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Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive, with consanguinity and founder alleles prominent in the reported families.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:12116250 SUPPORT Human Clinical

"Leukocyte adhesion deficiency (LAD) type II is a rare autosomal recessive syndrome"

States the inheritance mode directly.

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Discussions and Knowledge Gaps

3

Why is lymphocyte function preserved in LAD II when selectin ligands are absent from all leukocytes?

INTERPRETATION OPEN interpretation_lymphocyte_compartment_sparing

Attached to

animal_models#Slc35c1-deficient mouse pathophysiology#Loss of Sialyl-Lewis X Selectin Ligands

A disease that removes selectin ligands globally should compromise lymphocyte homing as much as neutrophil trafficking, and yet lymphocyte function in patients is reported as surprisingly normal. The knockout mouse gives a mechanistic answer by splitting the compartments: homing to lymph nodes fell to 1-2% of normal while trafficking to the spleen was completely normal, and the humoral response failed in lymph nodes but not in spleen. The reason is anatomical rather than molecular. Lymph node entry runs through high endothelial venules and depends on the selectin-mediated rolling step this disease abolishes; splenic entry does not use that route. So the disease is not sparing lymphocytes - it is sparing one lymphoid compartment, and that compartment is sufficient for the humoral responses that get measured clinically. This is worth stating because it predicts where a lymphocyte defect should be detectable in patients if anyone looked for it in the right place.

Which specific fucosylated glycoproteins or glycolipids, when hypofucosylated, produce the growth failure and intellectual disability of LAD II?

KNOWLEDGE GAP OPEN gap_neurodevelopmental_substrates

Attached to

pathophysiology#Growth Failure and Neurodevelopmental Impairment

The immune branch of this disease is mechanistically closed: the missing glycan is named, its receptor is named, and the cellular step it blocks is measurable. The neurodevelopmental branch has nothing equivalent. It is attributed to hypofucosylation of substrates needed for growth-factor signalling and neurodevelopment, but no particular substrate has been tied to the phenotype, which is why the node carries INDIRECT_UNKNOWN_INTERMEDIATES and PROVISIONAL confidence. This matters practically, not just descriptively. Oral fucose improved psychomotor capability in the index patient, so the branch is at least partly reversible - but without knowing the substrates there is no way to predict which patients' neurological features will respond or to measure the response other than clinically.

How much residual GDP-fucose transport is enough to spare the immune phenotype, and why does the growth and neurodevelopmental branch appear more sensitive?

INTERPRETATION OPEN interpretation_partial_defect_immune_sparing

Attached to

pathophysiology#Failure of Leukocyte Rolling on Activated Endothelium phenotypes#Persistent Leukocytosis

The compound-heterozygous brothers had measurably impaired neutrophil rolling and marked changes in plasma glycoprotein glycoform distribution, yet no leukocytosis and no recurrent infection - only short stature and developmental delay. The authors call this a surprising degree of immune redundancy. Read against the pathograph, it says the two branches have different thresholds: enough residual fucosylation to keep the adhesion cascade functional was not enough to protect growth or neurodevelopment. That has a diagnostic consequence worth stating, since it means SLC35C1 disease can present to an endocrinologist or a developmental paediatrician with no immunological signal at all, and the leukocyte count - the feature the disease is named for - can be entirely normal.

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Pathophysiology

8

Biallelic SLC35C1 Loss-of-Function Variants

Both copies of SLC35C1 carry variants that disable the Golgi GDP-fucose transporter. The founding patient carried R147C in the fourth transmembrane region, and overexpressing that mutant protein in the patient's own cells failed to rescue fucosylation - which is what established the substitution as causal rather than incidental.

Genetic context SLC35C1 hgnc:20197 variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Homozygous in the reported founder families; compound heterozygous in the milder sibling pair curated below. Loss of function is asserted on the strength of the failed rescue experiment rather than inferred from variant class alone.

Downstream

Impaired Golgi GDP-Fucose Import The gene product is the transporter, so a disabling variant removes the transport step directly.

Show evidence (2 references)

PMID:11326279 SUPPORT In Vitro

"The corresponding endogenous protein in LAD II cells had an R147C amino acid change in the conserved fourth transmembrane region."

Identifies the causal substitution in the founding patient.

PMID:11326279 SUPPORT In Vitro

"Overexpression of this mutant protein in cells from a patient with LAD II did not rescue fucosylation, demonstrating that the point mutation affected the activity of the protein."

The rescue-failure experiment that makes this loss of function rather than a coincidental variant.

Impaired Golgi GDP-Fucose Import

GDP-fucose is made in the cytosol but consumed in the Golgi lumen, so it must cross a membrane to reach the enzymes that use it. That crossing is what fails here. The defect was localised to transport specifically by excluding the alternatives: neither fucosyltransferase activity nor the enzymes of GDP-fucose biosynthesis were deficient, while transport into isolated Golgi vesicles was reduced.

GDP-fucose transmembrane transport GO:0015783 ↓ DECREASED

GDP-fucose transmembrane transporter activity GO:0005457 ⇓ LOSS OF FUNCTION

Golgi apparatus GO:0005794

Experimental models

CHO-gmt5 SLC35C1-knockout cell line CELL LINE Reproduces the primary lesion - absent SLC35C1 function with consequent loss of glycan fucosylation - in a tractable system.

Downstream

Global Hypofucosylation of Glycoconjugates Substrate starvation of the luminal fucosyltransferases, which are themselves normal.

Show evidence (1 reference)

PMID:11326279 SUPPORT In Vitro

"No deficiency in fucosyltransferase activities or in the activities of enzymes involved in GDP-fucose biosynthesis has been found. Instead, the transport of GDP-fucose into isolated Golgi vesicles of LAD II cells appeared to be reduced."

Localises the lesion to transport by exclusion - the enzymes and the biosynthetic pathway are intact, and only the membrane step is impaired.

Global Hypofucosylation of Glycoconjugates

With no donor substrate reaching them, the Golgi fucosyltransferases cannot fucosylate their targets, and the deficit is general rather than selective - N-glycans, O-glycans and glycolipids alike. This node is the branch point of the entry: everything below it is a separate consequence of the same missing modification, not a step in a common chain.

fucose metabolic process GO:0006004 ↓ DECREASED

fucosyltransferase activity GO:0008417 ↓ DECREASED

Downstream

Loss of Sialyl-Lewis X Selectin Ligands Sialyl-Lewis X is a fucosylated tetrasaccharide; without fucose it is not built.

Loss of Red Cell H-Antigen Fucosylation The H antigen is made by alpha-1,2 fucosylation of its precursor, which fails for the same reason.

Growth Failure and Neurodevelopmental Impairment Attributed to hypofucosylation of glycoproteins and glycolipids needed for normal growth and neurodevelopment, but the responsible substrates have not been identified, so the intermediate steps are genuinely unknown.

Show evidence (2 references)

PMID:11326279 SUPPORT Human Clinical

"Leukocyte adhesion deficiency II (LAD II) is characterized by the lack of fucosylated glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and growth retardation."

States the general absence of fucosylated glycoconjugates and names the three consequence branches curated below it.

PMID:12116250 SUPPORT Human Clinical

"It is attributed to a general absence of fucosylated glycans on the cell surface."

Confirms the deficit is general rather than restricted to one glycan class.

Loss of Sialyl-Lewis X Selectin Ligands

Sialyl-Lewis X on the neutrophil surface is the carbohydrate that E-, P- and L-selectin recognise. Without its fucose it is not assembled, so the neutrophil presents no ligand for the endothelial selectins to catch.

neutrophil CL:0000775

Downstream

Failure of Leukocyte Rolling on Activated Endothelium Rolling is selectin-mediated, so removing the ligand removes the interaction.

Show evidence (1 reference)

PMID:24403049 SUPPORT Human Clinical

"inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis and recurrent infections"

Names sialyl-Lewis X as the fucosylated molecule whose loss drives the immune phenotype.

Failure of Leukocyte Rolling on Activated Endothelium

Rolling is the first step of the adhesion cascade: without it the neutrophil never slows enough to engage integrins, never firmly adheres, and never crosses into tissue. The circulating pool therefore rises while the tissue pool falls - which is why the blood count and the infection risk move in opposite directions here.

neutrophil CL:0000775 blood vessel endothelial cell CL:0000071

leukocyte tethering or rolling GO:0050901 ↓ DECREASED leukocyte cell-cell adhesion GO:0007159 ↓ DECREASED

Animal models

Slc35c1-deficient mouse Mouse recapitulates Reproduces the defining cellular lesion directly and in vivo: selectin-dependent rolling in cremaster venules is essentially abolished, with firm adhesion strongly but incompletely reduced downstream of it.

Downstream

Impaired Neutrophil Extravasation to Infection Sites Extravasation requires the rolling step that has been lost.

Show evidence (1 reference)

PMID:24403049 SUPPORT Human Clinical

"While neutrophil rolling on endothelial selectins was partially impeded, residual adhesion proved sufficient to avoid leukocytosis or recurrent infection."

PARTIAL because it documents the rolling defect while simultaneously showing it is not always sufficient for the clinical phenotype - the partial-defect siblings had impaired rolling and no immune disease. Cited here to keep that qualification attached to the node it qualifies.

Impaired Neutrophil Extravasation to Infection Sites

Neutrophils remain in the circulation instead of reaching tissue, producing the characteristic combination of recurrent bacterial infection with a raised rather than lowered neutrophil count. Periodontal disease follows from the same failure of routine neutrophil surveillance at the gingival sulcus.

inflammatory response GO:0006954 ↓ DECREASED

Animal models

Slc35c1-deficient mouse Mouse recapitulates Neutrophil migration into an inflamed compartment is quantified, giving the extravasation node a measured value rather than an inference from rolling.

Show evidence (1 reference)

PMID:10590041 SUPPORT Human Clinical

"This disorder leads to an immunodeficiency caused by the absence of carbohydrate-based selectin ligands on the surface of neutrophils"

States the causal route from absent selectin ligands to immunodeficiency.

Loss of Red Cell H-Antigen Fucosylation

The H antigen that ABO antigens are built on requires alpha-1,2 fucosylation of its precursor. Without it, red cells type as Bombay (hh). This branch is diagnostically valuable and clinically silent - it causes no anaemia and no haemolysis - and it is curated separately for exactly that reason: it shares a cause with the immune phenotype but nothing else.

erythrocyte CL:0000232

Show evidence (1 reference)

PMID:12116250 SUPPORT Human Clinical

"characterized by recurrent infections, typical dysmorphic features, the Bombay blood phenotype and severe growth and psychomotor retardation"

Lists the Bombay blood phenotype as a defining feature alongside the other branches.

Growth Failure and Neurodevelopmental Impairment

Severe growth retardation and intellectual disability accompany the disorder in the classically affected patients. PROVISIONAL because the mechanism is genuinely open: the phenotype is attributed to hypofucosylation of glycoproteins and glycolipids required for normal growth-factor signalling and neurodevelopment, but the specific fucosylated substrates responsible have not been identified, and no model links a named substrate to the neurodevelopmental outcome. The partial-defect siblings are informative here too - they had short stature and developmental delay as their only presenting signs, which suggests this branch is more sensitive to residual transporter activity than the immune branch is.

Show evidence (2 references)

PMID:11326279 SUPPORT Human Clinical

"causing immunodeficiency and severe mental and growth retardation"

Attributes the neurodevelopmental and growth phenotype to the same hypofucosylation that causes the immunodeficiency, without specifying intermediates.

PMID:24403049 SUPPORT Human Clinical

"show that short stature and developmental delay may be the sole presenting signs in this disorder"

Establishes that this branch can present in isolation, which is the basis for curating it as parallel to the immune branch rather than downstream of it.

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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

5

Blood 1

Persistent Leukocytosis VERY_FREQUENT Increased total leukocyte count HP:0001974

Show evidence (2 references)

PMID:24403049 SUPPORT Human Clinical

"inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis and recurrent infections"

Ties the leukocytosis to the same sialyl-Lewis X defect as the infection phenotype.

PMID:10590041 SUPPORT Human Clinical

"elevated neutrophil counts returned to normal"

Confirms the counts were elevated at baseline, by reporting their normalisation on fucose therapy.

Head and Neck 1

Chronic Severe Periodontitis VERY_FREQUENT HP:0000704

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:11213799 SUPPORT Human Clinical

"The infectious episodes and the severity are much milder than those observed in LAD I, and the only persistent clinical symptom is chronic severe periodontitis."

States the periodontal phenotype directly for LAD II, and sets it against LAD I - which is the comparison that matters here, since the periodontal literature for leukocyte adhesion deficiency is dominated by LAD I.

Nervous System 1

Severe Intellectual Disability VERY_FREQUENT HP:0010864

Show evidence (1 reference)

PMID:10590041 SUPPORT Human Clinical

"as well as to severe psychomotor and mental retardation"

States the neurodevelopmental severity in the classical presentation.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:24403049 SUPPORT Human Clinical

"We report two brothers with short stature and developmental delay who are compound heterozygotes for novel mutations in SLC35C1"

Documents short stature in molecularly confirmed patients.

