Pyrimidine 5-Nucleotidase Deficiency

Mendelian MONDO:0009946 Pathograph 12 Show in embeddings browser Congenital nonspherocytic hemolytic anemia Red cell enzymopathy Inborn disorder of pyrimidine metabolism

Pyrimidine 5-nucleotidase deficiency is an autosomal recessive congenital nonspherocytic hemolytic anemia caused by biallelic NT5C3A variants. It is the third most common red-cell enzymopathy after glucose-6-phosphate dehydrogenase and pyruvate kinase deficiency, and the most common of the nucleotide-metabolism defects. The mechanism turns on something the mature erythrocyte cannot do. During reticulocyte maturation the cell dismantles its ribosomes, and the pyrimidine nucleotides released from ribosomal RNA are charged and therefore cannot cross the membrane. Pyrimidine 5-nucleotidase dephosphorylates them to diffusible nucleosides so they can leave. Without it the pyrimidine nucleotides are trapped: total erythrocyte nucleotide rises several-fold and around 80 percent of the pool becomes pyrimidine, where a normal red cell is 97 percent or more adenine. What the blood film shows follows directly. The undegraded ribosomal RNA aggregates into the coarse basophilic stippling that is the diagnostic hallmark of the disease, and the affected cells are cleared early, giving a chronic compensated-to-moderate hemolysis with reticulocytosis, unconjugated hyperbilirubinemia and pigment gallstones. Two features of the history are worth keeping in view. The disorder was originally named for a raised red-cell ATP, because the accumulated nucleotides were assumed to be adenine phosphates; they are pyrimidines, and the associated ribose phosphate pyrophosphokinase deficiency the first reports emphasised was an epiphenomenon. And the same enzyme deficiency is produced acquired by lead, which is why lead poisoning reproduces both the hemolysis and the stippling.

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1
Inheritance
6
Pathophys.
7
Phenotypes
2
Gaps
12
Pathograph
3
Genes
5
Variants
2
Medical Actions
1
Differentials
13
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Only homozygotes and compound heterozygotes are affected. Biochemical heterozygotes are hematologically normal, which makes carriers hard to identify by enzyme assay and is one reason the disease is underdiagnosed.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:10916681 SUPPORT Human Clinical
"Genetic transmission is via the autosomic recessive mode, and only homozygous or compound heterozygous are clinically affected. Family members who are biochemically heterozygous are haematologically normal and difficult to detect."
States the inheritance mode and, in the same passage, the carrier detection problem it creates.
PMID:4372252 SUPPORT Human Clinical
"While comparatively few family members have been available thus far for study, initial data are compatible with an autosomal, recessive mode of transmission of the deficiency."
The original inference of recessive inheritance, quoted with the authors' own hedge about how few families it rested on.
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Discussions and Knowledge Gaps

2
By what mechanism does pyrimidine nucleotide accumulation actually shorten erythrocyte survival?
KNOWLEDGE GAP p5n_hemolysis_mechanism
Attached to
pathophysiology#Shortened Erythrocyte Survival
Every step from the gene to the stippled cell is well characterised, and the last one is not. Reviews written forty years after the disease was described still call the hemolytic mechanism unclear. Two long-standing observations are unexplained and may be part of the answer: reduced glutathione is raised rather than lowered in patient cells, which is the opposite of the oxidative picture in other red cell enzymopathies, and the ribose phosphate pyrophosphokinase deficiency that dominated the earliest reports was set aside as an epiphenomenon without ever being explained. A third observation constrains any answer: residual enzyme activity does not correlate with the degree of hemolysis. Whatever the destructive step is, it is not a simple function of how much enzyme is left, which is why this node is recorded as HYPOTHETICAL rather than merely unmeasured.
Basophilic stippling, the diagnostic hallmark of this disease, has no term in the Human Phenotype Ontology.
CURATION TODO p5n_basophilic_stippling_has_no_hp_term
Attached to
phenotypes#Erythrocyte inclusion bodies
HPO carries Erythrocyte inclusion bodies (HP:0020080) with three children - Pappenheimer bodies, Heinz bodies and Howell-Jolly bodies - and no term for basophilic stippling. The entry binds the parent and carries the specific concept in preferred_term. Pappenheimer bodies (HP:0020081) must not be used instead: its HPO definition happens to contain the words "basophilic stippling", but Pappenheimer bodies are iron-containing siderotic granules, a different entity with a different cause, so that term is an inviting wrong answer rather than a usable approximation. An HPO term request would let this and lead poisoning both bind the finding precisely. The gap is not theoretical. The OpenScientist deep-research report for this disease offered HP:0011273 as "basophilic stippling of erythrocytes"; HPO calls that term Anisocytosis, defined as abnormally increased variability in erythrocyte size. The report's own term-validation section caught it. A missing term does not stay missing: something plausible gets bound in its place.
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Pathophysiology

6
Biallelic NT5C3A Loss-of-Function Variants
Missense, nonsense, splice-site and in-frame deletion variants on both NT5C3A alleles. The gene sits on chromosome 7, has 10 exons with alternative splicing of exon 2, and encodes proteins of 286 and 297 amino acids. Molecular diagnosis was delayed by nearly three decades after the clinical description, partly because P5N pseudogenes on chromosomes 4 and 7 complicate the sequencing.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of Erythrocyte Pyrimidine 5-Nucleotidase Activity
Show evidence (2 references)
PMID:11369620 SUPPORT Human Clinical
"It is found on chromosome 7, consists of 10 exons with alternative splicing of exon 2, and produces proteins 286 and 297 amino acids long."
The gene structure this node describes, from the paper that identified it.
PMID:11369620 SUPPORT Human Clinical
"Three homozygous mutations were identified in this gene in 4 subjects with P5'N-1 deficiency: codon 98 GAT-->GTT, Asp-->Val (linked to a silent polymorphism codon 92, TAC-->TAT), codon 177, CAA-->TAA, Gln-->termination, and IVS9-1, G-->T."
The first three disease alleles, showing the missense, nonsense and splice classes this node covers.
Loss of Erythrocyte Pyrimidine 5-Nucleotidase Activity
Enzyme activity in affected red cells falls to under 14 percent, usually under 10 percent, of normal. The deficit is larger than it looks on a raw assay: the enzyme is normally enriched in reticulocytes, so a reticulocyte-rich hemolytic sample should read high, and reading low against that expectation means the true deficit is greater than the ratio to normal whole blood suggests. In one severe case Western blot showed no detectable protein at all.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
pyrimidine 5-nucleotidase activity GO:0008253 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased pyrimidine 5-nucleotidase activity, annotated with 5'-nucleotidase activity (GO:0008253). GO:0008253 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Intraerythrocytic Pyrimidine Nucleotide Accumulation
Show evidence (2 references)
PMID:4372252 SUPPORT Human Clinical
"The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased."
Quantifies the residual activity and makes the reticulocyte correction that this node depends on.
PMID:36434495 SUPPORT Human Clinical
"Western blot showed no sign of the presence of 5'-nucleotidase protein in the erythrocytes of both studied patients."
A case in which the loss is of the protein itself rather than of its catalytic activity.
Intraerythrocytic Pyrimidine Nucleotide Accumulation
Pyrimidine nucleotides released by ribosomal RNA breakdown during reticulocyte maturation carry a phosphate and cannot cross the membrane. Undephosphorylated, they are trapped. Total nucleotide rises three- to six-fold and roughly 80 percent of the pool becomes pyrimidine, against 97 percent or more adenine in a normal red cell - a compositional inversion, not merely an excess.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
erythrocyte pyrimidine nucleotide catabolism GO:0006244 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased erythrocyte pyrimidine nucleotide catabolism, annotated with pyrimidine nucleotide catabolic process (GO:0006244). GO:0006244 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Retarded Ribosomal RNA Degradation
Show evidence (2 references)
PMID:4372252 SUPPORT Human Clinical
"Total nucleotides in patient cells were present in amounts 3-6 times greater than normal, and approximately 80% contained pyrimidine."
The magnitude and the compositional shift this node asserts.
PMID:4372252 SUPPORT Human Clinical
"Patient erythrocytes uniquely contained large amounts of pyrimidine 5'-ribonucleotides."
Identifies the accumulating species as pyrimidine ribonucleotides specifically.
Retarded Ribosomal RNA Degradation
Mechanism confidence: Provisional
The accumulated pyrimidine ribonucleotides feed back on the dismantling of ribosomal RNA, so undegraded rRNA persists in the maturing cell. This is the step the original authors proposed to connect the biochemical lesion to the morphological one, and it remains the standard account. The mechanism by which the cell is then destroyed is not equally well established.
reticulocyte CL:0000558 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves reticulocyte (CL:0000558). CL:0000558 is a cell type from the Cell Ontology.
ribosomal RNA degradation during reticulocyte maturation GO:0016075 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosomal RNA degradation during reticulocyte maturation, annotated with rRNA catabolic process (GO:0016075). GO:0016075 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Coarse Basophilic Stippling
Shortened Erythrocyte Survival
Show evidence (1 reference)
PMID:4372252 SUPPORT Human Clinical
"It is postulated that the prominent basophilic stippling results from retarded ribosomal RNA degradation secondary to accumulation of degradation products, namely pyrimidine 5'-ribonucleotides."
The proposed link from nucleotide accumulation to stippling, quoted with the authors' own "It is postulated" so the epistemic status is visible.
Coarse Basophilic Stippling
Aggregated undegraded ribosomal RNA visible on a Romanowsky-stained film as coarse blue granules throughout the erythrocyte. It is the diagnostic hallmark of the disease and, together with a nonspherocytic hemolytic picture and normal G6PD and pyruvate kinase, is what prompts the enzyme assay or the NT5C3A sequencing.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Erythrocyte inclusion bodies
Show evidence (1 reference)
PMID:11369620 SUPPORT Human Clinical
"Pyrimidine 5' nucleotidase (P5'N-1) deficiency is an autosomal recessive condition causing hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte."
Names the stippling as the characterising feature alongside the nucleotide accumulation that causes it.
Shortened Erythrocyte Survival
Mechanism confidence: Hypothetical
Chronic extravascular hemolysis, ranging from fully compensated to transfusion-requiring. The step from the loaded, stippled cell to its premature clearance is the least well understood part of the chain: reviews describe the hemolytic mechanism as still unclear, and the raised reduced glutathione seen in patient cells has never been explained. The entry therefore records this edge as indirect with unknown intermediates rather than asserting a mechanism. One candidate has real support and is worth naming rather than leaving out. Beyond the nucleotide load itself, inhibition of hexose monophosphate shunt activity in young erythrocytes has been proposed as a second contributor, which would make the cells oxidant-vulnerable. The evidence for it is indirect and comes from a co-inheritance experiment: in a family segregating both this deficiency and hemoglobin E, the doubly homozygous individual had severe hemolysis while each single homozygote was mild or asymptomatic, and globin-chain work traced that to marked instability of Hb E specifically in enzyme-deficient cells, with free alpha-chains accumulating on the membrane. Note the tension with the raised glutathione: an oxidative account has to accommodate a finding that points the other way, and no cited source reconciles them.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Nonspherocytic hemolytic anemia
Reticulocytosis
Unconjugated hyperbilirubinemia
Show evidence (4 references)
PMID:23992312 SUPPORT Human Clinical
"cN-III was first linked to a genetic defect , hereditary pyrimidine nucleotidase deficiency, associated to a nonspherocyt ic hemolytic anemia disorder of still unclear mechanism but metabolically characterized by abnormally high levels of pyrimidine compounds and ribonucleoproteins in..."
A review stating that the hemolytic mechanism remains unclear even though the metabolic lesion is well characterised. Quoted verbatim including the source's own typesetting artefacts.
PMID:16522554 SUPPORT Human Clinical
"No correlation has been found between residual activity and degree of hemolysis."
The dissociation between how much enzyme activity remains and how much hemolysis results. This is the strongest single reason this node is recorded as HYPOTHETICAL: if the amount of enzyme lost does not predict the amount of destruction, the step between them is not a simple dose-response and is not understood.
PMID:4372252 SUPPORT Human Clinical
"The mechanism responsible for increased red cell GSH is unknown."
The unexplained glutathione finding that has accompanied the disease since its description and is part of why the hemolytic step is unresolved.
+ 1 more reference
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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 Pyrimidine 5-Nucleotidase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Blood 4
Nonspherocytic hemolytic anemia OBLIGATE HP:0001930 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonspherocytic hemolytic anemia (HP:0001930), qualified as temporality chronic. HP:0001930 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:39967523 SUPPORT Human Clinical
"Among intrinsic causes of hemolysis, pyrimidine 5'-nucleotidase (P5N) deficiency is a notable condition, often presenting as nonspherocytic hemolytic anemia."
Names the hemolytic picture that defines the clinical presentation.
Erythrocyte inclusion bodies VERY_FREQUENT HP:0020080 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse basophilic stippling of erythrocytes, annotated with Erythrocyte inclusion bodies (HP:0020080). HP:0020080 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:4372252 SUPPORT Human Clinical
"The syndrome was characterized by marked increases above normal in red cell basophilic stippling, total nucleotides, and GSH and by a fairly severe deficiency of ribosephosphate pyrophosphokinase (EC 2.7.6.1.)."
The original characterisation, with stippling named first among the defining features.
Reticulocytosis HP:0001923 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reticulocytosis (HP:0001923). HP:0001923 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:4372252 SUPPORT INDIRECT Human Clinical
"The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased."
Supports the assay-confounder claim through the observation that the enzyme is increased in reticulocyte-rich blood. The quote is indirect for the presence of reticulocytosis itself, which is why directness is recorded as INDIRECT.
Macrocytic anemia HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocytic anemia (HP:0001972). HP:0001972 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39967523 SUPPORT Human Clinical
"The patient exhibited macrocytic anemia and basophilic stippling on peripheral blood smear, with normal results from osmotic fragility tests and G6PD levels."
Records the macrocytosis together with the two negative tests that distinguish this disorder from its main differentials.
Cardiovascular 1
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6254919 SUPPORT Human Clinical
"Other features are chronic hemolytic anemia, splenomegaly, and a profound increase in basophilic stippling on the stained blood film."
Lists splenomegaly among the defining features alongside the hemolysis and the stippling.
Digestive 1
Cholelithiasis FREQUENT HP:0001081 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pigment gallstones, annotated with Cholelithiasis (HP:0001081), qualified as temporality chronic. HP:0001081 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:25153905 SUPPORT Human Clinical
"Both patients developed gallstones; however the father, who had undergone surgery for the removal of stones, had extremely severe intrahepatic cholestasis"
Gallstones in both affected members of one family, and the severe post-surgical course in one of them, which is why the entry recommends biliary surveillance rather than treating stones as incidental.
Metabolism 1
Unconjugated hyperbilirubinemia HP:0008282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Unconjugated hyperbilirubinemia (HP:0008282). HP:0008282 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39967523 SUPPORT INDIRECT Human Clinical
"Hemolytic anemia can shorten erythrocyte lifespan, leading to varying clinical presentations depending on whether hemolysis occurs intravascularly or extravascularly."
Supports the hemolytic origin of the bilirubin load rather than naming hyperbilirubinemia directly, so directness is recorded as INDIRECT.
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Genetic Associations

