SLC35A1-Congenital Disorder of Glycosylation

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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic SLC35A1 variants. The index patient was compound heterozygous for two truncating alleles; the third reported patient was compound heterozygous for two missense alleles. Heterozygous carriers are unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:15576474 SUPPORT In Vitro

"The inactivation of one patient allele by a double microdeletion inducing a premature stop codon at position 327 and a splice mutation of the other allele inducing a 130-base pair (bp) deletion and a premature stop codon at position 684 are proposed to be the causal defects of this disease."

Documents the biallelic architecture in the index patient, with a distinct loss-of-function change on each allele.

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Discussions and Knowledge Gaps

2

What determines whether an SLC35A1-CDG patient expresses the hematologic arm, the neurological arm, or both?

KNOWLEDGE GAP slc35a1_branch_expression_across_patients

Attached to

pathophysiology#Global Hyposialylation of Glycoconjugates

Across the three proven patients the arms combine differently: the second has both, the third has the neurological arm with explicitly no hematological abnormality, and the index patient has the hematologic arm with every neurological feature recorded as *not reported* rather than absent. So one of the three data points is an ascertainment gap rather than a negative finding, which is a distinction the published comparison table makes explicitly and which matters for any attempt to read a pattern off three patients. Genotype does not explain the variation: the patient with both arms is homozygous for a missense allele retaining 50% of transport activity, which is the mildest reported genotype and the broadest reported phenotype.

Resolving this needs systematic assessment of both systems in every patient, not only the system that prompted referral. The index patient was found through a leukocyte adhesion workup and the third through exome sequencing for encephalopathy, and the published table shows how much of the resulting picture is "not reported".

Is the proposed ganglioside and polysialic-acid mechanism actually what produces the encephalopathy in SLC35A1-CDG, given that no model of the neurological branch exists?

HUMAN MODEL MISMATCH slc35a1_no_neurological_model

Attached to

pathophysiology#Deficient Brain Sialoglycan Synthesis pathophysiology#Impaired Neuronal Connectivity and Excitability

The hematologic branch has a conditional mouse that reproduces it. The neurological branch has no model at all: the existing mouse deletes Slc35a1 only in megakaryocytes and platelets, so it cannot develop a brain phenotype. Everything downstream of the hyposialylation node on the neurological side rests on what gangliosides and polysialic acid are known to do in other settings, plus the observation that a patient with reduced Golgi sialic acid transport had an encephalopathy. That is a plausible chain, but no step of it has been measured in an SLC35A1-deficient nervous system. Recorded as a human-model mismatch rather than a plain knowledge gap because the model-system evidence that does exist covers the other branch, and its success there could be mistaken for support of the entry as a whole.

A neuron-specific or whole-body conditional knockout, or patient-derived neurons, would test whether brain sialoglycan deficiency is sufficient for the phenotype.

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Pathophysiology

8

SLC35A1 Transporter Loss of Function

Biallelic SLC35A1 variants leave the cell without a working Golgi CMP-sialic acid transporter. Truncating alleles abolish the protein; the reported missense alleles reduce transport rather than abolishing it, which is the likely reason their carriers present differently.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

CMP-N-acetylneuraminate transmembrane transporter activity GO:0005456 ↓ DECREASED

Golgi membrane GO:0000139

Downstream

Golgi CMP-Sialic Acid Donor Depletion

Show evidence (1 reference)

PMID:15576474 SUPPORT In Vitro

"We conclude that this defect is a new type of congenital disorder of glycosylation (CDG) of type IIf affecting the transport of CMP-sialic acid into the Golgi apparatus."

The original identification of the transporter defect as the disease lesion.

Golgi CMP-Sialic Acid Donor Depletion

The Golgi lumen is deprived of CMP-Neu5Ac, the activated donor every sialyltransferase requires. Cytosolic sialic acid synthesis is unaffected, so the cell is not short of sialic acid; it is short of sialic acid in the compartment where it is used. That distinction is what makes dietary sialic acid an ineffective strategy here.

Golgi membrane GO:0000139

Downstream

Global Hyposialylation of Glycoconjugates

Show evidence (1 reference)

PMID:32303557 SUPPORT BACKGROUND Other

"Slc35a1 encodes the cytidine-5'-monophosphate (CMP)-sialic acid transporter that transports CMP-sialic acid from the cytoplasm into the Golgi apparatus for sialylation."

States the transported species and its destination compartment, which is what this node claims is depleted. Marked BACKGROUND because the sentence opens the mouse study's abstract as a statement of what the gene encodes, not as one of its results. Graded OTHER rather than MODEL_ORGANISM for the same reason: no animal experiment established what the transporter carries, so MODEL_ORGANISM would assert that this mouse study measured it. IN_VITRO is not used either, because the cited paper does not say where the fact was established and this entry does not grade a source on unstated provenance.

Global Hyposialylation of Glycoconjugates

Without the donor, sialyltransferases cannot cap glycans, and N-glycans, O-glycans and glycolipids across the cell are left without their terminal sialic acid. The p.Glu196Lys allele adds a second route to the same endpoint by decoupling the transporter from the sialyltransferase ST3Gal4.

sialylation GO:0097503 ↓ DECREASED

Downstream

Platelet Desialylation and Hepatic Clearance

Impaired Megakaryocytopoiesis

Loss of Leukocyte Sialyl-Lewis-x

Deficient Brain Sialoglycan Synthesis

Show evidence (2 references)

PMID:28856833 SUPPORT Human Clinical

"Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid."

Direct measurement of the hyposialylation in patient material, across both glycan classes.

PMID:36257191 SUPPORT In Vitro

"We showed that SLC35A1 associates with ST3Gal4, the main α2,3-sialyltransferase acting on N-glycans. This phenomenon is compromised by the E196K (but not T156R) mutation in the SLC35A1 gene."

Establishes the second, allele-specific route to hyposialylation, and the contrast with the other missense allele that makes it allele-specific rather than general.

Platelet Desialylation and Hepatic Clearance

Loss of terminal sialic acid on platelet surface glycoproteins exposes the subterminal galactose that hepatic clearance receptors recognise, so circulating platelets are removed by the liver. In the conditional mouse the clearing cells are hepatic Kupffer cells. The hepatocyte Ashwell-Morell receptor route is established for desialylated platelets in immune thrombocytopenia and is the mechanism generally invoked here; it has not been shown directly in SLC35A1-CDG, so the evidence for that step is marked indirect.

platelet CL:0000233 Kupffer cell CL:0000091

Animal models

Platelet and megakaryocyte-specific Slc35a1 conditional knockout mouse Mouse recapitulates Reproduces the clearance arm, identifying hepatic Kupffer cells as the clearing population.

Show evidence (2 references)

PMID:32303557 SUPPORT Model Organism

"In addition, an increased number of desialylated platelets was cleared by Küpffer cells in the liver of Plt Slc35a1–/– mice."

Demonstrates hepatic clearance of desialylated platelets in the Slc35a1 conditional knockout, and names Kupffer cells as the clearing population. This is the animal evidence for the clearance arm of this node.

PMID:26185093 SUPPORT INDIRECT Model Organism

"This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell receptors, which is fundamentally different from the classical Fc-FcγR-dependent macrophage phagocytosis."

Establishes the desialylation-to-hepatic-clearance mechanism, but in immune thrombocytopenia rather than in SLC35A1-CDG. Marked INDIRECT because applying it here requires the inference that platelets desialylated by a transporter defect are cleared the same way as platelets desialylated by antibody-triggered sialidase translocation.

