| domain | high-confidence annotation | suggested ontology/identifier | evidence caveat |
|---|---|---|---|
| Disease entity | Purine nucleoside phosphorylase deficiency; rare inborn error of purine metabolism with immunodeficiency and neurologic/autoimmune manifestations | MONDO:0013171; category suggestion: inborn error of metabolism / inborn error of immunity (pqac-00000000, pqac-00000001) | MONDO supported by OpenTargets context; some classifications differ between metabolic and immunologic taxonomies |
| Synonyms | PNP deficiency; purine nucleoside phosphorylase defect; PNP-deficient SCID/combined immunodeficiency | MeSH/OMIM/Orphanet mapping suggestion only; exact IDs not confirmed here (pqac-00000001, pqac-00000003) | Exact synonym lists and external IDs should be verified in OMIM/Orphanet/MeSH |
| Causal gene | Biallelic pathogenic variants in PNP cause disease | PNP; Ensembl: ENSG00000198805; HGNC symbol: PNP (pqac-00000000, pqac-00000001) | Gene-disease link is high confidence; transcript-level reference not specified here |
| Inheritance | Autosomal recessive loss-of-function disorder | Inheritance suggestion: HP term for autosomal recessive inheritance; gene mechanism suggestion: loss of function (pqac-00000001, pqac-00000002) | Exact HPO inheritance ID not supplied to avoid invention |
| Core biochemical defect | Deficiency of purine nucleoside phosphorylase activity impairs phosphorolysis of inosine/guanosine and deoxy forms, causing toxic purine metabolite accumulation | GO suggestion: purine nucleoside phosphorylase activity; Reactome/KEGG suggestion: purine metabolism / salvage pathway (pqac-00000001, pqac-00000004) | Exact GO/Reactome IDs not confirmed here |
| Key metabolites/biomarkers | Elevated inosine and guanosine in blood/urine; elevated guanosine and deoxyguanosine reported; reduced uric acid | CHEBI suggestions: inosine, guanosine, deoxyguanosine, uric acid (pqac-00000001, pqac-00000002, pqac-00000006) | Exact CHEBI IDs not provided; biomarker patterns may vary by assay and timing |
| Mechanistic toxic intermediate | Deoxyguanosine is phosphorylated to dGTP, producing dNTP imbalance and ribonucleotide reductase inhibition with lymphocyte toxicity | GO suggestions: apoptotic process, mitochondrial apoptotic pathway, nucleotide metabolic process (pqac-00000001, pqac-00000004) | dGTP mechanism is strongly supported, but exact downstream pathways vary by model/system |
| Immune phenotype | Profound T-cell lymphopenia/combined immunodeficiency with recurrent severe infections; B-cell compartment may be less affected than T cells | HPO suggestions: T-cell lymphopenia, combined immunodeficiency, recurrent infections, immunodeficiency; NCIT suggestion: Severe Combined Immunodeficiency (pqac-00000001, pqac-00000003, pqac-00000004) | Exact HPO/NCIT IDs not confirmed; some patients are described as SCID, others as CID/leaky SCID |
| Neurologic phenotype | Neurologic manifestations reported in approximately two-thirds of cases; includes ataxia, developmental delay, intellectual disability, spasticity/paraplegia in some reports | HPO suggestions: ataxia, developmental delay, intellectual disability, spastic paraplegia (pqac-00000001, pqac-00000003, pqac-00000006) | Frequency estimate is from review-level synthesis; patient-level prevalence varies |
| Autoimmune phenotype | Autoimmune manifestations reported in approximately one-third of cases; examples include immune thrombocytopenia, thyroiditis, lupus/SLE-like disease, autoimmune hemolytic anemia, inflammatory arthritis/MAS-like presentations | HPO suggestions: autoimmune thrombocytopenia, thyroiditis, systemic lupus erythematosus, autoimmune hemolytic anemia; disease feature suggestion: autoimmunity (pqac-00000001, pqac-00000002, pqac-00000003, pqac-00000006) | Frequency estimate is approximate; specific autoimmune diagnoses are heterogeneous and often case-based |