3
NT5C3A (Causal biallelic variant)
Gene: NT5C3A hgnc:17820 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NT5C3A (hgnc:17820). hgnc:17820 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:11369620 SUPPORT Human Clinical
"The DNA analysis was complicated by P5'N-1 pseudogenes found on chromosomes 4 and 7."
The pseudogene problem, from the study that first sequenced the gene.
PMID:36434495 SUPPORT Human Clinical
"Altogether, our results may substantiate the hypothesis of the heterogeneity of the molecular basis of the defect involving both the mutation presented here and negative regulation of expression of the "normal" allele."
The authors' proposal that a heterozygous coding genotype can still give the full phenotype through allele-specific expression.
PMID:29463777 NO_EVIDENCE In Vitro
"The enzyme pyrimidine 5'-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells."
Recorded as NO_EVIDENCE deliberately. The paper establishes a real non-erythroid function for the gene, but says nothing about the hemolytic disease, and no immunological phenotype has been reported in patients. It is cited so that a reader who finds this literature is not left to infer a disease claim from it.
UGT1A1 (Modifier of the hyperbilirubinemia)
Gene: UGT1A1 hgnc:12530 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UGT1A1 (hgnc:12530). hgnc:12530 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:25153905 SUPPORT Human Clinical
"Investigation of the promoter polymorphism of the uridine diphospho glucuronosyl transferase 1A (UGT1A) gene revealed that the father was homozygous for the allele (TA7) and the daughter heterozygous (TA6/TA7)."
The UGT1A1 genotypes in a family where the paper's own title states that Gilbert syndrome influences clinical expression.
HBB (Modifier when a hemoglobin variant is co-inherited)
Gene: HBB hgnc:4827 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HBB (hgnc:4827). hgnc:4827 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (2 references)
PMID:8839873 SUPPORT Human Clinical
"An individual homozygous for both these conditions has a severe hemolytic anemia, whereas family members who are homozygous for Hb E are asymptomatic and those homozygous for pyrimidine 5' nucleotidase deficiency have the mild hemolytic anemia that is characteristic of this disorder."
The genotype-by-genotype breakdown that establishes the interaction as more than additive.
PMID:15571242 SUPPORT Human Clinical
"A P5N-I gene mutation (IVS8 + 1-2delGT) was found in the family, confirming that the severe phenotype results from the interaction between two genetic diseases."
The molecular follow-up that confirms the severe phenotype is the product of two genetic lesions rather than of an unusually severe single one.
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Variants

5
NT5C3A c.444_446delGTT (p.F149del)
In-frame single-codon deletion reported in two Polish brothers, inherited from an asymptomatic mother, with no detectable 5-nucleotidase protein on Western blot.
Show evidence (1 reference)
PMID:36434495 SUPPORT Human Clinical
"Heterozygous deletion in the NT5C3A gene (c.444_446delGTT), inherited most likely from their asymptomatic mother, resulted in a single amino acid residue deletion (p.F149del) in cytosolic pyrimidine 5'-nucleotidase."
The variant, its consequence and its parental origin.
NT5C3A c.693+1G>A
Homozygous splice-donor variant reported in a 65-year-old woman with systemic lupus erythematosus and prior splenectomy, classified as possibly pathogenic on ACMG criteria.
Show evidence (1 reference)
PMID:39967523 SUPPORT Human Clinical
"Genetic testing revealed a homozygous c.693+1G>A variant in the NT5C3A gene, classified as possibly pathogenic based on ACMG criteria."
The variant and the classification the reporting authors assigned it.
NT5C3A c.773T>C (p.I258T), c.830A>G (p.D277G) and c.252+1G>A
Three alleles from the first NT5C3A genotypes published from China: a compound heterozygous 15-year-old carrying p.I258T and p.D277G, each traced to one parent, and a 54-year-old born to first cousins homozygous for the c.252+1G>A splice-donor variant. Both patients also carried Gilbert-type UGT1A1 alleles. No evidence item is attached. The source (PMID:34547876) is a Chinese-language report whose cached record holds no English body text, so no snippet from it can pass this repository's gates - a Chinese sentence is counted as one word by check-snippet-length, and the only English string in the record is the title, which check-title-snippets rejects. The variant is recorded with its source named in prose rather than dropped, and the tooling limitation is described in this entry's notes.
NT5C3A p.R56G
Homozygous missense variant in a highly conserved region, reported in an African-descendant father and daughter born to first cousins and named pyrimidine-5-nucleotidase Campinas.
Show evidence (1 reference)
PMID:25153905 SUPPORT Human Clinical
"P5'NI gene (NT5C3) gene sequencing revealed a further change in homozygosity at amino acid position 56 (p.R56G), located in a highly conserved region."
The variant, its zygosity and its position in a conserved region.
NT5C3A IVS8+1-2delGT
Splice variant identified in the Bangladeshi family segregating both this deficiency and hemoglobin E, and the allele that confirmed the severe phenotype in that family was a two-gene interaction.
Show evidence (1 reference)
PMID:15571242 SUPPORT Human Clinical
"A P5N-I gene mutation (IVS8 + 1-2delGT) was found in the family, confirming that the severe phenotype results from the interaction between two genetic diseases."
The variant and the conclusion it supported.
💊

Medical Actions

2
Supportive care and transfusion
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
Platform: Other
There is no treatment for the enzyme defect. Management is folate support, monitoring of the hemolysis, and transfusion during severe crises. Because both reported Chinese patients carried Gilbert-type UGT1A1 alleles and one had already developed gallstones, biliary surveillance is part of routine care.
Target Phenotypes: Nonspherocytic hemolytic anemia HP:0001930 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Nonspherocytic hemolytic anemia (HP:0001930). HP:0001930 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39967523 SUPPORT Human Clinical
"This case underscores the necessity for genetic counseling for affected individuals and their families, as well as the importance of continued follow-up and supportive care in managing hemolytic anemia related to enzyme deficiencies."
Names supportive care and follow-up as the management, which is the absence of a disease-modifying option stated positively.
Splenectomy
Action: SplenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Splenectomy (NCIT:C15328). NCIT:C15328 is a clinical intervention from the NCI Thesaurus. NCIT:C15328
Platform: Surgery
Reported in patients with this disease, not established as effective, and with a documented harm. The 65-year-old case had undergone splenectomy and was nonetheless admitted for persistent hemolytic crises, so the entry records splenectomy as something that is done rather than something that works. The harm is worth stating alongside the absent benefit. In one reported patient, splenectomy was followed by extreme sustained thrombocytosis and extensive portal, splenic and mesenteric vein thrombosis, despite standard antithrombotic prophylaxis. Post-splenectomy thrombocytosis is common and usually transient; this was neither. On the evidence in this entry the procedure has no demonstrated benefit in this disease and one severe reported complication, which is an unfavourable balance rather than an open question.
Show evidence (3 references)
PMID:39967523 SUPPORT Human Clinical
"We report a case of a 65-year-old female patient with systemic lupus erythematosus and a history of splenectomy, who was admitted for evaluation of persistent hemolytic crises."
Records both that splenectomy was performed and that hemolysis persisted after it. It does not support efficacy.
PMID:24287477 REFUTE Human Clinical
"We report a rare case of haemolytic anaemia where splenectomy was carried out following trauma to a massively enlarged spleen and was followed by extreme sustained thrombocytosis associated with extensive portal, splenic and mesenteric vein thrombosis despite standard antithrombotic prophylaxis."
A severe thrombotic complication of splenectomy in this disease. Graded REFUTE against splenectomy as a management option, since it is evidence of harm rather than of absent benefit.
PMID:24287477 SUPPORT Human Clinical
"Reactive and redistributional thrombocytosis is a well-known postsplenectomy occurrence .Usually it is transient and it rarely reaches extreme levels."
The background that makes the reported case unusual rather than expected. Quoted verbatim including the source's own spacing error.
🌍

Environmental Factors

1
Lead exposure
No ECTO exposure term is bound. ECTO was searched for a lead-exposure term matching this claim and the candidates found describe route-specific exposures rather than the systemic lead intoxication the cited work reports, so the field is left unbound rather than approximated.
Lead inhibits erythrocyte pyrimidine 5-nucleotidase, producing an acquired copy of the inherited enzyme defect. In a patient with lead intoxication, nucleotidase activity fell to about 25 percent of normal and 12 percent of erythrocyte nucleotides contained cytidine, where pyrimidine nucleotides are virtually absent from normal red cells. This is the mechanistic reason lead poisoning shows the same hemolysis and the same basophilic stippling, and it is why an acquired cause has to be excluded before the inherited disease is diagnosed.
Show evidence (1 reference)
PMID:965496 SUPPORT Human Clinical
"The present report documents that lead-induced deficiency when sufficiently severe gives rise to findings similar to the hereditary disorder."
The phenocopy claim itself, stated by the same group that described the inherited disease.
Mechanism Target:
TRIGGERS Loss of Erythrocyte Pyrimidine 5-Nucleotidase Activity — Lead phenocopies the disease at exactly this node, inhibiting the same enzyme rather than acting anywhere else in the chain.
Show evidence (1 reference)
PMID:965496 SUPPORT Human Clinical
"Lead intoxication is accompanied by an acquired deficiency of erythrocyte pryimidine-specific, 5'-nucleotidase."
States that lead acts by producing a deficiency of this specific enzyme. Quoted verbatim including the source's misspelling of pyrimidine.
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Biochemical Markers

2
Erythrocyte pyrimidine 5-nucleotidase activity
Show evidence (2 references)
PMID:4372252 SUPPORT Human Clinical
"The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased."
The measured residual activity and the reticulocyte correction that has to be applied to it.
PMID:16522554 SUPPORT Human Clinical
"No correlation has been found between residual activity and degree of hemolysis."
Why this assay diagnoses without grading: the value does not predict how severe the disease will be.
Erythrocyte nucleotide pool composition
Show evidence (2 references)
PMID:4372252 SUPPORT Human Clinical
"Total nucleotides in patient cells were present in amounts 3-6 times greater than normal, and approximately 80% contained pyrimidine."
The magnitude and the compositional inversion that define the signature.
PMID:4372252 SUPPORT Human Clinical
"The ultraviolet spectral curves of deproteinized red cell extracts exhibited a shift in maximum absorbance from the usual 256-257 nm to approximately 266-270 nm, and absorbance at 250, 270, 280, and 290 nm, expressed as a ratio of that at 260 nm, differed greatly from normal."
The spectral shift that the screening procedure rests on, with its wavelengths.
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Diagnosis