Impaired Megakaryocytopoiesis

Hyposialylation also acts upstream of the circulating platelet, on its production. The conditional mouse shows both fewer bone marrow megakaryocytes and impaired maturation of the ones present, so the thrombocytopenia is a production defect as well as a clearance defect.

megakaryocyte CL:0000556

Animal models

Platelet and megakaryocyte-specific Slc35a1 conditional knockout mouse Mouse recapitulates Reproduces the production arm of the thrombocytopenia directly, in the cell type the node names.

Show evidence (1 reference)

PMID:32303557 SUPPORT Model Organism

"megakaryocyte maturation was also impaired"

The production arm of the thrombocytopenia mechanism, distinct from the clearance arm recorded on the neighbouring node.

Loss of Leukocyte Sialyl-Lewis-x

Sialyl-Lewis-x is the selectin ligand that lets leukocytes roll on and adhere to activated endothelium, and its terminal sialic acid is not optional: without sialylation the ligand is not made. Its complete absence on polymorphonuclear cells was the finding that identified the index patient, and it makes the infection susceptibility an adhesion defect on top of the neutropenia rather than a consequence of low counts alone.

neutrophil CL:0000775

Show evidence (1 reference)

PMID:27387429 SUPPORT BACKGROUND Human Clinical

"characterized by macrothrombocytopenia, neutropenia and complete lack of the sialyl-Lex antigen"

Records the complete absence of the sialyl-Lewis-x antigen on polymorphonuclear cells. Marked BACKGROUND because the sentence is this 2016 paper's recapitulation of the authors' own 2005 clinical report, not a result of the splice-variant work it reports.

Deficient Brain Sialoglycan Synthesis

The brain's two major sialoglycan families, gangliosides and polysialic acid on NCAM, both require the same Golgi donor. Their deficiency is the proposed basis of the neurological branch. This step is an inference from what these glycans are known to require and to do, not a measurement made in an SLC35A1-CDG brain, and no model reproducing the encephalopathy has been reported.

neuron CL:0000540

ganglioside biosynthetic process GO:0001574 ↓ DECREASED

Animal models

Platelet and megakaryocyte-specific Slc35a1 conditional knockout mouse Mouse fails to recapitulate The model cannot address the neurological branch at all, because the deletion is restricted to the megakaryocyte and platelet lineage.

Downstream

Impaired Neuronal Connectivity and Excitability

Show evidence (1 reference)

PMID:24692354 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid."

Identifies the two brain sialoglycan families whose synthesis this node claims is deficient. Marked INDIRECT and REVIEW_SYNTHESIS: it is a review establishing what these glycans are, from which the deficiency in a sialylation-donor defect follows by inference rather than by measurement in this disease.

Impaired Neuronal Connectivity and Excitability

Ganglioside deficiency is linked to disturbed axon-myelin interactions, axon stability and nerve cell excitability; polysialic acid deficiency to disturbed neurite outgrowth and synaptic connectivity. Together these are the proposed substrate of the developmental delay, hypotonia, seizures and encephalopathy seen in the neurological presentation.

neuron CL:0000540

Show evidence (1 reference)

PMID:24692354 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability."

States what ganglioside deficiency does to neurons, from mouse genetics and other human ganglioside disorders. Marked INDIRECT because the inference to this disease's encephalopathy is a step the source does not take.

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Pathograph

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Phenotypes

13

Blood 3

Macrothrombocytopenia HP:0040185

Show evidence (2 references)

PMID:27387429 SUPPORT BACKGROUND Human Clinical

"characterized by macrothrombocytopenia, neutropenia and complete lack of the sialyl-Lex antigen"

Names macrothrombocytopenia as a defining feature of the disorder. Marked BACKGROUND because this 2016 paper is restating the authors' 2005 clinical description rather than reporting a new patient.

PMID:28856833 REFUTE DIRECT Human Clinical

"Macrothrombocytopenia | Yes | Yes | No"

Table I row across the three reported patients, in the order first, second, third: the third patient's cell reads No, not NR, so this is an assessed absence rather than an unreported feature. DIRECT because the row names this phenotype itself.

Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:27387429 SUPPORT BACKGROUND Human Clinical

"macrothrombocytopenia, neutropenia and complete lack of the sialyl-Lex antigen"

Names neutropenia among the defining features. Marked BACKGROUND for the same reason as the macrothrombocytopenia item: the sentence restates the 2005 report.

Abnormal bleeding HP:0001892

Show evidence (2 references)

PMID:23873973 SUPPORT Human Clinical

"The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter."

Records the bleeding diathesis and, in the same sentence, its combination with the neurological presentation in one patient.

PMID:28856833 REFUTE INDIRECT Human Clinical

"She has never had coagulation abnormalities nor issues with infections"

The third patient is stated to have had no coagulation abnormalities, and Table I records her Coagulopathy cell as No rather than NR. Graded REFUTE as an assessed negative in that patient, and INDIRECT because the sentence denies the coagulopathy this phenotype bundles rather than bleeding events themselves.

Head and Neck 2

Microcephaly OCCASIONAL HP:0000252

Show evidence (1 reference)

PMID:28856833 SUPPORT Human Clinical

"This patient showed macrothrombocytopenia and severe neurological problems including microcephaly, severe developmental disability, hypotonia and seizures"

Records microcephaly in the second patient.

Dysmorphic features OCCASIONAL Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:28856833 SUPPORT Human Clinical

"Dysmorphic features | NR | Yes | No"

Table I row across the three reported patients, in the order first, second, third: dysmorphic features are present in the second, explicitly absent in the third, and not reported in the first. That is the same Yes/No/NR shape that carries the OCCASIONAL frequency on Microcephaly above.

Immune 1

Recurrent infections HP:0002719

Show evidence (2 references)

PMID:27387429 SUPPORT INDIRECT BACKGROUND Human Clinical

"neutropenia and complete lack of the sialyl-Lex antigen (NeuAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc-R) on polymorphonuclear cells"

Records the two neutrophil defects. Marked INDIRECT because the quote establishes the adhesion-ligand loss and the low count rather than stating an infection rate, and the susceptibility follows from them by inference.

PMID:28856833 REFUTE DIRECT Human Clinical

"She has never had coagulation abnormalities nor issues with infections"

The third patient is stated to have had no problems with infection. Graded REFUTE because it is an assessed negative for this phenotype in that patient rather than a silent cell in the comparison table, and DIRECT because the sentence is about infection itself rather than about a predisposing defect.

Metabolism 1

Type II transferrin isoform profile HP:0012301

Show evidence (2 references)

PMID:26307094 SUPPORT Human Clinical

"Diagnostic screening of the congenital disorders of glycosylation (CDG) generally involves isoelectric focusing of plasma transferrin, a robust method easily integrated in medical laboratories."

Establishes transferrin glycoform analysis as the first-line CDG screen. The sentence naming SLC35A1-CDG among the CDG-II defects this assay resolves could not be quoted: it carries each subtype as a bracketed span, and the reference validator strips bracketed spans from the query side but not from the cached text, so a verbatim quote of it fails to match (dismech#10192). The type II assignment for this disease is carried by the next evidence item instead.

PMID:15576474 SUPPORT In Vitro

"We conclude that this defect is a new type of congenital disorder of glycosylation (CDG) of type IIf affecting the transport of CMP-sialic acid into the Golgi apparatus."

Assigns this disease to CDG type II, which is what determines the transferrin pattern the screen above detects.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:28856833 SUPPORT Human Clinical

"This patient showed macrothrombocytopenia and severe neurological problems including microcephaly, severe developmental disability, hypotonia and seizures"

Records hypotonia in the second patient. This is also the sentence that establishes that the hematologic and neurological arms co-occur, which is why the entry no longer treats them as mutually exclusive.

