Sialuria

Mendelian MONDO:0010028 Pathograph 12 Show in embeddings browser

Sialuria is an ultra-rare autosomal dominant inborn error of sialic acid metabolism, and it is the mechanistic mirror image of the far better known recessive GNE myopathy: both are caused by variants in GNE, the bifunctional UDP-N-acetylglucosamine 2-epimerase / N-acetylmannosamine kinase that runs the first, rate-limiting steps of sialic acid biosynthesis, but where GNE myopathy is a hypomorphic loss of function that starves tissue of sialic acid, sialuria is a gain of function that floods it. The lesion is exquisitely specific. A single heterozygous missense change at the allosteric CMP-N-acetylneuraminic acid (CMP-Neu5Ac) feedback site in the epimerase domain — clustered at two arginine residues, historically numbered Arg263 and Arg266 and now Arg294 and Arg297 — leaves the enzyme catalytically normal but deaf to the end-product feedback that normally shuts it off. The result is a constitutively active epimerase that overproduces free (unconjugated) N-acetylneuraminic acid, which accumulates in the cytoplasm (not the lysosome, which is what separates it from the recessive free sialic acid storage disorders ISSD and Salla disease, caused by SLC17A5) and spills into the urine in gram quantities. Clinically it is a mild and easily missed disorder: mildly coarse facies, hepatomegaly, variable developmental delay, prolonged neonatal jaundice, and recurrent infections in infancy, with substantial improvement over childhood — one of the diagnostic adults was ascertained only because her son was affected. Fewer than a dozen patients have been reported worldwide, and the true prevalence is thought to be grossly underestimated because urinary free sialic acid is not routinely assayed.

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1
Inheritance
6
Pathophys.
11
Phenotypes
1
Hypotheses
12
Pathograph
1
Genes
3
Medical Actions
2
Differentials
2
Models
6
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant. The dominance has a biochemical basis: a single mutant allele produces a constitutively active, feedback-resistant enzyme, which overproduces sialic acid regardless of the normal allele. Most affected individuals were thought to represent new (de novo) mutations; parent-to-child transmission was confirmed in one family, in which the affected mother was diagnosed retrospectively after her son.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:11326336 SUPPORT Human Clinical
"the heterozygous R266Q mutation was detected in the patient's mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, for the first time, the dominant mode of inheritance of this inborn error."
Confirms dominant inheritance through documented vertical transmission.
PMID:11326336 SUPPORT Human Clinical
"sialuria is an autosomal dominant disorder and that affected individuals represent new mutations"
Records the earlier inference that most cases are de novo dominant mutations.
◈

Mechanistic Hypotheses

1
NCAM polysialylation as a route to developmental delay
ncam_polysialylation_delay EMERGING
Evidence balance 1 support
The hypothesis that increased intracellular sialic acid drives increased NCAM polysialylation, which in turn contributes to the developmental delay of sialuria. Support is currently limited to a transgenic mouse and cell models; the transgenic-mouse authors frame it explicitly as a possibility ("could play a role"). No direct human evidence links NCAM polysialylation to the delay.
Pathograph links
Increased NCAM Polysialylation -> Global developmental delay INDIRECT UNKNOWN INTERMEDIATES A proposed link from increased NCAM polysialylation to the neurodevelopmental phenotype, supported so far only by model systems.
Show evidence (1 reference)
PMID:27966821 SUPPORT Model Organism
"Our results suggest that the intracellular sialic acid concentration regulates polysialylation on NCAM in vivo; this could play a role in the manifestation of the developmental delays in sialuria patients."
The model-organism study proposing, tentatively, the NCAM-polysialylation route to developmental delay.
⚙

Pathophysiology

6
GNE Allosteric-Site Missense Variant
A single heterozygous missense variant in GNE at the allosteric CMP-Neu5Ac binding (feedback) site of the UDP-GlcNAc 2-epimerase domain. Reported changes cluster at two arginine residues, R263 and R266 in the original NM_005476 numbering (R266W, R266Q, R263L), now designated Arg294 and Arg297. Crystallography of the epimerase domain places these residues at the dimer-dimer interface where the carboxyl group of the Neu5Ac moiety of the inhibitor is coordinated, which is why single substitutions at Arg263/Arg266 abolish feedback binding.
GNE hgnc:23657 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GNE (hgnc:23657). hgnc:23657 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context GNE hgnc:23657 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns GNE (hgnc:23657). hgnc:23657 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense (allosteric CMP-Neu5Ac feedback site) variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
A heterozygous missense variant at the allosteric feedback site that leaves catalysis intact but abolishes CMP-Neu5Ac feedback inhibition, a gain of function acting in the heterozygous state.
Downstream
Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase The substitution sits in the allosteric site, so it directly disrupts inhibitor binding rather than catalysis.
Show evidence (2 references)
PMID:10330343 SUPPORT Human Clinical
"Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266."
The gene-defining study identifying the heterozygous allosteric-site variants in sialuria patients.
PMID:29923088 SUPPORT Human Clinical
"To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE."
Confirms that all reported variants are heterozygous allosteric-site missense changes and records the current residue renumbering.
Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase
The mutant epimerase retains normal catalytic activity but is no longer inhibitable by its downstream product CMP-Neu5Ac. Normal fibroblast epimerase is inhibited 79-100% by 100 microM CMP-Neu5Ac; sialuria enzyme is inhibited only 19-27%, and in some patients not at all. Because feedback inhibition is the enzyme's sole regulatory brake and does not affect the ManNAc kinase activity, its loss leaves a constitutively active, rate-limiting enzyme even in the heterozygous state — the biochemical basis of the dominant inheritance.
UDP-N-acetylglucosamine 2-epimerase activity (feedback-resistant) GO:0008761 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves UDP-N-acetylglucosamine 2-epimerase activity (feedback-resistant), annotated with UDP-N-acetylglucosamine 2-epimerase activity (GO:0008761), qualified as gain of function. GO:0008761 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Experimental models
R266Q sialuria patient fibroblasts with allele-specific siRNA silencing PRIMARY CELL CULTURE
Downstream
Unregulated Overproduction of Free N-Acetylneuraminic Acid
Show evidence (4 references)
PMID:11326336 SUPPORT INDIRECT Human Clinical
"Thus, even in the heterozygous state, the mutant allele produces a constitutively active, rate-limiting enzyme that achieves sufficient NeuAc synthesis to cause overproduction of free sialic acid."
States the qualitative gain of function: loss of feedback control yields a constitutively active enzyme in the heterozygote.
PMID:10356312 SUPPORT In Vitro
"fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)."
Quantifies the loss of feedback inhibition in a patient's fibroblasts.
PMID:26980148 SUPPORT In Vitro
"The feedback inhibition is highly positively cooperative and it does not affect the ManNAc kinase activity"
Establishes that CMP-Neu5Ac feedback acts specifically on the epimerase, so its loss deregulates the epimerase step while leaving kinase activity intact.
+ 1 more reference
Unregulated Overproduction of Free N-Acetylneuraminic Acid
With feedback removed, the epimerase runs unchecked and the sialic acid biosynthetic pathway overproduces free N-acetylneuraminic acid (Neu5Ac). Patients synthesize sialic acid in gram quantities.
N-acetylneuraminate biosynthetic process GO:0046380 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased N-acetylneuraminate biosynthetic process (GO:0046380). GO:0046380 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
R266Q sialuria patient fibroblasts with allele-specific siRNA silencing PRIMARY CELL CULTURE
Downstream
Cytoplasmic Free Sialic Acid Accumulation
Massive Urinary Free Sialic Acid Excretion
Show evidence (4 references)
PMID:10330343 SUPPORT Human Clinical
"Overproduction of NeuAc is believed to result from loss of feedback inhibition of uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac)."
States that overproduction of free sialic acid follows from the loss of feedback inhibition.
PMID:16137682 SUPPORT In Vitro
"Expression of the sialuria-mutated GNE leads to a dramatic increase of both cellular sialic acid and polysialic acid on NCAM."
Direct in vitro demonstration that a sialuria GNE variant increases cellular sialic acid.
PMID:40413313 SUPPORT In Vitro
"This mutant protein dramatically increased the intracellular concentrations of CMP-Neu5Ac, reaching the maximal level as with the addition of ManNAc."
A sialuria-type GNE mutant engineered into CHO cells raises intracellular activated sialic acid, confirming increased pathway flux.
+ 1 more reference
Cytoplasmic Free Sialic Acid Accumulation
The overproduced free Neu5Ac accumulates in the cytoplasm of cells, not in the lysosome. In patient fibroblasts about 59% of recovered free NeuAc is in the soluble cytoplasmic fraction. This cytoplasmic (as opposed to intralysosomal) localization is the cell-biological feature that distinguishes sialuria from the recessive lysosomal free sialic acid storage disorders (ISSD and Salla disease), which are caused by defective lysosomal egress via SLC17A5, a different gene and mechanism.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
GNE R263L transgenic mouse Mouse recapitulates
Downstream
Hepatomegaly
Coarse facial features Mildly coarse facies is part of the same homogeneous storage-attributable somatic cluster as hepatomegaly in reported sialuria (both are listed together as core features); the route from cytoplasmic free sialic acid accumulation to the facial phenotype is not mechanistically resolved, hence an indirect link with unknown intermediates rather than an asserted mechanism.
Increased NCAM Polysialylation
Show evidence (2 references)
PMID:11326336 SUPPORT In Vitro
"only 21% of the recovered NeuAc was found in the lysosomes, and 59% of the recovered NeuAc was in the soluble fraction representing the cytoplasm"
Quantifies the cytoplasmic (non-lysosomal) distribution of accumulated free sialic acid in patient fibroblasts.
PMID:11326336 SUPPORT In Vitro
"the intracellular distribution of NeuAc primarily in the cytoplasm, as opposed to its intralysosomal accumulation in ISSD cells"
Establishes the cytoplasmic localization as the feature distinguishing sialuria from the lysosomal free sialic acid storage disorders.
Massive Urinary Free Sialic Acid Excretion
The overproduced free sialic acid is excreted in the urine in gram quantities (greater than 1 g/day), the biochemical hallmark of the disorder and the basis of its name. Urinary free NeuAc is markedly elevated (reported to thousands of micromol per mmol creatinine, against a control of less than 74).
Animal models
GNE R263L transgenic mouse Mouse recapitulates
Show evidence (2 references)
PMID:11326336 SUPPORT Human Clinical
"urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc)."
Documents the gram-scale urinary excretion that defines sialuria.
PMID:29923088 SUPPORT Human Clinical
"cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid"
Independent statement of the gram-scale urinary excretion.
Increased NCAM Polysialylation
The enlarged intracellular sialic acid pool increases polysialylation of the neural cell adhesion molecule (NCAM). This has been shown both in cells expressing sialuria-mutated GNE and in the brains of a transgenic sialuria mouse, and is a proposed (not established) route to the developmental delay seen in patients.
NCAM polysialylation as a route to developmental delay
protein sialylation (NCAM polysialylation) GO:0097503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein sialylation (NCAM polysialylation), annotated with sialylation (GO:0097503). GO:0097503 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Global developmental delay A proposed link from increased NCAM polysialylation to the neurodevelopmental phenotype, supported so far only by model systems. NCAM polysialylation as a route to developmental delay
Show evidence (2 references)
PMID:27966821 SUPPORT Model Organism
"Analyzing the (poly)sialylation of neural cell adhesion molecule (NCAM) revealed increased polysialylation in brains of transgenic mice compared to wild-type."
Demonstrates increased NCAM polysialylation in a sialuria mouse model.
PMID:16137682 SUPPORT In Vitro
"Expression of the sialuria-mutated GNE leads to a dramatic increase of both cellular sialic acid and polysialic acid on NCAM."
In vitro confirmation that sialuria-type GNE raises NCAM polysialylation.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Sialuria Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Blood 1
Hypochromic microcytic anemia VERY_RARE HP:0004840 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypochromic microcytic anemia (HP:0004840). HP:0004840 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"The patient reported here and the original French patient also had microcytic anemia."
Reports microcytic anemia in two of the described patients.
Digestive 2
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29923088 SUPPORT Human Clinical
"The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice."
Lists hepatomegaly among the homogeneous core features across reported cases.
PMID:11486897 SUPPORT Human Clinical
"Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development."
Documents massive hepatomegaly in a longitudinally followed patient.
Prolonged neonatal jaundice FREQUENT HP:0006579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged neonatal jaundice (HP:0006579). HP:0006579 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29923088 SUPPORT Human Clinical
"clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice."
Lists prolonged neonatal jaundice among the core features.
Head and Neck 1
Coarse facial features FREQUENT HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"manifests with mildly coarse facies, slight motor delay, and urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc)."
Reports mildly coarse facies as a core manifestation.
Immune 1
Recurrent respiratory infections FREQUENT HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"Excessive rhinorrhea and recurrent respiratory infections were present throughout infancy."
Documents recurrent respiratory infections in infancy.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"The mild hypotonia persisted, but patient 1 was an alert child"
Documents persistent hypotonia in a reported patient.
Nervous System 2
Global developmental delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay (variable, often mild), annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29923088 SUPPORT Human Clinical
"The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice."
Lists developmental delay among the homogeneous core features.
PMID:10356312 SUPPORT Human Clinical
"a 7-year-old Portuguese girl with developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19 micromol of free NeuAc/mg creatinine."
A representative patient with developmental delay.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures (including febrile convulsions), annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"Frank seizures, which were controlled with barbititurates, were observed in two instances"
Documents seizures in a subset of the reported cases (source spelling retained).
Growth 2
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"failure to thrive (FTT) was documented"
Documents failure to thrive in a reported patient.
Small for gestational age FREQUENT HP:0001518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small for gestational age (HP:0001518). HP:0001518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"As newborn infants, the patients were small for their gestational age but had normal head circumferences."
Reports small-for-gestational-age birth across the case series.
Other 1
Airway obstruction HP:0006536 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small airway obstruction on pulmonary function testing, annotated with Airway obstruction (HP:0006536). HP:0006536 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11486897 SUPPORT Human Clinical
"Pulmonary function testing showed minimal small airway obstruction."
Documents small-airway obstruction in a longitudinally studied patient.
🧬