1
Basophilic stippling with normal G6PD and pyruvate kinase
The disease is found by looking at the film. Marked basophilic stippling in a nonspherocytic hemolytic anemia, with normal osmotic fragility and normal G6PD and pyruvate kinase activity, is the trigger for either a P5N enzyme assay or NT5C3A sequencing. A cheap screening alternative exists and is underused: deproteinized red cell extract shows a shifted ultraviolet absorbance maximum, from the usual 256-257 nm to about 266-270 nm, which requires no enzyme assay at all.
Show evidence (2 references)
PMID:4372252 SUPPORT Human Clinical
"The spectral characteristics of extracts provide the basis of a readily performed screening procedure, which does not require enzyme assay."
The screening test and the fact that it avoids the enzyme assay.
PMID:4372252 SUPPORT Human Clinical
"The ultraviolet spectral curves of deproteinized red cell extracts exhibited a shift in maximum absorbance from the usual 256-257 nm to approximately 266-270 nm, and absorbance at 250, 270, 280, and 290 nm, expressed as a ratio of that at 260 nm, differed greatly from normal."
The measurement the screening procedure rests on, with the wavelengths.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists. Reported family counts are the only figure available and they have grown steadily: about 35 unrelated families by 2000, more than 60 by 2022. Relative rank is better established than absolute frequency - it is the third most common red cell enzymopathy behind G6PD and pyruvate kinase deficiency.
Show evidence (2 references)
PMID:10916681 SUPPORT Human Clinical
"Twenty-five years after its description, P5N deficiency has been reported in about 35 unrelated families from different parts of the world, and it has become one commonly identified cause of hereditary non-spherocytic haemolytic anaemia due to RBC enzymopathy."
The published family count at 25 years, standing in for a prevalence estimate that has never been made.
PMID:36434495 SUPPORT Human Clinical
"The least numerous and the rarest is the group of erythrocyte disorders involved in nucleotide metabolism."
Places the nucleotide-metabolism enzymopathies, of which this is the commonest, as the rarest group of red cell enzyme disorders.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Pyrimidine 5-Nucleotidase Deficiency:

Lead poisoning MONDO:0018019
Overlapping Features The acquired phenocopy, and the differential that matters most because it is treatable and preventable. Lead inhibits the same enzyme, so the film, the hemolysis and the enzyme assay all look the same.
Distinguishing Features
  • A blood lead level, which is normal in the inherited disease.
  • Lead-induced enzyme deficiency is partial (about 25 percent of normal activity reported) where the inherited deficiency is usually under 10 percent.
  • Biallelic NT5C3A variants are present in the inherited disease and absent in lead poisoning.
Show evidence (1 reference)
PMID:965496 SUPPORT Human Clinical
"Nucleotidase activity was about 25% that in normal erythrocytes and 15% or less of that expected in comparable reticulocyte-rich blood."
The residual activity in lead intoxication, which is the figure the distinguishing feature above compares against.
{ }

Source YAML

click to show 
name: Pyrimidine 5-Nucleotidase Deficiency
creation_date: "2026-09-09T14:00:00Z"
category: Mendelian
synonyms:
- P5N deficiency
- P5'N-1 deficiency
- UMPH1 deficiency
- uridine 5-prime monophosphate hydrolase deficiency
- hemolytic anemia due to pyrimidine 5' nucleotidase deficiency
- NT5C3A deficiency
- cN-III deficiency
description: >-
  Pyrimidine 5-nucleotidase deficiency is an autosomal recessive congenital
  nonspherocytic hemolytic anemia caused by biallelic NT5C3A variants. It is the
  third most common red-cell enzymopathy after glucose-6-phosphate dehydrogenase
  and pyruvate kinase deficiency, and the most common of the nucleotide-metabolism
  defects.

  The mechanism turns on something the mature erythrocyte cannot do. During
  reticulocyte maturation the cell dismantles its ribosomes, and the pyrimidine
  nucleotides released from ribosomal RNA are charged and therefore cannot cross
  the membrane. Pyrimidine 5-nucleotidase dephosphorylates them to diffusible
  nucleosides so they can leave. Without it the pyrimidine nucleotides are
  trapped: total erythrocyte nucleotide rises several-fold and around 80 percent
  of the pool becomes pyrimidine, where a normal red cell is 97 percent or more
  adenine.

  What the blood film shows follows directly. The undegraded ribosomal RNA
  aggregates into the coarse basophilic stippling that is the diagnostic hallmark
  of the disease, and the affected cells are cleared early, giving a chronic
  compensated-to-moderate hemolysis with reticulocytosis, unconjugated
  hyperbilirubinemia and pigment gallstones.

  Two features of the history are worth keeping in view. The disorder was
  originally named for a raised red-cell ATP, because the accumulated nucleotides
  were assumed to be adenine phosphates; they are pyrimidines, and the associated
  ribose phosphate pyrophosphokinase deficiency the first reports emphasised was
  an epiphenomenon. And the same enzyme deficiency is produced acquired by lead,
  which is why lead poisoning reproduces both the hemolysis and the stippling.
disease_term:
  preferred_term: hemolytic anemia due to pyrimidine 5' nucleotidase deficiency
  term:
    id: MONDO:0009946
    label: hemolytic anemia due to pyrimidine 5' nucleotidase deficiency
parents:
- Congenital nonspherocytic hemolytic anemia
- Red cell enzymopathy
- Inborn disorder of pyrimidine metabolism
references:
- reference: PMID:4372252
  title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
- reference: PMID:10916681
  title: "Chronic non-spherocytic haemolytic anaemia due to congenital pyrimidine 5' nucleotidase deficiency: 25 years later."
- reference: PMID:11369620
  title: "Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency."
- reference: PMID:23992312
  title: "The enzymology of cytosolic pyrimidine 5'-nucleotidases: functional analysis and physiopathological implications."
- reference: PMID:965496
  title: "Lead poisoning: association with hemolytic anemia, basophilic stippling, erythrocyte pyrimidine 5'-nucleotidase deficiency, and intraerythrocytic accumulation of pyrimidines."
- reference: PMID:36434495
  title: "A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency."
- reference: PMID:39967523
  title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
- reference: PMID:15571242
  title: "The genetic basis of the interaction between pyrimidine 5' nucleotidase I deficiency and hemoglobin E."
- reference: PMID:8839873
  title: "Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency."
- reference: PMID:6254919
  title: Erythrocyte disorders of purine and pyrimidine metabolism.
- reference: PMID:16522554
  title: "Hereditary erythrocyte pyrimidine 5'-nucleotidase deficiency: a biochemical, genetic and clinical overview."
- reference: PMID:25153905
  title: "Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression."
- reference: PMID:24287477
  title: "Splenectomy complicated by sustained extreme thrombocytosis and extensive portosplenomesenteric vein thrombosis in pyrimidine 5'-nucleotidase deficiency."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Only homozygotes and compound heterozygotes are affected. Biochemical
    heterozygotes are hematologically normal, which makes carriers hard to
    identify by enzyme assay and is one reason the disease is underdiagnosed.
  evidence:
  - reference: PMID:10916681
    reference_title: "Chronic non-spherocytic haemolytic anaemia due to congenital pyrimidine 5' nucleotidase deficiency: 25 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic transmission is via the autosomic recessive mode, and only homozygous or compound heterozygous are clinically affected. Family members who are biochemically heterozygous are haematologically normal and difficult to detect.
    explanation: >-
      States the inheritance mode and, in the same passage, the carrier
      detection problem it creates.
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While comparatively few family members have been available thus far for study, initial data are compatible with an autosomal, recessive mode of transmission of the deficiency.
    explanation: >-
      The original inference of recessive inheritance, quoted with the
      authors' own hedge about how few families it rested on.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. Reported family counts are the only figure
    available and they have grown steadily: about 35 unrelated families by 2000,
    more than 60 by 2022. Relative rank is better established than absolute
    frequency - it is the third most common red cell enzymopathy behind G6PD and
    pyruvate kinase deficiency.
  evidence:
  - reference: PMID:10916681
    reference_title: "Chronic non-spherocytic haemolytic anaemia due to congenital pyrimidine 5' nucleotidase deficiency: 25 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-five years after its description, P5N deficiency has been reported in about 35 unrelated families from different parts of the world, and it has become one commonly identified cause of hereditary non-spherocytic haemolytic anaemia due to RBC enzymopathy.
    explanation: >-
      The published family count at 25 years, standing in for a prevalence
      estimate that has never been made.
  - reference: PMID:36434495
    reference_title: "A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The least numerous and the rarest is the group of erythrocyte disorders involved in nucleotide metabolism.
    explanation: >-
      Places the nucleotide-metabolism enzymopathies, of which this is the
      commonest, as the rarest group of red cell enzyme disorders.
pathophysiology:
- name: Biallelic NT5C3A Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Missense, nonsense, splice-site and in-frame deletion variants on both
    NT5C3A alleles. The gene sits on chromosome 7, has 10 exons with alternative
    splicing of exon 2, and encodes proteins of 286 and 297 amino acids.
    Molecular diagnosis was delayed by nearly three decades after the clinical
    description, partly because P5N pseudogenes on chromosomes 4 and 7
    complicate the sequencing.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Loss of Erythrocyte Pyrimidine 5-Nucleotidase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36434495
      reference_title: "A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Only residual activity of pyrimidine 5'-nucleotidase in the brothers' erythrocytes could be observed when compared with the controls, including their asymptomatic father and sister.
      explanation: >-
        Ties a specific NT5C3A genotype to the loss of enzyme activity in the
        patients' own red cells, with unaffected relatives as the comparison.
  evidence:
  - reference: PMID:11369620
    reference_title: "Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is found on chromosome 7, consists of 10 exons with alternative splicing of exon 2, and produces proteins 286 and 297 amino acids long.
    explanation: >-
      The gene structure this node describes, from the paper that identified it.
  - reference: PMID:11369620
    reference_title: "Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three homozygous mutations were identified in this gene in 4 subjects with P5'N-1 deficiency: codon 98 GAT-->GTT, Asp-->Val (linked to a silent polymorphism codon 92, TAC-->TAT), codon 177, CAA-->TAA, Gln-->termination, and IVS9-1, G-->T.
    explanation: >-
      The first three disease alleles, showing the missense, nonsense and splice
      classes this node covers.
- name: Loss of Erythrocyte Pyrimidine 5-Nucleotidase Activity
  biological_scale: MOLECULAR
  description: >-
    Enzyme activity in affected red cells falls to under 14 percent, usually
    under 10 percent, of normal. The deficit is larger than it looks on a raw
    assay: the enzyme is normally enriched in reticulocytes, so a
    reticulocyte-rich hemolytic sample should read high, and reading low against
    that expectation means the true deficit is greater than the ratio to normal
    whole blood suggests. In one severe case Western blot showed no detectable
    protein at all.
  molecular_functions:
  - preferred_term: pyrimidine 5-nucleotidase activity
    modifier: DECREASED
    term:
      id: GO:0008253
      label: 5'-nucleotidase activity
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Intraerythrocytic Pyrimidine Nucleotide Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:4372252
      reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The pyrimidine 5'-ribonucleotides are presumably derived from RNA degradation and, not being diffusible, accumulate when the enzyme catalyzing their dephosphorylation is deficient.
      explanation: >-
        States the causal step this edge asserts, and the reason the substrate
        cannot simply leave the cell instead.
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased.
    explanation: >-
      Quantifies the residual activity and makes the reticulocyte correction
      that this node depends on.
  - reference: PMID:36434495
    reference_title: "A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Western blot showed no sign of the presence of 5'-nucleotidase protein in the erythrocytes of both studied patients.
    explanation: >-
      A case in which the loss is of the protein itself rather than of its
      catalytic activity.
- name: Intraerythrocytic Pyrimidine Nucleotide Accumulation
  biological_scale: CELLULAR
  description: >-
    Pyrimidine nucleotides released by ribosomal RNA breakdown during
    reticulocyte maturation carry a phosphate and cannot cross the membrane.
    Undephosphorylated, they are trapped. Total nucleotide rises three- to
    six-fold and roughly 80 percent of the pool becomes pyrimidine, against 97
    percent or more adenine in a normal red cell - a compositional inversion, not
    merely an excess.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: erythrocyte pyrimidine nucleotide catabolism
    modifier: DECREASED
    term:
      id: GO:0006244
      label: pyrimidine nucleotide catabolic process
  downstream:
  - target: Retarded Ribosomal RNA Degradation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total nucleotides in patient cells were present in amounts 3-6 times greater than normal, and approximately 80% contained pyrimidine.
    explanation: >-
      The magnitude and the compositional shift this node asserts.
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient erythrocytes uniquely contained large amounts of pyrimidine 5'-ribonucleotides.
    explanation: >-
      Identifies the accumulating species as pyrimidine ribonucleotides
      specifically.
- name: Retarded Ribosomal RNA Degradation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The accumulated pyrimidine ribonucleotides feed back on the dismantling of
    ribosomal RNA, so undegraded rRNA persists in the maturing cell. This is the
    step the original authors proposed to connect the biochemical lesion to the
    morphological one, and it remains the standard account. The mechanism by
    which the cell is then destroyed is not equally well established.
  cell_types:
  - preferred_term: reticulocyte
    term:
      id: CL:0000558
      label: reticulocyte
  biological_processes:
  - preferred_term: ribosomal RNA degradation during reticulocyte maturation
    modifier: DECREASED
    term:
      id: GO:0016075
      label: rRNA catabolic process
  downstream:
  - target: Coarse Basophilic Stippling
    causal_link_type: DIRECT
  - target: Shortened Erythrocyte Survival
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is postulated that the prominent basophilic stippling results from retarded ribosomal RNA degradation secondary to accumulation of degradation products, namely pyrimidine 5'-ribonucleotides.
    explanation: >-
      The proposed link from nucleotide accumulation to stippling, quoted with
      the authors' own "It is postulated" so the epistemic status is visible.
- name: Coarse Basophilic Stippling
  biological_scale: CELLULAR
  description: >-
    Aggregated undegraded ribosomal RNA visible on a Romanowsky-stained film as
    coarse blue granules throughout the erythrocyte. It is the diagnostic
    hallmark of the disease and, together with a nonspherocytic hemolytic
    picture and normal G6PD and pyruvate kinase, is what prompts the enzyme assay
    or the NT5C3A sequencing.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Erythrocyte inclusion bodies
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11369620
    reference_title: "Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyrimidine 5' nucleotidase (P5'N-1) deficiency is an autosomal recessive condition causing hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte.
    explanation: >-
      Names the stippling as the characterising feature alongside the nucleotide
      accumulation that causes it.
- name: Shortened Erythrocyte Survival
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Chronic extravascular hemolysis, ranging from fully compensated to
    transfusion-requiring. The step from the loaded, stippled cell to its
    premature clearance is the least well understood part of the chain: reviews
    describe the hemolytic mechanism as still unclear, and the raised reduced
    glutathione seen in patient cells has never been explained. The entry
    therefore records this edge as indirect with unknown intermediates rather
    than asserting a mechanism.