Other 1

Recurrent Bacterial Infections VERY_FREQUENT HP:0002718

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:12116250 SUPPORT Human Clinical

"characterized by recurrent infections, typical dysmorphic features, the Bombay blood phenotype and severe growth and psychomotor retardation"

Names recurrent infection as a defining feature of the syndrome.

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Genetic Associations

1

SLC35C1

Gene: SLC35C1 hgnc:20197 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:11326279 SUPPORT In Vitro

"Thus, we have identified the first putative GDP-fucose transporter, which has been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II."

The gene-disease assignment, from the cloning study that made it.

PMID:12116250 SUPPORT Human Clinical

"The amount of mRNA of the GDP-L-fucose transporter in cells from Arab patients and their parents are comparable to controls."

Excludes reduced transcript abundance as the mechanism, which is why this entry curates the lesion as a functional transport failure.

PMID:12116250 SUPPORT Human Clinical

"Genotype/phenotype correlation studies show that the two different mutations are distinguished by differences in response to fucose supplementation and in the clinical phenotypes."

The allele-specific treatment response, which is why fucose therapy is curated below as genotype-dependent rather than as a uniform option.

+ 1 more reference

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Medical Actions

4

Oral Fucose Supplementation

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Agent: L-fucose CHEBI:18287

Oral L-fucose, which is rational rather than empirical: fucose entering by the salvage pathway raises the cytosolic GDP-fucose pool, and a higher substrate concentration can drive enough flux through a crippled transporter to restore fucosylation. It treats the substrate side of a transport problem rather than the transporter. In the index patient the effect was measurable at the molecular level and then at the clinical one: fucosylated selectin ligands reappeared on neutrophils, serum glycoproteins regained core fucosylation, and over nine months infections and fever stopped while the neutrophil count normalised. It does not work for everyone, and the reason is genotypic rather than a matter of dose or adherence - the founder-mutation study found the two alleles differed in their response. Treatment is therefore reasonably attempted and must be assessed per patient.

Mechanism Target:

Impaired Golgi GDP-Fucose Import — Raises substrate availability upstream of the failed transport step rather than correcting the transporter, which is why residual transport activity determines whether it works.

Show evidence (1 reference)

PMID:10590041 SUPPORT In Vitro

"The fucosylation defect in LAD II fibroblasts can be corrected by addition of L-fucose to the culture medium."

The in-vitro correction that supplied the rationale for treating the substrate side of the defect.

Show evidence (3 references)

PMID:10590041 SUPPORT Human Clinical

"Oral supplementation of fucose in this patient induced the expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins."

The molecular response - the treatment restores the specific glycan whose absence defines the disease.

PMID:10590041 SUPPORT Human Clinical

"During 9 months of treatment, infections and fever disappeared, elevated neutrophil counts returned to normal, and psychomotor capabilities improved."

The clinical response over a defined period in the index patient.

PMID:12116250 SUPPORT Human Clinical

"Genotype/phenotype correlation studies show that the two different mutations are distinguished by differences in response to fucose supplementation and in the clinical phenotypes."

PARTIAL because it qualifies the treatment rather than supporting it: response is allele-dependent, so this is not a uniformly effective therapy.

AVTX-803 (oral L-fucose, regulatory-track product)

Action: Pharmacotherapy NCIT:C15986

Agent: L-fucose CHEBI:18287

A purpose-built oral L-fucose product carrying the same substrate-replacement rationale as compassionate-use fucose, but developed as a drug and now in a randomised Phase 3 withdrawal trial with an open-label extension. It is curated separately from the supplementation record above because the difference is not cosmetic: the 1999 report is a single patient given a sugar, while this is a controlled test of whether the benefit persists and depends on continued dosing. The trial's primary endpoint is leukocyte sialyl-Lewis X expression - the same measurement used diagnostically - so efficacy is assessed directly against the mechanism rather than through an infection-count proxy that would be underpowered in a disease this rare.

Mechanism Target:

Impaired Golgi GDP-Fucose Import — Same mechanism as dietary fucose - raising substrate availability upstream of the failed transport step - delivered as a controlled product.

Show evidence (1 reference)

clinicaltrials:NCT05462587 SUPPORT Human Clinical

"The primary objective of this study is to evaluate the efficacy and safety of AVTX-803 compared to withdrawal in patients with Leukocyte Adhesion Deficiency, Type II (LAD II)."

Establishes AVTX-803 as an agent under controlled evaluation in this disease. Note this is a statement of objective from a registration record, not a result - the trial is recruiting and no efficacy outcome is available.

Infection Prophylaxis and Management

Action: Pharmacotherapy NCIT:C15986

Antimicrobial prophylaxis and prompt treatment of intercurrent infection, which is supportive rather than mechanism-directed. Recorded because it is what patients who do not respond to fucose actually receive.

Mechanism Target:

Impaired Neutrophil Extravasation to Infection Sites — Compensates for the missing neutrophil response rather than restoring it.

Genetic Counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive inheritance with a 25% recurrence risk per pregnancy for carrier couples. Founder alleles and consanguinity are prominent in the reported families, so carrier testing of extended relatives is informative where a family allele is known.

Show evidence (1 reference)

PMID:12116250 SUPPORT Human Clinical

"All three children reported by us are homozygous for one single founder mutation, different from that reported in the Turkish child."

Documents the founder-allele structure that makes targeted carrier testing useful.

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Diagnosis

3

Flow Cytometry for Neutrophil Sialyl-Lewis X (CD15s)

Flow cytometry showing absent or markedly reduced sialyl-Lewis X on the neutrophil surface. This is the functional test that reads out the disease mechanism directly - it measures the missing glycan itself rather than a downstream consequence - and it is also what the pivotal treatment trial uses as its primary endpoint, so the diagnostic assay and the efficacy measure are the same measurement.

flow cytometry NCIT:C16585

Show evidence (2 references)

PMID:10590041 SUPPORT Human Clinical

"Oral supplementation of fucose in this patient induced the expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins."

Demonstrates neutrophil fucosylated selectin ligand expression being measured as a readout in patients, which is the assay this record describes.

PMID:11213799 SUPPORT Human Clinical

"The exact defect in the system is absence of the SLeX, which is an important ligand for the selectin on the leukocyte"

States directly that absent sialyl-Lewis X is the defect, which is what this assay is looking for.

Bombay (hh) Blood Group Typing

Red-cell typing showing the Bombay phenotype. In combination with recurrent infection, leukocytosis and developmental delay it is close to pathognomonic, because the combination of an immunodeficiency with this blood group has essentially one cause. It is a useful pointer precisely because it is incidental - blood typing is done for unrelated reasons, and an unexpected Bombay result in a child with infections is a reason to think of this disease.

blood typing test NCIT:C210738

Show evidence (1 reference)

PMID:11213799 SUPPORT Human Clinical

"Apart from the leukocyte defect, these patients suffer from severe growth and mental retardation and exhibit the rare Bombay blood group type."

Establishes the Bombay blood group as a feature of the patient population, alongside the growth and neurodevelopmental phenotype.

SLC35C1 Sequencing

Molecular confirmation by sequencing SLC35C1. Because the milder presentations can lack any immune signal at all - short stature and developmental delay alone - exome or genome sequencing is the realistic route in patients who are not suspected clinically.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:24403049 SUPPORT Human Clinical

"We report two brothers with short stature and developmental delay who are compound heterozygotes for novel mutations in SLC35C1"

A molecularly made diagnosis in patients whose presentation gave no immunological clue, which is the case for sequencing rather than functional testing.

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Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Ultra-rare. The founder-effect series describes the total reported literature at that time as three Arab Israeli patients plus one Turkish child; a handful of further families have been reported since. No population frequency has been estimated, and the count below should be read as a literature census rather than an occurrence measure.

Show evidence (1 reference)

PMID:12116250 SUPPORT Human Clinical

"Three Arab Israeli patients and one Turkish child have been reported so far."

A direct literature census at the time of the founder-effect report, which is the basis for the ultra-rare band rather than any population estimate.

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Clinical Trials

3

NCT05462587 PHASE_III RECRUITING

LADDER - a randomized, double-blind, two-period crossover withdrawal study of AVTX-803, a purpose-built oral L-fucose product, in LAD II. The withdrawal design is the informative part: patients already on fucose are randomised to continue or withdraw, which tests whether the observed benefit depends on continued treatment rather than comparing against a never-treated group that would be hard to assemble in a disease this rare.

Target Phenotypes: Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

clinicaltrials:NCT05462587 SUPPORT Human Clinical

"The primary objective of this study is to evaluate the efficacy and safety of AVTX-803 compared to withdrawal in patients with Leukocyte Adhesion Deficiency, Type II (LAD II)."

The registration record's statement of the trial's objective and withdrawal design.

NCT05754450 PHASE_III RECRUITING

Open-label extension assessing long-term safety and efficacy of AVTX-803. Relevant to this entry because fucose supplementation is a substrate-replacement strategy that must be continued indefinitely - the transporter is not repaired - so long-term data is the question that matters clinically.

Show evidence (1 reference)

clinicaltrials:NCT05754450 SUPPORT Human Clinical

"The primary objective of this extension study is to assess the long-term safety and efficacy of AVTX-803 in subjects with LAD II (SLC35C1-CDG)."

States the extension study's objective and confirms it targets the same SLC35C1 entity.

NCT03354533 PHASE_II COMPLETED

Completed Phase 1/2 study of ORL-1F, an oral L-fucose formulation - the earlier regulatory-track attempt at the same substrate-replacement strategy. Recorded as PHASE_II because the registration lists it as Phase 1/Phase 2 and the schema enum has no combined value.

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Experimental Models

1

CHO-gmt5 SLC35C1-knockout cell line CELL_LINE

A Chinese hamster ovary line in which Slc35c1 was knocked out by zinc-finger nuclease on a background already lacking the CMP-sialic acid transporter, giving N-glycans deficient in both fucose and sialic acid. It was built to solve a specific problem - there was no suitable mutant line for structure-function work on the transporter - and it is the system in which the functional elements of SLC35C1 were mapped.

Publication

PMID:22492235

Pathograph links

Impaired Golgi GDP-Fucose Import recapitulates fidelity: moderate Reproduces the primary lesion - absent SLC35C1 function with consequent loss of glycan fucosylation - in a tractable system.

Limitations: A rodent ovary-derived cell line carrying a second engineered defect in the CMP-sialic acid transporter, so its glycans differ from a patient's in more than one way. It models the transporter's biochemistry, not the disease: there is no leukocyte, no endothelium, and therefore nothing about rolling, extravasation or neurodevelopment. The double defect was chosen partly for antibody-engineering utility rather than for disease fidelity.

Readouts

Aleuria aurantia lectin binding to cell-surface glycans

Direction: DECREASED

Interpretation: Lectin binding reports cell-surface fucosylation, so it is the functional readout of transport activity and was the basis for mapping which residues matter.

Show evidence (1 reference)

PMID:22492235 SUPPORT In Vitro

"we found that this impact can be independently contributed by a cluster of three lysine residues and a Glu-Met (EM) sequence within the C terminus"

Reports the structure-function mapping this readout produced.

Show evidence (1 reference)

PMID:22492235 SUPPORT In Vitro

"Here we report a novel Chinese hamster ovary (CHO) mutant, CHO-gmt5, generated by the zinc-finger nuclease technology, in which the Slc35c1 gene was knocked out"

Establishes the model as an SLC35C1 knockout and therefore informative for the transport node.

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Animal Models

1

Slc35c1-deficient mouse

A constitutive Slc35c1 knockout, made specifically because leukocyte trafficking cannot be studied in vivo in patients with a disease this rare. It covers the immune branch of the pathograph that the CHO cell line cannot reach - there are leukocytes, endothelium and an inflamed tissue to migrate into.

Species

Mouse

Genotype

Slc35c1 -/-

Publication

PMID:18541720

Pathograph links

Failure of Leukocyte Rolling on Activated Endothelium recapitulates fidelity: high Reproduces the defining cellular lesion directly and in vivo: selectin-dependent rolling in cremaster venules is essentially abolished, with firm adhesion strongly but incompletely reduced downstream of it.

Limitations: A constitutive whole-animal knockout rather than a patient missense allele, so it models complete loss rather than the partial transport that several patients have - and the partial-defect siblings curated in this entry show that distinction decides whether the immune phenotype appears at all.

Readouts

Selectin-dependent leukocyte rolling in cremaster venules

Direction: DECREASED

Interpretation: Intravital measurement of the rolling step itself, across all three selectins.

Show evidence (1 reference)

PMID:18541720 SUPPORT Model Organism

"We found that E-, L-, and P-selectin-dependent leukocyte rolling in cremaster muscle venules was virtually absent. This was accompanied by a strong but not complete decrease in firm leukocyte adhesion."

The rolling and adhesion measurements, with the qualification that adhesion is reduced rather than abolished.

Show evidence (1 reference)

PMID:18541720 SUPPORT Model Organism

"Since the study of in vivo leukocyte trafficking in patients with LAD II is experimentally limited, we analyzed this process in mice deficient for Slc35c1."

States why the model exists and that it is the Slc35c1 orthologue of this disease.

Impaired Neutrophil Extravasation to Infection Sites recapitulates fidelity: high Neutrophil migration into an inflamed compartment is quantified, giving the extravasation node a measured value rather than an inference from rolling.