Genetic Associations

1
GNE allosteric feedback-site variant
Gene: GNE hgnc:23657 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNE (hgnc:23657). hgnc:23657 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:10330343 SUPPORT Human Clinical
"The heterozygous nature of the mutant allele in all three patients reveals a dominant mechanism of inheritance for sialuria."
Establishes the heterozygous, dominant genetic basis.
PMID:26980148 SUPPORT In Vitro
"Sialuria is an autosomal dominant disorder which is related to GNE mutation in one of the two arginine residues 263 and 266 (R263L, R266Q or R266W)"
Enumerates the recurrent allosteric-site arginine substitutions.
PMID:29923088 SUPPORT Human Clinical
"specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE."
Records the current residue numbering for the recurrent variants.
💊

Medical Actions

3
Supportive care and multisystem monitoring
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
There is no disease-specific therapy for sialuria. Management is supportive and directed at the individual manifestations, with recommended longitudinal monitoring of liver and pulmonary function given the reported hepatomegaly, transaminase elevation, and small-airway obstruction.
Show evidence (1 reference)
PMID:11486897 SUPPORT Human Clinical
"We recommend close monitoring of liver and pulmonary function in sialuria patients."
Basis for the recommended supportive monitoring.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling for an autosomal dominant disorder, addressing the 50% transmission risk for an affected parent and the possibility of de novo mutation, and the mild and variable expressivity that can leave carriers undiagnosed.
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"the heterozygous R266Q mutation was detected in the patient's mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, for the first time, the dominant mode of inheritance of this inborn error."
Documents dominant transmission, the basis for counseling on recurrence risk.
Allele-specific RNA interference (investigational)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Investigational, not clinically available. Because sialuria is a dominant gain-of-function disorder, silencing only the mutant allele while leaving the normal allele to provide regulated enzyme is a rational strategy. In R266Q patient fibroblasts, a mutant-allele-specific siRNA lowered free sialic acid to the normal range and restored feedback inhibition, a cell-culture proof of concept only — no in vivo or clinical data exist.
Show evidence (1 reference)
PMID:18653764 SUPPORT In Vitro
"These findings indicate that allele-specific silencing of a mutated allele is a viable therapeutic strategy for autosomal dominant diseases, including sialuria."
Establishes allele-specific silencing as a proposed therapeutic strategy, demonstrated so far only in patient fibroblasts.
🔬

Biochemical Markers

2
Urinary free N-acetylneuraminic acid
Show evidence (1 reference)
PMID:11326336 SUPPORT Human Clinical
"urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc)."
Establishes gram-scale urinary free sialic acid as the biochemical marker.
Reduced CMP-Neu5Ac inhibition of fibroblast UDP-GlcNAc 2-epimerase
Show evidence (1 reference)
PMID:10356312 SUPPORT In Vitro
"fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)."
Quantifies the diagnostic loss of feedback inhibition in patient cells.
🔬

Diagnosis

4
Urine free sialic acid measurement
Markedly elevated urine free (unconjugated) sialic acid is the screening biomarker. It is shared with the SLC17A5 free sialic acid storage disorders (ISSD/Salla), so it identifies the biochemical class rather than the specific gene; a non-specific elevation can also occur in acute pneumococcal sepsis, an important false-positive caveat.
urine free sialic acid measurement
Show evidence (2 references)
PMID:36000484 SUPPORT Human Clinical
"Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria (GNE variants) and infantile sialic acid storage disease/Salla disease (SLC17A5 variants)."
Establishes urine free sialic acid as the screening biomarker shared by sialuria and the SLC17A5 storage disorders.
PMID:36000484 SUPPORT Human Clinical
"We identified three cases of increased UFSA detected by UMSMS screening that were secondary to S. pneumoniae sepsis."
Records the pneumococcal-sepsis false-positive caveat on the hallmark urinary biomarker.
Fibroblast subcellular fractionation
Subcellular fractionation of cultured fibroblasts localizes the accumulated free sialic acid to the cytoplasm rather than the lysosome, discriminating sialuria from the lysosomal free sialic acid storage disorders (ISSD/Salla).
fibroblast subcellular fractionation
Show evidence (1 reference)
PMID:11326336 SUPPORT In Vitro
"the intracellular distribution of NeuAc primarily in the cytoplasm, as opposed to its intralysosomal accumulation in ISSD cells"
Cytoplasmic (non-lysosomal) localization on fractionation is the compartment discriminator from ISSD/Salla.
CMP-Neu5Ac feedback-inhibition enzyme assay
Assay of fibroblast UDP-GlcNAc 2-epimerase inhibition by CMP-Neu5Ac confirms the loss of feedback inhibition (greatly reduced % inhibition versus controls) that is the biochemical lesion of sialuria.
CMP-Neu5Ac feedback-inhibition enzyme assay
Show evidence (1 reference)
PMID:10356312 SUPPORT In Vitro
"fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)."
The reduced CMP-Neu5Ac inhibition of the patient enzyme confirms loss of feedback control.
GNE allosteric-site sequencing
Targeted sequencing of the GNE epimerase-domain allosteric codons (the Arg263/Arg266, now Arg294/Arg297, cluster) provides the molecular diagnosis.
GNE allosteric-codon sequencing
Show evidence (1 reference)
PMID:10330343 SUPPORT Human Clinical
"Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266."
Identifies the recurrent allosteric-site GNE variants that molecular testing targets.
📈

Progression

1
Course
The course is generally mild and non-progressive, with substantial clinical improvement over childhood; some retrospectively diagnosed adults considered themselves unaffected. This relatively benign, improving course helps distinguish sialuria prognostically from the free sialic acid storage disorders.
Show evidence (1 reference)
PMID:11486897 SUPPORT Human Clinical
"Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development."
Documents the relatively benign course on longitudinal follow-up.
📊

Prevalence

1
Worldwide, cases reported in the literature
Cases In Literature Ultra Rare
Ultra-rare. Nine cases had been reported worldwide as of 2019 (eight previously published plus the ninth). The true prevalence is thought to be grossly underestimated because the phenotype is mild and variable and urinary free sialic acid is not routinely assayed.
Show evidence (2 references)
PMID:29923088 SUPPORT Human Clinical
"Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE."
Establishes the reported case count (ninth patient) as of 2019.
PMID:11326336 SUPPORT Human Clinical
"The prevalence of sialuria is probably grossly underestimated."
States that the disorder is likely underdiagnosed.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Sialuria:

Free sialic acid storage disorders (ISSD/Salla disease) MONDO:0019366
Distinguishing Features
  • Both show elevated urine free sialic acid, but the storage disorders are autosomal recessive SLC17A5 defects with lysosomal (not cytoplasmic) accumulation from defective lysosomal egress; sialuria is dominant GNE overproduction with cytoplasmic localization on fibroblast fractionation.
Show evidence (1 reference)
PMID:11326336 SUPPORT In Vitro
"the intracellular distribution of NeuAc primarily in the cytoplasm, as opposed to its intralysosomal accumulation in ISSD cells"
The cytoplasmic-vs-lysosomal localization distinguishes sialuria from ISSD.
GNE myopathy MONDO:0011603
Distinguishing Features
  • The other GNE disease, but its mechanistic mirror image: recessive loss-of-function reducing sialic acid with adult-onset distal myopathy, versus sialuria's dominant gain-of-function overproducing sialic acid in infancy without myopathy.
Show evidence (1 reference)
PMID:26980148 SUPPORT In Vitro
"Sialuria is an autosomal dominant disorder which is related to GNE mutation in one of the two arginine residues 263 and 266 (R263L, R266Q or R266W)"
Anchors sialuria to the dominant allosteric-site GNE variants, distinct from the recessive loss-of-function of GNE myopathy.
🧫

Experimental Models

1
R266Q sialuria patient fibroblasts with allele-specific siRNA silencing PRIMARY_CELL_CULTURE
Primary fibroblasts from an R266Q sialuria patient, used to test allele-specific knockdown. A synthetic siRNA targeting the mutant c.797G>A (p.R266Q) allele lowered mutant transcript, reduced free sialic acid to within the normal range, and restored CMP-sialic acid feedback inhibition of GNE-epimerase — a rescue experiment that both confirms the causal mechanism and is a therapeutic proof-of-concept for the dominant allele.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Publication
PMID:18653764
Pathograph links
Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase rescues fidelity: moderate
Limitations: A single patient fibroblast line and a single (R266Q) allele; the rescue is allele-specific and was demonstrated only at the cellular/biochemical level, not in an organism.
Readouts
CMP-sialic acid feedback inhibition of GNE-epimerase after silencing
Direction: RESTORED
Interpretation: Silencing the mutant allele restored feedback inhibition, showing the mutant allele is responsible for its loss.
Show evidence (1 reference)
PMID:18653764 SUPPORT In Vitro
"Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing"
Restoration of feedback inhibition on knockdown of the mutant allele.
Show evidence (1 reference)
PMID:18653764 SUPPORT In Vitro
"mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range. Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing"
Knockdown of only the mutant allele rescues both the biochemical overproduction and the feedback defect, establishing this model as informative for the node.
Unregulated Overproduction of Free N-Acetylneuraminic Acid rescues fidelity: moderate
Limitations: Single R266Q fibroblast line; effect shown only in cultured cells.
Readouts
Free sialic acid in fibroblasts after mutant-allele silencing
Direction: RESTORED
Interpretation: Free sialic acid fell to within the normal range after silencing the mutant allele.
Show evidence (1 reference)
PMID:18653764 SUPPORT In Vitro
"mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range."
Direct readout of reduced free sialic acid on mutant-allele knockdown.
Show evidence (1 reference)
PMID:18653764 SUPPORT In Vitro
"Sialuria is a dominant disorder caused by missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid biosynthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes..."
States the causal chain from allosteric-site mutation through lost feedback to overproduction, which the rescue reverses.
🐁