    One candidate has real support and is worth naming rather than leaving out.
    Beyond the nucleotide load itself, inhibition of hexose monophosphate shunt
    activity in young erythrocytes has been proposed as a second contributor,
    which would make the cells oxidant-vulnerable. The evidence for it is
    indirect and comes from a co-inheritance experiment: in a family segregating
    both this deficiency and hemoglobin E, the doubly homozygous individual had
    severe hemolysis while each single homozygote was mild or asymptomatic, and
    globin-chain work traced that to marked instability of Hb E specifically in
    enzyme-deficient cells, with free alpha-chains accumulating on the membrane.
    Note the tension with the raised glutathione: an oxidative account has to
    accommodate a finding that points the other way, and no cited source
    reconciles them.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Nonspherocytic hemolytic anemia
    causal_link_type: DIRECT
  - target: Reticulocytosis
    causal_link_type: DIRECT
  - target: Unconjugated hyperbilirubinemia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23992312
    reference_title: "The enzymology of cytosolic pyrimidine 5'-nucleotidases: functional analysis and physiopathological implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cN-III was first linked to a genetic defect , hereditary pyrimidine nucleotidase deficiency, associated to a nonspherocyt ic hemolytic anemia disorder of still unclear mechanism but metabolically characterized by abnormally high levels of pyrimidine compounds and ribonucleoproteins in erythrocytes, as evidenced by occurrence of basophilic stippling on blood smearings.
    explanation: >-
      A review stating that the hemolytic mechanism remains unclear even though
      the metabolic lesion is well characterised. Quoted verbatim including the
      source's own typesetting artefacts.
  - reference: PMID:16522554
    reference_title: "Hereditary erythrocyte pyrimidine 5'-nucleotidase deficiency: a biochemical, genetic and clinical overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No correlation has been found between residual activity and degree of hemolysis.
    explanation: >-
      The dissociation between how much enzyme activity remains and how much
      hemolysis results. This is the strongest single reason this node is
      recorded as HYPOTHETICAL: if the amount of enzyme lost does not predict
      the amount of destruction, the step between them is not a simple
      dose-response and is not understood.
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mechanism responsible for increased red cell GSH is unknown.
    explanation: >-
      The unexplained glutathione finding that has accompanied the disease since
      its description and is part of why the hemolytic step is unresolved.
  - reference: PMID:8839873
    reference_title: "Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      In view of the increasing evidence that the hemolysis associated with pyrimidine 5' nucleotidase deficiency results not only from an increase in the level of erythrocyte pyrimidines, but also from inhibition of the hexose monophosphate shunt activity in young erythrocytes, it is likely that the marked instability of Hb E in the enzyme-deficient cells results from oxidant damage acting on a mildly unstable Hb variant.
    explanation: >-
      Names the hexose-monophosphate-shunt candidate for the hemolytic step.
      Recorded as INDIRECT because the observation is about Hb E instability in
      deficient cells rather than about hemolysis in the isolated disorder, and
      quoted with the source's own "increasing evidence" and "it is likely".
phenotypes:
- name: Nonspherocytic hemolytic anemia
  category: Hematologic
  description: >-
    Chronic hemolysis without spherocytes, with normal osmotic fragility and
    normal G6PD and pyruvate kinase activity. Severity ranges from a compensated
    picture found incidentally to persistent transfusion-requiring crises.
  phenotype_term:
    preferred_term: Nonspherocytic hemolytic anemia
    term:
      id: HP:0001930
      label: Nonspherocytic hemolytic anemia
    temporality: CHRONIC
  frequency: OBLIGATE
  evidence:
  - reference: PMID:39967523
    reference_title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among intrinsic causes of hemolysis, pyrimidine 5'-nucleotidase (P5N) deficiency is a notable condition, often presenting as nonspherocytic hemolytic anemia.
    explanation: >-
      Names the hemolytic picture that defines the clinical presentation.
- name: Erythrocyte inclusion bodies
  category: Hematologic
  description: >-
    Coarse basophilic stippling: dense blue granules of aggregated ribosomal RNA
    scattered through the erythrocyte on a stained film. Bound to the general
    erythrocyte-inclusion term because HPO has no term for basophilic stippling
    itself; see notes.
  phenotype_term:
    preferred_term: Coarse basophilic stippling of erythrocytes
    term:
      id: HP:0020080
      label: Erythrocyte inclusion bodies
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The syndrome was characterized by marked increases above normal in red cell basophilic stippling, total nucleotides, and GSH and by a fairly severe deficiency of ribosephosphate pyrophosphokinase (EC 2.7.6.1.).
    explanation: >-
      The original characterisation, with stippling named first among the
      defining features.
- name: Reticulocytosis
  category: Hematologic
  description: >-
    Marrow compensation for the shortened red cell lifespan. It is also an
    assay confounder: the enzyme is normally enriched in reticulocytes, so a
    reticulocytosis raises the expected activity that the measured value must be
    read against.
  phenotype_term:
    preferred_term: Reticulocytosis
    term:
      id: HP:0001923
      label: Reticulocytosis
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased.
    explanation: >-
      Supports the assay-confounder claim through the observation that the
      enzyme is increased in reticulocyte-rich blood. The quote is indirect for
      the presence of reticulocytosis itself, which is why directness is
      recorded as INDIRECT.
    directness: INDIRECT
- name: Unconjugated hyperbilirubinemia
  category: Hepatobiliary
  description: >-
    The bilirubin load from chronic hemolysis, presenting as scleral icterus and
    jaundice. Co-inherited UGT1A1 Gilbert alleles were found in both reported
    Chinese cases and would be expected to worsen it.
  phenotype_term:
    preferred_term: Unconjugated hyperbilirubinemia
    term:
      id: HP:0008282
      label: Unconjugated hyperbilirubinemia
  evidence:
  - reference: PMID:39967523
    reference_title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemolytic anemia can shorten erythrocyte lifespan, leading to varying clinical presentations depending on whether hemolysis occurs intravascularly or extravascularly.
    explanation: >-
      Supports the hemolytic origin of the bilirubin load rather than naming
      hyperbilirubinemia directly, so directness is recorded as INDIRECT.
    directness: INDIRECT
- name: Macrocytic anemia
  category: Hematologic
  description: >-
    Raised mean corpuscular volume, driven by the reticulocytosis rather than by
    any defect of DNA synthesis.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  evidence:
  - reference: PMID:39967523
    reference_title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient exhibited macrocytic anemia and basophilic stippling on peripheral blood smear, with normal results from osmotic fragility tests and G6PD levels.
    explanation: >-
      Records the macrocytosis together with the two negative tests that
      distinguish this disorder from its main differentials.
- name: Splenomegaly
  category: Hematologic
  description: >-
    Splenic enlargement from chronic extravascular red cell destruction.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:6254919
    reference_title: Erythrocyte disorders of purine and pyrimidine metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other features are chronic hemolytic anemia, splenomegaly, and a profound increase in basophilic stippling on the stained blood film.
    explanation: >-
      Lists splenomegaly among the defining features alongside the hemolysis and
      the stippling.
- name: Cholelithiasis
  category: Hepatobiliary
  description: >-
    Pigment gallstones from chronic hemolysis, and the complication most likely
    to bring an undiagnosed patient to surgery. Reported in roughly a third of
    patients, and in both members of one father-and-daughter pair, where the
    father went on to severe intrahepatic cholestasis after stone removal.
  phenotype_term:
    preferred_term: Pigment gallstones
    term:
      id: HP:0001081
      label: Cholelithiasis
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:25153905
    reference_title: "Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients developed gallstones; however the father, who had undergone surgery for the removal of stones, had extremely severe intrahepatic cholestasis
    explanation: >-
      Gallstones in both affected members of one family, and the severe
      post-surgical course in one of them, which is why the entry recommends
      biliary surveillance rather than treating stones as incidental.
biochemical:
- name: Erythrocyte pyrimidine 5-nucleotidase activity
  notes: >-
    The diagnostic enzyme assay. Two things make it harder to read than a raw
    ratio suggests. The enzyme is normally enriched in reticulocytes, so a
    reticulocyte-rich hemolytic sample should read high and a normal-looking
    value in that setting is already abnormal. And residual activity does not
    predict severity, so the number diagnoses the disease without grading it.
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased.
    explanation: >-
      The measured residual activity and the reticulocyte correction that has to
      be applied to it.
  - reference: PMID:16522554
    reference_title: "Hereditary erythrocyte pyrimidine 5'-nucleotidase deficiency: a biochemical, genetic and clinical overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No correlation has been found between residual activity and degree of hemolysis.
    explanation: >-
      Why this assay diagnoses without grading: the value does not predict how
      severe the disease will be.
- name: Erythrocyte nucleotide pool composition
  notes: >-
    The biochemical signature, and the finding that gave the disease its correct
    name after two wrong ones. Total erythrocyte nucleotide is three- to
    six-fold raised and roughly 80 percent of the pool is pyrimidine, where a
    normal red cell is 97 percent or more adenine. A screening proxy exists and
    needs no enzyme assay: the ultraviolet absorbance maximum of a deproteinized
    extract shifts from 256-257 nm to about 266-270 nm.
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total nucleotides in patient cells were present in amounts 3-6 times greater than normal, and approximately 80% contained pyrimidine.
    explanation: >-
      The magnitude and the compositional inversion that define the signature.
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ultraviolet spectral curves of deproteinized red cell extracts exhibited a shift in maximum absorbance from the usual 256-257 nm to approximately 266-270 nm, and absorbance at 250, 270, 280, and 290 nm, expressed as a ratio of that at 260 nm, differed greatly from normal.
    explanation: >-
      The spectral shift that the screening procedure rests on, with its
      wavelengths.
genetic:
- name: NT5C3A
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: NT5C3A
    term:
      id: hgnc:17820
      label: NT5C3A
  notes: >-
    Encodes cytosolic 5-nucleotidase III-A (cN-IIIA, P5N-1), on chromosome 7.
    Formerly written P5'N-1 or UMPH1 in the older literature.

    Two practical points about sequencing this gene. P5N pseudogenes on
    chromosomes 4 and 7 complicated the original mutation analysis and are still
    a source of mapping artefact. And at least one reported family shows a
    genotype that does not read as straightforwardly biallelic: two brothers
    carried a heterozygous in-frame deletion yet expressed only the mutant
    transcript, so the authors proposed negative regulation of the normal allele
    rather than a second coding variant. A heterozygous NT5C3A finding in a
    patient with the biochemical phenotype should therefore not be dismissed
    without transcript-level work.

    NT5C3A also has a function outside the red cell that is not part of this
    disease: it is interferon-inducible in many cell types and represses NF-kB
    driven cytokine transcription. No immunological phenotype has been reported
    in P5N-deficient patients, and this entry makes no claim that one exists.
  evidence:
  - reference: PMID:11369620
    reference_title: "Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The DNA analysis was complicated by P5'N-1 pseudogenes found on chromosomes 4 and 7.
    explanation: >-
      The pseudogene problem, from the study that first sequenced the gene.
  - reference: PMID:36434495
    reference_title: "A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether, our results may substantiate the hypothesis of the heterogeneity of the molecular basis of the defect involving both the mutation presented here and negative regulation of expression of the "normal" allele.
    explanation: >-
      The authors' proposal that a heterozygous coding genotype can still give
      the full phenotype through allele-specific expression.
  - reference: PMID:29463777
    reference_title: The intracellular pyrimidine 5'-nucleotidase NT5C3A is a negative epigenetic factor in interferon and cytokine signaling.
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: >-
      The enzyme pyrimidine 5'-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells.
    explanation: >-
      Recorded as NO_EVIDENCE deliberately. The paper establishes a real
      non-erythroid function for the gene, but says nothing about the hemolytic
      disease, and no immunological phenotype has been reported in patients. It
      is cited so that a reader who finds this literature is not left to infer a
      disease claim from it.
- name: UGT1A1
  association: Modifier of the hyperbilirubinemia
  relationship_type: MODIFIER
  gene_term:
    preferred_term: UGT1A1
    term:
      id: hgnc:12530
      label: UGT1A1
  notes: >-
    Co-inherited Gilbert-type UGT1A1 alleles do not cause the hemolysis but
    change how it presents. UGT1A1 conjugates bilirubin; a reduced-activity
    allele on top of a chronic hemolytic load raises unconjugated bilirubin
    further, deepening the jaundice and, plausibly, the gallstone risk. In the
    father-and-daughter pair below the father was homozygous and the daughter
    heterozygous for the TA7 promoter allele, and the reporting paper's own
    title states that Gilbert syndrome influences clinical expression here.
    This is a modifier of clinical expression, not of the enzymopathy.