Limitations: Sterile chemical peritonitis is not bacterial infection at a mucosal surface, so it measures the trafficking defect rather than the clinical consequence.

Readouts

Neutrophil migration to inflamed peritoneum

Direction: DECREASED

Interpretation: An 89% reduction quantifies how much of the extravasation response is lost.

Show evidence (1 reference)

PMID:18541720 SUPPORT Model Organism

"Moreover, neutrophil migration to the inflamed peritoneum was strongly reduced by 89%."

The quantified extravasation defect.

Show evidence (1 reference)

PMID:18541720 SUPPORT Model Organism

"Taken together, Slc35c1(-/-) mice show strongly defective leukocyte trafficking but normal lymphocyte homing to the spleen, which may explain normal lymphocyte functions in LAD II."

The authors' summary, which also carries the compartment dissociation curated as a discussion below.

{ }

Source YAML

click to show

name: Leukocyte Adhesion Deficiency Type II
creation_date: '2026-08-26T21:00:00Z'
category: Mendelian
disease_term:
  preferred_term: leukocyte adhesion deficiency type II
  term:
    id: MONDO:0009953
    label: leukocyte adhesion deficiency type II
synonyms:
- LAD II
- LAD2
- congenital disorder of glycosylation type IIc
- CDG-IIc
- SLC35C1-CDG
description: 'An autosomal recessive disorder in which a Golgi GDP-fucose transporter fails, so the
  fucosyltransferases waiting inside the Golgi lumen are starved of their donor substrate and almost
  nothing in the cell gets fucosylated.

  What makes the entry worth curating is that a single biochemical lesion produces several clinically
  unrelated consequences through entirely separate downstream branches. Loss of sialyl-Lewis X on
  neutrophils removes the ligand selectins bind, so leukocytes cannot roll along activated endothelium
  and never leave the bloodstream - giving recurrent bacterial infection alongside a paradoxically
  high blood neutrophil count. Loss of alpha-1,2 fucosylation on the red-cell H-antigen precursor
  gives the Bombay blood phenotype, which is diagnostically useful and pathophysiologically inert.
  Growth failure and severe intellectual disability arise from hypofucosylation of substrates that
  remain largely unidentified. The entry models these as parallel branches rather than a chain, because
  the evidence supports a shared cause and not a shared route.

  Two further things are curated deliberately rather than smoothed over. The immune phenotype is
  not obligate: a compound-heterozygous sibling pair with a partial transport defect had impaired
  neutrophil rolling yet enough residual adhesion to avoid leukocytosis and recurrent infection entirely,
  presenting only with short stature and developmental delay. And oral fucose - a genuinely rational
  therapy, since it refills the substrate pool by an alternative salvage route - works for some genotypes
  and not others, a difference the founder-mutation literature states outright.'
parents:
- Congenital Disorder of Glycosylation
- Leukocyte Adhesion Deficiency
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: Ultra-rare. The founder-effect series describes the total reported literature at that time
    as three Arab Israeli patients plus one Turkish child; a handful of further families have been
    reported since. No population frequency has been estimated, and the count below should be read
    as a literature census rather than an occurrence measure.
  evidence:
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three Arab Israeli patients and one Turkish child have been reported so far.
    explanation: A direct literature census at the time of the founder-effect report, which is the
      basis for the ultra-rare band rather than any population estimate.
pathophysiology:
- name: Biallelic SLC35C1 Loss-of-Function Variants
  role: trigger
  biological_scale: MOLECULAR
  description: Both copies of SLC35C1 carry variants that disable the Golgi GDP-fucose transporter.
    The founding patient carried R147C in the fourth transmembrane region, and overexpressing that
    mutant protein in the patient's own cells failed to rescue fucosylation - which is what established
    the substitution as causal rather than incidental.
  genetic_context:
    gene:
      preferred_term: SLC35C1
      term:
        id: hgnc:20197
        label: SLC35C1
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: Homozygous in the reported founder families; compound heterozygous in the milder
      sibling pair curated below. Loss of function is asserted on the strength of the failed rescue
      experiment rather than inferred from variant class alone.
  downstream:
  - target: Impaired Golgi GDP-Fucose Import
    causal_link_type: DIRECT
    description: The gene product is the transporter, so a disabling variant removes the transport
      step directly.
  evidence:
  - reference: PMID:11326279
    reference_title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose
      transporter.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The corresponding endogenous protein in LAD II cells had an R147C amino acid change
      in the conserved fourth transmembrane region.
    explanation: Identifies the causal substitution in the founding patient.
  - reference: PMID:11326279
    reference_title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose
      transporter.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Overexpression of this mutant protein in cells from a patient with LAD II did not rescue
      fucosylation, demonstrating that the point mutation affected the activity of the protein.
    explanation: The rescue-failure experiment that makes this loss of function rather than a coincidental
      variant.
- name: Impaired Golgi GDP-Fucose Import
  role: central_effector
  biological_scale: MOLECULAR
  description: 'GDP-fucose is made in the cytosol but consumed in the Golgi lumen, so it must cross
    a membrane to reach the enzymes that use it. That crossing is what fails here. The defect was
    localised to transport specifically by excluding the alternatives: neither fucosyltransferase
    activity nor the enzymes of GDP-fucose biosynthesis were deficient, while transport into isolated
    Golgi vesicles was reduced.'
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  molecular_functions:
  - preferred_term: GDP-fucose transmembrane transporter activity
    term:
      id: GO:0005457
      label: GDP-fucose transmembrane transporter activity
    modifier: LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: GDP-fucose transmembrane transport
    term:
      id: GO:0015783
      label: GDP-fucose transmembrane transport
    modifier: DECREASED
  downstream:
  - target: Global Hypofucosylation of Glycoconjugates
    causal_link_type: DIRECT
    description: Substrate starvation of the luminal fucosyltransferases, which are themselves normal.
  evidence:
  - reference: PMID:11326279
    reference_title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose
      transporter.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: No deficiency in fucosyltransferase activities or in the activities of enzymes involved
      in GDP-fucose biosynthesis has been found. Instead, the transport of GDP-fucose into isolated
      Golgi vesicles of LAD II cells appeared to be reduced.
    explanation: Localises the lesion to transport by exclusion - the enzymes and the biosynthetic
      pathway are intact, and only the membrane step is impaired.
- name: Global Hypofucosylation of Glycoconjugates
  role: central_effector
  biological_scale: MOLECULAR
  description: 'With no donor substrate reaching them, the Golgi fucosyltransferases cannot fucosylate
    their targets, and the deficit is general rather than selective - N-glycans, O-glycans and glycolipids
    alike. This node is the branch point of the entry: everything below it is a separate consequence
    of the same missing modification, not a step in a common chain.'
  molecular_functions:
  - preferred_term: fucosyltransferase activity
    term:
      id: GO:0008417
      label: fucosyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: fucose metabolic process
    term:
      id: GO:0006004
      label: fucose metabolic process
    modifier: DECREASED
  downstream:
  - target: Loss of Sialyl-Lewis X Selectin Ligands
    causal_link_type: DIRECT
    description: Sialyl-Lewis X is a fucosylated tetrasaccharide; without fucose it is not built.
  - target: Loss of Red Cell H-Antigen Fucosylation
    causal_link_type: DIRECT
    description: The H antigen is made by alpha-1,2 fucosylation of its precursor, which fails for
      the same reason.
  - target: Growth Failure and Neurodevelopmental Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Attributed to hypofucosylation of glycoproteins and glycolipids needed for normal
      growth and neurodevelopment, but the responsible substrates have not been identified, so the
      intermediate steps are genuinely unknown.
  evidence:
  - reference: PMID:11326279
    reference_title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose
      transporter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Leukocyte adhesion deficiency II (LAD II) is characterized by the lack of fucosylated
      glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and
      growth retardation.
    explanation: States the general absence of fucosylated glycoconjugates and names the three consequence
      branches curated below it.
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is attributed to a general absence of fucosylated glycans on the cell surface.
    explanation: Confirms the deficit is general rather than restricted to one glycan class.
- name: Loss of Sialyl-Lewis X Selectin Ligands
  role: effector
  biological_scale: CELLULAR
  description: Sialyl-Lewis X on the neutrophil surface is the carbohydrate that E-, P- and L-selectin
    recognise. Without its fucose it is not assembled, so the neutrophil presents no ligand for the
    endothelial selectins to catch.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  downstream:
  - target: Failure of Leukocyte Rolling on Activated Endothelium
    causal_link_type: DIRECT
    description: Rolling is selectin-mediated, so removing the ligand removes the interaction.
  evidence:
  - reference: PMID:24403049
    reference_title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature
      and developmental delay with minimal adhesion defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis
      and recurrent infections
    explanation: Names sialyl-Lewis X as the fucosylated molecule whose loss drives the immune phenotype.
- name: Failure of Leukocyte Rolling on Activated Endothelium
  role: effector
  biological_scale: TISSUE
  description: 'Rolling is the first step of the adhesion cascade: without it the neutrophil never
    slows enough to engage integrins, never firmly adheres, and never crosses into tissue. The circulating
    pool therefore rises while the tissue pool falls - which is why the blood count and the infection
    risk move in opposite directions here.'
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: leukocyte tethering or rolling
    term:
      id: GO:0050901
      label: leukocyte tethering or rolling
    modifier: DECREASED
  - preferred_term: leukocyte cell-cell adhesion
    term:
      id: GO:0007159
      label: leukocyte cell-cell adhesion
    modifier: DECREASED
  downstream:
  - target: Impaired Neutrophil Extravasation to Infection Sites
    causal_link_type: DIRECT
    description: Extravasation requires the rolling step that has been lost.
  evidence:
  - reference: PMID:24403049
    reference_title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature
      and developmental delay with minimal adhesion defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While neutrophil rolling on endothelial selectins was partially impeded, residual adhesion
      proved sufficient to avoid leukocytosis or recurrent infection.
    explanation: PARTIAL because it documents the rolling defect while simultaneously showing it
      is not always sufficient for the clinical phenotype - the partial-defect siblings had impaired
      rolling and no immune disease. Cited here to keep that qualification attached to the node it
      qualifies.
- name: Impaired Neutrophil Extravasation to Infection Sites
  role: effector
  biological_scale: ORGANISM
  description: Neutrophils remain in the circulation instead of reaching tissue, producing the characteristic
    combination of recurrent bacterial infection with a raised rather than lowered neutrophil count.
    Periodontal disease follows from the same failure of routine neutrophil surveillance at the gingival
    sulcus.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: DECREASED
  evidence:
  - reference: PMID:10590041
    reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This disorder leads to an immunodeficiency caused by the absence of carbohydrate-based
      selectin ligands on the surface of neutrophils
    explanation: States the causal route from absent selectin ligands to immunodeficiency.
- name: Loss of Red Cell H-Antigen Fucosylation
  role: effector
  biological_scale: CELLULAR
  description: 'The H antigen that ABO antigens are built on requires alpha-1,2 fucosylation of its
    precursor. Without it, red cells type as Bombay (hh). This branch is diagnostically valuable
    and clinically silent - it causes no anaemia and no haemolysis - and it is curated separately
    for exactly that reason: it shares a cause with the immune phenotype but nothing else.'
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by recurrent infections, typical dysmorphic features, the Bombay blood
      phenotype and severe growth and psychomotor retardation
    explanation: Lists the Bombay blood phenotype as a defining feature alongside the other branches.
- name: Growth Failure and Neurodevelopmental Impairment
  role: effector
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: 'Severe growth retardation and intellectual disability accompany the disorder in the
    classically affected patients. PROVISIONAL because the mechanism is genuinely open: the phenotype
    is attributed to hypofucosylation of glycoproteins and glycolipids required for normal growth-factor
    signalling and neurodevelopment, but the specific fucosylated substrates responsible have not
    been identified, and no model links a named substrate to the neurodevelopmental outcome.