Animal Models

1
GNE R263L transgenic mouse
A transgenic mouse expressing the sialuria GNE R263L allele; the only reported in vivo model of sialuria (correcting the deep-research report's claim that no animal model exists).
Species
Mouse
Genotype
GNE R263L (sialuria allele) transgene
Publication
PMID:27966821
Pathograph links
Massive Urinary Free Sialic Acid Excretion recapitulates fidelity: moderate
Limitations: Transgenic overexpressor of the mutant allele rather than a knock-in, and the clinical (developmental) phenotype of the mice was not characterized.
Readouts
Urinary N-acetylneuraminic acid excretion
Direction: INCREASED
Interpretation: Recapitulates the gram-scale urinary overexcretion of patients.
Show evidence (1 reference)
PMID:27966821 SUPPORT Model Organism
"The transgenic mice that expressed the mutated RNA excreted up to 400 times more N-acetylneuraminic acid than wild-type mice."
Direct measurement of urinary sialic-acid overexcretion in the model.
Show evidence (1 reference)
PMID:27966821 SUPPORT Model Organism
"The transgenic mice that expressed the mutated RNA excreted up to 400 times more N-acetylneuraminic acid than wild-type mice."
The model reproduces the urinary free-sialic-acid overexcretion node.
Cytoplasmic Free Sialic Acid Accumulation recapitulates fidelity: moderate
Limitations: Brain cytoplasmic sialic acid was measured rather than the hepatic compartment emphasized clinically; transgenic overexpressor, not a knock-in.
Readouts
Brain cytoplasmic sialic acid concentration
Direction: INCREASED
Interpretation: Recapitulates the cytoplasmic free-sialic-acid accumulation node.
Show evidence (1 reference)
PMID:27966821 SUPPORT Model Organism
"Additionally, we found higher sialic acid concentration in the brain cytoplasm."
Direct measurement of cytoplasmic sialic-acid accumulation in the model.
Show evidence (1 reference)
PMID:27966821 SUPPORT Model Organism
"Additionally, we found higher sialic acid concentration in the brain cytoplasm."
The model reproduces the cytoplasmic free-sialic-acid accumulation node.
{ }