    A second, independent series reports the same co-inheritance - both patients
    carrying UGT1A1 c.211G>A (p.G71R) - and concludes that establishing the
    UGT1A1 genotype is necessary to read the NT5C3A genotype-phenotype
    relationship accurately. That report (PMID:34547876) is not cited with an
    evidence item, for a tooling reason recorded in this entry's notes rather
    than because the finding is in doubt.
  evidence:
  - reference: PMID:25153905
    reference_title: "Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigation of the promoter polymorphism of the uridine diphospho glucuronosyl transferase 1A (UGT1A) gene revealed that the father was homozygous for the allele (TA7) and the daughter heterozygous (TA6/TA7).
    explanation: >-
      The UGT1A1 genotypes in a family where the paper's own title states that
      Gilbert syndrome influences clinical expression.
- name: HBB
  association: Modifier when a hemoglobin variant is co-inherited
  relationship_type: MODIFIER
  gene_term:
    preferred_term: HBB
    term:
      id: hgnc:4827
      label: HBB
  notes: >-
    Co-inheritance of hemoglobin E converts this from a mild disorder into a
    severe one, and the direction of the interaction is the informative part:
    it is not additive. In the reported Bangladeshi family, individuals
    homozygous for Hb E alone were asymptomatic and those homozygous for the
    enzyme deficiency alone had the usual mild anemia, while the doubly
    homozygous individual had severe hemolytic anemia. Globin-chain work traced
    this to marked instability of Hb E specifically in enzyme-deficient red
    cells, with free alpha-chains accumulating on the membrane. This is the
    observation behind the oxidative-vulnerability candidate recorded on the
    hemolysis node.
  evidence:
  - reference: PMID:8839873
    reference_title: "Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An individual homozygous for both these conditions has a severe hemolytic anemia, whereas family members who are homozygous for Hb E are asymptomatic and those homozygous for pyrimidine 5' nucleotidase deficiency have the mild hemolytic anemia that is characteristic of this disorder.
    explanation: >-
      The genotype-by-genotype breakdown that establishes the interaction as
      more than additive.
  - reference: PMID:15571242
    reference_title: "The genetic basis of the interaction between pyrimidine 5' nucleotidase I deficiency and hemoglobin E."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A P5N-I gene mutation (IVS8 + 1-2delGT) was found in the family, confirming that the severe phenotype results from the interaction between two genetic diseases.
    explanation: >-
      The molecular follow-up that confirms the severe phenotype is the product
      of two genetic lesions rather than of an unusually severe single one.
variants:
- name: NT5C3A c.444_446delGTT (p.F149del)
  description: >-
    In-frame single-codon deletion reported in two Polish brothers, inherited
    from an asymptomatic mother, with no detectable 5-nucleotidase protein on
    Western blot.
  evidence:
  - reference: PMID:36434495
    reference_title: "A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous deletion in the NT5C3A gene (c.444_446delGTT), inherited most likely from their asymptomatic mother, resulted in a single amino acid residue deletion (p.F149del) in cytosolic pyrimidine 5'-nucleotidase.
    explanation: >-
      The variant, its consequence and its parental origin.
- name: NT5C3A c.693+1G>A
  description: >-
    Homozygous splice-donor variant reported in a 65-year-old woman with
    systemic lupus erythematosus and prior splenectomy, classified as possibly
    pathogenic on ACMG criteria.
  evidence:
  - reference: PMID:39967523
    reference_title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing revealed a homozygous c.693+1G>A variant in the NT5C3A gene, classified as possibly pathogenic based on ACMG criteria.
    explanation: >-
      The variant and the classification the reporting authors assigned it.
- name: NT5C3A c.773T>C (p.I258T), c.830A>G (p.D277G) and c.252+1G>A
  description: >-
    Three alleles from the first NT5C3A genotypes published from China: a
    compound heterozygous 15-year-old carrying p.I258T and p.D277G, each traced
    to one parent, and a 54-year-old born to first cousins homozygous for the
    c.252+1G>A splice-donor variant. Both patients also carried Gilbert-type
    UGT1A1 alleles.

    No evidence item is attached. The source (PMID:34547876) is a
    Chinese-language report whose cached record holds no English body text, so
    no snippet from it can pass this repository's gates - a Chinese sentence is
    counted as one word by check-snippet-length, and the only English string in
    the record is the title, which check-title-snippets rejects. The variant is
    recorded with its source named in prose rather than dropped, and the tooling
    limitation is described in this entry's notes.
- name: NT5C3A p.R56G
  description: >-
    Homozygous missense variant in a highly conserved region, reported in an
    African-descendant father and daughter born to first cousins and named
    pyrimidine-5-nucleotidase Campinas.
  evidence:
  - reference: PMID:25153905
    reference_title: "Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      P5'NI gene (NT5C3) gene sequencing revealed a further change in homozygosity at amino acid position 56 (p.R56G), located in a highly conserved region.
    explanation: >-
      The variant, its zygosity and its position in a conserved region.
- name: NT5C3A IVS8+1-2delGT
  description: >-
    Splice variant identified in the Bangladeshi family segregating both this
    deficiency and hemoglobin E, and the allele that confirmed the severe
    phenotype in that family was a two-gene interaction.
  evidence:
  - reference: PMID:15571242
    reference_title: "The genetic basis of the interaction between pyrimidine 5' nucleotidase I deficiency and hemoglobin E."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A P5N-I gene mutation (IVS8 + 1-2delGT) was found in the family, confirming that the severe phenotype results from the interaction between two genetic diseases.
    explanation: >-
      The variant and the conclusion it supported.
environmental:
- name: Lead exposure
  description: >-
    Lead inhibits erythrocyte pyrimidine 5-nucleotidase, producing an acquired
    copy of the inherited enzyme defect. In a patient with lead intoxication,
    nucleotidase activity fell to about 25 percent of normal and 12 percent of
    erythrocyte nucleotides contained cytidine, where pyrimidine nucleotides are
    virtually absent from normal red cells. This is the mechanistic reason lead
    poisoning shows the same hemolysis and the same basophilic stippling, and it
    is why an acquired cause has to be excluded before the inherited disease is
    diagnosed.
  influences_mechanisms:
  - target: Loss of Erythrocyte Pyrimidine 5-Nucleotidase Activity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Lead phenocopies the disease at exactly this node, inhibiting the same
      enzyme rather than acting anywhere else in the chain.
    evidence:
    - reference: PMID:965496
      reference_title: "Lead poisoning: association with hemolytic anemia, basophilic stippling, erythrocyte pyrimidine 5'-nucleotidase deficiency, and intraerythrocytic accumulation of pyrimidines."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lead intoxication is accompanied by an acquired deficiency of erythrocyte pryimidine-specific, 5'-nucleotidase.
      explanation: >-
        States that lead acts by producing a deficiency of this specific enzyme.
        Quoted verbatim including the source's misspelling of pyrimidine.
  evidence:
  - reference: PMID:965496
    reference_title: "Lead poisoning: association with hemolytic anemia, basophilic stippling, erythrocyte pyrimidine 5'-nucleotidase deficiency, and intraerythrocytic accumulation of pyrimidines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present report documents that lead-induced deficiency when sufficiently severe gives rise to findings similar to the hereditary disorder.
    explanation: >-
      The phenocopy claim itself, stated by the same group that described the
      inherited disease.
  notes: >-
    No ECTO exposure term is bound. ECTO was searched for a lead-exposure term
    matching this claim and the candidates found describe route-specific
    exposures rather than the systemic lead intoxication the cited work reports,
    so the field is left unbound rather than approximated.
treatments:
- name: Supportive care and transfusion
  description: >-
    There is no treatment for the enzyme defect. Management is folate support,
    monitoring of the hemolysis, and transfusion during severe crises. Because
    both reported Chinese patients carried Gilbert-type UGT1A1 alleles and one
    had already developed gallstones, biliary surveillance is part of routine
    care.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Nonspherocytic hemolytic anemia
    term:
      id: HP:0001930
      label: Nonspherocytic hemolytic anemia
  evidence:
  - reference: PMID:39967523
    reference_title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case underscores the necessity for genetic counseling for affected individuals and their families, as well as the importance of continued follow-up and supportive care in managing hemolytic anemia related to enzyme deficiencies.
    explanation: >-
      Names supportive care and follow-up as the management, which is the
      absence of a disease-modifying option stated positively.
- name: Splenectomy
  description: >-
    Reported in patients with this disease, not established as effective, and
    with a documented harm. The 65-year-old case had undergone splenectomy and
    was nonetheless admitted for persistent hemolytic crises, so the entry
    records splenectomy as something that is done rather than something that
    works.

    The harm is worth stating alongside the absent benefit. In one reported
    patient, splenectomy was followed by extreme sustained thrombocytosis and
    extensive portal, splenic and mesenteric vein thrombosis, despite standard
    antithrombotic prophylaxis. Post-splenectomy thrombocytosis is common and
    usually transient; this was neither. On the evidence in this entry the
    procedure has no demonstrated benefit in this disease and one severe
    reported complication, which is an unfavourable balance rather than an
    open question.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  evidence:
  - reference: PMID:39967523
    reference_title: "Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a case of a 65-year-old female patient with systemic lupus erythematosus and a history of splenectomy, who was admitted for evaluation of persistent hemolytic crises.
    explanation: >-
      Records both that splenectomy was performed and that hemolysis persisted
      after it. It does not support efficacy.
  - reference: PMID:24287477
    reference_title: "Splenectomy complicated by sustained extreme thrombocytosis and extensive portosplenomesenteric vein thrombosis in pyrimidine 5'-nucleotidase deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a rare case of haemolytic anaemia where splenectomy was carried out following trauma to a massively enlarged spleen and was followed by extreme sustained thrombocytosis associated with extensive portal, splenic and mesenteric vein thrombosis despite standard antithrombotic prophylaxis.
    explanation: >-
      A severe thrombotic complication of splenectomy in this disease. Graded
      REFUTE against splenectomy as a management option, since it is evidence of
      harm rather than of absent benefit.
  - reference: PMID:24287477
    reference_title: "Splenectomy complicated by sustained extreme thrombocytosis and extensive portosplenomesenteric vein thrombosis in pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reactive and redistributional thrombocytosis is a well-known postsplenectomy occurrence .Usually it is transient and it rarely reaches extreme levels.
    explanation: >-
      The background that makes the reported case unusual rather than expected.
      Quoted verbatim including the source's own spacing error.
diagnosis:
- name: Basophilic stippling with normal G6PD and pyruvate kinase
  description: >-
    The disease is found by looking at the film. Marked basophilic stippling in
    a nonspherocytic hemolytic anemia, with normal osmotic fragility and normal
    G6PD and pyruvate kinase activity, is the trigger for either a P5N enzyme
    assay or NT5C3A sequencing. A cheap screening alternative exists and is
    underused: deproteinized red cell extract shows a shifted ultraviolet
    absorbance maximum, from the usual 256-257 nm to about 266-270 nm, which
    requires no enzyme assay at all.
  evidence:
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The spectral characteristics of extracts provide the basis of a readily performed screening procedure, which does not require enzyme assay.
    explanation: >-
      The screening test and the fact that it avoids the enzyme assay.
  - reference: PMID:4372252
    reference_title: "Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ultraviolet spectral curves of deproteinized red cell extracts exhibited a shift in maximum absorbance from the usual 256-257 nm to approximately 266-270 nm, and absorbance at 250, 270, 280, and 290 nm, expressed as a ratio of that at 260 nm, differed greatly from normal.
    explanation: >-
      The measurement the screening procedure rests on, with the wavelengths.
differential_diagnoses:
- name: Lead poisoning
  disease_term:
    preferred_term: lead poisoning
    term:
      id: MONDO:0018019
      label: lead poisoning
  description: >-
    The acquired phenocopy, and the differential that matters most because it is
    treatable and preventable. Lead inhibits the same enzyme, so the film, the
    hemolysis and the enzyme assay all look the same.
  distinguishing_features:
  - A blood lead level, which is normal in the inherited disease.
  - Lead-induced enzyme deficiency is partial (about 25 percent of normal activity reported) where the inherited deficiency is usually under 10 percent.
  - Biallelic NT5C3A variants are present in the inherited disease and absent in lead poisoning.
  evidence:
  - reference: PMID:965496
    reference_title: "Lead poisoning: association with hemolytic anemia, basophilic stippling, erythrocyte pyrimidine 5'-nucleotidase deficiency, and intraerythrocytic accumulation of pyrimidines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nucleotidase activity was about 25% that in normal erythrocytes and 15% or less of that expected in comparable reticulocyte-rich blood.
    explanation: >-
      The residual activity in lead intoxication, which is the figure the
      distinguishing feature above compares against.
discussions:
- discussion_id: p5n_hemolysis_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    By what mechanism does pyrimidine nucleotide accumulation actually shorten
    erythrocyte survival?
  attaches_to:
  - pathophysiology#Shortened Erythrocyte Survival
  rationale: >-
    Every step from the gene to the stippled cell is well characterised, and the
    last one is not. Reviews written forty years after the disease was described
    still call the hemolytic mechanism unclear. Two long-standing observations
    are unexplained and may be part of the answer: reduced glutathione is raised
    rather than lowered in patient cells, which is the opposite of the oxidative
    picture in other red cell enzymopathies, and the ribose phosphate
    pyrophosphokinase deficiency that dominated the earliest reports was set
    aside as an epiphenomenon without ever being explained.