    The partial-defect siblings are informative here too - they had short stature and developmental
    delay as their only presenting signs, which suggests this branch is more sensitive to residual
    transporter activity than the immune branch is.'
  evidence:
  - reference: PMID:11326279
    reference_title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose
      transporter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: causing immunodeficiency and severe mental and growth retardation
    explanation: Attributes the neurodevelopmental and growth phenotype to the same hypofucosylation
      that causes the immunodeficiency, without specifying intermediates.
  - reference: PMID:24403049
    reference_title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature
      and developmental delay with minimal adhesion defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: show that short stature and developmental delay may be the sole presenting signs in
      this disorder
    explanation: Establishes that this branch can present in isolation, which is the basis for curating
      it as parallel to the immune branch rather than downstream of it.
phenotypes:
- category: Immunologic
  name: Recurrent Bacterial Infections
  frequency: VERY_FREQUENT
  description: Recurrent bacterial infection without pus formation at the site, reflecting neutrophils
    that cannot reach tissue rather than neutrophils that are absent or non-functional.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by recurrent infections, typical dysmorphic features, the Bombay blood
      phenotype and severe growth and psychomotor retardation
    explanation: Names recurrent infection as a defining feature of the syndrome.
- category: Hematologic
  name: Persistent Leukocytosis
  frequency: VERY_FREQUENT
  description: A markedly raised circulating leukocyte count in the presence of active infection
    - the diagnostic paradox of this disease. The neutrophils are made and released normally but
    cannot exit the vasculature, so they accumulate in the compartment where they are counted and
    are missing from the compartment where they are needed.
  phenotype_term:
    preferred_term: Increased total leukocyte count
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:24403049
    reference_title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature
      and developmental delay with minimal adhesion defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis
      and recurrent infections
    explanation: Ties the leukocytosis to the same sialyl-Lewis X defect as the infection phenotype.
  - reference: PMID:10590041
    reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: elevated neutrophil counts returned to normal
    explanation: Confirms the counts were elevated at baseline, by reporting their normalisation
      on fucose therapy.
- category: Growth
  name: Short Stature
  frequency: VERY_FREQUENT
  description: Severe growth retardation, present from intrauterine life onward, and one of the two
    features that can present in isolation when transporter function is only partly lost.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24403049
    reference_title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature
      and developmental delay with minimal adhesion defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two brothers with short stature and developmental delay who are compound heterozygotes
      for novel mutations in SLC35C1
    explanation: Documents short stature in molecularly confirmed patients.
- category: Neurologic
  name: Severe Intellectual Disability
  frequency: VERY_FREQUENT
  description: Severe psychomotor and mental retardation in classically affected patients; milder
    developmental delay where residual transport persists.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:10590041
    reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: as well as to severe psychomotor and mental retardation
    explanation: States the neurodevelopmental severity in the classical presentation.
- category: Dental
  name: Chronic Severe Periodontitis
  frequency: VERY_FREQUENT
  description: 'Chronic severe periodontitis, described in the LAD II review literature as the one
    persistent clinical symptom of the disease. That framing is worth keeping: the infectious episodes
    in LAD II are milder than in LAD I, so what remains constant is the periodontal disease rather
    than the systemic infection.

    Mechanistically it follows from the same extravasation failure as the infection phenotype - the
    gingival sulcus depends on continuous neutrophil surveillance, and neutrophils that cannot leave
    the vasculature cannot provide it.'
  phenotype_term:
    preferred_term: Periodontitis
    term:
      id: HP:0000704
      label: Periodontitis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11213799
    reference_title: Leukocyte adhesion deficiency II-from A to almost Z.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The infectious episodes and the severity are much milder than those observed in LAD
      I, and the only persistent clinical symptom is chronic severe periodontitis.
    explanation: States the periodontal phenotype directly for LAD II, and sets it against LAD I
      - which is the comparison that matters here, since the periodontal literature for leukocyte
      adhesion deficiency is dominated by LAD I.
genetic:
- name: SLC35C1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SLC35C1
    term:
      id: hgnc:20197
      label: SLC35C1
  notes: 'The Golgi GDP-fucose transporter, formerly called FUCT1. Two mutation classes matter clinically
    and they are not equivalent: the founder alleles differ from one another in how they respond
    to fucose supplementation, and hypomorphic compound-heterozygous combinations can leave enough
    residual transport to spare the immune system.

    Transcript abundance is not the mechanism. In the Arab founder families the transporter mRNA
    level was comparable to controls, so the defect is in the protein''s activity or localisation
    rather than in how much of it is made.

    The allele-dependence of fucose response is documented at the level of specific families: supplementation
    was effective in the Turkish patient and gave no benefit in the patients of Arab origin, who
    carry a different founder allele. That is the concrete form of the genotype-phenotype correlation
    cited above, and it is why fucose is worth trying and worth stopping if it does not work.'
  evidence:
  - reference: PMID:11326279
    reference_title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose
      transporter.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Thus, we have identified the first putative GDP-fucose transporter, which has been highly
      conserved throughout evolution. A point mutation in its gene is responsible for the disease
      in this patient with LAD II.
    explanation: The gene-disease assignment, from the cloning study that made it.
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The amount of mRNA of the GDP-L-fucose transporter in cells from Arab patients and their
      parents are comparable to controls.
    explanation: Excludes reduced transcript abundance as the mechanism, which is why this entry
      curates the lesion as a functional transport failure.
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genotype/phenotype correlation studies show that the two different mutations are distinguished
      by differences in response to fucose supplementation and in the clinical phenotypes.
    explanation: The allele-specific treatment response, which is why fucose therapy is curated below
      as genotype-dependent rather than as a uniform option.
  - reference: PMID:11213799
    reference_title: Leukocyte adhesion deficiency II-from A to almost Z.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It seems that the primary defect is somewhat different and, therefore, fucose administration
      was effective in the Turkish child, but did not show any beneficial results in the patients
      of Arabic origin.
    explanation: Documents the allele-specific fucose response at the level of named families, which
      is the concrete basis for curating fucose therapy as genotype-dependent.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: Autosomal recessive, with consanguinity and founder alleles prominent in the reported
    families.
  evidence:
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Leukocyte adhesion deficiency (LAD) type II is a rare autosomal recessive syndrome
    explanation: States the inheritance mode directly.
treatments:
- name: Oral Fucose Supplementation
  therapeutic_modality: SMALL_MOLECULE
  description: 'Oral L-fucose, which is rational rather than empirical: fucose entering by the salvage
    pathway raises the cytosolic GDP-fucose pool, and a higher substrate concentration can drive
    enough flux through a crippled transporter to restore fucosylation. It treats the substrate side
    of a transport problem rather than the transporter.

    In the index patient the effect was measurable at the molecular level and then at the clinical
    one: fucosylated selectin ligands reappeared on neutrophils, serum glycoproteins regained core
    fucosylation, and over nine months infections and fever stopped while the neutrophil count normalised.

    It does not work for everyone, and the reason is genotypic rather than a matter of dose or adherence
    - the founder-mutation study found the two alleles differed in their response. Treatment is therefore
    reasonably attempted and must be assessed per patient.'
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: L-fucose
      term:
        id: CHEBI:18287
        label: L-fucose
  target_mechanisms:
  - target: Impaired Golgi GDP-Fucose Import
    description: Raises substrate availability upstream of the failed transport step rather than
      correcting the transporter, which is why residual transport activity determines whether it
      works.
    evidence:
    - reference: PMID:10590041
      reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The fucosylation defect in LAD II fibroblasts can be corrected by addition of L-fucose
        to the culture medium.
      explanation: The in-vitro correction that supplied the rationale for treating the substrate
        side of the defect.
  evidence:
  - reference: PMID:10590041
    reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oral supplementation of fucose in this patient induced the expression of fucosylated
      selectin ligands on neutrophils and core fucosylation of serum glycoproteins.
    explanation: The molecular response - the treatment restores the specific glycan whose absence
      defines the disease.
  - reference: PMID:10590041
    reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During 9 months of treatment, infections and fever disappeared, elevated neutrophil
      counts returned to normal, and psychomotor capabilities improved.
    explanation: The clinical response over a defined period in the index patient.
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genotype/phenotype correlation studies show that the two different mutations are distinguished
      by differences in response to fucose supplementation and in the clinical phenotypes.
    explanation: 'PARTIAL because it qualifies the treatment rather than supporting it: response
      is allele-dependent, so this is not a uniformly effective therapy.'
- name: AVTX-803 (oral L-fucose, regulatory-track product)
  therapeutic_modality: SMALL_MOLECULE
  description: 'A purpose-built oral L-fucose product carrying the same substrate-replacement rationale
    as compassionate-use fucose, but developed as a drug and now in a randomised Phase 3 withdrawal
    trial with an open-label extension.

    It is curated separately from the supplementation record above because the difference is not
    cosmetic: the 1999 report is a single patient given a sugar, while this is a controlled test
    of whether the benefit persists and depends on continued dosing. The trial''s primary endpoint
    is leukocyte sialyl-Lewis X expression - the same measurement used diagnostically - so efficacy
    is assessed directly against the mechanism rather than through an infection-count proxy that
    would be underpowered in a disease this rare.'
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-fucose
      term:
        id: CHEBI:18287
        label: L-fucose
  target_mechanisms:
  - target: Impaired Golgi GDP-Fucose Import
    description: Same mechanism as dietary fucose - raising substrate availability upstream of the
      failed transport step - delivered as a controlled product.
  evidence:
  - reference: clinicaltrials:NCT05462587
    reference_title: A Phase 3, Randomized, Double-blind, Two-period, Crossover, Withdrawal Study
      to Assess the Efficacy and Safety of AVTX-803 in Subjects With Leukocyte Adhesion Deficiency
      Type II (LAD II)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary objective of this study is to evaluate the efficacy and safety of AVTX-803
      compared to withdrawal in patients with Leukocyte Adhesion Deficiency, Type II (LAD II).
    explanation: Establishes AVTX-803 as an agent under controlled evaluation in this disease. Note
      this is a statement of objective from a registration record, not a result - the trial is recruiting
      and no efficacy outcome is available.
- name: Infection Prophylaxis and Management
  therapeutic_modality: SMALL_MOLECULE
  description: Antimicrobial prophylaxis and prompt treatment of intercurrent infection, which is
    supportive rather than mechanism-directed. Recorded because it is what patients who do not respond
    to fucose actually receive.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Impaired Neutrophil Extravasation to Infection Sites
    description: Compensates for the missing neutrophil response rather than restoring it.
  notes: Deliberately unevidenced. The LAD II literature cited here reports no prophylaxis trial
    or outcome series, and quoting a general immunodeficiency prophylaxis study would attach evidence
    about a different population to a claim about this disease.
- name: Genetic Counselling
  therapeutic_modality: BEHAVIORAL
  description: Autosomal recessive inheritance with a 25% recurrence risk per pregnancy for carrier
    couples. Founder alleles and consanguinity are prominent in the reported families, so carrier
    testing of extended relatives is informative where a family allele is known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:12116250
    reference_title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein
      (CDG) IIc founder effect and genotype/phenotype correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three children reported by us are homozygous for one single founder mutation, different
      from that reported in the Turkish child.
    explanation: Documents the founder-allele structure that makes targeted carrier testing useful.
diagnosis:
- name: Flow Cytometry for Neutrophil Sialyl-Lewis X (CD15s)
  description: Flow cytometry showing absent or markedly reduced sialyl-Lewis X on the neutrophil
    surface. This is the functional test that reads out the disease mechanism directly - it measures
    the missing glycan itself rather than a downstream consequence - and it is also what the pivotal
    treatment trial uses as its primary endpoint, so the diagnostic assay and the efficacy measure
    are the same measurement.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:10590041
    reference_title: Correction of leukocyte adhesion deficiency type II with oral fucose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oral supplementation of fucose in this patient induced the expression of fucosylated
      selectin ligands on neutrophils and core fucosylation of serum glycoproteins.
    explanation: Demonstrates neutrophil fucosylated selectin ligand expression being measured as
      a readout in patients, which is the assay this record describes.
  - reference: PMID:11213799
    reference_title: Leukocyte adhesion deficiency II-from A to almost Z.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The exact defect in the system is absence of the SLeX, which is an important ligand
      for the selectin on the leukocyte
    explanation: States directly that absent sialyl-Lewis X is the defect, which is what this assay
      is looking for.
- name: Bombay (hh) Blood Group Typing
  description: 'Red-cell typing showing the Bombay phenotype. In combination with recurrent infection,
    leukocytosis and developmental delay it is close to pathognomonic, because the combination of
    an immunodeficiency with this blood group has essentially one cause.