Nervous System 5

Encephalopathy HP:0001298

Show evidence (1 reference)

PMID:28856833 SUPPORT Human Clinical

"Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities."

Documents the neurological presentation and, in the same sentence, the absence of the hematologic features, which is what makes the two branches separable.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:28856833 SUPPORT INDIRECT Human Clinical

"We performed exome sequencing on an individual with a profound neurological presentation"

The abstract characterises the presentation as profoundly neurological without enumerating its components, so this is marked INDIRECT: developmental delay is part of that presentation as described in the paper body rather than a term the abstract uses.

Seizure HP:0001250

Show evidence (1 reference)

PMID:23873973 SUPPORT Human Clinical

"To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation."

Lists seizures among the presenting features of the patient who has both the neurological and the hematologic arms.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:23873973 SUPPORT Human Clinical

"The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter."

The authors' own summary of the neurological presentation, which names ataxia first and, in the same sentence, records its combination with bleeding diathesis.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:23873973 SUPPORT Human Clinical

"To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation."

Lists intellectual disability among the presenting features.

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Genetic Associations

1

SLC35A1

Gene: SLC35A1 hgnc:11021 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:15576474 SUPPORT In Vitro

"No complementation was obtained with either of the 2 patient alleles, whereas full restoration of the sialylated phenotype was obtained in the Lec2 cells transfected with the corresponding human wild-type transcript."

The complementation result that establishes causality: neither patient allele restores sialylation and the wild-type transcript does.

PMID:28856833 REFUTE Human Clinical

"Furthermore, later work from another laboratory determined one of the two variants identified by Martinez et al is very likely benign, since it was reported to be in the homozygous state in at least six unrelated healthy individuals"

Graded REFUTE against the claim that the index patient's reported pair are both pathogenic. It does not dispute that the index patient had the disease, only the validity of one of the two alleles assigned to it.

PMID:23873973 SUPPORT Human Clinical

"Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents."

The second patient's genotype, homozygous missense with confirmed parental heterozygosity. This is the genotype that refutes any correlation between allele class and which clinical arm appears.

+ 1 more reference

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External Assertions

1

OMIM congenital disorder of glycosylation type IIf record

OMIM disease record OMIM:603585

OMIM phenotype record for CDG-IIf, taken from MONDO's own cross-reference for MONDO:0011342 rather than from the deep-research report, which gave no OMIM number. Recorded here rather than under `mappings:` because the schema's DiseaseMappings container has only a mondo_mappings slot with no OMIM mapping slot.

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Medical Actions

2

Supportive Management

Action: Supportive Care NCIT:C15747

Platform: Other

No targeted or curative therapy exists. Management is symptomatic: transfusion and bleeding precautions for thrombocytopenia, infection prophylaxis and treatment, anti-seizure medication, and developmental therapies.

Sialidase Inhibition

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

A candidate strategy, not a treatment. Because the thrombocytopenia is driven in part by clearance of desialylated platelets, inhibiting the sialidase that strips the sialic acid is mechanistically rational. Sialidase inhibitors improved antibody-mediated thrombocytopenia in mice, but that was in immune thrombocytopenia, where the desialylation is enzymatic and reversible. In SLC35A1-CDG the platelets were never sialylated in the first place, so it is not obvious that blocking a sialidase would help. It has never been tested in this disorder.

Show evidence (1 reference)

PMID:26185093 SUPPORT INDIRECT Model Organism

"sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice"

The only evidence for this strategy, and it is in a different disease. Marked INDIRECT: transferring it to SLC35A1-CDG requires assuming a sialidase-inhibition benefit in a disorder where the sialylation never happened, which is a substantial inferential step and the reason this is curated as a candidate rather than a treatment.

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Biochemical Markers

2

Serum transferrin glycoform analysis (PRESENT)

Pathograph Readouts

Readout Of Global Hyposialylation of Glycoconjugates Present Absent

Transferrin is a serum glycoprotein whose sialylation state is directly readable, so its glycoform profile is a systemic readout of the hyposialylation node.

Show evidence (1 reference)

PMID:26307094 SUPPORT Human Clinical

"Moreover, in the group of Golgi trafficking defects and unsolved CDG-II patients, distinct profiles were observed, which facilitate identification of the specific CDG subtype."

Establishes that the transferrin glycoform profile resolves Golgi glycosylation defects into subtype-specific patterns, which is what makes it a readout of the hyposialylation node rather than only a screen.

Sialyl-Lewis-x on polymorphonuclear cells (ABSENT)

Pathograph Readouts

Readout Of Loss of Leukocyte Sialyl-Lewis-x Present Absent

Flow-cytometric detection of the antigen on polymorphonuclear cells is the direct measurement of the node it points at.

Show evidence (1 reference)

PMID:27387429 SUPPORT BACKGROUND Human Clinical

"complete lack of the sialyl-Lex antigen (NeuAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc-R) on polymorphonuclear cells"

The measurement in the index patient, on the cell type the node names. Cited to the 2016 paper's introduction, which restates the authors' own 2005 finding as a clinical observation. The 2005 abstract mentions the patient's sialyl-Lewis-x deficiency only inside the sentence describing the Lec2 complementation experiment, so quoting it there would grade a human observation as the in vitro assay it was a premise of.

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Diagnosis

1

Transferrin glycoform screen followed by molecular confirmation

Type II transferrin pattern on isoelectric focusing, capillary zone electrophoresis or intact-transferrin mass spectrometry, then biallelic SLC35A1 variants on exome, genome or a CDG panel. Complementation assay in CMP-sialic-acid-transport-deficient Lec2 cells can functionally confirm a novel variant, which is how the index alleles were established.

Show evidence (1 reference)

PMID:15576474 SUPPORT In Vitro

"These cells were used in complementation studies to test the activity of the 2 CMP-sialic acid transporter cDNA alleles of a patient devoid of sialyl-Le(x) expression on polymorphonuclear cells."

Describes the functional confirmation assay available for novel variants.

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Prevalence

1

Worldwide, reported cases

Cases In Literature Ultra Rare

Ultra-rare. The 2017 report describes its subject as the third patient with proven SLC35A1-CDG and tabulates all three, which is the full published series at that point. No population prevalence has been estimated and none is asserted here; an earlier version of this note said "fewer than ten reported worldwide", which no cited source supports.

Show evidence (1 reference)

PMID:28856833 SUPPORT Human Clinical

"the third patient with CMP-sialic acid transporter deficiency"

The only patient count available in the literature for this disorder.

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Animal Models

1

Platelet and megakaryocyte-specific Slc35a1 conditional knockout mouse

A conditional knockout with sialylation reduced specifically in megakaryocytes and platelets. Its major phenotype is thrombocytopenia, produced by both reduced and immature bone marrow megakaryocytes and increased hepatic clearance of desialylated platelets.

Species

Mouse

Genotype

Plt Slc35a1 conditional knockout (Slc35a1 floxed, megakaryocyte/platelet-restricted deletion)

Publication

PMID:32303557

Pathograph links

Impaired Megakaryocytopoiesis recapitulates fidelity: high observes: cellular Reproduces the production arm of the thrombocytopenia directly, in the cell type the node names.

Limitations: The deletion is restricted to the megakaryocyte and platelet lineage, so the model tests the consequence of hyposialylation in those cells rather than the systemic transporter deficiency the human disease has.

Readouts

Bone marrow megakaryocyte number and maturation

Direction: DECREASED

Interpretation: Direct histological measurement of the production defect.

Show evidence (1 reference)

PMID:32303557 SUPPORT Model Organism

"megakaryocyte maturation was also impaired"

Reports the maturation defect this readout measures.

Show evidence (1 reference)

PMID:32303557 SUPPORT Model Organism

"The major phenotype of Plt Slc35a1–/– mice was thrombocytopenia."