    A third observation constrains any answer: residual enzyme activity does not
    correlate with the degree of hemolysis. Whatever the destructive step is, it
    is not a simple function of how much enzyme is left, which is why this node
    is recorded as HYPOTHETICAL rather than merely unmeasured.
- discussion_id: p5n_basophilic_stippling_has_no_hp_term
  kind: CURATION_TODO
  prompt: >-
    Basophilic stippling, the diagnostic hallmark of this disease, has no term
    in the Human Phenotype Ontology.
  attaches_to:
  - phenotypes#Erythrocyte inclusion bodies
  rationale: >-
    HPO carries Erythrocyte inclusion bodies (HP:0020080) with three children -
    Pappenheimer bodies, Heinz bodies and Howell-Jolly bodies - and no term for
    basophilic stippling. The entry binds the parent and carries the specific
    concept in preferred_term. Pappenheimer bodies (HP:0020081) must not be used
    instead: its HPO definition happens to contain the words "basophilic
    stippling", but Pappenheimer bodies are iron-containing siderotic granules,
    a different entity with a different cause, so that term is an inviting wrong
    answer rather than a usable approximation. An HPO term request would let
    this and lead poisoning both bind the finding precisely.

    The gap is not theoretical. The OpenScientist deep-research report for this
    disease offered HP:0011273 as "basophilic stippling of erythrocytes"; HPO
    calls that term Anisocytosis, defined as abnormally increased variability in
    erythrocyte size. The report's own term-validation section caught it. A
    missing term does not stay missing: something plausible gets bound in its
    place.
notes: >-
  Naming. The disease has accumulated an unusual number of names because it was
  described before it was understood. It first appeared as a "high ATP syndrome"
  and as "ribose phosphate pyrophosphokinase deficiency", both of which turned
  out to be wrong: the accumulated nucleotides are pyrimidines rather than
  adenine phosphates, and the kinase deficiency was an epiphenomenon. The entry
  name uses the enzyme, and the older names are recorded as synonyms so the
  historical literature is findable.

  Apostrophes. The enzyme is universally written with a prime, "pyrimidine
  5'-nucleotidase", and the MONDO label keeps it. The entry name and filename
  drop it, because an apostrophe in a KB filename has caused shell-quoting
  breakage in this repository's tooling before. The primed form is carried in
  disease_term.preferred_term, in the synonyms, and in every quoted snippet.

  One reference in this entry cannot be cited with an evidence item, and the
  reason is tooling rather than doubt. PMID:34547876 reports the first NT5C3A
  genotypes from China, two novel variants, and the co-inherited Gilbert-type
  UGT1A1 alleles in both patients. It is a Chinese-language paper and its cached
  record contains no English body text. Every available snippet therefore fails
  a gate: check-snippet-length splits on whitespace, so a Chinese sentence of any
  length counts as one word, and the only English string in the record is the
  title, which check-title-snippets rejects. The findings are recorded in prose
  with the PMID named, in the UGT1A1 genetic notes and in the variants block.
  This is a coverage gap in the snippet gates for non-space-delimited languages,
  not a judgement about the source, and it is filed as dismech issue #11530.

  Ontology gaps encountered. Basophilic stippling has no HP term and is
  discussed above. The environmental lead entry is left with no ECTO
  exposure_term for the reason recorded in its notes.

  No GeneReviews chapter exists for this disease. PubMed was searched for
  "pyrimidine 5'-nucleotidase deficiency GeneReviews[All Fields]" with no
  results. The phenotype baseline is therefore the 1974 primary description, the
  2000 twenty-five-year review, and the recent case reports.
📚

References & Deep Research

References

13
PMID:4372252
Hereditary hemolytic anemia with human erythrocyte pyrimidine 5'-nucleotidase deficiency.
No top-level findings curated for this source.
PMID:10916681
Chronic non-spherocytic haemolytic anaemia due to congenital pyrimidine 5' nucleotidase deficiency: 25 years later.
No top-level findings curated for this source.
PMID:11369620
Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency.
No top-level findings curated for this source.
PMID:23992312
The enzymology of cytosolic pyrimidine 5'-nucleotidases: functional analysis and physiopathological implications.
No top-level findings curated for this source.
PMID:965496
Lead poisoning: association with hemolytic anemia, basophilic stippling, erythrocyte pyrimidine 5'-nucleotidase deficiency, and intraerythrocytic accumulation of pyrimidines.
No top-level findings curated for this source.
PMID:36434495
A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency.
No top-level findings curated for this source.
PMID:39967523
Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant).
No top-level findings curated for this source.
PMID:15571242
The genetic basis of the interaction between pyrimidine 5' nucleotidase I deficiency and hemoglobin E.
No top-level findings curated for this source.
PMID:8839873
Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency.
No top-level findings curated for this source.
PMID:6254919
Erythrocyte disorders of purine and pyrimidine metabolism.
No top-level findings curated for this source.
PMID:16522554
Hereditary erythrocyte pyrimidine 5'-nucleotidase deficiency: a biochemical, genetic and clinical overview.
No top-level findings curated for this source.
PMID:25153905
Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression.
No top-level findings curated for this source.
PMID:24287477
Splenectomy complicated by sustained extreme thrombocytosis and extensive portosplenomesenteric vein thrombosis in pyrimidine 5'-nucleotidase deficiency.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Pyrimidine 5-Nucleotidase Deficiency (NT5C3A, MONDO:0009946) · 2026-09-09T14:33:30Z · View source

De novo curation of pyrimidine 5'-nucleotidase deficiency, claimed on issue #11521. Deep research: one OpenScientist run (research/Pyrimidine_5_Nucleotidase_Deficiency-deep-research-openscientist.md, 59 min, 18 citations). The report had no reference_validation or term_validation frontmatter, so both were retro-fitted with just validate-research-reference and just validate-research-terms and are committed with it. References: 20/20 resolved, 0 unresolved, 0 unverifiable, 0 off topic, 1/1 quoted claim found in source. Terms: 34 checked, 32 resolved, 0 unresolved, 0 obsolete. The report proposed one wrong ontology binding and it is the important finding of this curation. It offered HP:0011273 as 'basophilic stippling of erythrocytes'. HPO calls HP:0011273 Anisocytosis, defined as abnormally increased variability in erythrocyte size, which is a different phenotype. The report's own term-validation section flagged it under 'Terms the report names something else', and it was not used. This matters because basophilic stippling is the diagnostic hallmark of this disease and HPO has no term for it: I had already bound the parent HP:0020080 Erythrocyte inclusion bodies with an explicit preferred_term and filed a CURATION_TODO discussion about the gap. The report independently demonstrated that a missing term does not stay missing - something plausible gets bound in its place. The discussion now records the incident. Note also that HP:0020081 Pappenheimer bodies is a second inviting wrong answer here: its HPO definition contains the words 'basophilic stippling', but Pappenheimer bodies are iron-containing siderotic granules, a different entity. It was deliberately not used. What the report contributed. A candidate mechanism for the one step this entry marks HYPOTHETICAL: inhibition of hexose monophosphate shunt activity in young erythrocytes as a second contributor to the hemolysis, beyond the nucleotide load. PMID:8839873 was fetched and cited for it, graded directness: INDIRECT because the observation is about hemoglobin E instability in enzyme-deficient cells rather than about hemolysis in the isolated disorder, and quoted with the source's own 'increasing evidence' and 'it is likely'. The node description also records the unresolved tension with the raised reduced glutathione, which points the other way and which no cited source reconciles. Splenomegaly was added as a phenotype from PMID:6254919. Fifteen report-only PMIDs were fetched into references_cache; they are committed because the report cites them. GeneReviews baseline: none exists. PubMed searched for "pyrimidine 5'-nucleotidase deficiency GeneReviews[All Fields]" with no results. The phenotype baseline is the 1974 primary description (PMID:4372252), the 2000 twenty-five-year review (PMID:10916681), and recent case reports. Naming decisions worth recording. The entry name and filename drop the prime from 'pyrimidine 5'-nucleotidase' because an apostrophe in a KB filename has broken this repository's shell tooling before; the primed form is carried in disease_term.preferred_term, in synonyms, and in every quoted snippet. The historical names 'high ATP syndrome' and 'ribose phosphate pyrophosphokinase deficiency' are recorded as synonyms because both were wrong and the older literature is filed under them. Two hedged mechanism nodes carry mechanism_confidence: the rRNA-degradation node is PROVISIONAL (its source says 'It is postulated that'), and the hemolysis node is HYPOTHETICAL. Validation run in this worktree: just validate passes, 35/35 snippets verified against cached references.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 18 citations 2026-09-09T14:28:46.617815

1. Disease Information

Overview. Pyrimidine 5'-nucleotidase (P5N) deficiency is a rare, inherited red-blood-cell enzymopathy causing chronic hereditary nonspherocytic hemolytic anemia (HNSHA). The deficient enzyme — cytosolic pyrimidine 5'-nucleotidase type I (P5'N-1 / cN-III) — normally dephosphorylates pyrimidine 5'-ribonucleotides (UMP, CMP) that are generated when the maturing reticulocyte degrades its ribosomal RNA. When the enzyme is absent, these pyrimidine nucleotides cannot be dephosphorylated to diffusible nucleosides and accumulate inside the erythrocyte, producing the disease's diagnostic hallmark: marked/coarse basophilic stippling on the blood film together with a shortened red-cell lifespan (PMID: 11369620, 23992312, 6254919). It is regarded as one of the more common HNSHA-causing enzymopathies — the third most frequent red-cell enzyme defect causing hemolysis after G6PD and pyruvate kinase deficiency (PMID: 16522554, 15604219).

Key identifiers. - OMIM (phenotype): #266120 — "Anemia, hemolytic, due to UMPH1 deficiency" - OMIM (gene): 606224 (NT5C3A) - Orphanet: ORPHA:35065 ("Pyrimidine 5'-nucleotidase deficiency") - MONDO: MONDO:0009946 - ICD-10: D55.3 (anemia due to disorders of nucleotide metabolism) / D55.8 - ICD-11: 3A11.Y (other specified enzyme deficiency anaemias) - MeSH: related terms "Anemia, Hemolytic, Congenital Nonspherocytic"; "Pyrimidine Nucleotidase"; "5'-Nucleotidase" - HGNC gene:* NT5C3A (HGNC:17820)

Synonyms / alternative names. - Pyrimidine 5'-nucleotidase type I (P5'N-1 / P5N-1 / PN-I / P5NI) deficiency - UMPH1 deficiency (uridine 5'-monophosphate hydrolase 1) - Uridine monophosphate hydrolase deficiency - Cytosolic 5'-nucleotidase III (cN-III) deficiency - Hemolytic anemia due to pyrimidine 5'-nucleotidase deficiency - Historic: "hereditary hemolytic anemia with high red-cell pyrimidine nucleotides"

Data source type. Individual-patient (case reports/EHR-style) for phenotype and variant data; aggregated disease-level resources (OMIM, Orphanet) for definitions and epidemiology.

2. Etiology

Primary cause (genetic). Biallelic loss-of-function variants in NT5C3A (formerly NT5C3, P5N-1, UMPH1) encoding cytosolic pyrimidine 5'-nucleotidase-I. Inheritance is autosomal recessive (PMID: 11369620, 12930399, 12714505). Disease arises when both alleles are non-functional (homozygous or compound heterozygous).

Genetic risk factors. - Causal variants: missense, nonsense, frameshift, and splice-site variants in NT5C3A (see §4). No common susceptibility loci — this is a Mendelian, single-gene disorder. - Modifier genes: co-inherited UGT1A1 promoter (Gilbert TA7 allele) worsens hyperbilirubinemia/cholestasis and gallstone/iron-overload risk; unstable hemoglobins (Hb E) and α-thalassemia interact to increase hemolytic severity (PMID: 25153905, 8839873, 23384910). - Consanguinity: a major contributor because the disorder is recessive and rare; many reported families are consanguineous (PMID: 30951028, 12714505).

Environmental risk factor (acquired phenocopy). Lead poisoning inhibits erythrocyte P5N and reproduces an essentially identical syndrome (anemia, basophilic stippling, pyrimidine nucleotide accumulation) — the principal non-genetic cause of the same biochemical phenotype (PMID: 915002, 2990276, 231420, 11594131). Occupational/industrial lead exposure and non-industrial sources (lead-glazed pottery, contaminated home-made wine/spirits, lead plumbing) are relevant exposures (PMID: 11594131).

Protective factors. No specific genetic or dietary protective alleles are established. Avoidance of lead exposure is protective against the acquired phenocopy. Because the anemia is usually mild-to-moderate and compensated, general good iron/health status and avoidance of additional oxidative stressors mitigate severity.

Gene–environment interactions. Lead and the hereditary deficiency converge on the same enzyme; a genetically borderline individual plus lead exposure could show additive enzyme suppression. Modifier alleles (UGT1A1, Hb E, thalassemia) modulate expressivity (epistasis; PMID: 25153905, 8839873).