    It is a useful pointer precisely because it is incidental - blood typing is done for unrelated
    reasons, and an unexpected Bombay result in a child with infections is a reason to think of this
    disease.'
  diagnosis_term:
    preferred_term: blood typing test
    term:
      id: NCIT:C210738
      label: Blood Typing Test
  evidence:
  - reference: PMID:11213799
    reference_title: Leukocyte adhesion deficiency II-from A to almost Z.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Apart from the leukocyte defect, these patients suffer from severe growth and mental
      retardation and exhibit the rare Bombay blood group type.
    explanation: Establishes the Bombay blood group as a feature of the patient population, alongside
      the growth and neurodevelopmental phenotype.
- name: SLC35C1 Sequencing
  description: Molecular confirmation by sequencing SLC35C1. Because the milder presentations can
    lack any immune signal at all - short stature and developmental delay alone - exome or genome
    sequencing is the realistic route in patients who are not suspected clinically.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:24403049
    reference_title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature
      and developmental delay with minimal adhesion defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two brothers with short stature and developmental delay who are compound heterozygotes
      for novel mutations in SLC35C1
    explanation: A molecularly made diagnosis in patients whose presentation gave no immunological
      clue, which is the case for sequencing rather than functional testing.
clinical_trials:
- name: NCT05462587
  phase: PHASE_III
  status: RECRUITING
  description: 'LADDER - a randomized, double-blind, two-period crossover withdrawal study of AVTX-803,
    a purpose-built oral L-fucose product, in LAD II. The withdrawal design is the informative part:
    patients already on fucose are randomised to continue or withdraw, which tests whether the observed
    benefit depends on continued treatment rather than comparing against a never-treated group that
    would be hard to assemble in a disease this rare.'
  target_phenotypes:
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: clinicaltrials:NCT05462587
    reference_title: A Phase 3, Randomized, Double-blind, Two-period, Crossover, Withdrawal Study
      to Assess the Efficacy and Safety of AVTX-803 in Subjects With Leukocyte Adhesion Deficiency
      Type II (LAD II)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary objective of this study is to evaluate the efficacy and safety of AVTX-803
      compared to withdrawal in patients with Leukocyte Adhesion Deficiency, Type II (LAD II).
    explanation: The registration record's statement of the trial's objective and withdrawal design.
- name: NCT05754450
  phase: PHASE_III
  status: RECRUITING
  description: Open-label extension assessing long-term safety and efficacy of AVTX-803. Relevant
    to this entry because fucose supplementation is a substrate-replacement strategy that must be
    continued indefinitely - the transporter is not repaired - so long-term data is the question
    that matters clinically.
  evidence:
  - reference: clinicaltrials:NCT05754450
    reference_title: A Phase 3, Open-Label, Extension Study to Assess the Long-term Safety and Efficacy
      of AVTX-803 in Subjects With Leukocyte Adhesion Deficiency Type II (LAD II)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary objective of this extension study is to assess the long-term safety and
      efficacy of AVTX-803 in subjects with LAD II (SLC35C1-CDG).
    explanation: States the extension study's objective and confirms it targets the same SLC35C1
      entity.
- name: NCT03354533
  phase: PHASE_II
  status: COMPLETED
  description: Completed Phase 1/2 study of ORL-1F, an oral L-fucose formulation - the earlier regulatory-track
    attempt at the same substrate-replacement strategy. Recorded as PHASE_II because the registration
    lists it as Phase 1/Phase 2 and the schema enum has no combined value.
  notes: 'No evidence item: the cached registration record''s content is a restatement of the trial
    title, and a title is not a finding. The trial is recorded here because the treatment history
    of this disease runs through it.'
experimental_models:
- name: CHO-gmt5 SLC35C1-knockout cell line
  experimental_model_type: CELL_LINE
  description: A Chinese hamster ovary line in which Slc35c1 was knocked out by zinc-finger nuclease
    on a background already lacking the CMP-sialic acid transporter, giving N-glycans deficient in
    both fucose and sialic acid. It was built to solve a specific problem - there was no suitable
    mutant line for structure-function work on the transporter - and it is the system in which the
    functional elements of SLC35C1 were mapped.
  publication: PMID:22492235
  modeled_mechanisms:
  - target: Impaired Golgi GDP-Fucose Import
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reproduces the primary lesion - absent SLC35C1 function with consequent loss of
      glycan fucosylation - in a tractable system.
    limitations: 'A rodent ovary-derived cell line carrying a second engineered defect in the CMP-sialic
      acid transporter, so its glycans differ from a patient''s in more than one way. It models the
      transporter''s biochemistry, not the disease: there is no leukocyte, no endothelium, and therefore
      nothing about rolling, extravasation or neurodevelopment. The double defect was chosen partly
      for antibody-engineering utility rather than for disease fidelity.'
    readouts:
    - name: Aleuria aurantia lectin binding to cell-surface glycans
      target: Impaired Golgi GDP-Fucose Import
      direction: DECREASED
      interpretation: Lectin binding reports cell-surface fucosylation, so it is the functional readout
        of transport activity and was the basis for mapping which residues matter.
      evidence:
      - reference: PMID:22492235
        reference_title: Identification of functional elements of the GDP-fucose transporter SLC35C1
          using a novel Chinese hamster ovary mutant.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: we found that this impact can be independently contributed by a cluster of three
          lysine residues and a Glu-Met (EM) sequence within the C terminus
        explanation: Reports the structure-function mapping this readout produced.
    evidence:
    - reference: PMID:22492235
      reference_title: Identification of functional elements of the GDP-fucose transporter SLC35C1
        using a novel Chinese hamster ovary mutant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report a novel Chinese hamster ovary (CHO) mutant, CHO-gmt5, generated by
        the zinc-finger nuclease technology, in which the Slc35c1 gene was knocked out
      explanation: Establishes the model as an SLC35C1 knockout and therefore informative for the
        transport node.
animal_models:
- name: Slc35c1-deficient mouse
  species: Mouse
  genotype: Slc35c1 -/-
  publication: PMID:18541720
  description: A constitutive Slc35c1 knockout, made specifically because leukocyte trafficking cannot
    be studied in vivo in patients with a disease this rare. It covers the immune branch of the pathograph
    that the CHO cell line cannot reach - there are leukocytes, endothelium and an inflamed tissue
    to migrate into.
  modeled_mechanisms:
  - target: Failure of Leukocyte Rolling on Activated Endothelium
    relationship: RECAPITULATES
    fidelity: HIGH
    description: 'Reproduces the defining cellular lesion directly and in vivo: selectin-dependent
      rolling in cremaster venules is essentially abolished, with firm adhesion strongly but incompletely
      reduced downstream of it.'
    limitations: A constitutive whole-animal knockout rather than a patient missense allele, so it
      models complete loss rather than the partial transport that several patients have - and the
      partial-defect siblings curated in this entry show that distinction decides whether the immune
      phenotype appears at all.
    readouts:
    - name: Selectin-dependent leukocyte rolling in cremaster venules
      target: Failure of Leukocyte Rolling on Activated Endothelium
      direction: DECREASED
      interpretation: Intravital measurement of the rolling step itself, across all three selectins.
      evidence:
      - reference: PMID:18541720
        reference_title: Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency
          II/congenital disorder of glycosylation IIc.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: We found that E-, L-, and P-selectin-dependent leukocyte rolling in cremaster muscle
          venules was virtually absent. This was accompanied by a strong but not complete decrease
          in firm leukocyte adhesion.
        explanation: The rolling and adhesion measurements, with the qualification that adhesion
          is reduced rather than abolished.
    evidence:
    - reference: PMID:18541720
      reference_title: Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency II/congenital
        disorder of glycosylation IIc.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Since the study of in vivo leukocyte trafficking in patients with LAD II is experimentally
        limited, we analyzed this process in mice deficient for Slc35c1.
      explanation: States why the model exists and that it is the Slc35c1 orthologue of this disease.
  - target: Impaired Neutrophil Extravasation to Infection Sites
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Neutrophil migration into an inflamed compartment is quantified, giving the extravasation
      node a measured value rather than an inference from rolling.
    limitations: Sterile chemical peritonitis is not bacterial infection at a mucosal surface, so
      it measures the trafficking defect rather than the clinical consequence.
    readouts:
    - name: Neutrophil migration to inflamed peritoneum
      target: Impaired Neutrophil Extravasation to Infection Sites
      direction: DECREASED
      interpretation: An 89% reduction quantifies how much of the extravasation response is lost.
      evidence:
      - reference: PMID:18541720
        reference_title: Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency
          II/congenital disorder of glycosylation IIc.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Moreover, neutrophil migration to the inflamed peritoneum was strongly reduced by
          89%.
        explanation: The quantified extravasation defect.
    evidence:
    - reference: PMID:18541720
      reference_title: Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency II/congenital
        disorder of glycosylation IIc.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Taken together, Slc35c1(-/-) mice show strongly defective leukocyte trafficking but
        normal lymphocyte homing to the spleen, which may explain normal lymphocyte functions in
        LAD II.
      explanation: The authors' summary, which also carries the compartment dissociation curated
        as a discussion below.
discussions:
- discussion_id: interpretation_lymphocyte_compartment_sparing
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - animal_models#Slc35c1-deficient mouse
  - pathophysiology#Loss of Sialyl-Lewis X Selectin Ligands
  prompt: Why is lymphocyte function preserved in LAD II when selectin ligands are absent from all
    leukocytes?
  rationale: 'A disease that removes selectin ligands globally should compromise lymphocyte homing
    as much as neutrophil trafficking, and yet lymphocyte function in patients is reported as surprisingly
    normal. The knockout mouse gives a mechanistic answer by splitting the compartments: homing to
    lymph nodes fell to 1-2% of normal while trafficking to the spleen was completely normal, and
    the humoral response failed in lymph nodes but not in spleen.

    The reason is anatomical rather than molecular. Lymph node entry runs through high endothelial
    venules and depends on the selectin-mediated rolling step this disease abolishes; splenic entry
    does not use that route. So the disease is not sparing lymphocytes - it is sparing one lymphoid
    compartment, and that compartment is sufficient for the humoral responses that get measured clinically.

    This is worth stating because it predicts where a lymphocyte defect should be detectable in patients
    if anyone looked for it in the right place.'
- discussion_id: gap_neurodevelopmental_substrates
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Growth Failure and Neurodevelopmental Impairment
  prompt: Which specific fucosylated glycoproteins or glycolipids, when hypofucosylated, produce
    the growth failure and intellectual disability of LAD II?
  rationale: 'The immune branch of this disease is mechanistically closed: the missing glycan is
    named, its receptor is named, and the cellular step it blocks is measurable. The neurodevelopmental
    branch has nothing equivalent. It is attributed to hypofucosylation of substrates needed for
    growth-factor signalling and neurodevelopment, but no particular substrate has been tied to the
    phenotype, which is why the node carries INDIRECT_UNKNOWN_INTERMEDIATES and PROVISIONAL confidence.

    This matters practically, not just descriptively. Oral fucose improved psychomotor capability
    in the index patient, so the branch is at least partly reversible - but without knowing the substrates
    there is no way to predict which patients'' neurological features will respond or to measure
    the response other than clinically.'
- discussion_id: interpretation_partial_defect_immune_sparing
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Leukocyte Rolling on Activated Endothelium
  - phenotypes#Persistent Leukocytosis
  prompt: How much residual GDP-fucose transport is enough to spare the immune phenotype, and why
    does the growth and neurodevelopmental branch appear more sensitive?
  rationale: 'The compound-heterozygous brothers had measurably impaired neutrophil rolling and marked
    changes in plasma glycoprotein glycoform distribution, yet no leukocytosis and no recurrent infection
    - only short stature and developmental delay. The authors call this a surprising degree of immune
    redundancy.

    Read against the pathograph, it says the two branches have different thresholds: enough residual
    fucosylation to keep the adhesion cascade functional was not enough to protect growth or neurodevelopment.
    That has a diagnostic consequence worth stating, since it means SLC35C1 disease can present to
    an endocrinologist or a developmental paediatrician with no immunological signal at all, and
    the leukocyte count - the feature the disease is named for - can be entirely normal.'
notes: 'GeneReviews. No current GeneReviews chapter covers SLC35C1 or leukocyte adhesion deficiency
  type II, so the GeneReviews baseline does not apply to this entry. A PubMed genereviews[book]
  search on SLC35C1 does return one hit, PMID:20301507, but that is the multi-pathway overview
  "Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview", which is retired
  and flagged for historical reference only. It indexes SLC35C1 because this disease is also
  SLC35C1-CDG, but it is neither current nor specific to the disease, so it is not cited here.

  Fucose supplementation evidence. PMID:10877554 ("Fucose supplementation in leukocyte adhesion deficiency
  type II") is listed in references but carries no evidence item: its cached record has an empty
  Content section, so no exact quote is available. It is listed because the fucose-response question
  is central to this entry and a reader following it up should know the paper exists. The allele-dependence
  of that response is evidenced from PMID:12116250, which does have quotable text.'
references:
- reference: PMID:11326279
  title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter.
- reference: PMID:10590041
  title: Correction of leukocyte adhesion deficiency type II with oral fucose.
- reference: PMID:10877554
  title: Fucose supplementation in leukocyte adhesion deficiency type II.
- reference: PMID:12116250
  title: Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc
    founder effect and genotype/phenotype correlation.
- reference: PMID:22492235
  title: Identification of functional elements of the GDP-fucose transporter SLC35C1 using a novel
    Chinese hamster ovary mutant.
- reference: PMID:24403049
  title: Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental
    delay with minimal adhesion defect.
- reference: PMID:11213799
  title: Leukocyte adhesion deficiency II-from A to almost Z.
- reference: PMID:18541720
  title: Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency II/congenital disorder
    of glycosylation IIc.

📚

References & Deep Research

References

8

PMID:11326279

The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter.

No top-level findings curated for this source.

PMID:10590041

Correction of leukocyte adhesion deficiency type II with oral fucose.

No top-level findings curated for this source.

PMID:10877554

Fucose supplementation in leukocyte adhesion deficiency type II.

No top-level findings curated for this source.

PMID:12116250

Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation.

No top-level findings curated for this source.

PMID:22492235

Identification of functional elements of the GDP-fucose transporter SLC35C1 using a novel Chinese hamster ovary mutant.

No top-level findings curated for this source.

PMID:24403049

Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect.

No top-level findings curated for this source.

PMID:11213799

Leukocyte adhesion deficiency II-from A to almost Z.

No top-level findings curated for this source.

PMID:18541720

Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency II/congenital disorder of glycosylation IIc.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Leukocyte Adhesion Deficiency Type II — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 33 citations 2026-08-27T03:37:45.468521

Leukocyte Adhesion Deficiency Type II — Comprehensive Research Report

1. Disease Information

Overview. Leukocyte Adhesion Deficiency Type II (LAD II) is an ultra-rare autosomal recessive congenital disorder of glycosylation caused by defective transport of GDP-fucose into the Golgi apparatus. The resulting global hypofucosylation of glycoconjugates abolishes selectin-ligand function on leukocytes (causing an immunodeficiency phenotype of recurrent infections and persistent leukocytosis) and produces the Bombay (hh) erythrocyte blood phenotype, together with severe psychomotor and growth retardation. It is classified simultaneously as a primary immunodeficiency (leukocyte adhesion defect) and as a congenital disorder of glycosylation (CDG).