| Age at onset / course | Typically presents from about 4 months to 6 years; severity is variable | HPO suggestions: infantile onset / childhood onset (pqac-00000001, pqac-00000006) | Exact onset distribution is not well quantified due to rarity |
| Major affected cells | Thymocytes/T-cell progenitors are especially vulnerable; B lymphocytes and macrophages are implicated in autoimmunity/TLR7 signaling | CL suggestions: thymocyte, T-cell progenitor, T lymphocyte, B lymphocyte, macrophage (pqac-00000002, pqac-00000004) | Exact CL IDs not confirmed; evidence spans human, mouse, and mechanistic systems |
| Major anatomy | Primary involvement of immune system, especially thymus and peripheral lymphoid tissues; nervous system involvement is common | UBERON suggestions: thymus, spleen, lymph node, peripheral blood, brain/nervous system (pqac-00000001, pqac-00000002) | Exact UBERON IDs not confirmed; organ involvement is inferred from phenotype and model data |
| Upstream/downstream pathway annotation | Upstream: PNP loss in purine salvage/catabolism. Downstream: purine nucleoside accumulation, dGTP excess, mitochondrial apoptosis, T-cell depletion; separate checkpoint links guanosine metabolites to TLR7-associated autoimmunity | GO suggestions: purine nucleoside metabolic process, intrinsic apoptotic signaling pathway, toll-like receptor signaling pathway, lymphocyte differentiation (pqac-00000002, pqac-00000004) | TLR7 checkpoint evidence is particularly strengthened by 2022 mechanistic work and model systems |
| Diagnosis | Diagnostic workup includes enzyme assay, metabolite profiling, and molecular testing of PNP; dried-blood-spot tandem mass spectrometry has been reported for early diagnosis/newborn detection | Diagnostic test suggestion: PNP enzyme activity assay; metabolomics/MS-MS; single-gene or panel sequencing of PNP (pqac-00000001, pqac-00000003) | Exact assay thresholds and sensitivity/specificity not available in retrieved evidence |
| Screening | Newborn screening is feasible using DBS tandem mass spectrometry, but not universally routine | Screening program suggestion: newborn screening for SCID/purine disorders (pqac-00000001, pqac-00000003) | Implementation is jurisdiction-dependent; broad population performance metrics not available here |
| Definitive treatment | Hematopoietic stem cell transplantation (HSCT) is the only established curative therapy for immune reconstitution | NCIT suggestion: Hematopoietic Stem Cell Transplantation / Bone Marrow Transplantation (pqac-00000001, pqac-00000006) | Strong consensus on immune benefit; exact NCIT code not confirmed |
| Treatment outcome caveat | HSCT generally restores immune function and reduces infections, but neurologic recovery is incomplete/variable | Outcome annotation suggestion: immune reconstitution; persistent neurodevelopmental impairment possible (pqac-00000001, pqac-00000003, pqac-00000006) | Disease-specific long-term survival percentages were not available in retrieved evidence |
| Residual activity / genotype-phenotype note | Near-normal immune and neurologic development may require roughly 8-11% residual PNP activity | Functional evidence annotation suggestion: residual enzyme activity modifier (pqac-00000001, pqac-00000006) | Review-derived estimate; should be confirmed against original patient series before KB hard-coding |
| Model organism | PNP-deficient/PNP-knockout mice support thymic/T-cell toxicity mechanisms and autoimmune checkpoint biology but incompletely recapitulate human disease | Model suggestion: mouse Pnp knockout / deficient mouse (pqac-00000001, pqac-00000002) | Mouse models show important limitations, including partial mismatch with human thymic/T-cell phenotype |


*Table: This table summarizes high-confidence, knowledge-base-ready annotations for purine nucleoside phosphorylase deficiency, including disease identity, gene, mechanism, phenotypes, diagnostics, and treatment. Ontology mappings are labeled as suggestions where exact identifiers were not confirmed in the available evidence.*