Source YAML

click to show 
name: Sialuria
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Sialuria
  term:
    id: MONDO:0010028
    label: sialuria
synonyms:
- sialuria, French type
- French type sialuria
- UDP-GlcNAc 2-epimerase, feedback-resistant
description: >-
  Sialuria is an ultra-rare autosomal dominant inborn error of sialic acid
  metabolism, and it is the mechanistic mirror image of the far better known
  recessive GNE myopathy: both are caused by variants in GNE, the bifunctional
  UDP-N-acetylglucosamine 2-epimerase / N-acetylmannosamine kinase that runs the
  first, rate-limiting steps of sialic acid biosynthesis, but where GNE myopathy
  is a hypomorphic loss of function that starves tissue of sialic acid, sialuria
  is a gain of function that floods it. The lesion is exquisitely specific. A
  single heterozygous missense change at the allosteric CMP-N-acetylneuraminic
  acid (CMP-Neu5Ac) feedback site in the epimerase domain — clustered at two
  arginine residues, historically numbered Arg263 and Arg266 and now Arg294 and
  Arg297 — leaves the enzyme catalytically normal but deaf to the end-product
  feedback that normally shuts it off. The result is a constitutively active
  epimerase that overproduces free (unconjugated) N-acetylneuraminic acid, which
  accumulates in the cytoplasm (not the lysosome, which is what separates it from
  the recessive free sialic acid storage disorders ISSD and Salla disease, caused
  by SLC17A5) and spills into the urine in gram quantities. Clinically it is a
  mild and easily missed disorder: mildly coarse facies, hepatomegaly, variable
  developmental delay, prolonged neonatal jaundice, and recurrent infections in
  infancy, with substantial improvement over childhood — one of the diagnostic
  adults was ascertained only because her son was affected. Fewer than a dozen
  patients have been reported worldwide, and the true prevalence is thought to be
  grossly underestimated because urinary free sialic acid is not routinely
  assayed.
pathophysiology:
- name: GNE Allosteric-Site Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A single heterozygous missense variant in GNE at the allosteric CMP-Neu5Ac
    binding (feedback) site of the UDP-GlcNAc 2-epimerase domain. Reported changes
    cluster at two arginine residues, R263 and R266 in the original NM_005476
    numbering (R266W, R266Q, R263L), now designated Arg294 and Arg297. Crystallography
    of the epimerase domain places these residues at the dimer-dimer interface where
    the carboxyl group of the Neu5Ac moiety of the inhibitor is coordinated, which is
    why single substitutions at Arg263/Arg266 abolish feedback binding.
  genes:
  - preferred_term: GNE
    term:
      id: hgnc:23657
      label: GNE
  genetic_context:
    genes:
    - preferred_term: GNE
      term:
        id: hgnc:23657
        label: GNE
    allele_type: missense (allosteric CMP-Neu5Ac feedback site)
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      A heterozygous missense variant at the allosteric feedback site that leaves
      catalysis intact but abolishes CMP-Neu5Ac feedback inhibition, a gain of
      function acting in the heterozygous state.
  downstream:
  - target: Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase
    causal_link_type: DIRECT
    description: >-
      The substitution sits in the allosteric site, so it directly disrupts
      inhibitor binding rather than catalysis.
    evidence:
    - reference: PMID:26980148
      reference_title: "Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria."
      explanation: >-
        The epimerase crystal structure localizes the sialuria variants to the
        inhibitor-binding site, establishing this edge from variant to loss of
        feedback binding.
  evidence:
  - reference: PMID:10330343
    reference_title: "Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266."
    explanation: >-
      The gene-defining study identifying the heterozygous allosteric-site variants
      in sialuria patients.
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE."
    explanation: >-
      Confirms that all reported variants are heterozygous allosteric-site missense
      changes and records the current residue renumbering.
- name: Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase
  biological_scale: MOLECULAR
  description: >-
    The mutant epimerase retains normal catalytic activity but is no longer
    inhibitable by its downstream product CMP-Neu5Ac. Normal fibroblast epimerase
    is inhibited 79-100% by 100 microM CMP-Neu5Ac; sialuria enzyme is inhibited
    only 19-27%, and in some patients not at all. Because feedback inhibition is
    the enzyme's sole regulatory brake and does not affect the ManNAc kinase
    activity, its loss leaves a constitutively active, rate-limiting enzyme even in
    the heterozygous state — the biochemical basis of the dominant inheritance.
  molecular_functions:
  - preferred_term: UDP-N-acetylglucosamine 2-epimerase activity (feedback-resistant)
    term:
      id: GO:0008761
      label: UDP-N-acetylglucosamine 2-epimerase activity
    modifier: GAIN_OF_FUNCTION
  chemical_entities:
  - preferred_term: CMP-N-acetylneuraminic acid (allosteric feedback inhibitor)
    term:
      id: CHEBI:16556
      label: CMP-N-acetyl-beta-neuraminic acid
  downstream:
  - target: Unregulated Overproduction of Free N-Acetylneuraminic Acid
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, even in the heterozygous state, the mutant allele produces a constitutively active, rate-limiting enzyme that achieves sufficient NeuAc synthesis to cause overproduction of free sialic acid."
    explanation: >-
      States the qualitative gain of function: loss of feedback control yields a
      constitutively active enzyme in the heterozygote.
  - reference: PMID:10356312
    reference_title: "Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)."
    explanation: >-
      Quantifies the loss of feedback inhibition in a patient's fibroblasts.
  - reference: PMID:26980148
    reference_title: "Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The feedback inhibition is highly positively cooperative and it does not affect the ManNAc kinase activity"
    explanation: >-
      Establishes that CMP-Neu5Ac feedback acts specifically on the epimerase, so
      its loss deregulates the epimerase step while leaving kinase activity intact.
  - reference: PMID:21436238
    reference_title: "Enhanced sialylation of recombinant human erythropoietin in Chinese hamster ovary cells by combinatorial engineering of selected genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "GNE/MNK-R263L-R266Q mutant showed 93.6% relative activity compared with wild type and did not display feedback inhibition."
    explanation: >-
      An engineered GNE carrying the two sialuria residues loses feedback inhibition
      while retaining near-normal catalytic activity, isolating loss of feedback
      (not loss of catalysis) as the lesion.
- name: Unregulated Overproduction of Free N-Acetylneuraminic Acid
  biological_scale: MOLECULAR
  description: >-
    With feedback removed, the epimerase runs unchecked and the sialic acid
    biosynthetic pathway overproduces free N-acetylneuraminic acid (Neu5Ac).
    Patients synthesize sialic acid in gram quantities.
  biological_processes:
  - preferred_term: N-acetylneuraminate biosynthetic process
    term:
      id: GO:0046380
      label: N-acetylneuraminate biosynthetic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: free N-acetylneuraminic acid
    term:
      id: CHEBI:17012
      label: N-acetylneuraminic acid
    modifier: INCREASED
  downstream:
  - target: Cytoplasmic Free Sialic Acid Accumulation
    causal_link_type: DIRECT
  - target: Massive Urinary Free Sialic Acid Excretion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10330343
    reference_title: "Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overproduction of NeuAc is believed to result from loss of feedback inhibition of uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac)."
    explanation: >-
      States that overproduction of free sialic acid follows from the loss of
      feedback inhibition.
  - reference: PMID:16137682
    reference_title: "The intracellular concentration of sialic acid regulates the polysialylation of the neural cell adhesion molecule."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of the sialuria-mutated GNE leads to a dramatic increase of both cellular sialic acid and polysialic acid on NCAM."
    explanation: >-
      Direct in vitro demonstration that a sialuria GNE variant increases cellular
      sialic acid.
  - reference: PMID:40413313
    reference_title: "Expression of GNE mutant proteins increases CHO intracellular CMP-Neu5Ac levels without impact on bioprocess performance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This mutant protein dramatically increased the intracellular concentrations of CMP-Neu5Ac, reaching the maximal level as with the addition of ManNAc."
    explanation: >-
      A sialuria-type GNE mutant engineered into CHO cells raises intracellular
      activated sialic acid, confirming increased pathway flux.
  - reference: PMID:21436238
    reference_title: "Enhanced sialylation of recombinant human erythropoietin in Chinese hamster ovary cells by combinatorial engineering of selected genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CMP-sialic acid concentration of engineered cells was significantly (>10-fold) increased by sialuria-mutated GNE/MNK (R263L-R266Q) expression."
    explanation: >-
      Expressing a sialuria-mutated GNE raises intracellular activated sialic acid
      more than tenfold, quantifying the gain of pathway flux.
- name: Cytoplasmic Free Sialic Acid Accumulation
  biological_scale: CELLULAR
  description: >-
    The overproduced free Neu5Ac accumulates in the cytoplasm of cells, not in the
    lysosome. In patient fibroblasts about 59% of recovered free NeuAc is in the
    soluble cytoplasmic fraction. This cytoplasmic (as opposed to intralysosomal)
    localization is the cell-biological feature that distinguishes sialuria from
    the recessive lysosomal free sialic acid storage disorders (ISSD and Salla
    disease), which are caused by defective lysosomal egress via SLC17A5, a
    different gene and mechanism.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Coarse facial features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mildly coarse facies is part of the same homogeneous storage-attributable
      somatic cluster as hepatomegaly in reported sialuria (both are listed
      together as core features); the route from cytoplasmic free sialic acid
      accumulation to the facial phenotype is not mechanistically resolved, hence
      an indirect link with unknown intermediates rather than an asserted mechanism.
  - target: Increased NCAM Polysialylation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "only 21% of the recovered NeuAc was found in the lysosomes, and 59% of the recovered NeuAc was in the soluble fraction representing the cytoplasm"
    explanation: >-
      Quantifies the cytoplasmic (non-lysosomal) distribution of accumulated free
      sialic acid in patient fibroblasts.
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the intracellular distribution of NeuAc primarily in the cytoplasm, as opposed to its intralysosomal accumulation in ISSD cells"
    explanation: >-
      Establishes the cytoplasmic localization as the feature distinguishing sialuria
      from the lysosomal free sialic acid storage disorders.
- name: Massive Urinary Free Sialic Acid Excretion
  biological_scale: ORGANISM
  description: >-
    The overproduced free sialic acid is excreted in the urine in gram quantities
    (greater than 1 g/day), the biochemical hallmark of the disorder and the basis
    of its name. Urinary free NeuAc is markedly elevated (reported to thousands of
    micromol per mmol creatinine, against a control of less than 74).
  chemical_entities:
  - preferred_term: free N-acetylneuraminic acid (urinary)
    term:
      id: CHEBI:17012
      label: N-acetylneuraminic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc)."
    explanation: >-
      Documents the gram-scale urinary excretion that defines sialuria.
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid"
    explanation: >-
      Independent statement of the gram-scale urinary excretion.
- name: Increased NCAM Polysialylation
  biological_scale: MOLECULAR
  description: >-
    The enlarged intracellular sialic acid pool increases polysialylation of the
    neural cell adhesion molecule (NCAM). This has been shown both in cells
    expressing sialuria-mutated GNE and in the brains of a transgenic sialuria
    mouse, and is a proposed (not established) route to the developmental delay
    seen in patients.
  biological_processes:
  - preferred_term: protein sialylation (NCAM polysialylation)
    term:
      id: GO:0097503
      label: sialylation
    modifier: INCREASED
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ncam_polysialylation_delay
    description: >-
      A proposed link from increased NCAM polysialylation to the neurodevelopmental
      phenotype, supported so far only by model systems.
  evidence:
  - reference: PMID:27966821
    reference_title: "Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analyzing the (poly)sialylation of neural cell adhesion molecule (NCAM) revealed increased polysialylation in brains of transgenic mice compared to wild-type."
    explanation: >-
      Demonstrates increased NCAM polysialylation in a sialuria mouse model.
  - reference: PMID:16137682
    reference_title: "The intracellular concentration of sialic acid regulates the polysialylation of the neural cell adhesion molecule."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of the sialuria-mutated GNE leads to a dramatic increase of both cellular sialic acid and polysialic acid on NCAM."
    explanation: >-
      In vitro confirmation that sialuria-type GNE raises NCAM polysialylation.
mechanistic_hypotheses:
- hypothesis_group_id: ncam_polysialylation_delay
  hypothesis_label: NCAM polysialylation as a route to developmental delay
  status: EMERGING
  description: >-
    The hypothesis that increased intracellular sialic acid drives increased NCAM
    polysialylation, which in turn contributes to the developmental delay of
    sialuria. Support is currently limited to a transgenic mouse and cell models;
    the transgenic-mouse authors frame it explicitly as a possibility ("could play
    a role"). No direct human evidence links NCAM polysialylation to the delay.
  evidence:
  - reference: PMID:27966821
    reference_title: "Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results suggest that the intracellular sialic acid concentration regulates polysialylation on NCAM in vivo; this could play a role in the manifestation of the developmental delays in sialuria patients."
    explanation: >-
      The model-organism study proposing, tentatively, the NCAM-polysialylation
      route to developmental delay.
phenotypes:
- name: Hepatomegaly
  category: Clinical
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  description: >-
    Hepatomegaly is a consistent feature, usually mild but occasionally massive.
  evidence:
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice."
    explanation: >-
      Lists hepatomegaly among the homogeneous core features across reported cases.
  - reference: PMID:11486897
    reference_title: "Clinical course and biochemistry of sialuria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development."
    explanation: >-
      Documents massive hepatomegaly in a longitudinally followed patient.
- name: Coarse facial features
  category: Clinical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  description: >-
    Mildly coarse facies, sometimes transient and improving with age, and a common
    reason sialuria is initially mistaken for a mucopolysaccharidosis.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifests with mildly coarse facies, slight motor delay, and urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc)."
    explanation: >-
      Reports mildly coarse facies as a core manifestation.
- name: Global developmental delay
  category: Clinical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Developmental delay (variable, often mild)
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Developmental delay is variable and typically mild, affecting motor and
    language skills; some patients improve markedly during childhood and a
    retrospectively diagnosed adult considered herself unaffected.
  evidence:
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice."
    explanation: >-
      Lists developmental delay among the homogeneous core features.
  - reference: PMID:10356312
    reference_title: "Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 7-year-old Portuguese girl with developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19 micromol of free NeuAc/mg creatinine."
    explanation: >-
      A representative patient with developmental delay.
- name: Prolonged neonatal jaundice
  category: Clinical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Prolonged neonatal jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  description: >-
    Prolonged neonatal jaundice is reported as a recurrent feature of the neonatal
    presentation.
  evidence:
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice."
    explanation: >-
      Lists prolonged neonatal jaundice among the core features.
- name: Hypotonia
  category: Clinical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Axial and generalized hypotonia is frequently noted in infancy and may persist.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mild hypotonia persisted, but patient 1 was an alert child"
    explanation: >-
      Documents persistent hypotonia in a reported patient.
- name: Failure to thrive
  category: Clinical
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  description: >-
    Transient failure to thrive, often in the setting of intercurrent infection and
    dehydration in infancy.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive (FTT) was documented"
    explanation: >-
      Documents failure to thrive in a reported patient.
- name: Recurrent respiratory infections
  category: Clinical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  description: >-
    Recurrent upper respiratory infections during infancy and early childhood.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive rhinorrhea and recurrent respiratory infections were present throughout infancy."
    explanation: >-
      Documents recurrent respiratory infections in infancy.
- name: Small for gestational age
  category: Clinical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  description: >-
    Affected newborns are small for gestational age but with normal head
    circumference.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As newborn infants, the patients were small for their gestational age but had normal head circumferences."
    explanation: >-
      Reports small-for-gestational-age birth across the case series.
- name: Seizure
  category: Clinical
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizures (including febrile convulsions)
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Seizures, including febrile convulsions, have been reported in a minority of
    patients.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frank seizures, which were controlled with barbititurates, were observed in two instances"
    explanation: >-
      Documents seizures in a subset of the reported cases (source spelling
      retained).
- name: Hypochromic microcytic anemia
  category: Clinical
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hypochromic microcytic anemia
    term:
      id: HP:0004840
      label: Hypochromic microcytic anemia
  description: >-
    Microcytic anemia has been reported in a small number of patients.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient reported here and the original French patient also had microcytic anemia."
    explanation: >-
      Reports microcytic anemia in two of the described patients.
- name: Airway obstruction