3. Phenotypes

Phenotype types: laboratory abnormalities and clinical signs/symptoms of chronic hemolysis. Onset is typically neonatal to early childhood, though mild cases are diagnosed in adulthood; course is chronic/lifelong, usually stable but with hemolytic crises possible.

Phenotype Type Onset / severity / frequency HPO suggestion
Chronic hemolytic anemia (Hb typically 8–11 g/dL) Lab/sign Neonatal–childhood; mild–moderate; near-universal HP:0004870 (nonspherocytic hemolytic anemia); HP:0001878 (hemolytic anemia)
Marked basophilic stippling of erythrocytes Lab Present throughout; hallmark; ~universal HP:0011273 (basophilic stippling of erythrocytes)
Reticulocytosis Lab Compensatory; common (e.g., ~7%) HP:0001923 (reticulocytosis)
Jaundice / unconjugated hyperbilirubinemia Sign Childhood; common HP:0000952 (jaundice); HP:0002904 (hyperbilirubinemia)
Splenomegaly Sign Childhood–adult; common HP:0001744 (splenomegaly)
Cholelithiasis (pigment gallstones) Sign Adolescence/adulthood; common, modifier-dependent HP:0001081 (cholelithiasis)
Elevated LDH; increased indirect bilirubin Lab Chronic; common HP:0025435 (increased LDH)
Pyrimidine nucleotide accumulation / low purine:pyrimidine ratio Lab Constant biochemical marker (no dedicated HP; laboratory)
Iron overload / raised ferritin (esp. post-splenectomy) Lab/sign Adult; variable HP:0011031 (abnormal iron homeostasis); HP:0040130 (increased ferritin)
Possible learning difficulties (reported, uncertain) Behavioral Variable; not established HP:0001328 (specific learning disability) — tentative

Note on neurocognitive association: The original P5'N-1 gene-cloning paper stated the deficiency "is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties" (PMID: 11369620). This link is unconfirmed — it likely reflects the confounding of the lead-poisoning phenocopy (lead itself is neurotoxic) rather than a proven effect of the hereditary enzyme defect on the CNS. No controlled neurocognitive data in genetically confirmed hereditary P5N deficiency are available (evidence gap).

Severity/progression. Generally mild-to-moderate, well-compensated hemolysis; most patients are not transfusion-dependent. Severity is variable and can be aggravated by co-inherited modifiers (Hb E, thalassemia, UGT1A1) (PMID: 8839873, 25153905). Basophilic stippling is unusually coarse and abundant, a distinguishing feature versus other HNSHAs.

Quality-of-life impact. Chronic anemia-related fatigue, jaundice, gallstone morbidity (possible cholecystectomy), and — where splenectomy is done — thrombotic risk. Standardized QoL instrument data specific to P5N deficiency are not available (evidence gap).

4. Genetic / Molecular Information

Causal gene. NT5C3A (aliases NT5C3, P5N-1, UMPH1, PN-I, cN-III; HGNC:17820; NCBI Gene 51251; Ensembl ENSG00000122643; UniProt Q9H0P0), chromosome 7p14.3 (mapped 7p15–p14). Structure: 10 exons, alternative splicing of exon 2, producing protein isoforms of 286 and 297 amino acids (PMID: 11369620). DNA analysis is complicated by P5'N-1 pseudogenes on chromosomes 4 and 7 (PMID: 11369620). Protein family: InterPro HAD-like hydrolase / Pfam PF05822 (5'-nucleotidase family).

Enzyme. Cytosolic 5'-nucleotidase type III (cN-III / P5'N-1; EC 3.1.3.5), a member of the haloacid dehalogenase (HAD) superfamily; it has both hydrolytic (pyrimidine 5'-monophosphate → nucleoside + Pi) and phosphotransferase activities and requires Mg²⁺ (PMID: 23992312). Recombinant human P5'N-1 is a relatively stable protein with essentially identical catalytic efficiency toward CMP and UMP (its two physiological substrates) (PMID: 15604219).

Representative pathogenic variants (all germline; loss-of-function). | Variant (nomenclature as reported) | Type | Population | Ref | |---|---|---|---| | c.693+1G>A (splice) | Splice-site LoF | Turkish | PMID: 39967523 | | c.393_394delTA (frameshift) | Frameshift LoF | Turkish | PMID: 30951028 | | p.R56G (c.166C>G) "Campinas" | Missense (conserved) | Brazilian/African descent | PMID: 25153905 | | p.Asp98Val (codon 98 GAT→GTT) | Missense | — | PMID: 11369620 | | p.Gln177Ter (CAA→TAA) | Nonsense | — | PMID: 11369620 | | IVS9-1 G>T / IVS9-1 g>c (loss of exon 9) | Splice-site | — | PMID: 11369620, 12930399 | | p.Asn190Ser (AAT→AGT) | Missense | Italian | PMID: 12930399 | | DelG576, InsGG743 (frameshift) | Frameshift LoF | Southern Italian / Turkish | PMID: 12930399, 12714505 | | 543T>G (Tyr181Ter) | Nonsense | Turkish | PMID: 12714505 | | 384-385insA | Frameshift | Turkish | PMID: 12714505 |

Variant classification / functional consequence. Reported variants are pathogenic/likely pathogenic (ACMG/AMP) and act via loss of enzyme function (reduced catalytic activity; enzyme activity often ~10–30% of normal, e.g., 15%). Frameshift/nonsense/ splice variants truncate or abolish protein; missense variants (R56G, D98V, N190S) affect conserved catalytic/structural residues (PMID: 11369620, 12930399, 8375297). Founder/geographic clustering: DelG576/InsGG743 in southern Italy; 743-744insGG recurrent in Turkish families (PMID: 12930399, 12714505).

Functional studies (in vitro, PS3-type evidence). Recombinant expression of missense mutants D87V, L131P, N179S, and G230R demonstrated that all "display impaired catalytic properties and/or reduced thermostability," and that mutations "affect amino acid residues unambiguously essential for the catalytic efficiency and/or protein stability" (PMID: 15604219, 16522554). ~15 distinct pathogenic mutations were catalogued by 2006. Notably, there is NO correlation between residual enzyme activity and degree of hemolysis, and some patients retain moderate RBC activity — implying compensation by other nucleotidases/alternative nucleotide pathways; thus nucleotidase activity is not a reliable prognostic indicator (PMID: 16522554, 15604219).

Allele frequency. Individually very rare in gnomAD/population databases (consistent with an ultra-rare recessive disorder); most are private/founder variants. Somatic origin — not applicable (constitutional germline).

Modifier genes. UGT1A1 (Gilbert), HBB (Hb E), α-globin (HBA1/HBA2, α-thalassemia) — modify severity (PMID: 25153905, 8839873, 23384910).

Epigenetic / chromosomal abnormalities. No disease-specific methylation or large-scale chromosomal changes are described; disease is caused by point-level NT5C3A lesions.

5. Environmental Information

  • Environmental / toxic factor: Lead (Pb²⁺) — direct enzyme inhibitor producing an acquired phenocopy (basophilic stippling, pyrimidine accumulation, hemolytic/hypoproliferative anemia) (PMID: 915002, 2990276, 231420). CHEBI:25016 (lead).
  • Lifestyle / exposure sources of lead: occupational (industry, smelting, battery, paint), and non-occupational — lead-contaminated food/water, lead plumbing, artisanal wine/spirits, lead-glazed ceramics (PMID: 11594131).
  • Infectious agents: Not applicable — no infectious etiology.

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function NT5C3A variants (or, in the acquired form, lead inhibition) → abolish cytosolic pyrimidine 5'-nucleotidase (P5'N-1/cN-III) activity (demonstrated; PMID: 11369620, 915002).
  2. Loss of P5'N-1 → failure to dephosphorylate pyrimidine 5'-ribonucleotides (UMP, CMP) that are produced when the maturing reticulocyte degrades ribosomal RNA (demonstrated; PMID: 6254919, 23992312).
  3. Because 5'-monophosphates (unlike nucleosides) cannot cross the RBC membrane, undegraded pyrimidine nucleotides accumulate intracellularly (7–80% of nucleotide pool in the lead phenocopy) (demonstrated; PMID: 915002).
  4. Accumulated ribonucleotides/ribonucleoprotein aggregate → visible as coarse basophilic stippling on the stained film (demonstrated correlate; PMID: 6254919, 23992312).
  5. Branch A — metabolic inhibition: high pyrimidine nucleotides act as metabolic inhibitors, and enzyme-deficient young cells show inhibition of the hexose-monophosphate (pentose phosphate) shunt → reduced NADPH/glutathione antioxidant capacity → oxidative denaturation of hemoglobin (demonstrated in Hb E co-inheritance; PMID: 8839873).
  6. Branch B — nucleotide-pool distortion / energy metabolism: abnormal pyrimidine nucleotides may compete with adenine nucleotides and perturb ATP-dependent processes and pyrimidine-dependent membrane-lipid synthesis (e.g., CDP-choline pathway) — inferred, exact step "still unclear"/"not elucidated" (PMID: 2558262, 23992312).
  7. Convergence → membrane/oxidative injury and reduced deformability → premature erythrocyte destruction (extravascular hemolysis, splenic) → chronic hemolytic anemia (demonstrated phenotype; PMID: 11369620).
  8. Downstream sequelae → reticulocytosis, unconjugated hyperbilirubinemia, jaundice, splenomegaly, pigment gallstones, and (variably) iron overload (demonstrated; PMID: 12930399, 25153905).

The precise biochemical step that shortens red-cell survival remains incompletely defined ("mechanism of still unclear mechanism"; PMID: 23992312; "the precise metabolic process … has not been elucidated yet", PMID: 2558262) — the strongest current evidence favors combined ribonucleoprotein burden plus HMP-shunt/antioxidant impairment.

Category checklist

  • Molecular pathways: pyrimidine nucleotide catabolism/salvage; pentose phosphate (HMP) shunt; glutathione redox. KEGG pyrimidine metabolism (hsa00240).
  • Cellular processes: ribosomal RNA turnover during reticulocyte maturation; oxidative stress response; premature erythrophagocytosis. GO:0006206 (pyrimidine nucleobase metabolic process); GO:0009117 (nucleotide metabolic process); GO:0006749 (glutathione metabolic process); GO:0034101 (erythrocyte homeostasis).
  • Protein dysfunction: loss of function of P5'N-1 (HAD-superfamily hydrolase); truncation/ destabilization/active-site disruption. GO:0008253 (5'-nucleotidase activity); GO:0002100 (tRNA/nucleotide dephosphorylation-related).
  • Metabolic changes: intracellular pyrimidine ribonucleotide (UMP/CMP/CDP-derivatives) accumulation; low purine:pyrimidine ratio; reduced NADPH regeneration.
  • Immune involvement: none primary (non-immune hemolysis; Coombs-negative).
  • Tissue damage mechanism: oxidative membrane/hemoglobin damage, reduced deformability, splenic sequestration.
  • Biochemical abnormality: enzyme deficiency (EC 3.1.3.5), pyrimidine 5'-nucleotide accumulation. CHEBI:17568 (UMP-related), CHEBI:17361 (CMP-related).

7. Anatomical Structures Affected

  • Organ / system level: Hematopoietic/erythroid system primary; spleen (splenomegaly, sequestration) and hepatobiliary system (jaundice, pigment gallstones, cholestasis in modifier cases) secondary; liver iron deposition/siderosis in some (PMID: 25153905). Body system: cardiovascular/hematologic. UBERON:0000178 (blood); UBERON:0002106 (spleen); UBERON:0002107 (liver); UBERON:0002110 (gallbladder); UBERON:0002371 (bone marrow).
  • Tissue / cell level: Erythrocytes / reticulocytes are the target cell population; erythroid precursors in marrow. CL:0000232 (erythrocyte); CL:0000558 (reticulocyte); CL:0000764 (erythroid lineage cell).
  • Subcellular level: Cytosol (site of P5'N-1 and pyrimidine nucleotide accumulation); ribosomes/ribonucleoprotein aggregates (basophilic stippling). GO:0005829 (cytosol); GO:0005840 (ribosome).
  • Localization / lateralization: systemic (circulating red cells); splenomegaly and organ effects are typically bilateral/systemic, not lateralized.

8. Temporal Development

  • Onset: usually neonatal to early childhood hemolytic anemia/jaundice; mild cases may present in adolescence or adulthood (including incidentally). Pattern chronic/insidious (PMID: 30951028, 8375297, 39967523).
  • Progression: stable chronic hemolysis in most; not typically progressive. Complications accrue over time (gallstones, iron overload). Hemolytic exacerbations can be episodic with intercurrent stress.
  • Disease course / duration: lifelong. No spontaneous remission (enzyme defect is constitutional). "Remission" of the acquired lead phenocopy follows removal of exposure and chelation.
  • Critical periods: neonatal jaundice window (kernicterus risk if severe, especially with UGT1A1 modifier); lead-exposure windows for the acquired form.