Key identifiers: - OMIM phenotype: #266265 — Congenital Disorder of Glycosylation, Type IIc (CDG2C) (OMIM) - OMIM gene: 605881 — SLC35C1 (OMIM) - Orphanet: ORPHA:99843 — Leukocyte adhesion deficiency type II (Orphanet) - HGNC gene ID: HGNC:20197 (SLC35C1) - NCBI GTR condition:* C0398739

Synonyms: LAD-II, LAD2; CDG-IIc / CDG2C; SLC35C1-CDG; GDP-fucose transporter deficiency; GDP-L-fucose transporter 1 deficiency; Rambam-Hasharon syndrome (after the hospital where early cases were characterized) (Wikipedia).

Data provenance. Because fewer than 30 cases have ever been reported (Orphanet states <10; a 2024 review cites 19 diagnosed cases — ScienceDirect 2024), essentially all available information derives from individual case reports and small case series (typically 1–3 patients each) rather than large aggregated cohorts or registries — this is a case-report-driven literature, not an EHR/registry-derived one.

2. Etiology

Disease Causal Factors. LAD II is a monogenic, purely genetic disorder — there is no known environmental or infectious causal contribution to disease initiation. It is caused by biallelic loss-of-function variants in SLC35C1 (11p11.2), encoding the Golgi GDP-fucose transporter (FUCT1) (Nature Genetics, Lübke et al. 2001, PMID:11326279).

Genetic Risk Factors. - Biallelic pathogenic SLC35C1 variants (homozygous or compound heterozygous) are necessary and sufficient. Two founder missense mutations dominate the earliest-reported cases: - p.Arg147Cys (R147C) — identified in the first reported (Turkish-derived) patient (Lübke et al. 2001). - p.Thr308Arg (T308R) — a founder mutation among Arab-Israeli families; genealogic review found two patients' great-grandmothers were sisters, and all three original Arab-Israeli patients lived within roughly a 10-square-mile area, indicating a common founder (Etzioni et al. 2002, PMID:12116250). Patients homozygous for T308R had a more severe growth and cognitive phenotype than the R147C patient. - Additional pathogenic alleles reported include splice-site, frameshift (e.g., compound heterozygous c.247_249delGTG + c.177_179delTAA), and other missense variants; a 2024 functional survey examined 11 distinct mutant SLC35C1 proteins and found differential residual transport activity correlating with phenotypic severity (ScienceDirect 2024). - Consanguinity/founder populations: reported cases cluster in consanguineous Turkish and Arab (Israeli/Palestinic) kindreds, consistent with a rare autosomal recessive founder-driven disorder. - No susceptibility loci or polygenic risk factors are described — this is a single-gene Mendelian disease.

Environmental Risk Factors. None established; age of onset and severity are gene-dosage/allele-dependent rather than environmentally triggered, although infectious burden (recurrent bacterial infections) is a consequence, not a cause, of the underlying glycosylation defect.

Protective Factors. - Genetic: None specific reported; however, residual/hypomorphic SLC35C1 alleles (rather than complete null alleles) are associated with the recently described milder phenotypic variant (see below), effectively acting as a modifying/protective genotype relative to classic severe LAD II. - Environmental/Dietary: Exogenous dietary L-fucose functions as a "protective"/corrective intervention rather than a naturally protective exposure — oral fucose supplementation can restore fucosylated glycan synthesis via a transporter-independent salvage pathway (see Mechanism and Treatment sections).

Gene-Environment Interactions. The central gene-environment interaction in LAD II is therapeutic rather than pathogenic: supplementing the diet with L-fucose bypasses the defective SLC35C1-dependent de novo GDP-fucose synthesis/transport pathway by feeding an alternative "salvage" route that preferentially uses exogenous fucose over de novo-synthesized GDP-fucose (Yu et al., J Biol Chem 2022, PMC9304781). This is the mechanistic basis for oral fucose therapy's efficacy in a subset of patients.

3. Phenotypes

LAD II phenotypes span three broad domains: immunodeficiency/hematologic, growth/neurodevelopmental, and dysmorphic/dental. Onset is typically infancy to early childhood.

Immunologic / Hematologic (laboratory abnormalities and clinical signs): - Persistent leukocytosis with neutrophilia, WBC counts reported in the range of 30,000–150,000/mm³ (HP: Leukocytosis, HP:0001974; HP: Neutrophilia, HP:0011897) (Wikipedia). - Recurrent bacterial infections — pneumonia, otitis media, cellulitis/skin infections, urinary tract infections, gum/periodontal infections (HP: Recurrent bacterial infections, HP:0002718; HP: Recurrent respiratory infections, HP:0002205; HP: Otitis media, HP:0000388). - Impaired neutrophil motility/chemotaxis and defective leukocyte rolling/adhesion due to absent selectin-ligand (sialyl-Lewis X) expression — a laboratory/functional finding rather than a symptom per se. - Unlike LAD I, most LAD II patients can form pus and abscesses, and infections tend to be milder and less life-threatening than in LAD I, though this is not universal across reports (StatPearls, NCBI Bookshelf NBK539770). - Bombay (hh) blood phenotype — absence of the H antigen on erythrocytes due to defective fucosylation, essentially pathognomonic when combined with the clinical picture (HP term candidates: Abnormal erythrocyte morphology is imprecise; best captured structurally rather than via a specific HP term — record via blood group/biochemical finding).

Growth (onset: infancy/early childhood, typically progressive/stable rather than episodic): - Severe growth retardation / short stature, often including intrauterine growth retardation and failure to thrive (HP: Short stature, HP:0004322; HP: Intrauterine growth retardation, HP:0001511; HP: Failure to thrive, HP:0001508). Severity varies with genotype (T308R > R147C in the founder cohort).

Neurodevelopmental (progressive but variably severe; dominates the adult clinical picture): - Severe intellectual disability / psychomotor retardation (HP: Intellectual disability, severe, HP:0010864). - Seizures (HP:0001250), ataxia (HP:0001251), cerebral atrophy (HP:0002059) reported in some patients (GARD). - Notably, in adulthood, intellectual deficit and growth retardation — not infections — dominate the clinical picture, reflecting relative stabilization of the immunologic phenotype with age and the persistence of the neurodevelopmental defect (Orphanet).

Dysmorphic/Craniofacial: - Distinctive facies, most consistently a depressed/flat nasal bridge; also described: micrognathia, coarse facial appearance (HP: Depressed nasal bridge, HP:0005280; HP: Micrognathia, HP:0000347).

Dental/Periodontal (age-dependent, progressive): - Severe periodontitis with gingival inflammation, alveolar bone loss, and early/premature loss of primary and permanent teeth — a hallmark late feature, mechanistically explained by defective neutrophil recruitment to the gingival sulcus (HP: Periodontitis, HP:0000704; HP: Gingivitis; recurring theme across LAD subtypes) (PLOS Pathogens, Moutsopoulos et al.).

Other reported features: chronic diarrhea, keratitis, anemia (variably reported per GARD).

A recently delineated milder phenotypic spectrum. Tahata et al. (2022, Am J Med Genet A 188(7):2005–2018, Wiley) and an earlier case report (PMID:24403049) describe patients with short stature and developmental delay but minimal or absent immune/hematologic manifestations — i.e., growth/neurodevelopmental phenotype without the classic recurrent-infection/leukocytosis picture. A 2020 Journal of Human Genetics report similarly described biallelic SLC35C1 variants causing isolated short stature with intellectual disability without an overt immunodeficiency (Nature/JHG 2020). This indicates a genotype-correlated phenotypic continuum from classic severe LAD II to a mild "SLC35C1-CDG" presentation.

Quality of life impact: Not systematically studied with validated instruments (no EQ-5D/SF-36 data identified); qualitatively, recurrent infections and periodontal disease impose major morbidity in childhood, while intellectual disability and short stature dominate long-term functional/QoL impact into adulthood.

4. Genetic/Molecular Information

Causal Gene: SLC35C1 (previously FUCT1), OMIM 605881, HGNC:20197, chromosome 11p11.2. Encodes a 10-transmembrane-domain Golgi antiporter* (364 amino acids, ~39.8 kDa) that imports cytosolic GDP-fucose into the Golgi lumen in exchange for GMP; transmembrane domains 3, 4, 7, and 9 are highly conserved (domains 4 and 9 notably hydrophilic), and the cytosolic C-terminus is essential for transport activity (GeneCards; PMID:22492235).

Pathogenic Variants: - Variant types: missense (R147C, T308R, G281D, and others), splice-region, and small in-frame/frameshift deletions (e.g., compound heterozygous c.247_249delGTG / c.177_179delTAA) are all reported (ClinVar; e.g. RCV000984510 for p.Gly281Asp, RCV001506269 for a synonymous/splice variant). - ACMG classification: ClinVar entries for SLC35C1 variants associated with LAD II are generally classified pathogenic/likely pathogenic in the context of biallelic inheritance. - Functional consequence: predominantly loss of function — reduced or absent GDP-fucose transport activity into the Golgi, producing global hypofucosylation. A 2024 functional screen of 11 mutant SLC35C1 proteins found a gradient of residual activity that tracks with clinical severity, providing a mechanistic explanation for the phenotypic spectrum (ScienceDirect 2024). - Allele frequency: Given extreme rarity and founder-effect clustering, population allele frequencies in gnomAD are expected to be very low/absent for the specific founder alleles (not independently verified in this search). - Somatic vs. germline: exclusively germline.

Modifier Genes / Alternative Pathways. - SLC35C2 is a putative paralogous transporter; a 2023 J Biol Chem study provided in vivo evidence for residual GDP-fucose transport in the combined absence of SLC35C1 and SLC35C2, indicating an additional, still-uncharacterized transport/salvage route (PMC10709068). - A parallel fucose salvage pathway (dietary/exogenous fucose → fucose kinase/GDP-fucose pyrophosphorylase → cytosolic GDP-fucose, independent of de novo synthesis) preferentially incorporates exogenous over de novo GDP-fucose and is the mechanistic basis for the efficacy of oral fucose therapy even in SLC35C1-null backgrounds (Yu et al. 2022, PMC9304781). - A 2006 report described "LAD II patients with a dual defect of the GDP-fucose transporter," suggesting additional genetic complexity/modifiers in some cases (Blood 107(10):3959).

Epigenetic Information: No disease-specific epigenetic (methylation/histone) mechanisms have been reported for LAD II; the defect is purely biosynthetic/transport-based at the level of nucleotide-sugar delivery, not gene expression regulation.

Chromosomal Abnormalities: Not applicable — LAD II is caused by point/small-indel variants within SLC35C1, not by large chromosomal rearrangements, aneuploidy, or CNVs.

5. Environmental Information

LAD II has no established environmental, lifestyle, or infectious causal contributors — it is a fully penetrant monogenic recessive disorder. The "environmental" dimension relevant to this disease is therapeutic (dietary fucose supplementation), not causal or risk-modifying in the pathogenic sense. No occupational, toxin, or pollutant exposures have been linked to disease risk or severity. No infectious agent triggers the underlying molecular defect (though the disease predisposes to opportunistic and recurrent bacterial infections as a downstream consequence).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Molecular defect (upstream): Biallelic loss-of-function SLC35C1 variants abolish or reduce Golgi GDP-fucose transporter (FUCT1) activity.
Biochemical consequence: GDP-fucose synthesized in the cytosol (via the de novo GDP-mannose → GDP-fucose pathway) cannot be efficiently transported across the Golgi membrane into the lumen, where fucosyltransferases require it as substrate.
Glycosylation consequence: Global hypofucosylation of N-glycans, O-glycans, and glycolipids — a Golgi/molecular-function-level defect (candidate GO term: fucosylation, GO:0036065; GDP-fucose transmembrane transporter activity, GO:0005457).
Cell-surface consequence on leukocytes: Failure to synthesize sialyl-Lewis X (SLeX/CD15s), the fucosylated tetrasaccharide ligand required for E-, P-, and L-selectin binding (candidate biological process: selectin ligand biosynthesis).
Functional consequence — leukocyte trafficking: Loss of selectin-ligand function abolishes leukocyte rolling on activated endothelium, the first step of the leukocyte adhesion cascade preceding firm adhesion and transendothelial migration. In the Slc35c1-knockout mouse, E-, L-, and P-selectin–dependent rolling in cremaster venules was virtually absent, firm adhesion was strongly reduced, and neutrophil migration to the inflamed peritoneum was reduced by ~89% (Blood 112(4):1472, Smith et al. / mouse model paper).
Clinical consequence: Impaired neutrophil extravasation to infection sites → recurrent bacterial infections, marked peripheral leukocytosis (neutrophils cannot leave the circulation), and periodontal disease (failure of neutrophil surveillance of the gingival sulcus).
Parallel, independent consequence — erythrocytes: Loss of α1,2-fucosylation of the H-antigen precursor on red cells produces the Bombay (hh) blood phenotype, a diagnostically useful but pathophysiologically separate readout of the same core biochemical defect.
Parallel, independent consequence — growth/CNS: Global hypofucosylation of glycoproteins/glycolipids required for normal growth-factor signaling and neurodevelopment is thought to underlie the severe growth retardation and intellectual disability, though the precise fucosylated substrates responsible for the neurodevelopmental phenotype are less well characterized than the selectin-ligand mechanism.