  category: Clinical
  phenotype_term:
    preferred_term: Small airway obstruction on pulmonary function testing
    term:
      id: HP:0006536
      label: Airway obstruction
  description: >-
    Minimal small-airway obstruction on pulmonary function testing was found on
    longitudinal follow-up, prompting a recommendation for pulmonary monitoring.
  evidence:
  - reference: PMID:11486897
    reference_title: "Clinical course and biochemistry of sialuria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary function testing showed minimal small airway obstruction."
    explanation: >-
      Documents small-airway obstruction in a longitudinally studied patient.
biochemical:
- name: Urinary free N-acetylneuraminic acid
  notes: >-
    Markedly elevated urinary excretion of free (unconjugated) N-acetylneuraminic
    acid is the biochemical hallmark of sialuria; gram-per-day quantities are
    excreted. Unlike sialidosis, the excreted sialic acid is free rather than
    bound in glycoconjugates, and unlike ISSD/Salla disease it reflects cytoplasmic
    overproduction rather than lysosomal storage.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc)."
    explanation: >-
      Establishes gram-scale urinary free sialic acid as the biochemical marker.
- name: Reduced CMP-Neu5Ac inhibition of fibroblast UDP-GlcNAc 2-epimerase
  notes: >-
    A confirmatory enzymatic assay: patient fibroblast UDP-GlcNAc 2-epimerase shows
    greatly reduced inhibition by CMP-Neu5Ac (19-27%, and in some patients none)
    versus 79-100% in controls.
  evidence:
  - reference: PMID:10356312
    reference_title: "Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)."
    explanation: >-
      Quantifies the diagnostic loss of feedback inhibition in patient cells.
experimental_models:
- name: R266Q sialuria patient fibroblasts with allele-specific siRNA silencing
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary fibroblasts from an R266Q sialuria patient, used to test allele-specific
    knockdown. A synthetic siRNA targeting the mutant c.797G>A (p.R266Q) allele
    lowered mutant transcript, reduced free sialic acid to within the normal range,
    and restored CMP-sialic acid feedback inhibition of GNE-epimerase — a rescue
    experiment that both confirms the causal mechanism and is a therapeutic
    proof-of-concept for the dominant allele.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  publication: PMID:18653764
  modeled_mechanisms:
  - target: Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: >-
      A single patient fibroblast line and a single (R266Q) allele; the rescue is
      allele-specific and was demonstrated only at the cellular/biochemical level,
      not in an organism.
    readouts:
    - name: CMP-sialic acid feedback inhibition of GNE-epimerase after silencing
      target: Loss of CMP-Neu5Ac Feedback Inhibition of UDP-GlcNAc 2-Epimerase
      direction: RESTORED
      interpretation: >-
        Silencing the mutant allele restored feedback inhibition, showing the
        mutant allele is responsible for its loss.
      evidence:
      - reference: PMID:18653764
        reference_title: "Allele-specific silencing of the dominant disease allele in sialuria by RNA interference."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing"
        explanation: >-
          Restoration of feedback inhibition on knockdown of the mutant allele.
    evidence:
    - reference: PMID:18653764
      reference_title: "Allele-specific silencing of the dominant disease allele in sialuria by RNA interference."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range. Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing"
      explanation: >-
        Knockdown of only the mutant allele rescues both the biochemical overproduction
        and the feedback defect, establishing this model as informative for the node.
  - target: Unregulated Overproduction of Free N-Acetylneuraminic Acid
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: >-
      Single R266Q fibroblast line; effect shown only in cultured cells.
    readouts:
    - name: Free sialic acid in fibroblasts after mutant-allele silencing
      target: Unregulated Overproduction of Free N-Acetylneuraminic Acid
      direction: RESTORED
      interpretation: >-
        Free sialic acid fell to within the normal range after silencing the mutant
        allele.
      evidence:
      - reference: PMID:18653764
        reference_title: "Allele-specific silencing of the dominant disease allele in sialuria by RNA interference."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range."
        explanation: >-
          Direct readout of reduced free sialic acid on mutant-allele knockdown.
    evidence:
    - reference: PMID:18653764
      reference_title: "Allele-specific silencing of the dominant disease allele in sialuria by RNA interference."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Sialuria is a dominant disorder caused by missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid biosynthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessive production of free sialic acid."
      explanation: >-
        States the causal chain from allosteric-site mutation through lost feedback to
        overproduction, which the rescue reverses.
genetic:
- name: GNE allosteric feedback-site variant
  gene_term:
    preferred_term: GNE
    term:
      id: hgnc:23657
      label: GNE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Sialuria is caused by a single heterozygous missense variant in GNE (9p13.3)
    affecting the allosteric CMP-Neu5Ac feedback site of the UDP-GlcNAc 2-epimerase
    domain. Reported variants cluster tightly at two arginine codons: R266W, R266Q,
    and R263L in the original NM_005476 numbering, now designated Arg297 and Arg294
    respectively (a 31-residue offset relative to the longer NM_001128227 transcript,
    the same offset seen in the GNE myopathy literature). The variant is a gain of
    function: it leaves catalysis intact but abolishes end-product feedback
    inhibition, so a single mutant allele suffices to deregulate the pathway. Most
    cases arise de novo as new dominant mutations; one family has confirmed
    parent-to-child transmission. The functional consequence is recorded on the
    GNE Allosteric-Site Missense Variant pathophysiology node as
    functional_impact_category GAIN_OF_FUNCTION.
  evidence:
  - reference: PMID:10330343
    reference_title: "Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The heterozygous nature of the mutant allele in all three patients reveals a dominant mechanism of inheritance for sialuria."
    explanation: >-
      Establishes the heterozygous, dominant genetic basis.
  - reference: PMID:26980148
    reference_title: "Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Sialuria is an autosomal dominant disorder which is related to GNE mutation in one of the two arginine residues 263 and 266 (R263L, R266Q or R266W)"
    explanation: >-
      Enumerates the recurrent allosteric-site arginine substitutions.
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE."
    explanation: >-
      Records the current residue numbering for the recurrent variants.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant. The dominance has a biochemical basis: a single mutant
    allele produces a constitutively active, feedback-resistant enzyme, which
    overproduces sialic acid regardless of the normal allele. Most affected
    individuals were thought to represent new (de novo) mutations; parent-to-child
    transmission was confirmed in one family, in which the affected mother was
    diagnosed retrospectively after her son.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the heterozygous R266Q mutation was detected in the patient's mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, for the first time, the dominant mode of inheritance of this inborn error."
    explanation: >-
      Confirms dominant inheritance through documented vertical transmission.
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sialuria is an autosomal dominant disorder and that affected individuals represent new mutations"
    explanation: >-
      Records the earlier inference that most cases are de novo dominant mutations.
prevalence:
- population: Worldwide, cases reported in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare. Nine cases had been reported worldwide as of 2019 (eight previously
    published plus the ninth). The true prevalence is thought to be grossly
    underestimated because the phenotype is mild and variable and urinary free
    sialic acid is not routinely assayed.
  evidence:
  - reference: PMID:29923088
    reference_title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE."
    explanation: >-
      Establishes the reported case count (ninth patient) as of 2019.
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of sialuria is probably grossly underestimated."
    explanation: >-
      States that the disorder is likely underdiagnosed.
treatments:
- name: Supportive care and multisystem monitoring
  description: >-
    There is no disease-specific therapy for sialuria. Management is supportive and
    directed at the individual manifestations, with recommended longitudinal
    monitoring of liver and pulmonary function given the reported hepatomegaly,
    transaminase elevation, and small-airway obstruction.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:11486897
    reference_title: "Clinical course and biochemistry of sialuria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend close monitoring of liver and pulmonary function in sialuria patients."
    explanation: >-
      Basis for the recommended supportive monitoring.
- name: Genetic counseling
  description: >-
    Genetic counseling for an autosomal dominant disorder, addressing the 50%
    transmission risk for an affected parent and the possibility of de novo
    mutation, and the mild and variable expressivity that can leave carriers
    undiagnosed.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the heterozygous R266Q mutation was detected in the patient's mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, for the first time, the dominant mode of inheritance of this inborn error."
    explanation: >-
      Documents dominant transmission, the basis for counseling on recurrence risk.
- name: Allele-specific RNA interference (investigational)
  description: >-
    Investigational, not clinically available. Because sialuria is a dominant
    gain-of-function disorder, silencing only the mutant allele while leaving the
    normal allele to provide regulated enzyme is a rational strategy. In R266Q
    patient fibroblasts, a mutant-allele-specific siRNA lowered free sialic acid to
    the normal range and restored feedback inhibition, a cell-culture proof of
    concept only — no in vivo or clinical data exist.
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:18653764
    reference_title: "Allele-specific silencing of the dominant disease allele in sialuria by RNA interference."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings indicate that allele-specific silencing of a mutated allele is a viable therapeutic strategy for autosomal dominant diseases, including sialuria."
    explanation: >-
      Establishes allele-specific silencing as a proposed therapeutic strategy,
      demonstrated so far only in patient fibroblasts.
diagnosis:
- name: Urine free sialic acid measurement
  description: >-
    Markedly elevated urine free (unconjugated) sialic acid is the screening
    biomarker. It is shared with the SLC17A5 free sialic acid storage disorders
    (ISSD/Salla), so it identifies the biochemical class rather than the specific
    gene; a non-specific elevation can also occur in acute pneumococcal sepsis,
    an important false-positive caveat.
  diagnosis_term:
    preferred_term: urine free sialic acid measurement
  evidence:
  - reference: PMID:36000484
    reference_title: "Free urinary sialic acid levels may be elevated in patients with pneumococcal sepsis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria (GNE variants) and infantile sialic acid storage disease/Salla disease (SLC17A5 variants)."
    explanation: >-
      Establishes urine free sialic acid as the screening biomarker shared by
      sialuria and the SLC17A5 storage disorders.
  - reference: PMID:36000484
    reference_title: "Free urinary sialic acid levels may be elevated in patients with pneumococcal sepsis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three cases of increased UFSA detected by UMSMS screening that were secondary to S. pneumoniae sepsis."
    explanation: >-
      Records the pneumococcal-sepsis false-positive caveat on the hallmark
      urinary biomarker.
- name: Fibroblast subcellular fractionation
  description: >-
    Subcellular fractionation of cultured fibroblasts localizes the accumulated
    free sialic acid to the cytoplasm rather than the lysosome, discriminating
    sialuria from the lysosomal free sialic acid storage disorders (ISSD/Salla).
  diagnosis_term:
    preferred_term: fibroblast subcellular fractionation
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the intracellular distribution of NeuAc primarily in the cytoplasm, as opposed to its intralysosomal accumulation in ISSD cells"
    explanation: >-
      Cytoplasmic (non-lysosomal) localization on fractionation is the
      compartment discriminator from ISSD/Salla.
- name: CMP-Neu5Ac feedback-inhibition enzyme assay
  description: >-
    Assay of fibroblast UDP-GlcNAc 2-epimerase inhibition by CMP-Neu5Ac
    confirms the loss of feedback inhibition (greatly reduced % inhibition versus
    controls) that is the biochemical lesion of sialuria.
  diagnosis_term:
    preferred_term: CMP-Neu5Ac feedback-inhibition enzyme assay
  evidence:
  - reference: PMID:10356312
    reference_title: "Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)."
    explanation: >-
      The reduced CMP-Neu5Ac inhibition of the patient enzyme confirms loss of
      feedback control.
- name: GNE allosteric-site sequencing
  description: >-
    Targeted sequencing of the GNE epimerase-domain allosteric codons (the
    Arg263/Arg266, now Arg294/Arg297, cluster) provides the molecular diagnosis.
  diagnosis_term:
    preferred_term: GNE allosteric-codon sequencing
  evidence:
  - reference: PMID:10330343
    reference_title: "Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266."
    explanation: >-
      Identifies the recurrent allosteric-site GNE variants that molecular
      testing targets.
differential_diagnoses:
- name: Free sialic acid storage disorders (ISSD/Salla disease)
  disease_term:
    preferred_term: free sialic acid storage disorder (SLC17A5; ISSD/Salla)
    term:
      id: MONDO:0019366
      label: free sialic acid storage disease
  distinguishing_features:
  - >-
    Both show elevated urine free sialic acid, but the storage disorders are
    autosomal recessive SLC17A5 defects with lysosomal (not cytoplasmic)
    accumulation from defective lysosomal egress; sialuria is dominant GNE
    overproduction with cytoplasmic localization on fibroblast fractionation.
  evidence:
  - reference: PMID:11326336
    reference_title: "Dominant inheritance of sialuria, an inborn error of feedback inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the intracellular distribution of NeuAc primarily in the cytoplasm, as opposed to its intralysosomal accumulation in ISSD cells"
    explanation: >-
      The cytoplasmic-vs-lysosomal localization distinguishes sialuria from ISSD.
- name: GNE myopathy
  disease_term:
    preferred_term: GNE myopathy
    term:
      id: MONDO:0011603
      label: GNE myopathy
  distinguishing_features:
  - >-
    The other GNE disease, but its mechanistic mirror image: recessive
    loss-of-function reducing sialic acid with adult-onset distal myopathy,
    versus sialuria's dominant gain-of-function overproducing sialic acid in
    infancy without myopathy.
  evidence:
  - reference: PMID:26980148
    reference_title: "Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Sialuria is an autosomal dominant disorder which is related to GNE mutation in one of the two arginine residues 263 and 266 (R263L, R266Q or R266W)"
    explanation: >-
      Anchors sialuria to the dominant allosteric-site GNE variants, distinct
      from the recessive loss-of-function of GNE myopathy.
progression:
- phase: Course
  notes: >-
    The course is generally mild and non-progressive, with substantial clinical
    improvement over childhood; some retrospectively diagnosed adults considered
    themselves unaffected. This relatively benign, improving course helps
    distinguish sialuria prognostically from the free sialic acid storage
    disorders.
  evidence:
  - reference: PMID:11486897
    reference_title: "Clinical course and biochemistry of sialuria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development."
    explanation: >-
      Documents the relatively benign course on longitudinal follow-up.
animal_models:
- name: GNE R263L transgenic mouse
  species: Mouse
  genotype: GNE R263L (sialuria allele) transgene
  publication: PMID:27966821
  description: >-
    A transgenic mouse expressing the sialuria GNE R263L allele; the only
    reported in vivo model of sialuria (correcting the deep-research report's
    claim that no animal model exists).
  modeled_mechanisms:
  - target: Massive Urinary Free Sialic Acid Excretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      Transgenic overexpressor of the mutant allele rather than a knock-in, and
      the clinical (developmental) phenotype of the mice was not characterized.
    readouts:
    - name: Urinary N-acetylneuraminic acid excretion
      target: Massive Urinary Free Sialic Acid Excretion
      direction: INCREASED
      interpretation: Recapitulates the gram-scale urinary overexcretion of patients.
      evidence:
      - reference: PMID:27966821
        reference_title: "Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The transgenic mice that expressed the mutated RNA excreted up to 400 times more N-acetylneuraminic acid than wild-type mice."
        explanation: Direct measurement of urinary sialic-acid overexcretion in the model.
    evidence:
    - reference: PMID:27966821
      reference_title: "Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The transgenic mice that expressed the mutated RNA excreted up to 400 times more N-acetylneuraminic acid than wild-type mice."
      explanation: The model reproduces the urinary free-sialic-acid overexcretion node.
  - target: Cytoplasmic Free Sialic Acid Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Brain cytoplasmic sialic acid was measured rather than the hepatic
      compartment emphasized clinically; transgenic overexpressor, not a knock-in.
    readouts:
    - name: Brain cytoplasmic sialic acid concentration
      target: Cytoplasmic Free Sialic Acid Accumulation
      direction: INCREASED
      interpretation: Recapitulates the cytoplasmic free-sialic-acid accumulation node.
      evidence:
      - reference: PMID:27966821
        reference_title: "Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Additionally, we found higher sialic acid concentration in the brain cytoplasm."
        explanation: Direct measurement of cytoplasmic sialic-acid accumulation in the model.
    evidence:
    - reference: PMID:27966821
      reference_title: "Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Additionally, we found higher sialic acid concentration in the brain cytoplasm."
      explanation: The model reproduces the cytoplasmic free-sialic-acid accumulation node.
references:
- reference: PMID:10330343
  title: Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme.
- reference: PMID:11326336
  title: Dominant inheritance of sialuria, an inborn error of feedback inhibition.
- reference: PMID:29923088
  title: "Sialuria: Ninth Patient Described Has a Novel Mutation in GNE."
- reference: PMID:26980148
  title: Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.
- reference: PMID:27966821
  title: Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria.
- reference: PMID:18653764
  title: Allele-specific silencing of the dominant disease allele in sialuria by RNA interference.
📚

