The original yeast assay used p.Tyr131His in cis with p.Ser308Arg and cannot establish the isolated common variant as causal. A normal adult transferrin result alone does not exclude every CDG.
  evidence: *id013
  resolved_date: '2026-09-21T05:04:09Z'
  resolution_note: PMID:32407885 reclassified the historical patient as NR2F1-related BBSOAS and documented normal glycosylation. The isolated p.Tyr131His variant is not accepted here as a causal ALG6-CDG allele; independent ALG6 findings are retained with other sources.
- discussion_id: gap_alg6_ple_causal_step
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which hypoglycosylated protein is responsible for enterocyte heparan sulfate loss in ALG6-CDG protein-losing enteropathy?
  attaches_to:
  - pathophysiology#Enterocyte Heparan Sulfate Loss
  rationale: The paired biopsy observation links enteropathy episodes with reduced heparan sulfate and syndecan-1 staining in one boy. Core-protein hypoglycosylation and impaired glycosylation of biosynthetic enzymes are alternative proposed explanations. Yeast growth-phase effects do not directly demonstrate enterocyte proliferation as the causal human intermediate. Neither a specific connecting protein nor rescue of human enteric leakage was established.
  proposed_experiments:
  - experiment_id: exp_alg6_ple_glycoproteomics
    name: Site-occupancy glycoproteomics of patient enterocytes
    description: Perform site-specific N-glycosylation occupancy measurement on intestinal biopsy material from ALG6-CDG patients during and after an enteropathy episode, comparing occupancy on heparan sulfate core proteins against occupancy on heparan sulfate biosynthetic enzymes.
- discussion_id: alg6_modifier_scope
  kind: INTERPRETATION
  status: RESOLVED
  prompt: Does p.Phe304Ser establish an ALG6-CDG severity modifier?
  rationale: The cited association compared severity groups in PMM2-CDG, not ALG6-CDG. It is retained as cross-disease context rather than an ALG6 structured modifier relationship. The later ALG6 cohort did not establish a clear genotype–phenotype correlation.
  evidence:
  - reference: PMID:11875054
    reference_title: A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the F304S genotype frequency in 55 CDG-Ia patients classified as mild/moderate (n = 28), or severe (n = 27) was significantly higher in severely affected patients (0.41) than in mild/moderately affected patients (0.21)
    explanation: The quantitative basis for treating p.Phe304Ser as a severity modifier in PMM2-CDG.
    quote_role: PRIMARY_RESULT
  resolved_date: '2026-09-21T05:04:09Z'
  resolution_note: Removed the PMM2-specific modifier association from the structured ALG6 genetic relationships; retained its scope in this interpretation discussion.
notes: 'Scope: ALG6-CDG (CDG-Ic), distinct from other per-gene CDGs. OMIM 603147 is the disease; 604566 is the ALG6 gene. The matching research report was used as a lead, with primary-source correction of unsupported activity thresholds, universal functional testing, speculative ER-stress/receptor pathways and the reclassified p.Tyr131His case.

  GeneReviews baseline: the complete NBK1332 N-linked glycosylation overview contains ALG6-specific clinical and inheritance information and general diagnosis, care, surveillance and family guidance. It is retired and used as historical guidance alongside the clinical utility card and newer primary reports. Its 2011 puberty citation predates the NR2F1 reclassification and was not carried forward.

  Cohort accounting: the 2016 study reports 41 clinical participants, including six without molecular results but characteristic LLO/transferrin findings, and incorporates the five South African cases and the original cardiomyopathy case. Its genetic registry and genotype–phenotype comparison use different denominators. Narrative phenotype counts are used rather than deriving new totals from internally inconsistent tables: duplicate patient labels/extra rows, a 42-case figure caption, and discrepancies in ages/deaths are present. Laboratory assessment was not systematic. A cohort-derived band is not population penetrance. Hypotonia is 40 in the narrative despite all in the abstract; ataxia is 20 and epilepsy 30, while nonspecific dysmorphism is 15 despite the abstract describing it as rare.