Names the model's principal phenotype, establishing it as informative for the thrombocytopenia mechanism this link points at.

Platelet Desialylation and Hepatic Clearance recapitulates fidelity: high observes: cellular Reproduces the clearance arm, identifying hepatic Kupffer cells as the clearing population.

Limitations: The clearing cell identified here is the Kupffer cell. The hepatocyte Ashwell-Morell route invoked for desialylated platelets generally is not tested by this model, so the two routes are not distinguished for this disease.

Show evidence (1 reference)

PMID:32303557 SUPPORT Model Organism

"an increased number of desialylated platelets was cleared by Küpffer cells in the liver"

Reports the hepatic clearance this link claims the model recapitulates, with the clearing cell type named.

Deficient Brain Sialoglycan Synthesis fails to recapitulate fidelity: low observes: cellular The model cannot address the neurological branch at all, because the deletion is restricted to the megakaryocyte and platelet lineage.

Limitations: Deletion is confined to megakaryocytes and platelets, so neurons retain normal sialylation and no brain sialoglycan deficiency is produced. No animal or cellular model reproducing the encephalopathy of SLC35A1-CDG has been reported, which is the main gap in the mechanistic evidence for the neurological branch.

Show evidence (1 reference)

PMID:32303557 SUPPORT Model Organism

"using a mouse line with significantly reduced sialylation in megakaryocytes and platelets"

States the tissue restriction that makes this model structurally unable to address the neurological branch. The negative claim rests on the model's design, not on a negative neurological result, which was never sought.

{ }

Source YAML

click to show

name: SLC35A1-Congenital Disorder of Glycosylation
category: Mendelian
creation_date: "2026-09-14T00:00:00Z"
synonyms:
- SLC35A1-CDG
- CDG-IIf
- CDG type IIf
- congenital disorder of glycosylation type 2F
- CMP-sialic acid transporter deficiency
description: >-
  SLC35A1-CDG is an autosomal recessive type II congenital disorder of glycosylation caused
  by biallelic loss of function of SLC35A1, the only known Golgi CMP-sialic acid transporter.
  The transporter imports the activated sialic acid donor CMP-Neu5Ac from the cytosol into
  the Golgi lumen, where sialyltransferases use it to cap N-glycans, O-glycans and
  glycolipids. When it fails, the cell makes globally hyposialylated glycoconjugates even
  though cytosolic sialic acid synthesis is intact.

  **The lesion is in delivery, not in supply, and that has a therapeutic consequence.**
  Several CDG subtypes respond to oral monosaccharide supplementation, because the missing
  sugar can be pushed in from the diet. Sialic acid supplementation cannot bypass an
  SLC35A1 defect: the cell already has sialic acid, and what has failed is the step that
  moves the activated donor across the Golgi membrane. This is why an otherwise analogous
  disorder has no dietary treatment.

  **One upstream lesion, two mechanistic branches, and they are not mutually exclusive.** The
  hyposialylation node branches into a hematologic arm (platelet desialylation and clearance,
  impaired megakaryocytopoiesis, loss of the leukocyte sialyl-Lewis-x ligand) and a
  neurological arm (deficient brain sialoglycans). The branch structure is mechanistic. It is
  *not* a claim that patients fall into two camps, and this entry previously made that
  mistake.

  Only three patients with proven SLC35A1-CDG are on record, and the published comparison of
  all three settles the point. Patient 1 (2005) is reported with macrothrombocytopenia and
  coagulopathy, with every neurological feature listed as *not reported* rather than absent.
  Patient 2 (2013) has both arms: intellectual disability, seizures, ataxia, microcephaly and
  hypotonia alongside macrothrombocytopenia and coagulopathy. Patient 3 (2017) has the
  neurological arm with explicitly no hematological abnormality. So one of three patients has
  both, one has one arm with the other unassessed, and one has a single arm.

  **No genotype-to-branch correlation survives those three patients.** Patient 2, who has
  both arms, is homozygous for a missense allele (p.Gln101His) with 50% residual transport -
  the mildest reported genotype and the broadest reported phenotype. An earlier version of
  this entry proposed that truncating alleles track with the hematologic picture and
  hypomorphic missense with the neurological one; Patient 2 refutes it, and no such
  correlation is asserted here.

  One missense allele has a second mechanism beyond reduced transport: p.Glu196Lys, but not
  p.Thr156Arg, disrupts the physical association between SLC35A1 and the sialyltransferase
  ST3Gal4. So the same gene produces sialylation failure by two routes, and one allele uses
  both.
disease_term:
  preferred_term: SLC35A1-congenital disorder of glycosylation
  term:
    id: MONDO:0011342
    label: SLC35A1-congenital disorder of glycosylation
parents:
- Congenital Disorder of Glycosylation
references:
- reference: PMID:15576474
  title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
- reference: PMID:23873973
  title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
- reference: PMID:24692354
  title: "Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration."
- reference: PMID:26185093
  title: Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
- reference: PMID:26307094
  title: High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation.
- reference: PMID:27387429
  title: A functional splice variant of the human Golgi CMP-sialic acid transporter.
- reference: PMID:28856833
  title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
- reference: PMID:32303557
  title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
- reference: PMID:34384782
  title: A three-pocket model for substrate coordination and selectivity by the nucleotide sugar transporters SLC35A1 and SLC35A2.
- reference: PMID:36257191
  title: An interaction between SLC35A1 and ST3Gal4 is differentially affected by CDG-causing mutations in the SLC35A1 gene.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic SLC35A1 variants. The index patient was compound heterozygous for two
    truncating alleles; the third reported patient was compound heterozygous for two missense
    alleles. Heterozygous carriers are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:15576474
    reference_title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The inactivation of one patient allele by a double microdeletion inducing a premature stop codon at position 327 and a splice mutation of the other allele inducing a 130-base pair (bp) deletion and a premature stop codon at position 684 are proposed to be the causal defects of this disease."
    explanation: >-
      Documents the biallelic architecture in the index patient, with a distinct
      loss-of-function change on each allele.
genetic:
- name: SLC35A1
  gene_term:
    preferred_term: SLC35A1
    term:
      id: hgnc:11021
      label: SLC35A1
  relationship_type: CAUSATIVE
  notes: >-
    Encodes the only known Golgi CMP-sialic acid transporter, a multipass nucleotide-sugar
    transporter of the SLC35 family. Reported disease alleles across the three proven
    patients are the index patient's pair, homozygous p.Gln101His in the second, and
    p.Thr156Arg with p.Glu196Lys in the third. Structure-guided mutagenesis has mapped three
    substrate pockets in the central cavity, which is the framework in which missense
    alleles' effects on transport are interpreted.