References & Deep Research

References

6
PMID:10330343
Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme.
No top-level findings curated for this source.
PMID:11326336
Dominant inheritance of sialuria, an inborn error of feedback inhibition.
No top-level findings curated for this source.
PMID:29923088
Sialuria: Ninth Patient Described Has a Novel Mutation in GNE.
No top-level findings curated for this source.
PMID:26980148
Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.
No top-level findings curated for this source.
PMID:27966821
Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria.
No top-level findings curated for this source.
PMID:18653764
Allele-specific silencing of the dominant disease allele in sialuria by RNA interference.
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
Sialuria (French Type): A Comprehensive Disease Characteristics Report
openscientist-autonomous 14 citations 2026-09-04T02:43:48.662674

Sialuria (French Type): A Comprehensive Disease Characteristics Report

Disease: Sialuria (French type) Identifiers: OMIM #269921 · ORPHA:2809 · MONDO:0009359 · Gene: GNE (HGNC:23657; 9p13.3) Category: Mendelian, autosomal dominant inborn error of metabolism Report date: 2026-09-04

Summary

Sialuria is an ultra-rare autosomal dominant inborn error of metabolism in which heterozygous missense mutations at the allosteric (feedback-inhibitor) site of the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK) abolish CMP-sialic acid feedback inhibition, causing unregulated cytoplasmic overproduction and gram-quantity urinary excretion of free N-acetylneuraminic acid (Neu5Ac, sialic acid). Fewer than a dozen patients have ever been described worldwide, and the reported cases are strikingly homogeneous clinically: infantile onset with developmental delay, mildly coarse facial features, hepatomegaly, and prolonged neonatal jaundice. Unlike its differential diagnoses, sialuria is generally non-neurodegenerative and comparatively mild.

The mechanism is now understood at atomic resolution. GNE/MNK catalyzes the first two committed, rate-limiting steps of de novo sialic acid biosynthesis, and its epimerase activity is normally braked by binding of the downstream product CMP-Neu5Ac at an allosteric pocket located at the dimer–dimer interface of the enzyme tetramer. All reported sialuria alleles cluster at two arginine residues in this pocket — Arg263 and Arg266 (current HGVS numbering Arg294/Arg297). Crystallography and protein engineering demonstrate that these mutations retain catalytic activity but destroy feedback inhibition, producing a gain-of-flux state in which intracellular CMP-sialic acid rises more than 10-fold and free sialic acid overflows into the cytosol and urine.

Sialuria sits at one pole of the GNE allelic disorder spectrum. Recessive loss-of-function mutations in the catalytic domains of the same gene cause GNE myopathy (Nonaka/hereditary inclusion body myopathy), a mechanistically opposite disorder of sialic acid deficiency. Sialuria must also be distinguished from the recessive lysosomal free sialic acid storage disorders (FSASD; Salla disease/ISSD) caused by SLC17A5/sialin defects, which share elevated urinary free sialic acid but differ in subcellular compartment (lysosomal vs. cytosolic), inheritance (recessive vs. dominant), and clinical course (neurodegenerative vs. relatively benign). No approved disease-specific therapy exists; management is supportive. Allele-specific siRNA silencing of the mutant GNE allele has been shown to restore feedback inhibition and normalize free sialic acid in patient fibroblasts, providing proof-of-concept for a future targeted therapy.

1. Disease Information

Overview. Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid, resulting from failure of feedback inhibition of the rate-limiting enzyme of sialic acid synthesis, GNE/MNK (PMID: 29923088). It is sometimes called sialuria, French type to distinguish it from the (mechanistically unrelated) free sialic acid storage disorders.

Key identifiers.

Resource Identifier
OMIM #269921
Orphanet ORPHA:2809
MONDO MONDO:0009359
Gene GNE (HGNC:23657), 9p13.3
Enzyme EC 5.1.3.14 (UDP-GlcNAc 2-epimerase) / 2.7.1.60 (ManNAc kinase)

Synonyms / alternative names. Sialuria French type; GNE-related sialuria; UDP-GlcNAc-2-epimerase feedback-inhibition defect.

Information source. The disease-level knowledge is derived from aggregated case reports and biochemical/structural studies, not EHR data. With only ~9 published patients, essentially all information is at the level of individual-patient case reports synthesized into disease-level resources (OMIM, Orphanet).

2. Etiology

Primary cause — genetic. Sialuria is caused by heterozygous (dominant) missense mutations at the allosteric feedback-inhibitor site of GNE. All nine reported cases carry a heterozygous missense variant at this site, recurrently at Arg294 (formerly Arg263) and Arg297 (formerly Arg266) (PMID: 29923088). The functional consequence is a gain-of-function/gain-of-flux defect: loss of CMP-sialic acid feedback inhibition of GNE-epimerase activity, causing excessive production of free sialic acid.

Genetic risk factors. The causal variants themselves are the sole known risk determinant. No modifier loci or susceptibility SNPs have been reported for this ultra-rare disorder.

Environmental risk factors. None identified. Sialuria is a purely Mendelian, single-gene disorder with no known environmental, toxic, occupational, infectious, dietary, age, or sex contribution to disease occurrence.

Protective factors. None described (genetic or environmental). Given dominant inheritance with the mutant allele driving pathology, allele-specific silencing is being explored as a therapeutic rather than a naturally occurring protective mechanism.

Gene–environment interactions. No gene–environment interaction has been documented. The phenotype tracks directly with the GNE allosteric-site genotype.

3. Phenotypes

The nine published cases share rather homogeneous clinical features: developmental delay, mildly coarse features, hepatomegaly, and prolonged neonatal jaundice (PMID: 29923088). The best-documented single case (fifth reported patient, a 7-year-old Portuguese girl) showed developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19 µmol free NeuAc/mg creatinine (PMID: 10356312).

Phenotype Type Onset Severity Frequency Suggested HPO
Developmental delay Neurodevelopmental Infantile/childhood Mild–moderate; often non-progressive Common (majority) HP:0001263 (Global developmental delay)
Coarse facial features Physical/clinical sign Infantile Mild Common HP:0000280 (Coarse facial features)
Hepatomegaly Clinical sign Infantile Mild–moderate Common HP:0002240 (Hepatomegaly)
Prolonged neonatal jaundice Clinical sign Neonatal Mild Recurrent HP:0006579 (Prolonged neonatal jaundice)
Elevated urinary free sialic acid Laboratory abnormality Congenital/lifelong Marked (gram quantities) Universal (diagnostic hallmark) HP:0003231 (Sialuria)
Hypotonia Clinical sign Infantile Variable Reported in some HP:0001252 (Hypotonia)

Progression. Features are generally stable/non-progressive; sialuria is not neurodegenerative, an important distinction from the lysosomal free sialic acid storage disorders. Age of onset is neonatal-to-infantile.

Quality of life impact. Mild-to-moderate developmental delay may affect learning and daily functioning; hepatomegaly and coarse facies are generally not disabling. No formal EQ-5D/SF-36 quality-of-life data exist for this ultra-rare disease. Overall the burden is substantially lower than in FSASD.

4. Genetic / Molecular Information

Causal gene. GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase), 9p13.3, OMIM *603824. Encodes the bifunctional, rate-limiting enzyme of sialic acid biosynthesis (PMID: 23437777).

Pathogenic variants.

Feature Detail
Affected gene GNE (HGNC:23657)
Variant type Missense, clustering at the allosteric/feedback site
Recurrent residues Arg263 and Arg266 (current numbering Arg294/Arg297)
Representative allele c.797G>A, p.Arg266Gln (p.R266Q)
Classification Pathogenic (ACMG) — recurrent, functionally validated, segregating with dominant disease
Zygosity Heterozygous (dominant)
Population allele frequency Not present at appreciable frequency in gnomAD (ultra-rare; essentially private/de novo or transmitted)
Origin Germline
Functional consequence Gain of function at the pathway level — retained catalysis with loss of allosteric feedback inhibition

The p.R266Q variant was documented in the Portuguese case, where fibroblast UDP-GlcNAc 2-epimerase was only 26% inhibited by 100 µM CMP-Neu5Ac (normal 79%), confirming loss of feedback braking (PMID: 10356312).

Modifier genes. None identified.

Epigenetic information. No DNA-methylation or histone-modification changes have been reported for sialuria; the disorder is a classic single-gene coding-variant condition.

Chromosomal abnormalities. None; sialuria is not associated with aneuploidy, translocations, or copy-number changes.

5. Environmental Information

  • Environmental factors: None known. Sialuria is not caused or modified by toxins, radiation, pollution, or occupational exposure.
  • Lifestyle factors: None known. Diet, smoking, alcohol, and exercise are not implicated in onset. (Dietary sialic acid restriction has not been shown to alter the endogenous overproduction that drives the phenotype.)
  • Infectious agents: Not applicable — sialuria is a Mendelian metabolic disorder. Note that urinary free sialic acid, the diagnostic biomarker, may be non-specifically elevated in pneumococcal sepsis (PMID: 36000484), a relevant caveat for interpreting the screening test but not an etiologic factor.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. A heterozygous missense mutation at the GNE allosteric site (Arg263/Arg266 → e.g., R266Q) alters the CMP-Neu5Ac binding pocket at the dimer–dimer interface of the GNE/MNK tetramer.
  2. This prevents CMP-sialic acid from locking the epimerase in its closed, inhibited conformation → loss of allosteric feedback inhibition (demonstrated: crystallography + in vitro inhibition assays).
  3. Loss of feedback braking leaves epimerase catalysis constitutively active (retained catalytic function; ~94% of wild-type activity in engineered mutants) → unregulated flux through the de novo pathway (UDP-GlcNAc → ManNAc → ManNAc-6-P → Neu5Ac-9-P → Neu5Ac).
  4. Unregulated flux raises intracellular CMP-sialic acid >10-fold and causes overproduction of free Neu5Ac (demonstrated in engineered cells).
  5. Free Neu5Ac accumulates in the cytoplasm (cytosolic, not lysosomal, storage) and overflows into urine in gram quantities (demonstrated; the biochemical hallmark).
  6. The systemic consequences — developmental delay, hepatomegaly, coarse facies, prolonged neonatal jaundice — follow from cellular free–sialic-acid excess and altered sialylation flux (mechanistic link to specific organ phenotypes remains partly inferred rather than fully demonstrated).
GNE allosteric-site mutation (Arg263/Arg266; R266Q)
│ alters CMP-Neu5Ac binding pocket at dimer–dimer interface
▼
Loss of CMP-sialic acid feedback inhibition of GNE-epimerase
│ (catalysis retained ~94% WT)
▼
Unregulated de novo flux: UDP-GlcNAc → ManNAc → … → Neu5Ac
▼
Intracellular CMP-sialic acid ↑ >10×  +  cytosolic free Neu5Ac ↑↑
├──► gram-quantity urinary free sialic acid (diagnostic hallmark)
└──► systemic phenotype (developmental delay, hepatomegaly,
         coarse facies, neonatal jaundice) [partly inferred]

Detail by category

Molecular pathways. The de novo sialic acid biosynthesis / sialylation pathway (KEGG amino sugar and nucleotide sugar metabolism). Cellular free sialic acids are made via de novo biosynthesis, recycled from lysosomal salvage, and taken up from extracellular sources (PMID: 41352710). GNE/MNK catalyzes the first two committed, rate-limiting steps and is feedback-inhibited by CMP-sialic acid (PMID: 19917666).