9. Inheritance and Population

  • Epidemiology: rare; exact prevalence not precisely established (Orphanet: <1/1,000,000 order; "ultrarare–rare"). It is the third most common erythrocyte enzyme abnormality causing hereditary nonspherocytic hemolytic anemia, after G6PD and pyruvate kinase deficiency (PMID: 16522554, 15604219). In nationwide HHA cohorts, RBC enzymopathies as a class account for only ~6–13% of hereditary hemolytic anemia cases (e.g., Korea 6.2–13.3%), of which P5N is a small fraction (PMID: 32830468, 24086942). ~60+ families reported worldwide.
  • Inheritance: Autosomal recessive (PMID: 11369620, 12714505).
  • Penetrance/expressivity: biochemical penetrance essentially complete in homozygotes; clinical expressivity variable, modifier-dependent (PMID: 25153905, 8839873).
  • Genetic anticipation: not applicable (no repeat expansion).
  • Germline mosaicism: not described.
  • Founder effects / geographic clustering: recurrent variants in southern Italian (DelG576) and Turkish (743insGG) populations; reported across Mediterranean, Middle Eastern, South Asian, East Asian, and South American (first in Brazil) populations (PMID: 12930399, 12714505, 25153905).
  • Consanguinity: important contributor; many homozygous cases from consanguineous unions (PMID: 30951028, 12714505).
  • Carrier frequency: not well quantified; heterozygous carriers are asymptomatic with ~50% enzyme activity.
  • Sex ratio: autosomal — no sex predilection (M:F ≈ 1:1).

10. Diagnostics

Clinical/laboratory tests. - Peripheral blood film: the key clue — coarse basophilic stippling with polychromasia, anisopoikilocytosis; can be recognized from the film alone (PMID: 23897698, 30951028). - Hemolysis panel: ↓Hb, ↑reticulocytes, ↑LDH, ↑indirect bilirubin, ↓haptoglobin; Coombs-negative (non-immune). Normal osmotic fragility and normal G6PD (helps exclude membranopathy/G6PD) (PMID: 39967523). - Biochemical confirmation: erythrocyte P5N enzyme assay (activity typically ~10–30% of normal) and demonstration of elevated intra-erythrocytic pyrimidine nucleotides — e.g., UV spectral scan of a nucleotide extract showing a shifted 260/280 absorbance ratio, or a decreased purine:pyrimidine ratio (1.07 vs 1.4–2.98) (PMID: 30951028, 23384910). LOINC: use nucleotidase enzyme activity and RBC count/retic panels. - Blood lead level: mandatory to exclude the acquired phenocopy (PMID: 915002).

Genetic testing. - NT5C3A single-gene sequencing or HNSHA/hemolytic anemia gene panels (NGS) are the definitive molecular test; WES/WGS used when panels are negative. Pseudogenes on chr 4/7 require careful primer/analysis design (PMID: 11369620, 39967523). GTR panels for "hereditary hemolytic anemia" include NT5C3A. - Chromosomal microarray/karyotype/FISH: not indicated (point mutations). mtDNA/repeat-expansion testing: not applicable.

Omics-based diagnostics. Metabolomic profiling of RBC nucleotides (pyrimidine accumulation) is diagnostic in research settings; not routine.

Clinical criteria / differential diagnosis. Diagnosis rests on HNSHA + basophilic stippling + enzyme/nucleotide/genetic confirmation. Differential: lead poisoning (check Pb, ALAD), thalassemia and hemoglobinopathies (basophilic stippling also seen), G6PD deficiency, pyruvate kinase deficiency, other HNSHA enzymopathies, hereditary spherocytosis (osmotic fragility), sideroblastic anemias (PMID: 34889365, 2990276).

Screening. No population newborn screening. Cascade/carrier testing offered in affected families; consider in consanguineous pedigrees.

11. Outcome / Prognosis

  • Survival/life expectancy: generally good; near-normal life expectancy. Anemia is usually mild-to-moderate and compensated; rarely transfusion-dependent (PMID: 8375297).
  • Morbidity: chronic anemia/fatigue, jaundice, pigment gallstones (may need cholecystectomy), iron overload/siderosis (especially post-splenectomy or with UGT1A1 modifier), and, if splenectomized, thrombotic complications (PMID: 25153905, 12930399, 24287477).
  • Complications: neonatal hyperbilirubinemia; gallstones; iron overload; post-splenectomy extreme thrombocytosis and portosplenomesenteric vein thrombosis (PMID: 24287477).
  • Prognostic factors: co-inherited modifiers (UGT1A1, Hb E, α-thalassemia) predict more severe disease/cholestasis/iron overload (PMID: 25153905, 8839873); baseline Hb and transfusion need. Residual enzyme activity is NOT prognostic — no correlation exists between residual P5'N-1 activity and degree of hemolysis, likely due to metabolic compensation by other nucleotidases (PMID: 16522554, 15604219).
  • Recovery: the acquired lead phenocopy is reversible with exposure removal + chelation; the hereditary form is lifelong.

12. Treatment

No curative pharmacotherapy exists; management is supportive (PMID: 8375297, 34889365). "No specific therapy for P5'N-1 deficiency is now available" (PMID: 16522554). - Supportive care (NCIT: Supportive Care): folic acid supplementation, transfusion during crises/severe anemia, monitoring and treatment of gallstones, and iron-overload surveillance with chelation when indicated (PMID: 12930399, 34889365). NCIT terms: C15277 (Blood Transfusion), C1734 (Deferoxamine)/iron chelation, C542 (Cholecystectomy) for gallstones. - Splenectomy (NCIT: C15355): generally ineffective for the anemia and carries significant thrombotic risk — reserved, if ever, for selected refractory cases; a reported case developed extreme thrombocytosis and extensive venous thrombosis post-splenectomy (PMID: 8375297, 24287477). - Lead-poisoning (acquired) form: remove exposure and administer chelation (e.g., calcium disodium EDTA) (PMID: 11594131). NCIT: C61815 (Edetate Calcium Disodium). - Advanced/experimental: red-cell enzymopathies are in principle amenable to hematopoietic stem-cell transplantation and gene therapy/gene editing, but none is established specifically for P5N deficiency (PMID: 34889365). No approved targeted, RNA-based, or cell therapies. - Pharmacogenomics: UGT1A1 genotype relevant for bilirubin handling and drug glucuronidation considerations.

13. Prevention

  • Primary prevention: for the acquired form, eliminate/limit lead exposure (industrial hygiene, safe water/plumbing, avoiding lead-glazed ware and artisanal lead-contaminated beverages) — CDC/WHO lead-control measures (PMID: 11594131). No primary prevention for the hereditary form beyond reproductive counseling.
  • Secondary prevention: early recognition via blood film in a patient with HNSHA; monitoring for gallstones and iron overload for early intervention.
  • Genetic screening/counseling: genetic counseling for autosomal recessive recurrence risk (25% per pregnancy for carrier couples); cascade carrier testing and, where desired, prenatal/preimplantation genetic testing in families with known NT5C3A variants; especially relevant in consanguineous families (PMID: 30951028, 12714505).
  • Tertiary prevention: avoid unnecessary splenectomy (thrombotic risk); manage iron overload and gallstones; monitor neonates for kernicterus risk when UGT1A1 modifier present.
  • Immunization / prophylaxis: if splenectomy is performed, standard asplenia vaccination (pneumococcal, Hib, meningococcal) and antibiotic prophylaxis apply.

14. Other Species / Natural Disease

  • Taxonomy: primary human disease. Homo sapiens NCBI:txid9606.
  • Orthologous genes: NT5C3A orthologs exist across mammals (mouse Nt5c3, NCBI Gene) and are broadly conserved (the enzyme is ubiquitously distributed in mammalian tissues; PMID: 23992312).
  • Natural animal disease: no well-characterized spontaneous P5N-deficiency hemolytic disease in companion animals is established; not a recognized OMIA entry of major veterinary importance.
  • Experimental cross-species relevance: rabbit lead-poisoning models reproduce partial P5N inhibition with basophilic stippling, informing the acquired mechanism (PMID: 231420).
  • Comparative biology: enzyme function (pyrimidine nucleotide dephosphorylation during reticulocyte RNA turnover) is evolutionarily conserved, supporting mechanistic translation.
  • Zoonotic potential: none (non-infectious).

15. Model Organisms

  • Model types available:
  • In vitro / biochemical: recombinant human cN-III/P5'N-1 enzymology (substrate specificity, hydrolase + phosphotransferase activities, HAD-superfamily mechanism) — the best-developed model system for structure–function (PMID: 23992312). Recombinant expression of patient missense mutants (D87V, L131P, N179S, G230R) enabled functional dissection of catalytic-efficiency vs thermostability defects (PMID: 15604219).
  • Animal (induced/toxicological): rabbit intravenous lead-acetate model producing anemia, microspherocytosis, and basophilic stippling with P5N effects (PMID: 231420).
  • Cellular: patient-derived erythrocytes/reticulocytes used to demonstrate nucleotide accumulation and HMP-shunt inhibition (PMID: 8839873, 915002).
  • Genetic models: a dedicated Nt5c3a knockout mouse recapitulating the human hemolytic phenotype is not prominently established in the literature reviewed (evidence gap); murine ortholog exists for future engineering (MGI).
  • Phenotype recapitulation / limitations: biochemical/enzymology and toxicological (lead) models reproduce the pyrimidine-accumulation and stippling features well, but a genetic animal model fully reproducing chronic hereditary hemolysis is lacking; species differences in reticulocyte RNA content and lead sensitivity limit direct extrapolation (PMID: 231420).
  • Applications: enzyme structure–function, substrate specificity, inhibitor (lead) studies, and mechanism of pyrimidine-nucleotide toxicity.
  • Resources: MGI (mouse Nt5c3), UniProt/PDB for enzyme structure, NCBI Gene for orthologs.

Supported vs Refuted Hypotheses

Supported: - P5N deficiency is an autosomal recessive NT5C3A loss-of-function disorder causing HNSHA with basophilic stippling and pyrimidine nucleotide accumulation (PMID: 11369620, 12930399). - Lead poisoning is an environmental phenocopy via enzyme inhibition (PMID: 915002, 2990276). - Hemolysis involves HMP-shunt inhibition / oxidant susceptibility in addition to nucleotide accumulation (PMID: 8839873). - Clinical expression is modified by UGT1A1, Hb E, and thalassemia (PMID: 25153905, 8839873, 23384910). - Splenectomy is generally ineffective and thrombogenic; care is supportive (PMID: 8375297, 24287477, 34889365).

Refuted / not supported: - That splenectomy corrects the anemia (it does not; PMID: 8375297). - That the disorder is immune-mediated (it is Coombs-negative, intrinsic; PMID: 39967523).

Uncertain / evidence gaps: - The exact biochemical step causing shortened RBC survival remains unresolved (PMID: 23992312, 2558262). - Association with learning difficulties is proposed but unproven (PMID: 11369620). - Precise prevalence, carrier frequency, and a definitive genetic animal model are lacking.

Limitations & Future Directions

  • Evidence derives from case reports/small series and biochemical reviews; no large registries give precise epidemiology or QoL metrics.
  • The downstream mechanism of hemolysis is incompletely defined — targeted metabolomic/redox studies in patient reticulocytes are warranted.
  • A faithful Nt5c3a-null animal model and structural (PDB/AlphaFold) genotype–activity maps would clarify variant pathogenicity and enable therapy testing (HSCT/gene editing).

Key Ontology Term Summary

  • MONDO: MONDO:0009946
  • Gene (HGNC): NT5C3A (HGNC:17820)
  • HPO: HP:0004870, HP:0011273, HP:0001923, HP:0000952, HP:0001744, HP:0001081, HP:0002904
  • GO: GO:0008253 (5'-nucleotidase activity), GO:0006206 (pyrimidine nucleobase metabolism), GO:0034101 (erythrocyte homeostasis), GO:0006749 (glutathione metabolism), GO:0005829 (cytosol)
  • CL: CL:0000232 (erythrocyte), CL:0000558 (reticulocyte)
  • UBERON: UBERON:0000178 (blood), UBERON:0002106 (spleen), UBERON:0002107 (liver)
  • CHEBI: CHEBI:25016 (lead), pyrimidine nucleotides (UMP/CMP)
  • NCIT: C15355 (Splenectomy), C15277 (Blood Transfusion), C61815 (Edetate Calcium Disodium)

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 20
Resolved 20
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 20
On topic 17
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 34
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 25
Terms named correctly 18
Terms named as a different term 3
Terms whose name is worth a second look 4

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:0009946 (4 mentions) - the report calls it "if available"; MONDO calls it hemolytic anemia due to pyrimidine 5' nucleotidase deficiency
  • HP:0011273 (2 mentions) - the report calls it "basophilic stippling of erythrocytes"; HP calls it Anisocytosis
  • CHEBI:17568 (1 mention) - the report calls it "UMP-related"; CHEBI calls it uracil

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:

  • HP:0025435 (1 mention) - the report calls it "increased LDH"; HP calls it Increased circulating lactate dehydrogenase concentration, and lists "Increased lactate dehydrogenase level" among its other names
  • GO:0006206 (2 mentions) - the report calls it "pyrimidine nucleobase metabolism"; GO calls it pyrimidine nucleobase metabolic process, and lists "pyrimidine base metabolism" among its other names
  • GO:0006749 (2 mentions) - the report calls it "glutathione metabolism"; GO calls it glutathione metabolic process, and lists "glutathione metabolism" among its other names
  • CHEBI:17361 (1 mention) - the report calls it "CMP-related"; CHEBI calls it cytidine 5'-monophosphate, and lists "CMP" among its other names

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.