    One caveat on the index genotype: later work found that one of the two variants reported
    in 2005 is very likely benign, having been seen homozygous in at least six unrelated
    healthy individuals. The index patient's molecular diagnosis therefore rests on less than
    the original report implies, and this entry does not treat that genotype as an
    established truncating pair.
  evidence:
  - reference: PMID:15576474
    reference_title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "No complementation was obtained with either of the 2 patient alleles, whereas full restoration of the sialylated phenotype was obtained in the Lec2 cells transfected with the corresponding human wild-type transcript."
    explanation: >-
      The complementation result that establishes causality: neither patient allele restores
      sialylation and the wild-type transcript does.
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, later work from another laboratory determined one of the two variants identified by Martinez et al is very likely benign, since it was reported to be in the homozygous state in at least six unrelated healthy individuals"
    explanation: >-
      Graded REFUTE against the claim that the index patient's reported pair are both
      pathogenic. It does not dispute that the index patient had the disease, only the
      validity of one of the two alleles assigned to it.
  - reference: PMID:23873973
    reference_title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents."
    explanation: >-
      The second patient's genotype, homozygous missense with confirmed parental
      heterozygosity. This is the genotype that refutes any correlation between allele class
      and which clinical arm appears.
  - reference: PMID:34384782
    reference_title: A three-pocket model for substrate coordination and selectivity by the nucleotide sugar transporters SLC35A1 and SLC35A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results suggest that three pockets in the central cavity of each transporter provide substrate specificity."
    explanation: >-
      Gives the structural framework used to interpret where missense alleles sit and why
      they reduce rather than abolish transport.
pathophysiology:
- name: SLC35A1 Transporter Loss of Function
  description: >-
    Biallelic SLC35A1 variants leave the cell without a working Golgi CMP-sialic acid
    transporter. Truncating alleles abolish the protein; the reported missense alleles
    reduce transport rather than abolishing it, which is the likely reason their carriers
    present differently.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: CMP-N-acetylneuraminate transmembrane transporter activity
    term:
      id: GO:0005456
      label: CMP-N-acetylneuraminate transmembrane transporter activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
  downstream:
  - target: Golgi CMP-Sialic Acid Donor Depletion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28856833
      reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Direct measurement of CMP-sialic acid transport into the Golgi showed a substantial decrease in overall rate of transport."
      explanation: >-
        Measures the transport step itself in patient material, which is the edge from the
        genetic lesion to donor depletion rather than either node alone.
  evidence:
  - reference: PMID:15576474
    reference_title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conclude that this defect is a new type of congenital disorder of glycosylation (CDG) of type IIf affecting the transport of CMP-sialic acid into the Golgi apparatus."
    explanation: The original identification of the transporter defect as the disease lesion.
- name: Golgi CMP-Sialic Acid Donor Depletion
  description: >-
    The Golgi lumen is deprived of CMP-Neu5Ac, the activated donor every sialyltransferase
    requires. Cytosolic sialic acid synthesis is unaffected, so the cell is not short of
    sialic acid; it is short of sialic acid in the compartment where it is used. That
    distinction is what makes dietary sialic acid an ineffective strategy here.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
  downstream:
  - target: Global Hyposialylation of Glycoconjugates
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32303557
    reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Slc35a1 encodes the cytidine-5'-monophosphate (CMP)-sialic acid transporter that transports CMP-sialic acid from the cytoplasm into the Golgi apparatus for sialylation."
    explanation: >-
      States the transported species and its destination compartment, which is what this node
      claims is depleted. Marked BACKGROUND because the sentence opens the mouse study's
      abstract as a statement of what the gene encodes, not as one of its results. Graded
      OTHER rather than MODEL_ORGANISM for the same reason: no animal experiment established
      what the transporter carries, so MODEL_ORGANISM would assert that this mouse study
      measured it. IN_VITRO is not used either, because the cited paper does not say where the
      fact was established and this entry does not grade a source on unstated provenance.
- name: Global Hyposialylation of Glycoconjugates
  description: >-
    Without the donor, sialyltransferases cannot cap glycans, and N-glycans, O-glycans and
    glycolipids across the cell are left without their terminal sialic acid. The p.Glu196Lys
    allele adds a second route to the same endpoint by decoupling the transporter from the
    sialyltransferase ST3Gal4.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: sialylation
    term:
      id: GO:0097503
      label: sialylation
    modifier: DECREASED
  downstream:
  - target: Platelet Desialylation and Hepatic Clearance
    causal_link_type: DIRECT
  - target: Impaired Megakaryocytopoiesis
    causal_link_type: DIRECT
  - target: Loss of Leukocyte Sialyl-Lewis-x
    causal_link_type: DIRECT
  - target: Deficient Brain Sialoglycan Synthesis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid."
    explanation: Direct measurement of the hyposialylation in patient material, across both glycan classes.
  - reference: PMID:36257191
    reference_title: An interaction between SLC35A1 and ST3Gal4 is differentially affected by CDG-causing mutations in the SLC35A1 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We showed that SLC35A1 associates with ST3Gal4, the main α2,3-sialyltransferase acting on N-glycans. This phenomenon is compromised by the E196K (but not T156R) mutation in the SLC35A1 gene."
    explanation: >-
      Establishes the second, allele-specific route to hyposialylation, and the contrast with
      the other missense allele that makes it allele-specific rather than general.
- name: Platelet Desialylation and Hepatic Clearance
  description: >-
    Loss of terminal sialic acid on platelet surface glycoproteins exposes the subterminal
    galactose that hepatic clearance receptors recognise, so circulating platelets are
    removed by the liver. In the conditional mouse the clearing cells are hepatic Kupffer
    cells. The hepatocyte Ashwell-Morell receptor route is established for desialylated
    platelets in immune thrombocytopenia and is the mechanism generally invoked here; it has
    not been shown directly in SLC35A1-CDG, so the evidence for that step is marked indirect.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  evidence:
  - reference: PMID:32303557
    reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, an increased number of desialylated platelets was cleared by Küpffer cells in the liver of Plt Slc35a1–/– mice."
    explanation: >-
      Demonstrates hepatic clearance of desialylated platelets in the Slc35a1 conditional
      knockout, and names Kupffer cells as the clearing population. This is the animal
      evidence for the clearance arm of this node.
  - reference: PMID:26185093
    reference_title: Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell receptors, which is fundamentally different from the classical Fc-FcγR-dependent macrophage phagocytosis."
    explanation: >-
      Establishes the desialylation-to-hepatic-clearance mechanism, but in immune
      thrombocytopenia rather than in SLC35A1-CDG. Marked INDIRECT because applying it here
      requires the inference that platelets desialylated by a transporter defect are cleared
      the same way as platelets desialylated by antibody-triggered sialidase translocation.
- name: Impaired Megakaryocytopoiesis
  description: >-
    Hyposialylation also acts upstream of the circulating platelet, on its production. The
    conditional mouse shows both fewer bone marrow megakaryocytes and impaired maturation of
    the ones present, so the thrombocytopenia is a production defect as well as a clearance
    defect.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:32303557
    reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "megakaryocyte maturation was also impaired"
    explanation: >-
      The production arm of the thrombocytopenia mechanism, distinct from the clearance arm
      recorded on the neighbouring node.
- name: Loss of Leukocyte Sialyl-Lewis-x
  description: >-
    Sialyl-Lewis-x is the selectin ligand that lets leukocytes roll on and adhere to
    activated endothelium, and its terminal sialic acid is not optional: without
    sialylation the ligand is not made. Its complete absence on polymorphonuclear cells was
    the finding that identified the index patient, and it makes the infection susceptibility
    an adhesion defect on top of the neutropenia rather than a consequence of low counts
    alone.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:27387429
    reference_title: A functional splice variant of the human Golgi CMP-sialic acid transporter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by macrothrombocytopenia, neutropenia and complete lack of the sialyl-Lex antigen"
    explanation: >-
      Records the complete absence of the sialyl-Lewis-x antigen on polymorphonuclear cells.
      Marked BACKGROUND because the sentence is this 2016 paper's recapitulation of the
      authors' own 2005 clinical report, not a result of the splice-variant work it reports.
- name: Deficient Brain Sialoglycan Synthesis
  description: >-
    The brain's two major sialoglycan families, gangliosides and polysialic acid on NCAM,
    both require the same Golgi donor. Their deficiency is the proposed basis of the
    neurological branch. This step is an inference from what these glycans are known to
    require and to do, not a measurement made in an SLC35A1-CDG brain, and no model
    reproducing the encephalopathy has been reported.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: ganglioside biosynthetic process
    term:
      id: GO:0001574
      label: ganglioside biosynthetic process
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Impaired Neuronal Connectivity and Excitability
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24692354
    reference_title: "Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid."
    explanation: >-
      Identifies the two brain sialoglycan families whose synthesis this node claims is
      deficient. Marked INDIRECT and REVIEW_SYNTHESIS: it is a review establishing what these
      glycans are, from which the deficiency in a sialylation-donor defect follows by
      inference rather than by measurement in this disease.
- name: Impaired Neuronal Connectivity and Excitability
  description: >-
    Ganglioside deficiency is linked to disturbed axon-myelin interactions, axon stability
    and nerve cell excitability; polysialic acid deficiency to disturbed neurite outgrowth
    and synaptic connectivity. Together these are the proposed substrate of the
    developmental delay, hypotonia, seizures and encephalopathy seen in the neurological
    presentation.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:24692354
    reference_title: "Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability."
    explanation: >-
      States what ganglioside deficiency does to neurons, from mouse genetics and other human