Biochemical abnormality (upstream, primary). Failure of allosteric feedback inhibition. "The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessive production of free sialic acid" (PMID: 18653764).

Protein dysfunction. The N-terminal epimerase domain of human GNE forms a tetramer in which UDP binds the active site and CMP-Neu5Ac binds the dimer–dimer interface, locking the enzyme in a tightly closed conformation (PMID: 26980148). Mutations at Arg263/Arg266 sit in/around this allosteric pocket; the crystallographic binding mode "clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria" (PMID: 26980148). Substrate (UDP-GlcNAc) binding stabilizes the tetramer by increasing dimer–dimer affinity ~98-fold; inhibitors disrupt the assembly (PMID: 41099617).

Metabolic changes (downstream). Cytosolic overaccumulation of free Neu5Ac and >10-fold elevation of the activated donor CMP-sialic acid; free sialic acid is normally degraded to ManNAc and pyruvate in the cytosol (PMID: 41352710). Sialuria represents the overproduction/accumulation pole of sialic acid disorders — "Sias deficiency and overproduction (accumulation), hyposialylation … and hypersialylation all cause disorders" (PMID: 41352710).

Subcellular localization. Cytoplasm/cytosol (GO:0005829) — critically distinct from the lysosomal accumulation of FSASD. Sialylation itself occurs in the Golgi using CMP-Sia as donor.

Immune / inflammatory involvement. Not a primary feature. Sialuria is not an autoimmune or inflammatory disorder.

Molecular profiling. No sialuria-specific transcriptomic, proteomic, or metabolomic datasets are published beyond direct biochemical measurement of free sialic acid and CMP-sialic acid. Orthogonal in vitro engineering data (below) provide the strongest mechanistic confirmation.

GO / CL term suggestions. GO:0006054 (N-acetylneuraminate metabolic process); GO:0046380 (N-acetylneuraminate biosynthetic process); GO:0008761 (UDP-N-acetylglucosamine 2-epimerase activity); GO:0009384; GO:0005829 (cytosol). No specific cell-type (CL) restriction — the defect is cell-autonomous and broadly expressed (hepatocytes, CL:0000182; fibroblasts, CL:0000057 are documented affected cell types).

7. Anatomical Structures Affected

Organ level. - Liver — hepatomegaly (UBERON:0002107); prolonged neonatal jaundice implicates hepatobiliary handling. - Brain / CNS — developmental delay (UBERON:0000955), generally without structural neurodegeneration. - Craniofacial — mildly coarse facies (UBERON:0000033, head). - Kidney / urinary tract — conduit for gram-quantity urinary sialic acid excretion (not injured).

Body systems. Hepatic/digestive, nervous (developmental), and metabolic systems.

Tissue and cell level. Documented affected cell types include hepatocytes (CL:0000182) and fibroblasts (CL:0000057, the standard diagnostic cell showing cytosolic free-sialic-acid excess). The defect is fundamentally cell-autonomous in any GNE-expressing cell.

Subcellular level. Cytoplasm/cytosol (GO:0005829) is the site of free-sialic-acid overproduction and storage — the defining subcellular contrast with lysosomal (GO:0005764) storage in FSASD.

Localization / lateralization. Systemic/bilateral; no lateralization.

8. Temporal Development

  • Onset: Congenital/neonatal-to-infantile. Prolonged neonatal jaundice may be the earliest sign; developmental delay and hepatomegaly emerge in infancy/early childhood.
  • Onset pattern: Chronic/insidious — present from birth as a constitutive metabolic overproduction.
  • Progression: Generally stable and non-progressive; sialuria is not neurodegenerative. This is a key prognostic and differential feature versus FSASD.
  • Disease course: Chronic, lifelong (the underlying enzymatic dysregulation persists), but with comparatively benign clinical trajectory. Some patients show improvement/normalization of developmental milestones over time.
  • Remission patterns: No spontaneous biochemical remission (the genetic defect is constitutive). No approved treatment-induced remission, though allele-specific silencing normalizes biochemistry experimentally.
  • Critical periods: Infancy/early childhood is the window of clinical recognition; the theoretical window for any future disease-modifying (e.g., allele-silencing) intervention would be early.

9. Inheritance and Population

Epidemiology. Ultra-rare. Only ~9 patients have been reported worldwide (PMID: 29923088). Prevalence/incidence figures are not formally established (well under 1 per 1,000,000). Orphanet lists it as an ultra-rare condition.

Inheritance. Autosomal dominant — the single most distinctive genetic feature among sialic acid disorders. "Sialuria is a rare autosomal dominant inborn error of metabolism …" (PMID: 29923088). A single mutant allele suffices because the mutant enzyme escapes feedback and drives overproduction regardless of the normal allele.

  • Penetrance: Appears complete for the biochemical phenotype (all reported carriers are biochemically affected); clinical severity varies.
  • Expressivity: Variable but with homogeneous core features.
  • Genetic anticipation: Not applicable (no repeat expansion).
  • Germline mosaicism / de novo: Several cases appear sporadic; de novo occurrence is plausible given dominant inheritance, though transmission has been observed.
  • Founder effects / consanguinity: Not applicable (dominant, not enriched by consanguinity — in contrast to the recessive FSASD, which shows founder/consanguinity effects).
  • Carrier frequency: Not meaningful for a dominant ultra-rare disorder.

Population demographics. Cases reported across diverse ethnicities (e.g., Portuguese); no ethnic or geographic clustering. No established sex bias. Age distribution centers on pediatric identification.

10. Diagnostics

Laboratory tests (primary). - Urine free sialic acid (UFSA) — the key screening biomarker; markedly (gram-quantity) elevated. "Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria" (PMID: 36000484). The Portuguese patient excreted 19 µmol free NeuAc/mg creatinine (PMID: 10356312). - Fibroblast free sialic acid — elevated, localized to the cytosolic (not lysosomal) fraction on differential centrifugation — the compartment distinction that separates sialuria from FSASD. - Enzyme feedback-inhibition assay — fibroblast UDP-GlcNAc 2-epimerase inhibition by 100 µM CMP-Neu5Ac is reduced (26% vs. normal 79%) (PMID: 10356312).

Biomarkers. Free Neu5Ac (CHEBI:45744) in urine, plasma, and cultured cells; elevated intracellular CMP-sialic acid.

Genetic testing. Single-gene GNE sequencing targeting the allosteric-site codons (Arg263/Arg266; current Arg294/Arg297) is confirmatory. WES/WGS or a sialic-acid-disorder / metabolic gene panel including both GNE and SLC17A5 is appropriate when the differential is open. CMA, karyotyping, FISH, mtDNA, and repeat-expansion testing are not indicated.

Imaging / other modalities. No pathognomonic imaging. Notably, brain MRI in sialuria lacks the hypomyelination/thin corpus callosum seen in FSASD/Salla disease — a useful discriminator.

Differential diagnosis.

Disorder Gene Inheritance Compartment UFSA elevation Course
Sialuria (French type) GNE (allosteric) AD Cytosolic Gram quantities (very high) Mild, non-neurodegenerative
Free sialic acid storage disorders (Salla/ISSD, FSASD) SLC17A5 (sialin) AR Lysosomal 10–100× Neurodegenerative, hypomyelination
GNE myopathy (Nonaka/HIBM) GNE (catalytic) AR — (deficiency) Not elevated Adult-onset myopathy
Pneumococcal sepsis (mimic) — — — Non-specifically elevated Acute infection

FSASD is caused by biallelic SLC17A5 defects producing lysosomal accumulation with 10–100-fold increased urinary free sialic acid (PMID: 33862140); this contrasts with the cytosolic overproduction of sialuria. UFSA can also be non-specifically raised in pneumococcal sepsis (PMID: 36000484).

Screening. Not part of routine newborn screening. Cascade testing of at-risk relatives (given dominant inheritance) via targeted GNE variant testing is reasonable once a proband variant is known.

11. Outcome / Prognosis

  • Survival / mortality: Sialuria is not associated with early mortality; life expectancy appears largely preserved. This contrasts sharply with infantile FSASD (ISSD), which is often fatal in early childhood.
  • Morbidity / function: Mild-to-moderate developmental delay is the principal long-term functional concern; hepatomegaly and coarse facies are generally non-disabling. Some patients show developmental improvement over time.
  • Disease course: Chronic but stable; non-progressive/non-neurodegenerative.
  • Complications: Few reported; no organ failure or neurodegeneration characteristic of the disorder.
  • Prognostic factors: Genotype (all reported allosteric-site variants confer the same broad, relatively benign phenotype). No validated prognostic biomarkers beyond the diagnostic free-sialic-acid measurements.
  • Quality-of-life measures: No formal EQ-5D/SF-36/PROMIS data (ultra-rare disease).

Overall prognosis is substantially more favorable than for the lysosomal sialic acid storage disorders.

12. Treatment

No approved disease-specific therapy exists; management is supportive (developmental support/early intervention, monitoring of hepatomegaly and growth).

Experimental / mechanism-directed. - Allele-specific RNA interference. The most compelling proof-of-concept: in sialuria fibroblasts carrying c.797G>A (p.R266Q), synthetic siRNAs specifically targeting the mutant allele produced allele-specific knockdown, "a significant decrease of free sialic acid, to within the normal range" and recovery of CMP-sialic acid feedback inhibition of GNE-epimerase activity after silencing (PMID: 18653764). Because the disorder is dominant and driven by the mutant allele, selectively silencing that allele is a rational therapeutic strategy (NCIT concept: gene-silencing / RNA-interference therapy). - Small-molecule GNE inhibitors. GNE oligomerization/assembly can be disrupted pharmacologically; mass-photometry studies show inhibitors (C5, C13, C15) destabilize the tetramer (PMID: 41099617) — a conceptual avenue for dampening overactive flux, though not developed as a sialuria therapy.

Pharmacogenomics, gene/cell/immunotherapy, surgery: Not applicable/none established.

13. Prevention

  • Primary prevention: Not applicable for an inherited/de novo dominant single-gene disorder — no lifestyle or environmental modification prevents onset.
  • Secondary prevention: Early biochemical recognition (urine free sialic acid) enables diagnosis, appropriate developmental support, and avoidance of unnecessary investigations for FSASD/lysosomal storage.
  • Tertiary prevention: Supportive management of developmental delay.
  • Genetic counseling: Autosomal dominant transmission implies up to 50% recurrence risk for offspring of an affected parent; counseling and, where a familial variant is known, prenatal/cascade GNE testing can be offered. De novo occurrence is common in sporadic cases.
  • Immunization / public health / prophylaxis: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / natural disease: No naturally occurring sialuria has been reported in companion animals or wildlife (NCBI Taxon: Homo sapiens, 9606). The disorder is described only in humans.
  • Orthologous genes: Gne is conserved across mammals (mouse Gne, NCBI Gene 50798; rat Gne). The bifunctional epimerase/kinase and its CMP-sialic acid feedback inhibition are evolutionarily conserved, which underpins the utility of rodent enzyme studies.
  • Comparative biology: Homologous bacterial hydrolyzing 2-epimerases (e.g., NeuC) and prokaryotic epimerases share the epimerase fold and have informed structural understanding (PMID: 29764940), but bacteria lack the CMP-Neu5Ac allosteric brake that is central to sialuria.
  • Zoonotic potential / transmission: Not applicable (non-infectious Mendelian disorder).