  Source availability: all original abstracts and actual cached full bodies were assessed. The 23430515 record is labeled full HTML but contains a subscription preview; the complete five-case paper was generated separately from its institutional PDF. Full 2016 cohort and GeneReviews sources were also recovered. The 32407885 abstract establishes diagnostic revision; publisher clinical/methods text was independently checked but its complete Results were not retrieved, and no disputed secondary NR2F1 residue was imported. Attempts to recover the complete 11106564 body through PMC and a PDF mirror were blocked; its model and biopsy claims remain restricted to the generated abstract. Gene-card PDF extraction has broken words; no test accuracy percentage or lifetime negative predictive value was generalized from it.

  Care scope: the retired GeneReviews chapter also gives a general precaution about acetaminophen and other liver-metabolized medicines. It does not demonstrate an ALG6-specific drug contraindication; medication review should reflect the individual hepatic findings. No blanket prohibition was inferred from that historical class-level advice.

  Treatment ontology scope: live NCIt search supports Nutritional Support, Rehabilitation, Eye Examination and Anticonvulsant Therapy. Patient Monitoring (NCIT:C53607) falls outside the treatment-action enum and was not forced into it. Searches for hematology consultation, psychiatric treatment and protein-losing-enteropathy treatment did not identify a matching specific allowed action; those multimodal plans remain descriptively curated.'
datasets: []
references:
- reference: PMID:10359825
  title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
- reference: PMID:10852543
  title: Clinical and biochemical characteristics of congenital disorder of glycosylation type Ic, the first recognized endoplasmic reticulum defect in N-glycan synthesis.
- reference: PMID:10914684
  title: Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic.
- reference: PMID:11106564
  title: Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation.
- reference: PMID:11875054
  title: A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency.
- reference: PMID:14517965
  title: Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.
- reference: PMID:20301507
  title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
  tags:
  - GeneReviews
- reference: PMID:20398363
  title: 'A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.'
- reference: PMID:21334936
  title: Pubertal development in ALG6 deficiency (congenital disorder of glycosylation type Ic).
- reference: PMID:23430515
  title: 'ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients.'
- reference: PMID:25052310
  title: 'Clinical utility gene card for: ALG6 defective congenital disorder of glycosylation.'
- reference: PMID:27287710
  title: 'ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.'
- reference: PMID:32103179
  title: Structure and mechanism of the ER-based glucosyltransferase ALG6.
- reference: PMID:32407885
  title: 'Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype.'
- reference: PMID:34851357
  title: A novel fission yeast platform to model N-glycosylation and the bases of congenital disorders of glycosylation type I.
- reference: PMID:36756224
  title: A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
- reference: PMID:39141102
  title: 'Psychiatric assessment and therapy in an adolescent with ALG6-CDG: a six-month follow-up case report.'
- reference: PMID:39923392
  title: Causes of mortality in the congenital disorders of glycosylation.
- reference: clinicaltrials:NCT04199000
  title: Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
- reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf
  title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2012 - ALG6-CDG in South Africa Genotype-phenotype description of five novel patients.pdf
- reference: url:https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
  title: https://natural-sciences.nwu.ac.za/sites/natural-sciences.nwu.ac.za/files/files/human-metabolomics/Pliem/research/2016 - ALG6-CDG a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioural and limb anomalies.pdf
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
  title: Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
review_notes: Reviewed the complete entry, matching research and generated source bodies. Primary full-text cohort data replace ambiguous abstract-based frequencies. The p.Tyr131His patient was reclassified, so that historical case no longer supplies ALG6 phenotypes or an unresolved pathogenicity gap. GeneReviews is retired and interpreted with its clinical, diagnostic, management and family scope. Molecular chemistry, heterologous rescue and patient tissue observations remain distinct. The source-availability and cohort discrepancies are detailed in notes.

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References & Deep Research

References

PMID:10359825

A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.