Cell types and processes involved (ontology anchors): - Cell types (CL): neutrophil (CL:0000775), erythrocyte (CL:0000232), vascular endothelial cell (CL:0000071) — the selectin-expressing "receiver" cell in the rolling interaction. - Molecular functions (GO): GDP-fucose transmembrane transporter activity (GO:0005457); fucosyltransferase activity (GO:0008417); selectin binding. - Biological processes (GO): protein fucosylation (GO:0036065); leukocyte cell-cell adhesion (GO:0007159); leukocyte tethering or rolling (GO:0050901); inflammatory response (GO:0006954). - Anatomical structures (UBERON): Golgi apparatus (subcellular; GO:0005794, cellular component) is the actual site of the primary molecular lesion.

Molecular Profiling. Direct transcriptomic/proteomic/metabolomic disease-specific profiling datasets were not identified in this search (consistent with the disease's extreme rarity and the case-report nature of the literature); the principal "omics" readout used clinically and in research is targeted glycomic analysis (serum glycoprotein core fucosylation, neutrophil CD15a/SLeX expression by flow cytometry) rather than genome-wide expression/proteomics.

Advanced technologies: No single-cell, spatial transcriptomic, or CRISPR functional-genomics screens specific to LAD II were identified; functional characterization has instead relied on site-directed mutagenesis of SLC35C1 in CHO mutant cell lines to map functional transmembrane domains (PMID:22492235).

7. Anatomical Structures Affected

Organ level: - Primary: hematopoietic/immune system (neutrophil dysfunction), skeletal/growth system (short stature), central nervous system (intellectual disability, seizures, cerebral atrophy), periodontium/oral cavity (severe periodontitis). - Secondary: respiratory system (recurrent pneumonia), skin/soft tissue (recurrent cellulitis/skin infections), ears (otitis media), gastrointestinal tract (chronic diarrhea in some patients), eyes (keratitis in some patients). - Body systems involved: immune, musculoskeletal (growth), nervous, integumentary, dental/periodontal.

Tissue and cell level: - Neutrophils/granulocytes (functionally defective selectin-ligand expression) — CL:0000775. - Vascular endothelium (the counterpart in the failed adhesion interaction) — CL:0000071. - Erythrocytes (Bombay phenotype) — CL:0000232. - Gingival/periodontal tissue (site of chronic inflammatory destruction).

Subcellular level: - Golgi apparatus — the primary site of the molecular lesion (GO Cellular Component: Golgi apparatus, GO:0005794; Golgi membrane, GO:0000139), where the defective GDP-fucose transporter normally resides and functions.

Localization: Systemic/multi-organ rather than focal; no lateralization pattern is described.

8. Temporal Development

Onset. First signs typically emerge in infancy or early childhood — recurrent infections and growth failure are usually the presenting features (Orphanet). Some growth impairment (intrauterine growth retardation) can be present prenatally/at birth.

Onset pattern: Insidious/chronic rather than acute, punctuated by episodes of recurrent bacterial infection.

Progression: - The immunologic/infectious phenotype tends to improve or stabilize with age, becoming less prominent in adolescence and adulthood. - The neurodevelopmental and growth phenotype is persistent and often progressive/dominant in the long term — "in adulthood, intellectual deficit and growth retardation, rather than infections, dominate the clinical picture" (Orphanet). - Periodontal disease is progressive, with cumulative alveolar bone loss and early loss of both primary and permanent dentition over childhood/adolescence.

Disease course pattern: Chronic, with infections occurring in a recurrent/relapsing pattern superimposed on a stable underlying biochemical defect; growth and cognitive impairment follow a more stable-to-progressive developmental trajectory rather than an episodic one.

Duration: Lifelong (the underlying molecular lesion is permanent), though clinical management (fucose supplementation, antimicrobial prophylaxis) can substantially modify the disease course.

Remission patterns: Treatment-induced clinical improvement (not cure) has been documented with oral fucose therapy — resolution of chronic skin infections and normalization of neutrophil counts/selectin ligand expression have been reported in fucose-responsive patients (Marquardt et al. 1999, PMID:10590041; Sturla et al. 2000, PMID:10877554). No spontaneous remission is described.

Critical periods: Early diagnosis and initiation of fucose therapy (and neurodevelopmental support) in infancy/early childhood appears most likely to yield developmental benefit, based on the reported catch-up growth/head circumference and cognitive improvement observed with early, sustained treatment (ScienceDirect L-fucose case report 2026).

9. Inheritance and Population

Epidemiology. LAD II is one of the rarest known primary immunodeficiencies/CDGs. Orphanet lists prevalence as fewer than 10 reported cases worldwide; a 2024 review states 19 diagnosed cases to date (ScienceDirect 2024). No formal incidence rate has been calculated given the extremely small denominator.

Inheritance pattern: Autosomal recessive. Both parents are obligate heterozygous carriers (typically asymptomatic); each pregnancy carries a 25% recurrence risk for an affected child, 50% carrier risk, and 25% unaffected/non-carrier risk.

Penetrance: Appears fully penetrant for biallelic loss-of-function genotypes, though expressivity is highly variable (see below) — ranging from the classic severe multi-system phenotype to a milder isolated short-stature/developmental-delay presentation with little or no immune involvement.

Expressivity: Variable, genotype-correlated. The R147C founder allele produced a milder phenotype than the T308R founder allele in the original Etzioni cohort (PMID:12116250); more recent reports of hypomorphic alleles produce an even milder "SLC35C1-CDG" phenotype (short stature/developmental delay without overt immunodeficiency) (Tahata et al. 2022; JHG 2020).

Genetic anticipation: Not applicable/not described (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for SLC35C1/LAD II in this search.

Founder effects: Well documented. The T308R mutation is a founder allele in an Arab-Israeli population (traced to a shared great-grandmother lineage, geographically clustered within ~10 square miles) (Etzioni et al. 2002). The R147C mutation was described in a Turkish-derived family. Both findings are consistent with rare-disease founder effects amplified by consanguinity.

Consanguinity: A recognized major risk factor — most/all early reported cases arose in consanguineous unions in Turkish and Arab-Israeli kindreds.

Carrier frequency: Not established in general population databases given the disease's extreme rarity; expected to be elevated locally within founder-affected consanguineous communities.

Population demographics: - Affected populations: predominantly reported in Turkish and Arab (Israeli/Middle Eastern) kindreds, reflecting founder-effect ascertainment rather than a demonstrated broader ethnic predisposition; sporadic cases have also been reported outside these populations. - Geographic distribution: Case clusters reported from Israel/Middle East and Turkey; isolated cases reported elsewhere (e.g., North America, per the Tahata et al. 2022 new-family report). - Sex ratio: No sex predilection is reported (autosomal recessive inheritance). - Age distribution: Diagnosis is typically made in infancy/early childhood; the surviving cohort described spans childhood through adulthood, with long-term follow-up reports available for some of the earliest-diagnosed patients.

10. Diagnostics

Clinical Tests: - Complete blood count: marked leukocytosis with neutrophilia (WBC often 30,000–150,000/mm³), a near-universal and easily obtained first clue. - Flow cytometry: demonstration of absent or markedly reduced sialyl-Lewis X (CD15s/CD15a) expression on neutrophils using a monoclonal antibody is the key functional immunologic test (StatPearls NBK539770). - Blood typing (ABO/H antigen typing): essential — the Bombay (hh) blood phenotype is present in essentially all reported LAD II patients and is exceedingly rare in the general population, making it a strong diagnostic pointer; there is a published report of LAD II being incidentally diagnosed via ABO typing (ScienceDirect, incidental diagnosis). - Serum glycoprotein core fucosylation analysis (glycomic/biochemical assay) can demonstrate global hypofucosylation and is used to monitor treatment response to oral fucose. - Neutrophil chemotaxis/rolling functional assays (research-level, not routine clinical) confirm the selectin-ligand defect.

Genetic Testing: - Recommended approach: targeted SLC35C1 single-gene sequencing or inclusion in a primary immunodeficiency/CDG gene panel is the standard confirmatory test once the clinical/biochemical phenotype (leukocytosis, absent SLeX, Bombay phenotype) raises suspicion (commercial test listed in NCBI GTR, e.g., Test ID 507358). - Whole-exome/whole-genome sequencing is increasingly the diagnostic route for atypical or mild presentations (e.g., isolated short stature with developmental delay) where the classic immunologic clues are absent or subtle, as illustrated by the JHG 2020 report identifying SLC35C1 variants in a short-stature/ID cohort without a primary CDG or immunodeficiency indication (Nature/JHG 2020). - Chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not relevant to LAD II diagnosis (it is a point-mutation/small-indel single-gene disorder).

Omics-Based Diagnostics: No standardized transcriptomic, proteomic, or liquid-biopsy diagnostic modality is used; targeted glycomics (as above) is the relevant "omics" adjunct.

Clinical Criteria / Differential Diagnosis: No formal consensus diagnostic-criteria statement (e.g., DSM/ICD-style) exists given the disease's rarity; diagnosis is a clinical-biochemical-genetic triad (leukocytosis + recurrent infection + growth/developmental delay, confirmed by absent SLeX/Bombay phenotype and SLC35C1 sequencing). Key differentials include: - LAD I (ITGB2/CD18 deficiency) — clinically more severe infections, delayed umbilical cord separation, absent pus formation, normal growth/cognition, normal blood group; distinguished by CD18 flow cytometry and ITGB2 sequencing. - LAD III (FERMT3/kindlin-3 deficiency) — LAD-like immunodeficiency plus a Glanzmann-like bleeding diathesis. - Other congenital disorders of glycosylation (CDG-I and other CDG-II subtypes) — distinguished by transferrin isoelectric focusing pattern and specific gene panels. - Other syndromic causes of growth failure/intellectual disability when the immunologic phenotype is mild or absent (the "mild LAD II variant" differential).

Screening: No population-based newborn or carrier screening program exists for LAD II given its extreme rarity; genetic counseling and targeted carrier testing are offered within affected founder-population kindreds/consanguineous families once an index case is identified.

11. Outcome/Prognosis

Survival and Mortality: No formal survival statistics (e.g., 5-/10-year survival rates) are available given the very small number of reported cases; published long-term follow-up reports (e.g., the JACI "long-term follow-up" report on an original index case, JACI) indicate that patients can survive into adulthood, particularly with modern infection management and, where applicable, fucose supplementation.

Morbidity: - Infections tend to become less frequent/severe with age, shifting the long-term morbidity burden toward intellectual disability, short stature, and periodontal disease/tooth loss. - Severe periodontitis is a major source of chronic morbidity, frequently resulting in complete or near-complete tooth loss by adolescence. - Neurodevelopmental impairment (severe intellectual disability in the classic phenotype) is typically lifelong and is the dominant determinant of functional outcome and quality of life.

Disease Course / Complications: - Recurrent bacterial infections (pneumonia, otitis media, skin/soft-tissue infection) in childhood. - Progressive periodontal destruction. - In the mouse model, female Slc35c1-null mice show reproductive complications (abortion, small litters, failure to nurture pups), raising the possibility of analogous reproductive/perinatal vulnerabilities, though this has not been systematically documented in human patients.

Recovery Potential: Not a degenerative/fatal disease in most surviving cases; the biochemical/immunologic defect can be substantially — though not completely — corrected pharmacologically with oral fucose in a subset of patients (see Treatment), improving infection frequency, growth parameters, and reportedly cognition/speech in treated individuals.

Prognostic Factors: - Genotype: patients with milder/hypomorphic SLC35C1 alleles have a substantially better growth/cognitive prognosis than those with classic null alleles (T308R vs. R147C comparison; the emerging "mild variant" spectrum). - Fucose-therapy responsiveness itself appears prognostic — patients who respond biochemically (rise in SLeX/CD15a expression, normalization of core fucosylation) tend to show the greatest clinical improvement; some genotypes (e.g., certain T308R-associated presentations) have historically shown limited or partial response. - Early initiation of supportive/pharmacologic therapy likely improves developmental outcome, based on catch-up growth and cognitive gains reported with sustained early treatment.

Prognostic Biomarkers: Neutrophil CD15a/sialyl-Lewis X expression by flow cytometry and serum glycoprotein core-fucosylation level serve as both diagnostic and treatment-response/prognostic biomarkers.