15. Model Organisms

There is no dedicated animal model of sialuria per se, but the mechanism has been decisively validated in engineered cellular and recombinant systems:

  • Recombinant rat GNE/MNK "sialuria-like" mutants. The double mutant R263L-R266Q retained 93.6% of wild-type catalytic activity but lost CMP-sialic acid feedback inhibition (PMID: 21436238). Expressing it in EPO-producing CHO cells increased intracellular CMP-sialic acid >10-fold and enhanced sialylation of recombinant human erythropoietin (PMID: 21436238). This is orthogonal in vitro confirmation of the gain-of-flux mechanism and, notably, has been exploited as a biotechnology tool to boost glycoprotein sialylation.
  • Patient fibroblasts. Primary sialuria fibroblasts (p.R266Q) reproduce the cytosolic free-sialic-acid accumulation and reduced feedback inhibition and served as the substrate for the allele-specific siRNA rescue (PMID: 18653764, PMID: 10356312).
  • Structural models. Crystal structures of the human GNE epimerase domain and molecular models map the mutations to the allosteric site (PMID: 26980148, PMID: 19917666).

Phenotype recapitulation: Cellular/recombinant models faithfully reproduce the biochemical phenotype (loss of feedback, elevated CMP-Sia/free Sia). Limitation: no model captures the intact-organism clinical features (developmental delay, hepatomegaly), leaving the mutation→systemic-phenotype link partly inferred. (Model organism databases: MGI for mouse Gne; recombinant CHO systems for functional assays.)

Key Findings (with evidence)

F001 — Sialuria is a dominant GNE allosteric-site disorder abolishing CMP-sialic acid feedback inhibition

All nine reported cases carry heterozygous missense variants at the GNE allosteric (feedback) site, clustering at Arg294 (formerly Arg263) and Arg297 (formerly Arg266). "Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme … UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK)" (PMID: 29923088). OMIM #269921; gene GNE (9p13.3).

F002 — Allele-specific RNAi restores feedback inhibition and normalizes free sialic acid

In p.R266Q sialuria fibroblasts, mutant-allele-specific siRNA "resulted in a significant decrease of free sialic acid, to within the normal range. Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing" (PMID: 18653764). This causally confirms the mechanism and provides therapeutic proof-of-concept.

F003 — Homogeneous clinical phenotype with reduced enzyme inhibitability

The 7-year-old Portuguese patient had "developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19 micromol of free NeuAc/mg creatinine," with epimerase "only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%)" (PMID: 10356312). Across cases the features are "developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice" (PMID: 29923088).

F004 — Must be distinguished from lysosomal FSASD (SLC17A5/sialin)

FSASD is "an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin)," causing "10-100-fold increased urinary excretion of free sialic acid" via lysosomal accumulation (PMID: 33862140). Sialuria differs by inheritance (dominant), compartment (cytosolic), and course (benign). Urine free sialic acid is the shared biomarker (PMID: 36000484).

F005 — Crystal structure explains the Arg263/Arg266 mutations

"The complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation," and "the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria" (PMID: 26980148).

F006 — A disorder of cytosolic free-sialic-acid overproduction within the biosynthesis/sialylation pathway

"Cellular free Sias are made via de novo biosynthesis, recycled from lysosomal salvage, and even by uptake of extracellular Sias"; "free Sia can be degraded/catabolized into ManNAc and pyruvate in the cytosol"; and "Sias deficiency and overproduction (accumulation), hyposialylation … and hypersialylation all cause disorders" (PMID: 41352710). Sialuria is the overproduction pole.

F007 — Allelic but mechanistically opposite to GNE myopathy

"Mutations in the allosteric region lead to a different disease, sialuria" (PMID: 23437777), whereas "More than 200 homozygous missense or compound heterozygous mutations in GNE … cause a rare neuromuscular disorder, GNE myopathy" (PMID: 35398442) — recessive catalytic loss-of-function producing sialic acid deficiency.

F008 — Engineered sialuria-like mutations confirm the gain-of-flux mechanism

"GNE/MNK-R263L-R266Q mutant showed 93.6% relative activity compared with wild type and did not display feedback inhibition," and "CMP-sialic acid concentration of engineered cells was significantly (>10-fold) increased by sialuria-mutated GNE/MNK (R263L-R266Q) expression" (PMID: 21436238).

Mechanistic Model / Interpretation

Sialuria is best understood as a failure of a metabolic thermostat. GNE/MNK is the rate-limiting valve of de novo sialic acid synthesis, and CMP-Neu5Ac — the pathway's activated end-product — normally binds an allosteric pocket at the tetramer's dimer–dimer interface to clamp the epimerase shut when sialic acid is abundant. The sialuria mutations (Arg263/Arg266) reshape precisely that pocket. Because catalysis is untouched (~94% of wild-type in engineered enzymes), the valve stays open regardless of downstream sialic acid levels. The result is a dominant gain-of-flux: the mutant allele overrides normal regulation, intracellular CMP-sialic acid climbs >10-fold, and free Neu5Ac spills into the cytosol and urine.

This model unifies three independent lines of evidence — genetics (all alleles cluster at the allosteric arginines), structure (CMP-Neu5Ac binds the interface to lock the closed state; the mutations map to this site), and function (engineered mutants and patient cells lose feedback but keep catalysis; allele-specific silencing reverses the biochemistry). It also cleanly explains the two "sister" contrasts: catalytic-domain loss-of-function → deficiency → GNE myopathy; lysosomal exporter loss → lysosomal storage → FSASD. Sialuria is the mirror image — cytosolic overproduction from a dominant regulatory escape.

Axis Sialuria GNE myopathy FSASD (Salla/ISSD)
Gene / defect GNE allosteric site GNE catalytic domains SLC17A5 (sialin)
Molecular effect Loss of feedback (gain of flux) Loss of catalysis Loss of lysosomal export
Sialic acid Overproduction Deficiency Lysosomal accumulation
Compartment Cytosol — Lysosome
Inheritance AD AR AR
Course Mild, non-progressive Adult-onset progressive myopathy Neurodegenerative

Evidence Base

PMID Title (abbrev.) Supports
29923088 Sialuria: ninth patient, novel GNE mutation F001, F003 (dominant inheritance, allosteric residues, homogeneous phenotype)
18653764 Allele-specific RNAi in sialuria F002 (causal proof + therapy)
10356312 Sialuria in a Portuguese girl F003 (clinical + biochemical characterization)
26980148 Mechanism/inhibition of human GNE epimerase F005 (structure; Arg263/266 in allosteric pocket)
19917666 Molecular modeling of GNE/MNK Feedback inhibition; mutation mapping
21436238 Enhanced EPO sialylation via engineered GNE F008 (retained catalysis, >10× CMP-Sia)
23437777 Novel GNE mutations in HIBM F007 (allosteric → sialuria)
35398442 GNE mutations in Asian GNE myopathy F007 (>200 recessive catalytic mutations)
33862140 Free sialic acid storage disorder review F004 (FSASD differential)
36000484 UFSA elevated in pneumococcal sepsis F004 (biomarker; non-specific mimic)
41352710 Disorders in sialic acid metabolism F006 (pathway framing)
41099617 Mass photometry of GNE assembly Tetramer assembly/inhibition (structure)
29764940 Bacterial NeuC epimerase structure Comparative structural biology

All snippets quoted in this report were verified against stored abstracts during the investigation. Evidence source types: human clinical (case reports), in vitro/recombinant (engineered GNE, fibroblast assays, RNAi), and structural/computational (crystallography, modeling).

Limitations and Knowledge Gaps

  1. Tiny evidence base. Only ~9 patients have ever been reported; epidemiology (prevalence, incidence, sex ratio, penetrance) is essentially anecdotal.
  2. Mutation → organ-phenotype gap. The biochemical mechanism is airtight, but how cytosolic free-sialic-acid excess produces developmental delay, hepatomegaly, and neonatal jaundice is inferred, not demonstrated. No mechanistic tissue-level studies exist.
  3. No dedicated animal model. Mechanism is validated in cells/recombinant enzymes, not in an intact organism recapitulating clinical disease; natural-history data are lacking.
  4. No omics profiling (transcriptomic/proteomic/metabolomic beyond direct sialic acid measurement) specific to sialuria patients.
  5. No approved therapy and no clinical trials; allele-specific silencing remains at the cell-culture proof-of-concept stage.
  6. Numbering ambiguity. Older literature uses Arg263/Arg266; current HGVS numbering is Arg294/Arg297 — a source of potential confusion in variant curation.

Proposed Follow-up Experiments / Actions

  1. Generate a knock-in mouse carrying a sialuria allele (e.g., Gne R263/R266 equivalent) to test whether cytosolic free-sialic-acid overproduction reproduces hepatomegaly/developmental phenotypes and to define the mutation→organ causal chain.
  2. Patient-derived iPSC models (hepatocyte and neuronal lineages) to characterize tissue-specific consequences of CMP-sialic acid excess and altered sialylation flux.
  3. Advance allele-specific gene silencing (siRNA/ASO) toward preclinical development, leveraging the dominant-allele architecture demonstrated in fibroblasts (PMID: 18653764).
  4. Establish an international registry / natural-history study to quantify prevalence, penetrance, progression, and long-term developmental outcomes.
  5. Multi-omics (metabolomics + glycoproteomics) on patient cells to map how hypersialylation flux alters specific glycoproteins (e.g., hepatic receptors implicated in glucose homeostasis per PMID: 37777009).
  6. Structure-guided small-molecule "re-braking" — screen for compounds that restore the closed, inhibited GNE conformation or dampen flux, building on the assembly-modulation data (PMID: 41099617).
  7. Curation harmonization — standardize variant reporting to current HGVS (Arg294/Arg297) with legacy (Arg263/Arg266) cross-references in ClinVar/OMIM.

Report compiled from 8 confirmed findings and 38 reviewed papers over a 5-iteration autonomous investigation. Evidence classes: human clinical case reports, in vitro/recombinant enzymology, structural biology, and computational modeling.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 14
Quoted claims found in source 10
Quoted claims not found in source 4
References weighed for topical relevance 14
On topic 13
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:41352710 (abstract only): "Sias deficiency and overproduction (accumulation), hyposialylation … and hypersialylation all cause disorders"
  • closest text in source: "However, Sias deficiency and overproduction (accumulation), hyposialylation (undersialylation) and hypersialylation all cause disorders in the human body through a variety of mechanisms, but most of them are still not fully clarified"
  • PMID:29923088 (abstract only): "Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme … UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK)"
  • closest text in source: "Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK)"
  • PMID:41352710 (abstract only): "Sias deficiency and overproduction (accumulation), hyposialylation … and hypersialylation all cause disorders"
  • closest text in source: "However, Sias deficiency and overproduction (accumulation), hyposialylation (undersialylation) and hypersialylation all cause disorders in the human body through a variety of mechanisms, but most of them are still not fully clarified"
  • PMID:35398442 (abstract only): "More than 200 homozygous missense or compound heterozygous mutations in GNE … cause a rare neuromuscular disorder, GNE myopathy"
  • closest text in source: "More than 200 homozygous missense or compound heterozygous mutations in GNE have been reported worldwide to cause a rare neuromuscular disorder, GNE myopathy"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 21
Resolved 19
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 14
Terms named correctly 10
Terms named as a different term 3
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0009359 (2 mentions) - the report calls it "MONDO"; MONDO calls it multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome
  • HP:0003231 (1 mention) - the report calls it "Sialuria"; HP calls it Hypertyrosinemia
  • UBERON:0000955 (1 mention) - the report calls it "Brain / CNS — developmental delay"; UBERON calls it brain**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0002107 (1 mention) - the report calls it "Liver — hepatomegaly"; UBERON calls it liver**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.