      ganglioside disorders. Marked INDIRECT because the inference to this disease's
      encephalopathy is a step the source does not take.
phenotypes:
- category: Hematologic
  name: Macrothrombocytopenia
  description: >-
    Low platelet count with abnormally large platelets. Reported in two of the three known
    patients, including the one who also has the full neurological picture; absent in the
    third.
  phenotype_term:
    preferred_term: Macrothrombocytopenia
    term:
      id: HP:0040185
      label: Macrothrombocytopenia
  evidence:
  - reference: PMID:27387429
    reference_title: A functional splice variant of the human Golgi CMP-sialic acid transporter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by macrothrombocytopenia, neutropenia and complete lack of the sialyl-Lex antigen"
    explanation: >-
      Names macrothrombocytopenia as a defining feature of the disorder. Marked BACKGROUND
      because this 2016 paper is restating the authors' 2005 clinical description rather than
      reporting a new patient.
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Macrothrombocytopenia | Yes | Yes | No"
    explanation: >-
      Table I row across the three reported patients, in the order first, second, third: the
      third patient's cell reads No, not NR, so this is an assessed absence rather than an
      unreported feature. DIRECT because the row names this phenotype itself.
- category: Hematologic
  name: Decreased total neutrophil count
  description: >-
    Neutropenia, reported in the index patient alongside macrothrombocytopenia and absent
    sialyl-Lewis-x.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:27387429
    reference_title: A functional splice variant of the human Golgi CMP-sialic acid transporter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "macrothrombocytopenia, neutropenia and complete lack of the sialyl-Lex antigen"
    explanation: >-
      Names neutropenia among the defining features. Marked BACKGROUND for the same reason as
      the macrothrombocytopenia item: the sentence restates the 2005 report.
- category: Immunologic
  name: Recurrent infections
  description: >-
    Susceptibility to infection following from two findings reported together in the index
    patient: the neutropenia, and the complete absence of the sialyl-Lewis-x selectin ligand
    needed for leukocyte rolling and adhesion. The cited sentence names those two findings
    rather than the infections themselves, so this is the consequence they predict and not a
    separately reported outcome. The third patient is separately reported as having had no
    trouble with infections, which is an assessed absence rather than an unreported feature.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:27387429
    reference_title: A functional splice variant of the human Golgi CMP-sialic acid transporter.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "neutropenia and complete lack of the sialyl-Lex antigen (NeuAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc-R) on polymorphonuclear cells"
    explanation: >-
      Records the two neutrophil defects. Marked INDIRECT because the quote establishes the
      adhesion-ligand loss and the low count rather than stating an infection rate, and the
      susceptibility follows from them by inference.
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has never had coagulation abnormalities nor issues with infections"
    explanation: >-
      The third patient is stated to have had no problems with infection. Graded REFUTE
      because it is an assessed negative for this phenotype in that patient rather than a
      silent cell in the comparison table, and DIRECT because the sentence is about infection
      itself rather than about a predisposing defect.
- category: Neurologic
  name: Encephalopathy
  description: >-
    Severe encephalopathy, the dominant feature in the third reported patient, who had no
    hematological abnormality. A neurological picture also occurs alongside the hematologic
    one in the second patient, so its presence does not imply the hematologic arm is spared.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities."
    explanation: >-
      Documents the neurological presentation and, in the same sentence, the absence of the
      hematologic features, which is what makes the two branches separable.
- category: Neurologic
  name: Global developmental delay
  description: Part of the neurological presentation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed exome sequencing on an individual with a profound neurological presentation"
    explanation: >-
      The abstract characterises the presentation as profoundly neurological without
      enumerating its components, so this is marked INDIRECT: developmental delay is part of
      that presentation as described in the paper body rather than a term the abstract uses.
- category: Neurologic
  name: Seizure
  description: Seizures, reported in the two patients with a neurological presentation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:23873973
    reference_title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation."
    explanation: >-
      Lists seizures among the presenting features of the patient who has both the
      neurological and the hematologic arms.
- category: Neurologic
  name: Ataxia
  description: Ataxia, part of the neurological presentation in both neurologically affected patients.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:23873973
    reference_title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter."
    explanation: >-
      The authors' own summary of the neurological presentation, which names ataxia first
      and, in the same sentence, records its combination with bleeding diathesis.
- category: Neurologic
  name: Intellectual disability
  description: Intellectual or developmental disability, reported in both neurologically affected patients.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:23873973
    reference_title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation."
    explanation: Lists intellectual disability among the presenting features.
- category: Neurologic
  name: Hypotonia
  description: >-
    Hypotonia, tabulated in both neurologically affected patients and not reported in the
    index patient.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient showed macrothrombocytopenia and severe neurological problems including microcephaly, severe developmental disability, hypotonia and seizures"
    explanation: >-
      Records hypotonia in the second patient. This is also the sentence that establishes
      that the hematologic and neurological arms co-occur, which is why the entry no longer
      treats them as mutually exclusive.
- category: Neurologic
  name: Microcephaly
  description: Microcephaly, reported in the second patient and explicitly absent in the third.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient showed macrothrombocytopenia and severe neurological problems including microcephaly, severe developmental disability, hypotonia and seizures"
    explanation: Records microcephaly in the second patient.
- category: Craniofacial
  name: Dysmorphic features
  description: >-
    Dysmorphic features, reported in the second patient and explicitly absent in the third.
    The report does not characterise them beyond the word, so the binding is the general
    HPO term rather than any named facial feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dysmorphic features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic features | NR | Yes | No"
    explanation: >-
      Table I row across the three reported patients, in the order first, second, third:
      dysmorphic features are present in the second, explicitly absent in the third, and not
      reported in the first. That is the same Yes/No/NR shape that carries the OCCASIONAL
      frequency on Microcephaly above.
- category: Hematologic
  name: Abnormal bleeding
  description: >-
    Bleeding diathesis with coagulopathy, reported alongside the macrothrombocytopenia in the
    first two patients and assessed as absent in the third.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:23873973
    reference_title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter."
    explanation: >-
      Records the bleeding diathesis and, in the same sentence, its combination with the
      neurological presentation in one patient.
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has never had coagulation abnormalities nor issues with infections"
    explanation: >-
      The third patient is stated to have had no coagulation abnormalities, and Table I
      records her Coagulopathy cell as No rather than NR. Graded REFUTE as an assessed
      negative in that patient, and INDIRECT because the sentence denies the coagulopathy
      this phenotype bundles rather than bleeding events themselves.
- category: Laboratory
  name: Type II transferrin isoform profile
  description: >-
    The first-line biochemical screen. SLC35A1-CDG produces a type II pattern on transferrin
    glycoform analysis, reflecting defective processing of glycans that were assembled
    normally, rather than the whole-glycan loss of the type I CDGs.
  diagnostic: true
  phenotype_term:
    preferred_term: Type II transferrin isoform profile
    term:
      id: HP:0012301
      label: Type II transferrin isoform profile
  evidence:
  - reference: PMID:26307094
    reference_title: High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnostic screening of the congenital disorders of glycosylation (CDG) generally involves isoelectric focusing of plasma transferrin, a robust method easily integrated in medical laboratories."
    explanation: >-
      Establishes transferrin glycoform analysis as the first-line CDG screen. The sentence
      naming SLC35A1-CDG among the CDG-II defects this assay resolves could not be quoted:
      it carries each subtype as a bracketed span, and the reference validator strips
      bracketed spans from the query side but not from the cached text, so a verbatim quote
      of it fails to match (dismech#10192). The type II assignment for this disease is
      carried by the next evidence item instead.
  - reference: PMID:15576474
    reference_title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conclude that this defect is a new type of congenital disorder of glycosylation (CDG) of type IIf affecting the transport of CMP-sialic acid into the Golgi apparatus."
    explanation: >-
      Assigns this disease to CDG type II, which is what determines the transferrin pattern
      the screen above detects.
prevalence:
- population: Worldwide, reported cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare. The 2017 report describes its subject as the third patient with proven
    SLC35A1-CDG and tabulates all three, which is the full published series at that point.
    No population prevalence has been estimated and none is asserted here; an earlier version
    of this note said "fewer than ten reported worldwide", which no cited source supports.
  evidence:
  - reference: PMID:28856833
    reference_title: "Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the third patient with CMP-sialic acid transporter deficiency"
    explanation: The only patient count available in the literature for this disorder.
biochemical:
- name: Serum transferrin glycoform analysis
  presence: PRESENT
  notes: >-
    Isoelectric focusing, capillary zone electrophoresis or high-resolution intact-transferrin
    mass spectrometry. A type II pattern indicates a Golgi processing defect and directs the
    workup to the CDG-II subtypes; mass spectrometry can distinguish SLC35A1-CDG among them.
  readouts:
  - target: Global Hyposialylation of Glycoconjugates
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    interpretation: >-
      Transferrin is a serum glycoprotein whose sialylation state is directly readable, so
      its glycoform profile is a systemic readout of the hyposialylation node.
    evidence:
    - reference: PMID:26307094