12. Treatment

Pharmacotherapy — Oral L-fucose supplementation (the central, disease-modifying therapy): - Mechanism: Exogenous dietary L-fucose is taken up and phosphorylated/converted to GDP-fucose via the cytosolic salvage pathway, which can supply the Golgi with GDP-fucose largely independent of the defective SLC35C1-mediated de novo route, restoring at least partial fucosylation capacity (Yu et al. 2022, PMC9304781). - Foundational evidence: Marquardt et al. (1999, Blood 94(12):3976–85, PMID:10590041) — "Correction of Leukocyte Adhesion Deficiency Type II With Oral Fucose": oral fucose supplementation induced expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins in the treated patient, with disappearance of chronic skin infections and improvement in behavior/attention span. - Sturla et al. (2000, Blood, PMID:10877554) — "Fucose supplementation in leukocyte adhesion deficiency type II" — corroborated reappearance of functional selectin ligands with normalization of neutrophil counts. - A subsequent case (27 months of therapy) showed improvement in speech and cognition, CD15 expression, and core fucosylation of serum glycoproteins ([review cited via 2024 search synthesis]). - A 2026 case report of a patient with a mono-allelic SLC35C1 variant and global hypofucosylation treated with L-fucose documented improvements in weight, head circumference, IgG normalization, and developmental catch-up (ScienceDirect 2026). - Not all patients respond equally — response appears genotype-dependent, and fucose therapy is generally regarded as beneficial but not curative. - NCIT term suggestion: Pharmacotherapy (NCIT:C15986); more specifically, dietary/nutritional supplementation (NCIT:C15433, used cautiously per curation guidance to avoid over-classifying as "dietary/behavioral" when the agent is a specific chemical compound — L-fucose is better modeled as a small-molecule pharmacotherapy with therapeutic_agent bound to the relevant CHEBI term for L-fucose).

Advanced/Investigational Therapeutics: - AVTX-803 (Avalo Therapeutics) — an investigational oral L-fucose formulation specifically developed for LAD II, granted FDA Fast Track Designation (FTD), Orphan Drug Designation (ODD), and Rare Pediatric Disease Designation (RPDD), making it potentially eligible for a Priority Review Voucher. - LADDER trial (NCT05462587): a pivotal, 16-week, randomized, double-blind, two-period crossover withdrawal study (n=2 enrolled at initiation) assessing AVTX-803 efficacy/safety in LAD II, with the primary endpoint being change in leukocyte sialyl-Lewis X (SLeX) antigen expression between treatment periods. As of an April 2026 ClinicalTrials.gov verification, the (now Phase 3) study status is RECRUITING, with estimated primary completion November 30, 2026 (Mayo Clinic trial listing; BioSpace press release). - Extension study (NCT05754450): assessing long-term safety/efficacy of AVTX-803. - An earlier related trial, NCT03354533 ("Study of ORL-1F [L-fucose] in Patients With Leukocyte Adhesion Deficiency Type II"), was a completed Phase 1/2 study of an L-fucose formulation (ClinicalTrials.gov). - This represents the most significant recent (2023–2026) translational development in LAD II — movement from off-label compassionate oral fucose use toward a regulatory-track, purpose-built oral fucose drug product with a pivotal registrational trial actively recruiting as of 2026.

Surgical/Interventional: No disease-specific surgical intervention; periodontal surgical management may be attempted for severe periodontitis but is often "recalcitrant to treatment," per the periodontal literature.

Supportive Care: - Aggressive antimicrobial prophylaxis/treatment of recurrent bacterial infections (NCIT:C15747, Supportive Care; consider antibiotic pharmacotherapy, NCIT:C15986). - Intensive dental/periodontal care and monitoring (NCIT category: dental/oral healthcare procedures) given the near-universal severe periodontal disease. - Nutritional support for growth failure/failure to thrive.

Rehabilitative: Developmental/early intervention services, physical/occupational/speech therapy for psychomotor and cognitive delay (NCIT:C15302 Physical Therapy; NCIT:C159273 Speech Therapy; NCIT:C121351 Occupational Therapy), particularly given reported cognitive gains coincident with fucose therapy.

Experimental: Beyond AVTX-803, no gene therapy, cell therapy, or RNA-based therapeutic approach specific to LAD II was identified in this search (contrast with LAD I, for which a lentiviral gene therapy trial, RP-L201, is registered as NCT03825783).

Treatment Outcomes: - Response rates to oral fucose are not formally quantified across a large cohort (reflecting the very small total patient population) but are reported as clinically meaningful in multiple case reports, with biochemical (SLeX/CD15a, core fucosylation) and clinical (infection frequency, growth, cognition/speech) endpoints improving in responders. - Side effects/adverse events specific to oral fucose supplementation were not detailed in the sources reviewed here beyond general tolerability implied by long-term (multi-year) use in case reports.

Treatment Strategy: Standard-of-care as currently practiced: "a trial of fucose supplementation is recommended in all patients diagnosed with LAD II" (StatPearls NBK539770), combined with proactive infection management, periodontal care, and developmental support — essentially monotherapy (fucose) plus multidisciplinary supportive care, rather than combination pharmacotherapy.

Personalized Medicine: Given genotype-phenotype correlation and genotype-dependent treatment responsiveness, SLC35C1 variant characterization (and functional assay of residual transporter activity where available) is increasingly relevant to anticipating both disease severity and likely response to fucose-based therapy — an emerging precision-medicine dimension for this ultra-rare disease.

13. Prevention

Primary Prevention: Not applicable in the population-based sense (no vaccination or modifiable risk-factor strategy prevents this monogenic recessive disorder). The only relevant "primary prevention" lever is reproductive/genetic: carrier screening and genetic counseling in known founder/consanguineous populations, and prenatal or preimplantation genetic testing for at-risk couples once a familial SLC35C1 pathogenic variant is identified.

Secondary Prevention: Early clinical recognition (leukocytosis + recurrent infection + growth delay triad) followed by prompt diagnostic confirmation (flow cytometry for SLeX, Bombay blood typing, SLC35C1 sequencing) allows earlier initiation of fucose therapy and infection-prevention measures — the closest analog to "secondary prevention" for this disorder, aimed at limiting downstream developmental and periodontal morbidity.

Tertiary Prevention: Ongoing antimicrobial prophylaxis, structured dental/periodontal surveillance and intervention, and developmental therapies to limit the functional impact of established intellectual disability and periodontal disease.

Immunization: No disease-specific vaccine strategy; standard childhood immunizations are presumably still indicated (not contraindicated), though no specific guidance was identified in this search.

Screening and Early Detection: - No population-based newborn screening program for LAD II exists. - Genetic/carrier screening within known founder-mutation communities (e.g., specific Arab-Israeli and Turkish kindreds carrying T308R/R147C) is the most relevant targeted screening strategy, alongside cascade testing of relatives of an index case. - Risk stratification: essentially pedigree-based (consanguinity, known carrier status) rather than population risk-score based.

Behavioral Interventions: Not applicable (no lifestyle-modifiable risk factor).

Counseling: Genetic counseling is central given autosomal recessive inheritance, especially in consanguineous/founder populations, covering recurrence risk (25% per pregnancy for carrier couples), carrier testing of relatives, and reproductive options (prenatal diagnosis, preimplantation genetic testing) once the familial pathogenic variant(s) are known.

Public Health / Environmental Interventions: Not applicable — there is no environmental exposure to mitigate.

Prophylaxis: Ongoing infection prophylaxis (e.g., antibiotic prophylaxis in high-risk periods) is a reasonable clinical practice extrapolated from general immunodeficiency management, though no LAD II-specific prophylactic regimen/guideline was identified in this search.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring LAD II has been reported in non-human species (companion animals, livestock, or wildlife) in the sources reviewed. This contrasts with LAD I, which has recognized naturally occurring bovine (BLAD, bovine leukocyte adhesion deficiency) and canine analogs.

Gene orthology: Slc35c1 is conserved across model organisms — mouse (MGI:2443301, Slc35c1), zebrafish (ZFIN: slc35c1, ZDB-GENE-041212-11), rat (RGD:1309463), and others — but no report of spontaneous/natural LAD II-like disease in these species was found; all animal data derive from engineered knockout models (see Section 15).

Comparative Biology: The core molecular mechanism (Golgi GDP-fucose transport supporting selectin-ligand fucosylation and leukocyte rolling) is evolutionarily conserved, as demonstrated by the concordant phenotype (leukocytosis, defective selectin-dependent rolling/adhesion) in the engineered mouse knockout, supporting cross-species conservation of the pathway even though the disease itself is human-specific/engineered rather than naturally occurring elsewhere.

Transmission/Zoonotic potential: Not applicable — LAD II is a non-communicable, purely genetic disorder with no zoonotic or cross-species transmission dimension.

15. Model Organisms

Model Type: Mammalian, genetically engineered (knockout).

Primary model — Slc35c1-knockout mouse: - Reported in Blood 112(4):1472 (2008), "Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency II/congenital disorder of glycosylation IIc" (ASH Publications). - Genetic model type: constitutive knockout (Slc35c1−/−). - Phenotype recapitulation: - Approximately half of surviving knockout mice were fertile; pregnant knockout females uniformly aborted or had very small litters and failed to nurture pups — a reproductive phenotype not systematically described in human LAD II patients, representing a potential model-specific or under-ascertained feature. - Prominent leukocytosis driven primarily by a ~5-fold increase in circulating neutrophils — directly recapitulates the hallmark human laboratory finding. - E-, L-, and P-selectin–dependent leukocyte rolling in cremaster muscle venules was virtually absent, with a strong (though incomplete) decrease in firm leukocyte adhesion — faithfully recapitulates the human selectin-ligand defect mechanism. - Neutrophil migration to the inflamed peritoneum was reduced by 89%, modeling the human recurrent-infection susceptibility mechanistically. - Lymphocyte homing to lymph nodes was reduced to 1–2% of normal, but homing to the spleen was completely normal — this dissociation is proposed to explain why LAD II patients do not show the profound lymphocyte-trafficking defects that might otherwise be predicted, i.e., a partial/tissue-selective recapitulation that helps explain a milder-than-expected component of the human phenotype. - Model limitations: the mouse model's reproductive/fertility phenotype (abortion, failure to nurture pups) has no clearly documented human correlate in the literature reviewed, and the degree of neurodevelopmental/growth phenotype recapitulation in the mouse was not detailed in the sources retrieved here — suggesting the mouse model may be most robust for the immunologic/selectin-trafficking axis of the disease rather than the growth/CNS axis. - Research applications: in vivo dissection of selectin-ligand biology, leukocyte rolling/adhesion dynamics, and testing of fucose-repletion strategies at the mechanistic level.

Other model systems: No Drosophila, C. elegans, zebrafish, or iPSC-based disease models specific to LAD II/SLC35C1 loss were identified in this search (zebrafish and other species carry an annotated slc35c1 ortholog per model-organism databases, but no disease-modeling publication using these orthologs was retrieved).

Cellular/functional models: CHO (Chinese hamster ovary) mutant cell lines lacking functional GDP-fucose transport have been used as an in vitro functional model to map SLC35C1 structure-function relationships (transmembrane domain mutagenesis) rather than to model organismal disease per se (PMID:22492235).

Resources: MGI (Slc35c1, MGI:2443301) for the mouse gene/allele records; no dedicated LAD II model-organism repository or IMPC/KOMP-specific disease-model resource was identified beyond standard gene-centric databases.

Summary of Suggested Ontology Term Bindings for KB Curation

Category	Term
Disease (MONDO)	Not confirmed in this search — recommend verifying directly via the MONDO/OxO API before binding (search results did not surface a definitive MONDO CURIE for LAD II specifically, only for LAD I, MONDO:0007293)
OMIM phenotype	266265
OMIM gene	605881
Orphanet	ORPHA:99843
HGNC gene	HGNC:20197 (SLC35C1)
GO Molecular Function	GO:0005457 (GDP-fucose transmembrane transporter activity)
GO Biological Process	GO:0036065 (fucosylation); GO:0050901 (leukocyte tethering or rolling); GO:0007159 (leukocyte cell-cell adhesion)
GO Cellular Component	GO:0005794 (Golgi apparatus)
CL	CL:0000775 (neutrophil); CL:0000071 (blood vessel endothelial cell); CL:0000232 (erythrocyte)
HP (representative)	HP:0001974 (Leukocytosis); HP:0011897 (Neutrophilia); HP:0002718 (Recurrent bacterial infections); HP:0004322 (Short stature); HP:0001511 (Intrauterine growth retardation); HP:0010864 (Severe intellectual disability); HP:0005280 (Depressed nasal bridge); HP:0000704 (Periodontitis); HP:0001250 (Seizure)
NCIT (treatment)	NCIT:C15986 (Pharmacotherapy) with `therapeutic_agent` bound to L-fucose (verify exact CHEBI CURIE before binding); NCIT:C15747 (Supportive Care)
Clinical trials	NCT05462587 (AVTX-803 LADDER, pivotal, recruiting as of 2026); NCT05754450 (AVTX-803 extension); NCT03354533 (ORL-1F, completed)

Note on ontology terms: the GO/CL/HP identifiers above are provided as strong candidate bindings based on standard, well-established ontology term meanings for these concepts, but per this repository's term-validation contract (dismech-terms skill), each should still be run through just validate-terms/OAK lookup before being committed to a KB entry, since this research pass did not itself query OAK/OLS directly.

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Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
On topic	7
Off topic	0

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Leukocyte Adhesion Deficiency Type II

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Leukocyte Adhesion Deficiency Type II — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Suggested Ontology Term Bindings for KB Curation

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