      reference_title: High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Moreover, in the group of Golgi trafficking defects and unsolved CDG-II patients, distinct profiles were observed, which facilitate identification of the specific CDG subtype."
      explanation: >-
        Establishes that the transferrin glycoform profile resolves Golgi glycosylation
        defects into subtype-specific patterns, which is what makes it a readout of the
        hyposialylation node rather than only a screen.
- name: Sialyl-Lewis-x on polymorphonuclear cells
  presence: ABSENT
  notes: >-
    Complete absence of the sialyl-Lewis-x antigen on polymorphonuclear cells is the
    distinctive biochemical finding in the index patient, and was what led to identification
    of the disorder. The three-patient comparison table in PMID:28856833 carries no row for
    it, so nothing is known about whether it is present in the two later patients.
  readouts:
  - target: Loss of Leukocyte Sialyl-Lewis-x
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    interpretation: >-
      Flow-cytometric detection of the antigen on polymorphonuclear cells is the direct
      measurement of the node it points at.
    evidence:
    - reference: PMID:27387429
      reference_title: "A functional splice variant of the human Golgi CMP-sialic acid transporter."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "complete lack of the sialyl-Lex antigen (NeuAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc-R) on polymorphonuclear cells"
      explanation: >-
        The measurement in the index patient, on the cell type the node names. Cited to the
        2016 paper's introduction, which restates the authors' own 2005 finding as a clinical
        observation. The 2005 abstract mentions the patient's sialyl-Lewis-x deficiency only
        inside the sentence describing the Lec2 complementation experiment, so quoting it
        there would grade a human observation as the in vitro assay it was a premise of.
animal_models:
- name: Platelet and megakaryocyte-specific Slc35a1 conditional knockout mouse
  species: Mouse
  genotype: Plt Slc35a1 conditional knockout (Slc35a1 floxed, megakaryocyte/platelet-restricted deletion)
  publication: PMID:32303557
  description: >-
    A conditional knockout with sialylation reduced specifically in megakaryocytes and
    platelets. Its major phenotype is thrombocytopenia, produced by both reduced and
    immature bone marrow megakaryocytes and increased hepatic clearance of desialylated
    platelets.
  modeled_mechanisms:
  - target: Impaired Megakaryocytopoiesis
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Reproduces the production arm of the thrombocytopenia directly, in the cell type the
      node names.
    limitations: >-
      The deletion is restricted to the megakaryocyte and platelet lineage, so the model
      tests the consequence of hyposialylation in those cells rather than the systemic
      transporter deficiency the human disease has.
    readouts:
    - name: Bone marrow megakaryocyte number and maturation
      target: Impaired Megakaryocytopoiesis
      direction: DECREASED
      interpretation: Direct histological measurement of the production defect.
      evidence:
      - reference: PMID:32303557
        reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "megakaryocyte maturation was also impaired"
        explanation: Reports the maturation defect this readout measures.
    evidence:
    - reference: PMID:32303557
      reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The major phenotype of Plt Slc35a1–/– mice was thrombocytopenia."
      explanation: >-
        Names the model's principal phenotype, establishing it as informative for the
        thrombocytopenia mechanism this link points at.
  - target: Platelet Desialylation and Hepatic Clearance
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Reproduces the clearance arm, identifying hepatic Kupffer cells as the clearing population.
    limitations: >-
      The clearing cell identified here is the Kupffer cell. The hepatocyte Ashwell-Morell
      route invoked for desialylated platelets generally is not tested by this model, so the
      two routes are not distinguished for this disease.
    evidence:
    - reference: PMID:32303557
      reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "an increased number of desialylated platelets was cleared by Küpffer cells in the liver"
      explanation: >-
        Reports the hepatic clearance this link claims the model recapitulates, with the
        clearing cell type named.
  - target: Deficient Brain Sialoglycan Synthesis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The model cannot address the neurological branch at all, because the deletion is
      restricted to the megakaryocyte and platelet lineage.
    limitations: >-
      Deletion is confined to megakaryocytes and platelets, so neurons retain normal
      sialylation and no brain sialoglycan deficiency is produced. No animal or cellular
      model reproducing the encephalopathy of SLC35A1-CDG has been reported, which is the
      main gap in the mechanistic evidence for the neurological branch.
    evidence:
    - reference: PMID:32303557
      reference_title: Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "using a mouse line with significantly reduced sialylation in megakaryocytes and platelets"
      explanation: >-
        States the tissue restriction that makes this model structurally unable to address
        the neurological branch. The negative claim rests on the model's design, not on a
        negative neurological result, which was never sought.
treatments:
- name: Supportive Management
  description: >-
    No targeted or curative therapy exists. Management is symptomatic: transfusion and
    bleeding precautions for thrombocytopenia, infection prophylaxis and treatment,
    anti-seizure medication, and developmental therapies.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    Recorded without an evidence item quoting a treatment study, because none exists. The
    supportive-care approach is what the reports describe rather than what any trial has
    tested, and no snippet in the cited literature asserts it as a finding.
- name: Sialidase Inhibition
  description: >-
    A candidate strategy, not a treatment. Because the thrombocytopenia is driven in part by
    clearance of desialylated platelets, inhibiting the sialidase that strips the sialic acid
    is mechanistically rational. Sialidase inhibitors improved antibody-mediated
    thrombocytopenia in mice, but that was in immune thrombocytopenia, where the desialylation
    is enzymatic and reversible. In SLC35A1-CDG the platelets were never sialylated in the
    first place, so it is not obvious that blocking a sialidase would help. It has never been
    tested in this disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:26185093
    reference_title: Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice"
    explanation: >-
      The only evidence for this strategy, and it is in a different disease. Marked INDIRECT:
      transferring it to SLC35A1-CDG requires assuming a sialidase-inhibition benefit in a
      disorder where the sialylation never happened, which is a substantial inferential step
      and the reason this is curated as a candidate rather than a treatment.
diagnosis:
- name: Transferrin glycoform screen followed by molecular confirmation
  description: >-
    Type II transferrin pattern on isoelectric focusing, capillary zone electrophoresis or
    intact-transferrin mass spectrometry, then biallelic SLC35A1 variants on exome, genome or
    a CDG panel. Complementation assay in CMP-sialic-acid-transport-deficient Lec2 cells can
    functionally confirm a novel variant, which is how the index alleles were established.
  evidence:
  - reference: PMID:15576474
    reference_title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These cells were used in complementation studies to test the activity of the 2 CMP-sialic acid transporter cDNA alleles of a patient devoid of sialyl-Le(x) expression on polymorphonuclear cells."
    explanation: Describes the functional confirmation assay available for novel variants.
external_assertions:
- name: OMIM congenital disorder of glycosylation type IIf record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:603585
  url: https://omim.org/entry/603585
  description: >-
    OMIM phenotype record for CDG-IIf, taken from MONDO's own cross-reference for
    MONDO:0011342 rather than from the deep-research report, which gave no OMIM number.
    Recorded here rather than under `mappings:` because the schema's DiseaseMappings
    container has only a mondo_mappings slot with no OMIM mapping slot.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:15576474
      reference_title: "Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "a new type of congenital disorder of glycosylation (CDG) of type IIf"
      explanation: Places the disorder among the inherited metabolic glycosylation disorders.
discussions:
- discussion_id: slc35a1_branch_expression_across_patients
  kind: KNOWLEDGE_GAP
  prompt: >-
    What determines whether an SLC35A1-CDG patient expresses the hematologic arm, the
    neurological arm, or both?
  attaches_to:
  - pathophysiology#Global Hyposialylation of Glycoconjugates
  rationale: >-
    Across the three proven patients the arms combine differently: the second has both, the
    third has the neurological arm with explicitly no hematological abnormality, and the
    index patient has the hematologic arm with every neurological feature recorded as *not
    reported* rather than absent. So one of the three data points is an ascertainment gap
    rather than a negative finding, which is a distinction the published comparison table
    makes explicitly and which matters for any attempt to read a pattern off three patients.
    Genotype does not explain the variation: the patient with both arms is homozygous for a
    missense allele retaining 50% of transport activity, which is the mildest reported
    genotype and the broadest reported phenotype.
  notes: >-
    Resolving this needs systematic assessment of both systems in every patient, not only the
    system that prompted referral. The index patient was found through a leukocyte adhesion
    workup and the third through exome sequencing for encephalopathy, and the published table
    shows how much of the resulting picture is "not reported".
- discussion_id: slc35a1_no_neurological_model
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Is the proposed ganglioside and polysialic-acid mechanism actually what produces the
    encephalopathy in SLC35A1-CDG, given that no model of the neurological branch exists?
  attaches_to:
  - pathophysiology#Deficient Brain Sialoglycan Synthesis
  - pathophysiology#Impaired Neuronal Connectivity and Excitability
  rationale: >-
    The hematologic branch has a conditional mouse that reproduces it. The neurological
    branch has no model at all: the existing mouse deletes Slc35a1 only in megakaryocytes and
    platelets, so it cannot develop a brain phenotype. Everything downstream of the
    hyposialylation node on the neurological side rests on what gangliosides and polysialic
    acid are known to do in other settings, plus the observation that a patient with reduced
    Golgi sialic acid transport had an encephalopathy. That is a plausible chain, but no step
    of it has been measured in an SLC35A1-deficient nervous system. Recorded as a
    human-model mismatch rather than a plain knowledge gap because the model-system evidence
    that does exist covers the other branch, and its success there could be mistaken for
    support of the entry as a whole.
  notes: >-
    A neuron-specific or whole-body conditional knockout, or patient-derived neurons, would
    test whether brain sialoglycan deficiency is sufficient for the phenotype.
notes: >-
  Curated from the primary SLC35A1 literature together with an OpenScientist deep-research
  report. Five notes on how the evidence here is graded, since most of it is weaker than a
  reader might assume from how confidently the mechanism reads.

  **The first version of this entry got its central framing wrong, and the correction is
  worth stating.** It claimed the hematologic and neurological presentations were mutually
  exclusive, and built the description, a discussion and two phenotype descriptions on that.
  The claim is refuted by the three-patient comparison table in PMID:28856833, a full text
  this entry already cited: the second patient has both arms, and the index patient's
  neurological features are recorded as *not reported* rather than absent. The branched
  pathograph is kept, because the branches are mechanistic and real, but nothing here now
  claims patients sort into two camps, and the genotype-to-branch correlation the first
  version proposed is contradicted by the patient with the mildest genotype and the broadest
  phenotype.

  **The neurological branch is inference throughout.** Both of its pathophysiology nodes
  carry `directness: INDIRECT` and `quote_role: REVIEW_SYNTHESIS` on their evidence, because
  the only sources are a review of brain sialoglycan biology. Nothing has been measured in an
  SLC35A1-deficient nervous system, and no model exists. See the `HUMAN_MODEL_MISMATCH`
  discussion.

  **The hepatocyte clearance step is borrowed from a different disease.** PMID:26185093
  establishes Ashwell-Morell-mediated clearance of desialylated platelets in immune
  thrombocytopenia, where a sialidase strips sialic acid from platelets that had it. In
  SLC35A1-CDG the platelets were never sialylated. The mechanism is likely the same and the
  item is graded `SUPPORT` with `directness: INDIRECT` to say that explicitly.

  **Six items are `quote_role: BACKGROUND`.** Five of them quote PMID:27387429, a 2016 paper
  on a splice variant of the transporter, whose sentence on the index patient's clinical
  picture is its introduction restating the authors' own 2005 report. Those five stay
  `evidence_source: HUMAN_CLINICAL` because the evidence the sentence describes is a human
  clinical observation; `quote_role` records that this is not the paper that produced it. The
  sixth is a different case. It quotes the mouse study PMID:32303557 for what the transporter
  carries and where it delivers it, which opens that paper's abstract as a statement of what
  the gene encodes rather than as one of its results. It is graded `OTHER`: the sentence
  describes no study of any kind, so `MODEL_ORGANISM` would assert that this mouse work
  measured the transporter's substrate, and `IN_VITRO` would assert a cell-based provenance
  the cited paper never states. `OTHER` plus `BACKGROUND` says exactly what is true - a
  definitional sentence, in a paper that is not where the definition came from.

  **Every snippet is the source's own characters.** Several of these abstracts carry
  non-ASCII characters inside the sentences that matter - an umlaut in "Küpffer", Greek
  letters in the sialyltransferase linkage and the platelet glycoprotein names, en dashes in
  the mouse genotype - and the reference validator normalises all of them, so the quotes are
  verbatim rather than truncated or transliterated. This was checked against the cache
  rather than assumed.

  No GeneReviews chapter exists for SLC35A1-CDG. The CDG overview chapter that PubMed
  returns (PMID:20301507) is marked RETIRED, FOR HISTORICAL REFERENCE ONLY, so it is not
  used as a phenotype baseline.

📚

References & Deep Research

References

10

PMID:15576474

Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter.