Prolidase Deficiency

Mendelian MONDO:0008221 Pathograph 18 Show in embeddings browser Inborn Error of Metabolism Inborn Error of Immunity

Prolidase deficiency is a rare autosomal recessive inborn error of peptide metabolism caused by biallelic loss-of-function variants in PEPD, which encodes prolidase (peptidase D), the only human enzyme able to hydrolyse imidodipeptides bearing a C-terminal proline or hydroxyproline. Prolidase catalyses the terminal, rate-limiting step of collagen catabolism, so its loss simultaneously (i) blocks clearance of the imidodipeptides released from collagen turnover, producing the massive imidodipeptiduria that is the disorder's biochemical signature, and (ii) interrupts recycling of proline back into collagen and other proline-rich proteins, degrading extracellular-matrix remodelling and wound healing. The clinical picture is protean rather than organ-limited: recalcitrant lower-limb skin ulceration and other dermatological lesions, characteristic facial dysmorphism, developmental delay or intellectual disability, splenomegaly, recurrent respiratory infection with chronic lung disease, cytopenias, and a striking burden of immune dysregulation (elevated IgE, hypocomplementemia, a systemic-lupus-erythematosus-like phenotype, Crohn disease, and hemophagocytic lymphohistiocytosis) that has led to the disorder being classified as an inborn error of immunity as well as of metabolism. Symptoms usually begin in early childhood but are nonspecific at onset, and ulcers appear later (median 12 years), so diagnosis is characteristically delayed by more than a decade. There is no correlation between residual enzyme activity or accumulated dipeptide levels and clinical severity, and the mechanistic route from the enzyme block to the immunological and neurodevelopmental features remains unresolved.

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1
Inheritance
9
Pathophys.
1
Histopath.
24
Phenotypes
2
Hypotheses
2
Gaps
18
Pathograph
1
Genes
3
Medical Actions
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Inheritance

1
Autosomal recessive HP:0000007
Prolidase deficiency is inherited in an autosomal recessive manner, requiring biallelic homozygous or compound heterozygous loss-of-function PEPD variants. Expressivity is markedly variable, including within families: reported phenotypes range from essentially asymptomatic to very severe, with onset from age 3 to the third decade, and neither residual enzyme activity nor accumulated dipeptide level predicts severity.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:38088248 SUPPORT Human Clinical
"rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD"
States the autosomal recessive, biallelic loss-of-function inheritance mechanism.
PMID:15378943 SUPPORT Human Clinical
"There was considerable heterogeneity in age at onset of symptoms (varying from 3-17 years), mental retardation and clinical manifestations (asymptomless to very severe)."
Documents the wide phenotypic range underlying the VARIABLE expressivity assignment.
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Mechanistic Hypotheses

2
Impaired proline recycling and matrix-remodelling failure
collagen_recycling_matrix_failure CANONICAL
Evidence balance 1 support
The accepted explanatory model: because prolidase performs the terminal, rate-limiting hydrolysis of collagen-derived imidodipeptides, its loss both traps proline in undegradable dipeptides and starves collagen resynthesis of recycled proline. The resulting defect in extracellular-matrix remodelling accounts for the impaired wound healing and the recalcitrant skin ulceration.
Pathograph links
PEPD Prolidase Catalytic Deficiency -> Impaired Proline Recycling for Collagen Resynthesis DIRECT Because prolidase liberates the proline that is re-used for collagen synthesis, the enzyme block interrupts the proline salvage loop.
Impaired Proline Recycling for Collagen Resynthesis -> Defective Matrix Remodeling and Wound Healing DIRECT Failure of the collagen degradation/resynthesis cycle degrades extracellular-matrix remodelling capacity, which is the process wound repair depends on.
Defective Matrix Remodeling and Wound Healing -> Chronic Cutaneous Ulceration DIRECT Non-healing of skin breaks produces the chronic, recalcitrant lower-limb ulceration that is the disorder's most characteristic manifestation.
Show evidence (1 reference)
PMID:34532344 SUPPORT Other
"mutations leading to loss of prolidase catalytic activity result in prolidase deficiency a rare autosomal recessive metabolic disorder characterized by defective wound healing"
Ties loss of prolidase catalytic activity to defective wound healing as the disorder's core mechanism.
Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
immune_dysregulation_arm EMERGING
Evidence balance 2 support
How the enzyme block produces the lupus-like autoimmunity is unresolved. The two candidate routes are not mutually exclusive: (i) a cell-intrinsic lymphocyte defect, supported by Pepd-null mice in which T cells activate spontaneously and independently of antigen-receptor specificity, and (ii) innate hyperinflammation, supported by high monocyte IL-1beta production and detectable serum IL-1beta and IL-18 in a patient, implying enhanced inflammasome activation. Classical alternatives - self-antigen exposure from chronic tissue damage, or chronic microbial burden - remain live.
Pathograph links
PEPD Prolidase Catalytic Deficiency -> Spontaneous T Cell Activation and Loss of Self-Tolerance INDIRECT UNKNOWN INTERMEDIATES Prolidase loss produces a cell-intrinsic T-cell activation phenotype in the mouse null model; the metabolic or non-enzymatic intermediate that couples the enzyme block to lymphocyte dysfunction is not established.
PEPD Prolidase Catalytic Deficiency -> Enhanced Inflammasome Activation INDIRECT UNKNOWN INTERMEDIATES Patient monocytes overproduce IL-1beta and serum carries both IL-1beta and IL-18, implicating inflammasome activation downstream of the enzyme defect; the activating signal is unidentified.
Spontaneous T Cell Activation and Loss of Self-Tolerance -> Systemic Autoimmunity INDIRECT KNOWN INTERMEDIATES Spontaneous effector T-cell expansion drives autoantibody production and immune-complex disease in the mouse model, but the model also requires extra-haematopoietic input, so the link is not a simple one-step relation.
Enhanced Inflammasome Activation -> Systemic Autoimmunity INDIRECT UNKNOWN INTERMEDIATES Innate IL-1/IL-18-driven inflammation is proposed to contribute to the autoimmune manifestations alongside the lymphocyte-intrinsic arm.
Show evidence (2 references)
PMID:36637239 SUPPORT Model Organism
"Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of Ag receptor specificity or antigenic stimulation"
Provides the cell-intrinsic lymphocyte-dysfunction arm of the hypothesis in a mouse null model.
PMID:38088248 SUPPORT Human Clinical
"High interleukin-1β (IL-1β) production by this patient's monocytes, together with the detection of both IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced inflammasome activation in PD"
Provides the innate/inflammasome arm of the hypothesis from human immunophenotyping.
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Discussions and Knowledge Gaps

2
By what route does loss of a single cytosolic dipeptidase produce a phenotype spanning skin, immune, neurodevelopmental, skeletal, and pulmonary systems, and why is severity uncoupled from residual enzyme activity and from accumulated dipeptide levels?
KNOWLEDGE GAP OPEN pd_pathophysiology_unresolved
Attached to
pathophysiology#PEPD Prolidase Catalytic Deficiency pathophysiology#Imidodipeptide Accumulation and Imidodipeptiduria pathophysiology#Impaired Host Defense and Recurrent Infection
The collagen-recycling model accounts convincingly for impaired wound healing and ulceration, but not for the neurodevelopmental, immunological, or haematological burden. Two independent reviews state explicitly that the pathophysiology is unresolved, and the absence of any correlation between either residual enzyme activity or accumulated dipeptide level and clinical severity argues that substrate accumulation is not the proximate injurious mechanism. A non-enzymatic role of prolidase in cell regulation has been proposed as an additional axis.
Proposed experiments
Genotype-stratified deep phenotyping of a multi-centre cohort
pd_genotype_stratified_phenotyping
Assemble a multi-centre prolidase deficiency cohort with paired genotype, residual erythrocyte/fibroblast enzyme activity, urinary imidodipeptide quantification, and systematic organ-by-organ phenotyping.
Would support
pathophysiology#Imidodipeptide Accumulation and Imidodipeptiduria
Would refute
pathophysiology#Imidodipeptide Accumulation and Imidodipeptiduria
Supporting outcome
  • An allele class, residual-activity band, or metabolite level that predicts organ involvement would support substrate accumulation or enzyme dosage as the proximate mechanism.
Refuting outcome
  • Continued absence of any genotype-, activity-, or metabolite-to-phenotype relation would refute dose-dependent substrate toxicity and redirect attention to modifier or non-enzymatic mechanisms.
Tissue-resolved omics of PEPD-null human cells
pd_tissue_resolved_omics
Transcriptomic and proteomic profiling of isogenic PEPD-null human fibroblasts, keratinocytes, monocytes, and neural cells.
Would support
pathophysiology#PEPD Prolidase Catalytic Deficiency
Would refute
pathophysiology#PEPD Prolidase Catalytic Deficiency
Supporting outcome
  • A shared downstream programme across all four lineages would support a single unifying mechanism for the multisystem phenotype.
Refuting outcome
  • Wholly lineage-specific programmes would refute a single unifying mechanism and favour tissue-specific consequences of the same enzyme block.
Decomposition of residual prolidase activity across a patient allele panel
pd_allele_panel_abundance_stability_catalysis
Express a panel of reported PEPD missense alleles alongside wild-type and a catalytically dead control in a cell-free transcription-translation system, and measure three quantities separately for each allele: how much protein accumulates, whether it is folded, and whether it turns over an imidodipeptide substrate. Clinical "residual prolidase activity" is assayed as one number in erythrocyte or fibroblast lysate, where low abundance of a normally catalytic enzyme and normal abundance of a dead one are indistinguishable. Separating them gives a per-allele measure to test against severity in place of the composite.
Model systems
Cell-free expressed PEPD allele panel
Each reported PEPD missense allele, wild type, and a catalytically dead control expressed from a linear DNA template in a reconstituted transcription-translation system, giving the isolated human enzyme in a defined reaction rather than in a patient cell.
OTHER
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Pathograph links
PEPD Prolidase Catalytic Deficiency measures fidelity: moderate observes: molecular Reports abundance, folding, and imidodipeptide turnover for each allele as three separately measured quantities, which is the decomposition the clinical lysate assay cannot make.
Limitations: A bacterial cell-free system supplies neither the human chaperone complement nor the cytosolic milieu, so a folding result is a property of the allele in this reaction and not a prediction of its stability in a patient cell.
Divergences from the human mechanism
boundary omission qualifying
The cytosol in which prolidase is proposed to act non-enzymatically lies outside the reaction boundary: there are no intact cells, no binding partners, and no signalling context. The model therefore constrains the enzymatic arm of the gap and is silent on the separation-of-function question, which needs a cellular system.
boundary omission qualifying
Human chaperones and post-translational modification machinery are absent from a bacterial extract, so misfolding seen here may be an artefact of the expression host rather than a property of the allele. Bears on the folding readout specifically, which is why it is recorded separately from the cytosolic omission above.
Readouts
Accumulated PEPD protein per allele
pathophysiology#PEPD Prolidase Catalytic Deficiency
Direction: ALTERED
Interpretation: Separates an allele that fails to accumulate from one that is present and inactive, which a single lysate activity figure cannot distinguish.
Thermal unfolding midpoint of purified PEPD per allele
pathophysiology#PEPD Prolidase Catalytic Deficiency
Direction: ALTERED
Interpretation: A reduced midpoint relative to wild type marks a destabilising allele, as against one that folds normally and cannot catalyse. Reports on the subunit rather than the assembled homodimer.
Imidodipeptide turnover per allele
pathophysiology#PEPD Prolidase Catalytic Deficiency
Direction: ALTERED
Interpretation: Substrate depletion or product formation gives catalytic competence independently of how much protein is present, which is the quantity the clinical assay conflates with abundance.
Decision criterion
The three measurements are read together per allele. Pathogenic alleles falling into more than one class — reduced accumulation with retained turnover, normal accumulation with abolished turnover, or loss of folding — establish that the clinical residual-activity figure is a composite. Pathogenic alleles all behaving alike establish that it is not.
Would support
pathophysiology#PEPD Prolidase Catalytic Deficiency
Would refute
pathophysiology#PEPD Prolidase Catalytic Deficiency
Supporting outcome
  • Alleles separating into distinct classes — reduced accumulation with retained specific activity, normal accumulation with abolished catalysis, or loss of folding — would show that the single residual-activity figure conflates three quantities, and would supply the per-allele measures the genotype-severity comparison has so far lacked.
Refuting outcome
  • Every pathogenic allele behaving alike, with accumulation and catalysis lost together, would show residual activity is already an adequate summary of the enzymatic lesion, and would place the source of the severity uncoupling outside the enzyme — in modifiers, or in the proposed non-enzymatic axis.
Executable protocols
Cell Free Protein Expression with HiBiT Quantification
Ginkgo Cloud Lab commercial cloud lab catalogue read 2026-10-01
Catalogue id: cell-free-protein-expression-validation-hibit
Supplies the abundance term: how much protein each allele accumulates, quantified by luminescence from the crude reaction without purification, so an allele that is simply unstable in the lysate is distinguished from one that is expressed and inactive.
pathophysiology#PEPD Prolidase Catalytic Deficiency
Requester supplies: Coding sequences for each allele, submitted as linear DNA templates
Protein Expression and Thermal Shift Assay
Ginkgo Cloud Lab commercial cloud lab catalogue read 2026-10-01
Catalogue id: protein-expression-and-thermal-shift-assay
Supplies the folding term: expression, Strep-II purification and a SYPRO Orange thermal unfolding curve, so a destabilising allele is separated from one that folds normally and cannot catalyse.
pathophysiology#PEPD Prolidase Catalytic Deficiency
Requester supplies: Coding sequences carrying a Strep-II tag, as a DNA template plate
Prolidase is a homodimeric metallopeptidase, so a thermal unfolding curve from the purified monomer reports on the subunit and not necessarily on the assembled holoenzyme.
Echo-MS Detection of Molecules from an Enzymatic Reaction in Cell Free Expression System
Ginkgo Cloud Lab commercial cloud lab catalogue read 2026-10-01
Catalogue id: echo-ms-detection-of-molecules-from-an-enzymatic-reaction-in-cell-free-expression-system
Supplies the catalysis term: substrate depletion or product formation measured by acoustic ejection mass spectrometry on the expressed enzyme, giving turnover per allele independently of how much protein is present.
pathophysiology#PEPD Prolidase Catalytic Deficiency
Requester supplies: Coding sequences as linear DNA templates, plus an imidodipeptide substrate and a proline product standard for the mass-spectrometry method
The provider's catalogue does not record whether this method is validated for an imidodipeptide substrate and free proline, and lists a separate Echo-MS method onboarding service, so method development should be assumed to be required.
The amount-versus-activity distinction this experiment turns on is the axis deferred in design decisions section 12 (Quantity kind: analyte amount vs catalytic activity), which names the residual-enzyme-activity genotype-severity question as one of its motivating cases; nothing here settles that decision. The limits of the cell-free system are recorded as typed divergences on the model system above rather than restated here.
Separation-of-function PEPD alleles
pd_separation_of_function_alleles
Engineer PEPD alleles that retain protein expression and any scaffolding role but abolish catalysis, and compare them with a full null.
Would support
pathophysiology#PEPD Prolidase Catalytic Deficiency
Would refute
pathophysiology#PEPD Prolidase Catalytic Deficiency
Supporting outcome
  • A phenotypic difference between catalytically dead and null alleles would support a distinct non-enzymatic contribution of prolidase.
Refuting outcome
  • Indistinguishable phenotypes between catalytically dead and null alleles would refute a separable non-enzymatic role.
Show evidence (3 references)
PMID:32455636 SUPPORT Human Clinical
"Physiopathology of PD is not clearly understood, as there is marked phenotypic variability among affected individuals"
Review states the pathophysiology is unresolved and links this to phenotypic variability.
PMID:18340504 SUPPORT Other
"The pathophysiology of PD is still poorly understood"
Independent review confirms the pathophysiology gap.
PMID:15378943 SUPPORT Human Clinical
"We were unable to find any correlation between degree of enzyme activity loss and severity of symptoms"
Absence of an activity-severity correlation is direct evidence for the gap.
Does the cell-intrinsic T-cell activation defect that drives lupus-like autoimmunity in Pepd-null mice also operate in human prolidase deficiency, or is the human autoimmunity primarily innate/B-cell driven?
HUMAN MODEL MISMATCH OPEN pd_mouse_autoimmunity_translation
Attached to
pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance pathophysiology#Enhanced Inflammasome Activation pathophysiology#Systemic Autoimmunity
The mechanistic case for T-cell-intrinsic loss of self-tolerance rests on the mouse null model, and even there the autoimmune phenotype is absent in mixed chimeras, implying a required contribution from outside the haematopoietic system. The available human mechanistic data point in a partly different direction - monocyte IL-1beta overproduction with serum IL-1beta and IL-18 (innate/inflammasome), and therapeutic response to B-cell depletion (CD20-positive B cells) - so the dominant human effector arm is not settled. This is a translational-validity question rather than an absence of evidence: evidence exists in the model, and its fidelity to human disease is the open issue.
Proposed experiments
Deep immunophenotyping of a patient cohort
pd_patient_deep_immunophenotyping
T-cell activation/exhaustion panels, TCR repertoire sequencing, and autoantibody profiling in prolidase deficiency patients versus matched controls.
Would support
pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance mechanistic_hypotheses#immune_dysregulation_arm
Would refute
pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
Supporting outcome
  • Antigen-independent effector T-cell expansion with a polyclonal repertoire in patients would support translation of the mouse mechanism to humans.
Refuting outcome
  • A normal T-cell activation state with an oligoclonal, antigen-driven repertoire would refute the mouse-predicted cell-intrinsic mechanism in humans.
Serial inflammasome readouts across multiple patients
pd_serial_inflammasome_readouts
Repeated serum IL-1beta and IL-18 measurement plus ex vivo monocyte stimulation assays in an unselected patient series.
Would support
pathophysiology#Enhanced Inflammasome Activation
Would refute
pathophysiology#Enhanced Inflammasome Activation
Supporting outcome
  • Reproducible elevation across multiple patients would establish inflammasome activation as a general feature rather than a single-patient observation.
Refuting outcome
  • Absence of elevation in other patients would confine the inflammasome finding to the index case.
Treatment-response discrimination of the effector arm
pd_treatment_response_effector_arm
Systematic collection of outcomes under B-cell depletion, IL-1 blockade, and T-cell-directed therapy in prolidase deficiency autoimmunity.
Would support
pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
Would refute
pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
Supporting outcome
  • Selective benefit from T-cell-directed therapy would support the T-cell arm as dominant in humans.
Refuting outcome
  • Benefit confined to B-cell depletion or IL-1 blockade would argue that the dominant human effector arm differs from the mouse.
Show evidence (2 references)
PMID:36637239 SUPPORT Model Organism
"The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden."
The authors state the human basis for autoimmunity is uncertain before offering mouse evidence.
PMID:38088248 SUPPORT INDIRECT Human Clinical
"whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD"
Human treatment-response data implicate B cells, which the mouse T-cell model does not predict as the dominant arm.
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Pathophysiology

9
PEPD Prolidase Catalytic Deficiency
Biallelic homozygous or compound heterozygous loss-of-function variants in PEPD abolish or severely reduce the activity of prolidase (peptidase D), a ubiquitously expressed cytosolic manganese metallopeptidase. Prolidase is the only human enzyme that can hydrolyse imidodipeptides carrying a C-terminal proline or hydroxyproline residue, so no other peptidase can compensate for its loss.
Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity Impaired proline recycling and matrix-remodelling failure
PEPD hgnc:8840 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PEPD (hgnc:8840). hgnc:8840 is a gene from the HUGO Gene Nomenclature Committee.
imidodipeptidase (X-Pro dipeptidase) activity GO:0102009 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased imidodipeptidase (X-Pro dipeptidase) activity, annotated with proline dipeptidase activity (GO:0102009). GO:0102009 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Imidodipeptide Accumulation and Imidodipeptiduria Loss of the terminal hydrolytic step leaves collagen-derived imidodipeptides undegraded, so they accumulate in cells and blood and are excreted in urine.
Impaired Proline Recycling for Collagen Resynthesis Because prolidase liberates the proline that is re-used for collagen synthesis, the enzyme block interrupts the proline salvage loop. Impaired proline recycling and matrix-remodelling failure
Spontaneous T Cell Activation and Loss of Self-Tolerance Prolidase loss produces a cell-intrinsic T-cell activation phenotype in the mouse null model; the metabolic or non-enzymatic intermediate that couples the enzyme block to lymphocyte dysfunction is not established. Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
Enhanced Inflammasome Activation Patient monocytes overproduce IL-1beta and serum carries both IL-1beta and IL-18, implicating inflammasome activation downstream of the enzyme defect; the activating signal is unidentified. Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
Impaired Host Defense and Recurrent Infection Recurrent, predominantly respiratory infection is one of the most frequent manifestations, but whether it reflects the immune dysregulation, structural airway/matrix compromise, or both is unresolved.
Show evidence (2 references)
PMID:34532344 SUPPORT Other
"the only enzyme capable of cleaving imidodipeptides containing C-terminal proline or hydroxyproline"
Establishes prolidase as the sole enzyme with this activity, so its loss cannot be compensated.
PMID:38088248 SUPPORT Human Clinical
"rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD"
Documents the biallelic loss-of-function genetic mechanism.
Imidodipeptide Accumulation and Imidodipeptiduria
Undegraded imidodipeptides - principally proline-glycine (Gly-Pro) and proline-hydroxyproline - accumulate in fibroblasts and blood and are massively excreted in urine. Because healthy individuals excrete negligible amounts, imidodipeptiduria is the disorder's essential biochemical marker. Accumulated dipeptide levels do not track clinical severity, so this node is best read as a biomarker branch rather than as the proximate cause of tissue injury.
Show evidence (3 references)
PMID:32455636 SUPPORT Human Clinical
"Analysis of urinary amino acids in all tested patients revealed a massive excretion of imidodipeptides such as proline-glycine or proline-hydroxyproline"
Identifies the specific accumulating imidodipeptides and their urinary excretion.
PMID:32455636 SUPPORT DIRECT Human Clinical
"In five patients, the levels of accumulated dipeptides did not correlate with the severity of the disease"
Argues against accumulated dipeptides being the direct determinant of disease severity.
PMID:15378943 SUPPORT Human Clinical
"a rare, autosomally inherited disorder causing iminodipeptiduria is associated with a number of clinical manifestations, the principle feature being chronic skin ulceration"
Confirms iminodipeptiduria as the defining biochemical consequence of the enzyme defect.
Impaired Proline Recycling for Collagen Resynthesis
Prolidase catalyses the rate-limiting terminal step of collagen catabolism and supplies the recycled proline used to resynthesise collagen and other proline-rich proteins. Loss of the enzyme therefore blocks the final stage of collagen degradation and simultaneously deprives collagen biosynthesis of its salvaged proline pool.
Impaired proline recycling and matrix-remodelling failure
collagen catabolic process GO:0030574 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen catabolic process (GO:0030574). GO:0030574 is a biological process from the Gene Ontology. ↓ DECREASED L-proline metabolic process GO:0006560 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal L-proline metabolic process (GO:0006560). GO:0006560 is a biological process from the Gene Ontology. ⚠ ABNORMAL collagen biosynthetic process GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Matrix Remodeling and Wound Healing Failure of the collagen degradation/resynthesis cycle degrades extracellular-matrix remodelling capacity, which is the process wound repair depends on. Impaired proline recycling and matrix-remodelling failure
Show evidence (2 references)
PMID:34532344 SUPPORT Other
"Prolidase catalyzes the rate-limiting step during collagen recycling and is essential in protein metabolism, collagen turnover, and matrix remodeling"
Establishes prolidase as the rate-limiting enzyme of collagen recycling and turnover.
PMID:18340504 SUPPORT Other
"It is relevant in the latest stage of protein catabolism, particularly of those molecules rich in imino acids such as collagens, thus being involved in matrix remodelling"
Places prolidase at the final stage of collagen catabolism and links it to matrix remodelling.
Defective Matrix Remodeling and Wound Healing
Impaired collagen turnover compromises extracellular-matrix remodelling in skin and other connective tissues, manifesting as defective wound healing. This is the mechanistic step that distinguishes prolidase deficiency ulcers from ischaemic or venous ulcers: vascular studies in affected patients have been normal.
Impaired proline recycling and matrix-remodelling failure
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Chronic Cutaneous Ulceration Non-healing of skin breaks produces the chronic, recalcitrant lower-limb ulceration that is the disorder's most characteristic manifestation. Impaired proline recycling and matrix-remodelling failure
Show evidence (1 reference)
PMID:34532344 SUPPORT Other
"mutations leading to loss of prolidase catalytic activity result in prolidase deficiency a rare autosomal recessive metabolic disorder characterized by defective wound healing"
Names defective wound healing as the characteristic consequence of lost prolidase activity.
Chronic Cutaneous Ulceration
Recalcitrant, often infected ulcers, predominantly on the lower legs, that resist conventional topical therapy and skin grafting. They may arise on skin already weakened by pruritic or eczematous lesions and appear at a median age of 12 years rather than at presentation.
Show evidence (1 reference)
PMID:17166065 SUPPORT Human Clinical
"Lower leg recalcitrant ulcerations are the most characteristic symptoms"
Characterises the ulcers as recalcitrant and lower-limb predominant.
Spontaneous T Cell Activation and Loss of Self-Tolerance
In the Pepd-null mouse, T cells activate and proliferate into the effector subset spontaneously, in a manner intrinsic to the cell and independent of antigen-receptor specificity or antigenic stimulation, with CD4 and CD8 effector T cells accumulating in spleen and liver. Notably the autoimmune phenotype is absent in mixed chimeras, indicating that a non-haematopoietic contribution is also required - so lymphocyte dysfunction is necessary but not sufficient.
Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
T cell activation GO:0042110 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T cell activation (GO:0042110). GO:0042110 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Systemic Autoimmunity Spontaneous effector T-cell expansion drives autoantibody production and immune-complex disease in the mouse model, but the model also requires extra-haematopoietic input, so the link is not a simple one-step relation. Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
Show evidence (1 reference)
PMID:36637239 SUPPORT Model Organism
"These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver"
Documents effector T-cell accumulation in the mouse null model.
Enhanced Inflammasome Activation
Innate hyperinflammation forms a parallel arm of the immune phenotype: patient monocytes overproduce IL-1beta, and both IL-1beta and IL-18 are detectable in serum, a pattern that implies increased inflammasome activity. This arm is based on a single patient's immunophenotyping and is not yet established as a general feature.
Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
positive regulation of interleukin-1 beta production GO:0032731 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of interleukin-1 beta production (GO:0032731). GO:0032731 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Systemic Autoimmunity Innate IL-1/IL-18-driven inflammation is proposed to contribute to the autoimmune manifestations alongside the lymphocyte-intrinsic arm. Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
Show evidence (1 reference)
PMID:38088248 SUPPORT Human Clinical
"High interleukin-1β (IL-1β) production by this patient's monocytes, together with the detection of both IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced inflammasome activation in PD"
Reports the IL-1beta/IL-18 signature interpreted as enhanced inflammasome activation.
Systemic Autoimmunity
Autoimmune disease is one of the defining burdens of prolidase deficiency: a systemic-lupus-erythematosus-like phenotype (sometimes full SLE, sometimes serology-only incomplete lupus), Crohn disease, arthritis, undifferentiated connective tissue disease, hypocomplementemia, and cytopenias. Hemophagocytic lymphohistiocytosis has also been reported. It is prominent enough that unexplained childhood autoimmunity is a recommended trigger for testing.
Show evidence (2 references)
PMID:34040193 SUPPORT Human Clinical
"Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis"
Quantifies the autoimmune burden and names the specific autoimmune diagnoses observed.
PMID:34040193 SUPPORT Human Clinical
"Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH"
Establishes autoimmunity and HLH as diagnostically salient features.
Impaired Host Defense and Recurrent Infection
Recurrent infections - predominantly respiratory (pneumonia, upper respiratory tract infection) - affect roughly three quarters of reported patients, and a substantial fraction develop chronic lung disease with cystic change, bronchiectasis, ground-glass attenuation, and in some cases progressive pulmonary fibrosis with excessive collagen deposition on biopsy.
Show evidence (2 references)
PMID:34040193 SUPPORT Human Clinical
"Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections"
Lists recurrent infection among the core manifestations of the disorder.
PMID:32455636 SUPPORT Human Clinical
"Recurrent infections, namely respiratory infections, pneumonia or upper respiratory tract infections ... are present in 76% (37/49) of patients (Figure 1a)."
The pooled review documents recurrent predominantly respiratory infection in 76% of reported patients.
✶

Histopathology

1
Diffuse alveolar fibrosis with excessive collagen deposition
Lung biopsy in a reported patient with prolidase deficiency and systemic lupus erythematosus showed diffuse alveolar fibrosis, excessive collagen deposition, architectural distortion, and alveolar cysts.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"His videothoracoscopic lung biopsy showed diffuse alveolar fibrosis with excessive collagen deposition, architectural distortion and alveolar cysts [48]."
Directly reports the pulmonary histopathology and collagen-deposition finding in a human case.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Prolidase 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.
●

Phenotypes

24
Blood 4
Anemia FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Anemia was reported in 76% (19/25) of patients"
Direct quantitative frequency (76%, 19/25) maps to the FREQUENT band.
Increased circulating IgE concentration FREQUENT HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated IgE, annotated with Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Hypergammaglobulinemia IgE was present in 64% (9/14) of patients"
Direct quantitative frequency (64%, 9/14) maps to the FREQUENT band.
Thrombocytopenia FREQUENT HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Thrombocytopenia was found in 56% (10/18) of patients"
Direct quantitative frequency (56%, 10/18) maps to the FREQUENT band.
Hemophagocytosis HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytic lymphohistiocytosis, annotated with Hemophagocytosis (HP:0012156). HP:0012156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34040193 SUPPORT Human Clinical
"Another immune finding was hemophagocytic lymphohistiocytosis"
Reports HLH as an observed immune finding without a frequency denominator.
Cardiovascular 2
Splenomegaly FREQUENT 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:32455636 SUPPORT Human Clinical
"Splenomegaly was found in 72% (31/43) of patients"
Direct quantitative frequency (72%, 31/43) maps to the FREQUENT band.
Telangiectasia FREQUENT HP:0001009 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telangiectasia (HP:0001009). HP:0001009 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Telangiectasias were present in 71% (10/14) of patients"
Direct quantitative frequency (71%, 10/14) maps to the FREQUENT band.
Digestive 1
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Hepatomegaly was present in 53% (8/15) of patients"
Direct quantitative frequency (53%, 8/15) maps to the FREQUENT band.
Head and Neck 2
Abnormal facial shape VERY_FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Facial dysmorphism was present in 93% (54/58) patients"
Direct quantitative frequency (93%, 54/58) maps to the VERY_FREQUENT band.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Of these, 12 patients were previously investigated by Besio et al. in the light of bone abnormalities, namely short stature, microcephaly, osteopenia and genu valgum"
Documents microcephaly among bone abnormalities evaluated in human patients.
Immune 6
Recurrent respiratory infections FREQUENT HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Recurrent infections, namely respiratory infections, pneumonia or upper respiratory tract infections ... are present in 76% (37/49) of patients (Figure 1a)."
Direct pooled frequency (76%, 37/49) maps to the FREQUENT band.
Skin rash FREQUENT HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin rash (HP:0000988). HP:0000988 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"A rash was reported in 67% (10/15) of patients"
Direct quantitative frequency (67%, 10/15) maps to the FREQUENT band.
Eczematoid dermatitis FREQUENT HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczema, annotated with Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Eczema or dermatitis were reported in 58% (18/31) of patients"
Direct quantitative frequency (58%, 18/31) maps to the FREQUENT band.
Reduced circulating complement concentration FREQUENT HP:0004431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocomplementemia, annotated with Reduced circulating complement concentration (HP:0004431). HP:0004431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Hypocomplementemia was present in 40% (4/10) of patients"
Direct quantitative frequency (40%, 4/10) maps to the FREQUENT band.
Systemic lupus erythematosus OCCASIONAL HP:0002725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Systemic lupus erythematosus (HP:0002725). HP:0002725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Systemic lupus erythematosus or SLE-like phenotype was reported in 29% (6/21) of patients"
Direct quantitative frequency (29%, 6/21) maps to the OCCASIONAL band (29-5%).
Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34040193 SUPPORT Human Clinical
"Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis"
Documents the autoimmune manifestations without a pooled category frequency.
Integument 2
Skin ulcer FREQUENT HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin ulcer (HP:0200042), qualified as temporality chronic. HP:0200042 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:32455636 SUPPORT Human Clinical
"61% (41/67) of patients were described with cutaneous ulcers"
Direct quantitative frequency (61%, 41/67) maps to the FREQUENT band.
PMID:34040193 SUPPORT Human Clinical
"Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old"
Supports the chronic temporality and later median age of onset.
Cutaneous photosensitivity FREQUENT HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photosensitivity, annotated with Cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Photosensitivity was reported in 33% (3/9) of patients"
Direct quantitative frequency (33%, 3/9) sits at the low end of the FREQUENT band (79-30%).
Limbs 1
Genu valgum HP:0002857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu valgum (HP:0002857). HP:0002857 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Of these, 12 patients were previously investigated by Besio et al. in the light of bone abnormalities, namely short stature, microcephaly, osteopenia and genu valgum"
Documents genu valgum among bone abnormalities evaluated in human patients.
Musculoskeletal 1
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Of these, 12 patients were previously investigated by Besio et al. in the light of bone abnormalities, namely short stature, microcephaly, osteopenia and genu valgum"
Documents osteopenia among bone abnormalities evaluated in human patients.
Nervous System 2
Global developmental delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Developmental delay or intellectual disability (moderate, mild or severe) was present in 71% (48/68) patients"
Direct quantitative frequency (71%, 48/68) maps to the FREQUENT band.
Intellectual disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Developmental delay or intellectual disability (moderate, mild or severe) was present in 71% (48/68) patients"
The source reports developmental delay and intellectual disability as a single pooled 71% (48/68) figure.
Respiratory 1
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"cystic changes, bronchiectasis, diffuse ground glass attenuation and linear atelectasis"
Documents the chronic structural lung findings on CT imaging.
Growth 2
Failure to thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Fifty-three percent (21/40) of patients presented a failure to thrive"
Direct quantitative frequency (53%, 21/40) maps to the FREQUENT band.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Of these, 12 patients were previously investigated by Besio et al. in the light of bone abnormalities, namely short stature, microcephaly, osteopenia and genu valgum"
Documents short stature among bone abnormalities evaluated in human patients.
🧬

Genetic Associations

1
PEPD
Gene: PEPD hgnc:8840 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PEPD (hgnc:8840). hgnc:8840 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:18340504 SUPPORT Other
"Single amino acid substitutions, exon splicing, deletions and a duplication were described as causative for the disease and are mainly located at highly conserved amino acids"
Summarises the reported PEPD variant classes and their location at conserved residues.
PMID:38088248 SUPPORT Human Clinical
"a novel homozygous intragenic deletion in PEPD"
Documents intragenic copy-number variation as a disease mechanism at this locus.
💊

Medical Actions

3
Topical glycine-proline ointment for recalcitrant ulcers
Action: wound care managementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is wound care management (NCIT:C116681). NCIT:C116681 is a clinical intervention from the NCI Thesaurus. Ontology label: Wound Care Management NCIT:C116681
Agent: L-proline CHEBI:17203 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-proline (CHEBI:17203). CHEBI:17203 is a therapeutic agent from Chemical Entities of Biological Interest. glycine CHEBI:15428 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses glycine (CHEBI:15428). CHEBI:15428 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
Topical application of a proline 5% / glycine 5% water-emulsive ointment is a mechanism-motivated local therapy: it supplies the amino acids that the blocked proline salvage loop fails to deliver to healing skin. It is used for ulcers refractory to conventional topical treatment and skin grafting, and the reported response is variable - partial improvement with fewer admissions for superinfection in the published case.
Mechanism Target:
BYPASSES Impaired Proline Recycling for Collagen Resynthesis — Exogenous topical proline and glycine bypass the blocked salvage step by supplying its products directly to healing skin, rather than restoring prolidase activity.
Show evidence (1 reference)
PMID:17166065 SUPPORT INDIRECT Human Clinical
"Pharmacy service draws up an elaboration guide and a patient information leaflet of a proline 5%-glycine 5% water emulsive ointment"
Documents the amino-acid composition of the ointment, which is the basis of the bypass rationale.
Target Phenotypes: Skin ulcer HP:0200042 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Skin ulcer (HP:0200042). HP:0200042 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17166065 SUPPORT Human Clinical
"Topical application of a glycine-proline ointment is an alternative for the treatment of recalcitrant ulcerations and it has resulted in variable response"
Single-patient report; the authors themselves describe the response as variable.
Rituximab for refractory autoimmune manifestations
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
There is no consensus treatment for the autoimmune manifestations of prolidase deficiency, and steroids plus conventional synthetic DMARDs may fail while causing infectious complications. B-cell depletion with rituximab produced sustained recession of mucocutaneous ulceration in one patient with PD-associated vasculitis and undifferentiated connective tissue disease, allowing steroid tapering - implying a role for CD20-positive B cells in the immunopathogenesis.
Mechanism Target:
INHIBITS Systemic Autoimmunity — B-cell depletion suppresses the autoimmune arm of the disorder; it does not address the underlying enzyme deficiency.
Show evidence (1 reference)
PMID:38088248 SUPPORT Human Clinical
"whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD"
Links the therapeutic effect to B-cell-mediated autoimmune pathogenesis.
Target Phenotypes: Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38088248 SUPPORT Human Clinical
"Introduction of rituximab (RTX) treatment in this patient led to sustained recession of mucocutaneous ulceration, enabling tapering of steroids"
Single-patient evidence of rituximab efficacy for the autoimmune/mucocutaneous manifestations.
PMID:38088248 SUPPORT Human Clinical
"So far, there is no consensus regarding treatment of PD and its autoimmune manifestations."
Documents the absence of a consensus treatment standard, which frames rituximab as an off-label option.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Counseling and carrier testing are offered to families based on autosomal recessive inheritance. Founder enrichment in some populations (Druze and Arab Muslim minority populations in Israel) raises the value of targeted testing there.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"but is more frequent in some populations, as the Druze and Arab Muslim minority in Israel"
Population enrichment is the counseling-relevant fact supporting targeted carrier testing.
🔬

Biochemical Markers

2
Urinary imidodipeptides (imidodipeptiduria) (INCREASED)
Context: Massive urinary excretion of imidodipeptides bearing C-terminal proline or hydroxyproline - principally proline-glycine and proline-hydroxyproline - is the essential biochemical marker of the disorder, because healthy individuals excrete negligible amounts. The dipeptides also accumulate in fibroblasts and blood, at lower levels in serum than in urine. Standard urine amino-acid quantification may require prior hydrolysis (boiling) to reveal the markedly elevated proline.
Pathograph Readouts
Readout Of Imidodipeptide Accumulation and Imidodipeptiduria Positive Diagnostic
Urinary imidodipeptide excretion directly reports the accumulation of the substrates prolidase can no longer hydrolyse.
Show evidence (2 references)
PMID:32455636 SUPPORT Human Clinical
"Imidopeptiduria is therefore an essential biochemical marker for the diagnosis"
Establishes imidodipeptiduria as the essential diagnostic biochemical marker.
PMID:36757671 SUPPORT Human Clinical
"quantitative urine amino acids demonstrated a markedly elevated proline level, confirming the diagnosis"
Shows urine amino-acid quantification (after hydrolysis) confirming the diagnosis.
Erythrocyte and fibroblast prolidase activity (DECREASED)
Context: Prolidase activity measured in erythrocyte haemolysates or cultured dermal fibroblasts is deficient, especially against glycyl-proline. On FPLC separation, activity of the major isoform (I) is markedly reduced while the minor isoform (II) is unaltered. Residual activity does not predict clinical severity.
Pathograph Readouts
Readout Of PEPD Prolidase Catalytic Deficiency Negative Diagnostic
Measured enzyme activity is the direct functional readout of the PEPD molecular defect.
Show evidence (2 references)
PMID:15378943 SUPPORT Human Clinical
"Prolidase activity was found to be deficient, especially against gly-pro."
Documents deficient erythrocyte and fibroblast prolidase activity, notably against Gly-Pro.
PMID:15378943 SUPPORT Human Clinical
"We were unable to find any correlation between degree of enzyme activity loss and severity of symptoms"
Establishes the absence of an enzyme-activity/severity correlation.
🔬

Diagnosis

2
Urinary amino acid and imidodipeptide analysis
Quantitative urinary amino acid analysis, with hydrolysis of the sample where needed, detects the massive imidodipeptide excretion (proline-glycine, proline-hydroxyproline) that is the disorder's biochemical signature.
urine chemistry measurement NCIT:C61044 NCI Thesaurus (NCIT)
Results: Markedly elevated urinary imidodipeptides / proline; negligible excretion in unaffected individuals.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"Analysis of urinary amino acids in all tested patients revealed a massive excretion of imidodipeptides such as proline-glycine or proline-hydroxyproline"
Describes the diagnostic urinary finding across all tested patients.
PEPD molecular genetic testing
Identification of biallelic pathogenic PEPD variants establishes the diagnosis; missense, splice, deletion, and duplication alleles have all been reported, and copy-number variation may be missed by sequencing alone.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic or likely pathogenic PEPD variants.
Show evidence (1 reference)
PMID:36757671 SUPPORT Human Clinical
"Diagnosis is dependent on the detection of a pathologic gene variant."
States that diagnosis rests on detecting a pathogenic PEPD variant.
📈

Progression

2
Early-childhood nonspecific onset with delayed diagnosis
Most patients become symptomatic in early childhood, but the presenting features (infections, dysmorphism, developmental delay, splenomegaly) are nonspecific, and about half of published patients were symptomatic by age 4 while diagnosis lagged by a mean of 11.6 years.
Show evidence (1 reference)
PMID:34040193 SUPPORT Human Clinical
"Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years)"
Natural-history study quantifies early symptomatic onset and the diagnostic delay.
Later-onset cutaneous ulceration
Skin ulcers, the manifestation most characteristic of the disorder, are usually not the presenting feature; they appear at a median age of 12 years, which is part of why the diagnosis is missed early.
Show evidence (1 reference)
PMID:34040193 SUPPORT Human Clinical
"Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old"
Establishes that ulcers are a later manifestation rather than a presenting sign.
📊

Prevalence

2
Worldwide
Birth Prevalence 0.15 per 100,000 (0.1–0.2) 1–9 per 1,000,000 (births)
Reported incidence of 1-2 per 1,000,000 births. Fewer than one hundred molecularly confirmed patients had been reported as of 2020.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"The incidence of PD is of 1–2 per 1 million births"
Review states the birth incidence of prolidase deficiency as 1-2 per million.
Druze and Arab Muslim minority populations in Israel
Unknown Unknown
Founder enrichment is reported in the Druze and Arab Muslim minority populations of Israel; no numeric rate is given for these populations in the cited source, so only the qualitative enrichment is recorded here.
Show evidence (1 reference)
PMID:32455636 SUPPORT Human Clinical
"but is more frequent in some populations, as the Druze and Arab Muslim minority in Israel"
Documents population enrichment without a quantitative rate.
{ }

Source YAML

click to show 
name: Prolidase Deficiency
category: Mendelian
creation_date: '2026-08-01T00:00:00Z'
synonyms:
- PD
- PEPD-related prolidase deficiency
- Peptidase D deficiency
- Imidodipeptidase deficiency
- Hyperimidodipeptiduria
description: >
  Prolidase deficiency is a rare autosomal recessive inborn error of peptide
  metabolism caused by biallelic loss-of-function variants in PEPD, which encodes
  prolidase (peptidase D), the only human enzyme able to hydrolyse imidodipeptides
  bearing a C-terminal proline or hydroxyproline. Prolidase catalyses the terminal,
  rate-limiting step of collagen catabolism, so its loss simultaneously (i) blocks
  clearance of the imidodipeptides released from collagen turnover, producing the
  massive imidodipeptiduria that is the disorder's biochemical signature, and
  (ii) interrupts recycling of proline back into collagen and other proline-rich
  proteins, degrading extracellular-matrix remodelling and wound healing. The
  clinical picture is protean rather than organ-limited: recalcitrant lower-limb
  skin ulceration and other dermatological lesions, characteristic facial
  dysmorphism, developmental delay or intellectual disability, splenomegaly,
  recurrent respiratory infection with chronic lung disease, cytopenias, and a
  striking burden of immune dysregulation (elevated IgE, hypocomplementemia, a
  systemic-lupus-erythematosus-like phenotype, Crohn disease, and hemophagocytic
  lymphohistiocytosis) that has led to the disorder being classified as an inborn
  error of immunity as well as of metabolism. Symptoms usually begin in early
  childhood but are nonspecific at onset, and ulcers appear later (median 12 years),
  so diagnosis is characteristically delayed by more than a decade. There is no
  correlation between residual enzyme activity or accumulated dipeptide levels and
  clinical severity, and the mechanistic route from the enzyme block to the
  immunological and neurodevelopmental features remains unresolved.
disease_term:
  preferred_term: prolidase deficiency
  term:
    id: MONDO:0008221
    label: prolidase deficiency
parents:
- Inborn Error of Metabolism
- Inborn Error of Immunity
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.15
  rate_low: 0.1
  rate_high: 0.2
  notes: >
    Reported incidence of 1-2 per 1,000,000 births. Fewer than one hundred
    molecularly confirmed patients had been reported as of 2020.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of PD is of 1–2 per 1 million births"
    explanation: Review states the birth incidence of prolidase deficiency as 1-2 per million.
- population: Druze and Arab Muslim minority populations in Israel
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >
    Founder enrichment is reported in the Druze and Arab Muslim minority
    populations of Israel; no numeric rate is given for these populations in the
    cited source, so only the qualitative enrichment is recorded here.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but is more frequent in some populations, as the Druze and Arab Muslim minority in Israel"
    explanation: Documents population enrichment without a quantitative rate.
progression:
- phase: Early-childhood nonspecific onset with delayed diagnosis
  notes: >
    Most patients become symptomatic in early childhood, but the presenting
    features (infections, dysmorphism, developmental delay, splenomegaly) are
    nonspecific, and about half of published patients were symptomatic by age 4
    while diagnosis lagged by a mean of 11.6 years.
  evidence:
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of published patients were symptomatic by age 4 \nand had a delayed diagnosis (mean delay 11.6 years)"
    explanation: Natural-history study quantifies early symptomatic onset and the diagnostic delay.
- phase: Later-onset cutaneous ulceration
  notes: >
    Skin ulcers, the manifestation most characteristic of the disorder, are
    usually not the presenting feature; they appear at a median age of 12 years,
    which is part of why the diagnosis is missed early.
  evidence:
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ulcers were present \ninitially in only 30% of cases, with a median age of onset at 12 years old"
    explanation: Establishes that ulcers are a later manifestation rather than a presenting sign.
mechanistic_hypotheses:
- hypothesis_group_id: collagen_recycling_matrix_failure
  hypothesis_label: Impaired proline recycling and matrix-remodelling failure
  status: CANONICAL
  description: >
    The accepted explanatory model: because prolidase performs the terminal,
    rate-limiting hydrolysis of collagen-derived imidodipeptides, its loss both
    traps proline in undegradable dipeptides and starves collagen resynthesis of
    recycled proline. The resulting defect in extracellular-matrix remodelling
    accounts for the impaired wound healing and the recalcitrant skin ulceration.
  evidence:
  - reference: PMID:34532344
    reference_title: "PROLIDASE: A Review from Discovery to its Role in Health and Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mutations leading to loss of prolidase catalytic activity result in prolidase \ndeficiency a rare autosomal recessive metabolic disorder characterized by \ndefective wound healing"
    explanation: Ties loss of prolidase catalytic activity to defective wound healing as the disorder's core mechanism.
- hypothesis_group_id: immune_dysregulation_arm
  hypothesis_label: Cell-intrinsic lymphocyte dysfunction and inflammasome activation as the route to autoimmunity
  status: EMERGING
  description: >
    How the enzyme block produces the lupus-like autoimmunity is unresolved. The
    two candidate routes are not mutually exclusive: (i) a cell-intrinsic
    lymphocyte defect, supported by Pepd-null mice in which T cells activate
    spontaneously and independently of antigen-receptor specificity, and
    (ii) innate hyperinflammation, supported by high monocyte IL-1beta production
    and detectable serum IL-1beta and IL-18 in a patient, implying enhanced
    inflammasome activation. Classical alternatives - self-antigen exposure from
    chronic tissue damage, or chronic microbial burden - remain live.
  evidence:
  - reference: PMID:36637239
    reference_title: "Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pepd deficiency leads to spontaneous T cell activation and \nproliferation into the effector subset, which is cell intrinsic and independent \nof Ag receptor specificity or antigenic stimulation"
    explanation: Provides the cell-intrinsic lymphocyte-dysfunction arm of the hypothesis in a mouse null model.
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High interleukin-1β \n(IL-1β) production by this patient's monocytes, together with the detection of \nboth IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced \ninflammasome activation in PD"
    explanation: Provides the innate/inflammasome arm of the hypothesis from human immunophenotyping.
pathophysiology:
- name: PEPD Prolidase Catalytic Deficiency
  biological_scale: MOLECULAR
  description: >
    Biallelic homozygous or compound heterozygous loss-of-function variants in
    PEPD abolish or severely reduce the activity of prolidase (peptidase D), a
    ubiquitously expressed cytosolic manganese metallopeptidase. Prolidase is the
    only human enzyme that can hydrolyse imidodipeptides carrying a C-terminal
    proline or hydroxyproline residue, so no other peptidase can compensate for
    its loss.
  genes:
  - preferred_term: PEPD
    term:
      id: hgnc:8840
      label: PEPD
  molecular_functions:
  - preferred_term: imidodipeptidase (X-Pro dipeptidase) activity
    term:
      id: GO:0102009
      label: proline dipeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:34532344
    reference_title: "PROLIDASE: A Review from Discovery to its Role in Health and Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the only enzyme capable of cleaving imidodipeptides \ncontaining C-terminal proline or hydroxyproline"
    explanation: Establishes prolidase as the sole enzyme with this activity, so its loss cannot be compensated.
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rare autosomal recessive inborn error of immunity \ncaused by biallelic homozygous or compound heterozygous loss-of-function \nmutations in PEPD"
    explanation: Documents the biallelic loss-of-function genetic mechanism.
  downstream:
  - target: Imidodipeptide Accumulation and Imidodipeptiduria
    causal_link_type: DIRECT
    description: >
      Loss of the terminal hydrolytic step leaves collagen-derived imidodipeptides
      undegraded, so they accumulate in cells and blood and are excreted in urine.
    evidence:
    - reference: PMID:36757671
      reference_title: "Prolidase deficiency: A novel PEPD missense variant in exon 2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Altered collagen homeostasis results in the intracellular \naccumulation of imidodipeptides, which contain proline and hydroxyproline"
      explanation: Directly links the enzyme block to intracellular imidodipeptide accumulation.
  - target: Impaired Proline Recycling for Collagen Resynthesis
    causal_link_type: DIRECT
    description: >
      Because prolidase liberates the proline that is re-used for collagen
      synthesis, the enzyme block interrupts the proline salvage loop.
    hypothesis_groups:
    - collagen_recycling_matrix_failure
    evidence:
    - reference: PMID:27040799
      reference_title: "Prolidase-proline dehydrogenase/proline oxidase-collagen biosynthesis axis as a potential interface of apoptosis/autophagy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The enzyme plays an \nimportant role in the recycling of proline from imidodipeptides for resynthesis \nof collagen and other proline-containing proteins"
      explanation: Establishes prolidase as the enzyme supplying recycled proline for collagen resynthesis.
  - target: Spontaneous T Cell Activation and Loss of Self-Tolerance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Prolidase loss produces a cell-intrinsic T-cell activation phenotype in the
      mouse null model; the metabolic or non-enzymatic intermediate that couples
      the enzyme block to lymphocyte dysfunction is not established.
    hypothesis_groups:
    - immune_dysregulation_arm
    evidence:
    - reference: PMID:36637239
      reference_title: "Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Pepd deficiency leads to spontaneous T cell activation and \nproliferation into the effector subset, which is cell intrinsic and independent \nof Ag receptor specificity or antigenic stimulation"
      explanation: Shows the T-cell activation phenotype is cell-intrinsic to prolidase loss, without defining intermediates.
  - target: Enhanced Inflammasome Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Patient monocytes overproduce IL-1beta and serum carries both IL-1beta and
      IL-18, implicating inflammasome activation downstream of the enzyme defect;
      the activating signal is unidentified.
    hypothesis_groups:
    - immune_dysregulation_arm
    evidence:
    - reference: PMID:38088248
      reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "High interleukin-1β \n(IL-1β) production by this patient's monocytes, together with the detection of \nboth IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced \ninflammasome activation in PD"
      explanation: Human immunophenotyping infers enhanced inflammasome activation without specifying the trigger.
  - target: Impaired Host Defense and Recurrent Infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Recurrent, predominantly respiratory infection is one of the most frequent
      manifestations, but whether it reflects the immune dysregulation, structural
      airway/matrix compromise, or both is unresolved.
    evidence:
    - reference: PMID:32455636
      reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recurrent infections, including pneumonia, are a major complication for
        PD, which can compromise the survival
      explanation: Identifies recurrent infection as a major, potentially life-limiting manifestation.
- name: Imidodipeptide Accumulation and Imidodipeptiduria
  biological_scale: ORGANISM
  description: >
    Undegraded imidodipeptides - principally proline-glycine (Gly-Pro) and
    proline-hydroxyproline - accumulate in fibroblasts and blood and are massively
    excreted in urine. Because healthy individuals excrete negligible amounts,
    imidodipeptiduria is the disorder's essential biochemical marker. Accumulated
    dipeptide levels do not track clinical severity, so this node is best read as
    a biomarker branch rather than as the proximate cause of tissue injury.
  chemical_entities:
  - preferred_term: imidodipeptide (C-terminal proline/hydroxyproline dipeptide)
    term:
      id: CHEBI:46761
      label: dipeptide
    modifier: INCREASED
  - preferred_term: L-proline
    term:
      id: CHEBI:17203
      label: L-proline
  - preferred_term: trans-4-hydroxy-L-proline
    term:
      id: CHEBI:18095
      label: trans-4-hydroxy-L-proline
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of urinary amino acids in all tested patients revealed a massive excretion of imidodipeptides such as proline-glycine or proline-hydroxyproline"
    explanation: Identifies the specific accumulating imidodipeptides and their urinary excretion.
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five patients, the levels of accumulated dipeptides did not correlate with the severity of the disease"
    explanation: Argues against accumulated dipeptides being the direct determinant of disease severity.
  - reference: PMID:15378943
    reference_title: "Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare, autosomally inherited \ndisorder causing iminodipeptiduria is associated with a number of clinical \nmanifestations, the principle feature being chronic skin ulceration"
    explanation: Confirms iminodipeptiduria as the defining biochemical consequence of the enzyme defect.
- name: Impaired Proline Recycling for Collagen Resynthesis
  biological_scale: CELLULAR
  description: >
    Prolidase catalyses the rate-limiting terminal step of collagen catabolism and
    supplies the recycled proline used to resynthesise collagen and other
    proline-rich proteins. Loss of the enzyme therefore blocks the final stage of
    collagen degradation and simultaneously deprives collagen biosynthesis of its
    salvaged proline pool.
  biological_processes:
  - preferred_term: collagen catabolic process
    term:
      id: GO:0030574
      label: collagen catabolic process
    modifier: DECREASED
  - preferred_term: L-proline metabolic process
    term:
      id: GO:0006560
      label: L-proline metabolic process
    modifier: ABNORMAL
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:34532344
    reference_title: "PROLIDASE: A Review from Discovery to its Role in Health and Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prolidase catalyzes the \nrate-limiting step during collagen recycling and is essential in protein \nmetabolism, collagen turnover, and matrix remodeling"
    explanation: Establishes prolidase as the rate-limiting enzyme of collagen recycling and turnover.
  - reference: PMID:18340504
    reference_title: "Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is relevant in the latest stage \nof protein catabolism, particularly of those molecules rich in imino acids such \nas collagens, thus being involved in matrix remodelling"
    explanation: Places prolidase at the final stage of collagen catabolism and links it to matrix remodelling.
  downstream:
  - target: Defective Matrix Remodeling and Wound Healing
    causal_link_type: DIRECT
    description: >
      Failure of the collagen degradation/resynthesis cycle degrades
      extracellular-matrix remodelling capacity, which is the process wound repair
      depends on.
    hypothesis_groups:
    - collagen_recycling_matrix_failure
    evidence:
    - reference: PMID:18340504
      reference_title: "Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It is relevant in the latest stage \nof protein catabolism, particularly of those molecules rich in imino acids such \nas collagens, thus being involved in matrix remodelling"
      explanation: Links the collagen catabolic step directly to matrix remodelling.
- name: Defective Matrix Remodeling and Wound Healing
  biological_scale: TISSUE
  description: >
    Impaired collagen turnover compromises extracellular-matrix remodelling in
    skin and other connective tissues, manifesting as defective wound healing.
    This is the mechanistic step that distinguishes prolidase deficiency ulcers
    from ischaemic or venous ulcers: vascular studies in affected patients have
    been normal.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DECREASED
  evidence:
  - reference: PMID:34532344
    reference_title: "PROLIDASE: A Review from Discovery to its Role in Health and Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mutations leading to loss of prolidase catalytic activity result in prolidase \ndeficiency a rare autosomal recessive metabolic disorder characterized by \ndefective wound healing"
    explanation: Names defective wound healing as the characteristic consequence of lost prolidase activity.
  downstream:
  - target: Chronic Cutaneous Ulceration
    causal_link_type: DIRECT
    description: >
      Non-healing of skin breaks produces the chronic, recalcitrant lower-limb
      ulceration that is the disorder's most characteristic manifestation.
    hypothesis_groups:
    - collagen_recycling_matrix_failure
    evidence:
    - reference: PMID:15378943
      reference_title: "Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the principle feature being chronic skin ulceration"
      explanation: Identifies chronic skin ulceration as the principal clinical consequence.
- name: Chronic Cutaneous Ulceration
  biological_scale: TISSUE
  description: >
    Recalcitrant, often infected ulcers, predominantly on the lower legs, that
    resist conventional topical therapy and skin grafting. They may arise on skin
    already weakened by pruritic or eczematous lesions and appear at a median age
    of 12 years rather than at presentation.
  evidence:
  - reference: PMID:17166065
    reference_title: "[Effective therapy with a glycine-proline ointment in a patient with recurrent ulcers from prolidase deficiency]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower leg recalcitrant \nulcerations are the most characteristic symptoms"
    explanation: Characterises the ulcers as recalcitrant and lower-limb predominant.
- name: Spontaneous T Cell Activation and Loss of Self-Tolerance
  biological_scale: CELLULAR
  description: >
    In the Pepd-null mouse, T cells activate and proliferate into the effector
    subset spontaneously, in a manner intrinsic to the cell and independent of
    antigen-receptor specificity or antigenic stimulation, with CD4 and CD8
    effector T cells accumulating in spleen and liver. Notably the autoimmune
    phenotype is absent in mixed chimeras, indicating that a non-haematopoietic
    contribution is also required - so lymphocyte dysfunction is necessary but
    not sufficient.
  biological_processes:
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
    modifier: INCREASED
  evidence:
  - reference: PMID:36637239
    reference_title: "Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These \nfeatures are associated with an accumulation of CD4 and CD8 effector T cells in \nthe spleen and liver"
    explanation: Documents effector T-cell accumulation in the mouse null model.
  downstream:
  - target: Systemic Autoimmunity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Spontaneous effector T-cell expansion drives autoantibody production and
      immune-complex disease in the mouse model, but the model also requires
      extra-haematopoietic input, so the link is not a simple one-step relation.
    hypothesis_groups:
    - immune_dysregulation_arm
    evidence:
    - reference: PMID:36637239
      reference_title: "Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Pepd-null mice have increased antinuclear \nautoantibodies and raised serum IgA, accompanied by kidney immune complex \ndeposition, consistent with a systemic lupus erythematosus-like disease"
      explanation: Connects the T-cell phenotype to an SLE-like autoimmune readout in the null mouse.
- name: Enhanced Inflammasome Activation
  biological_scale: CELLULAR
  description: >
    Innate hyperinflammation forms a parallel arm of the immune phenotype: patient
    monocytes overproduce IL-1beta, and both IL-1beta and IL-18 are detectable in
    serum, a pattern that implies increased inflammasome activity. This arm is
    based on a single patient's immunophenotyping and is not yet established as a
    general feature.
  biological_processes:
  - preferred_term: positive regulation of interleukin-1 beta production
    term:
      id: GO:0032731
      label: positive regulation of interleukin-1 beta production
    modifier: INCREASED
  evidence:
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High interleukin-1β \n(IL-1β) production by this patient's monocytes, together with the detection of \nboth IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced \ninflammasome activation in PD"
    explanation: Reports the IL-1beta/IL-18 signature interpreted as enhanced inflammasome activation.
  downstream:
  - target: Systemic Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Innate IL-1/IL-18-driven inflammation is proposed to contribute to the
      autoimmune manifestations alongside the lymphocyte-intrinsic arm.
    hypothesis_groups:
    - immune_dysregulation_arm
    evidence:
    - reference: PMID:38088248
      reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD"
      explanation: The authors frame PD immunopathogenesis as multi-cellular and complex rather than a single established route.
- name: Systemic Autoimmunity
  biological_scale: ORGANISM
  description: >
    Autoimmune disease is one of the defining burdens of prolidase deficiency: a
    systemic-lupus-erythematosus-like phenotype (sometimes full SLE, sometimes
    serology-only incomplete lupus), Crohn disease, arthritis, undifferentiated
    connective tissue disease, hypocomplementemia, and cytopenias. Hemophagocytic
    lymphohistiocytosis has also been reported. It is prominent enough that
    unexplained childhood autoimmunity is a recommended trigger for testing.
  evidence:
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune \ndisorders were found in 6/19, including Crohn disease, systemic lupus \nerythematosus, and arthritis"
    explanation: Quantifies the autoimmune burden and names the specific autoimmune diagnoses observed.
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Testing for this disorder should be considered in any child with unexplained \nautoimmunity, lower extremity ulcers, splenomegaly, or HLH"
    explanation: Establishes autoimmunity and HLH as diagnostically salient features.
- name: Impaired Host Defense and Recurrent Infection
  biological_scale: ORGANISM
  description: >
    Recurrent infections - predominantly respiratory (pneumonia, upper
    respiratory tract infection) - affect roughly three quarters of reported
    patients, and a substantial fraction develop chronic lung disease with cystic
    change, bronchiectasis, ground-glass attenuation, and in some cases
    progressive pulmonary fibrosis with excessive collagen deposition on biopsy.
  evidence:
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prolidase deficiency is a rare inborn error of metabolism causing \nulcers and other skin disorders, splenomegaly, developmental delay, and \nrecurrent infections"
    explanation: Lists recurrent infection among the core manifestations of the disorder.
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent infections, namely respiratory infections, pneumonia or upper
      respiratory tract infections ... are present in 76% (37/49) of patients
      (Figure 1a).
    explanation: >-
      The pooled review documents recurrent predominantly respiratory infection
      in 76% of reported patients.
phenotypes:
- name: Abnormal facial shape
  frequency: VERY_FREQUENT
  description: >
    Characteristic facial dysmorphism, reported in 93% (54/58) of molecularly
    confirmed patients, including proptosis and/or hypertelorism and saddle nose.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism was present in 93% (54/58) patients"
    explanation: Direct quantitative frequency (93%, 54/58) maps to the VERY_FREQUENT band.
- name: Recurrent respiratory infections
  frequency: FREQUENT
  description: >
    Recurrent respiratory infections and pneumonia were present in 76% (37/49)
    of pooled reported patients; in a retrospective 21-patient Israeli series,
    57% had recurrent pulmonary infections and 47% had chronic lung disease.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  reports_on:
  - target: Impaired Host Defense and Recurrent Infection
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Recurrent respiratory infection is the clinical readout of the impaired
      host-defense node.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent infections, namely respiratory infections, pneumonia or upper
      respiratory tract infections ... are present in 76% (37/49) of patients
      (Figure 1a).
    explanation: Direct pooled frequency (76%, 37/49) maps to the FREQUENT band.
- name: Anemia
  frequency: FREQUENT
  description: >
    Anemia in 76% (19/25) of patients; it may be microcytic hypochromic with iron
    deficiency or hemolytic with a positive Coombs test.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anemia was reported in 76% (19/25) of patients"
    explanation: Direct quantitative frequency (76%, 19/25) maps to the FREQUENT band.
- name: Splenomegaly
  frequency: FREQUENT
  description: >
    Splenomegaly in 72% (31/43) of patients, occasionally requiring splenectomy.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenomegaly was found in 72% (31/43) of patients"
    explanation: Direct quantitative frequency (72%, 31/43) maps to the FREQUENT band.
- name: Global developmental delay
  frequency: FREQUENT
  description: >
    Developmental delay or intellectual disability of mild, moderate, or severe
    degree in 71% (48/68) of patients.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay or intellectual disability (moderate, mild or severe) was present in 71% (48/68) patients"
    explanation: Direct quantitative frequency (71%, 48/68) maps to the FREQUENT band.
- name: Intellectual disability
  frequency: FREQUENT
  description: >
    Intellectual disability is reported together with developmental delay in 71%
    (48/68) of patients, spanning mild to severe degrees. The cited source pools
    the two, so the frequency band is shared rather than independently derived.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay or intellectual disability (moderate, mild or severe) was present in 71% (48/68) patients"
    explanation: The source reports developmental delay and intellectual disability as a single pooled 71% (48/68) figure.
- name: Telangiectasia
  frequency: FREQUENT
  description: >
    Telangiectasias in 71% (10/14) of patients, mainly on the lower limbs but also
    on cheeks, shoulders, and knees.
  phenotype_term:
    preferred_term: Telangiectasia
    term:
      id: HP:0001009
      label: Telangiectasia
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Telangiectasias were present in 71% (10/14) of patients"
    explanation: Direct quantitative frequency (71%, 10/14) maps to the FREQUENT band.
- name: Skin rash
  frequency: FREQUENT
  description: >
    Rash in 67% (10/15) of patients, variably persistent and scaling, erythematous
    with secondary crusts, fine purpuric, maculopapular, or eczema-like.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A rash was reported in 67% (10/15) of patients"
    explanation: Direct quantitative frequency (67%, 10/15) maps to the FREQUENT band.
- name: Increased circulating IgE concentration
  frequency: FREQUENT
  description: >
    Hypergammaglobulinemia with elevated IgE in 64% (9/14) of patients; the
    picture can be striking enough to be mistaken for hyper-IgE syndrome.
  phenotype_term:
    preferred_term: Elevated IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypergammaglobulinemia IgE was present in 64% (9/14) of patients"
    explanation: Direct quantitative frequency (64%, 9/14) maps to the FREQUENT band.
- name: Skin ulcer
  frequency: FREQUENT
  description: >
    Cutaneous ulcers, the most characteristic manifestation, in 61% (41/67) of
    patients. They are chronic and recalcitrant, predominantly on the lower legs,
    and typically appear at a median age of 12 years rather than at presentation.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
    temporality: CHRONIC
  reports_on:
  - target: Chronic Cutaneous Ulceration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Skin ulceration is the direct clinical manifestation of the chronic
      cutaneous ulceration node.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "61% (41/67) of patients were described with cutaneous ulcers"
    explanation: Direct quantitative frequency (61%, 41/67) maps to the FREQUENT band.
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ulcers were present \ninitially in only 30% of cases, with a median age of onset at 12 years old"
    explanation: Supports the chronic temporality and later median age of onset.
- name: Eczematoid dermatitis
  frequency: FREQUENT
  description: >
    Eczema or dermatitis in 58% (18/31) of patients; crusting dermatitis of the
    face and extremities was frequent in the Druze cohort. Ulcers may develop on
    skin already weakened by these lesions.
  phenotype_term:
    preferred_term: Eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eczema or dermatitis were reported in 58% (18/31) of patients"
    explanation: Direct quantitative frequency (58%, 18/31) maps to the FREQUENT band.
- name: Thrombocytopenia
  frequency: FREQUENT
  description: >
    Thrombocytopenia in 56% (10/18) of patients, part of the cytopenia component
    of the immune-dysregulation phenotype.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia was found in 56% (10/18) of patients"
    explanation: Direct quantitative frequency (56%, 10/18) maps to the FREQUENT band.
- name: Hepatomegaly
  frequency: FREQUENT
  description: Hepatomegaly in 53% (8/15) of patients, often accompanying splenomegaly.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly was present in 53% (8/15) of patients"
    explanation: Direct quantitative frequency (53%, 8/15) maps to the FREQUENT band.
- name: Failure to thrive
  frequency: FREQUENT
  description: >
    Failure to thrive in 53% (21/40) of patients, reported in the same pooled
    clinical series used for the other frequency-banded phenotypes.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-three percent (21/40) of patients presented a failure to thrive"
    explanation: Direct quantitative frequency (53%, 21/40) maps to the FREQUENT band.
- name: Reduced circulating complement concentration
  frequency: FREQUENT
  description: >
    Hypocomplementemia in 40% (4/10) of patients, part of the lupus-like
    serological profile. The cited pooled finding does not resolve which
    complement component was reduced in each patient.
  phenotype_term:
    preferred_term: Hypocomplementemia
    term:
      id: HP:0004431
      label: Reduced circulating complement concentration
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypocomplementemia was present in 40% (4/10) of patients"
    explanation: Direct quantitative frequency (40%, 4/10) maps to the FREQUENT band.
- name: Cutaneous photosensitivity
  frequency: FREQUENT
  description: Photosensitivity in 33% (3/9) of patients.
  phenotype_term:
    preferred_term: Photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Photosensitivity was reported in 33% (3/9) of patients"
    explanation: Direct quantitative frequency (33%, 3/9) sits at the low end of the FREQUENT band (79-30%).
- name: Systemic lupus erythematosus
  frequency: OCCASIONAL
  description: >
    Systemic lupus erythematosus or an SLE-like phenotype in 29% (6/21) of
    patients, ranging from serology-only incomplete lupus to full-blown SLE.
  phenotype_term:
    preferred_term: Systemic lupus erythematosus
    term:
      id: HP:0002725
      label: Systemic lupus erythematosus
  reports_on:
  - target: Systemic Autoimmunity
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      The SLE-like phenotype is the most specific clinical readout of the systemic
      autoimmunity node.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic lupus erythematosus or SLE-like phenotype was reported in 29% (6/21) of patients"
    explanation: Direct quantitative frequency (29%, 6/21) maps to the OCCASIONAL band (29-5%).
- name: Autoimmunity
  description: >
    Autoimmune disease is a defining burden of the disorder; in the natural-history
    cohort 6/19 patients had an autoimmune diagnosis (Crohn disease, systemic lupus
    erythematosus, arthritis). No frequency band is asserted here because the broad
    "autoimmunity" category is not itself tabulated with a denominator in the cited
    sources.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  reports_on:
  - target: Systemic Autoimmunity
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Clinical autoimmune disease is the organism-level readout of the systemic
      autoimmunity node.
  evidence:
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune \ndisorders were found in 6/19, including Crohn disease, systemic lupus \nerythematosus, and arthritis"
    explanation: Documents the autoimmune manifestations without a pooled category frequency.
- name: Hemophagocytosis
  description: >
    Hemophagocytic lymphohistiocytosis has been reported as an immune manifestation
    and is one of the presentations that should prompt testing. Reported as a
    finding rather than with a denominator, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Hemophagocytic lymphohistiocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:34040193
    reference_title: "Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Another immune finding was hemophagocytic \nlymphohistiocytosis"
    explanation: Reports HLH as an observed immune finding without a frequency denominator.
- name: Bronchiectasis
  description: >
    Chronic lung disease with bronchiectasis, cystic change, diffuse ground-glass
    attenuation, and linear atelectasis on CT; progressive pulmonary fibrosis with
    excessive collagen deposition has been documented on lung biopsy. Frequency is
    reported only within a single retrospective series, so no band is asserted.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cystic changes, bronchiectasis, diffuse ground glass attenuation and linear atelectasis"
    explanation: Documents the chronic structural lung findings on CT imaging.
- name: Short stature
  description: >
    Short stature is named among the human bone abnormalities investigated in a
    12-patient series. The review does not provide a per-feature numerator, so no
    frequency band is asserted.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, 12 patients were previously investigated by Besio et al. in the
      light of bone abnormalities, namely short stature, microcephaly, osteopenia
      and genu valgum
    explanation: Documents short stature among bone abnormalities evaluated in human patients.
- name: Microcephaly
  description: >
    Microcephaly is named among the human bone and growth abnormalities
    investigated in a 12-patient series. The review does not provide a
    per-feature numerator, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, 12 patients were previously investigated by Besio et al. in the
      light of bone abnormalities, namely short stature, microcephaly, osteopenia
      and genu valgum
    explanation: Documents microcephaly among bone abnormalities evaluated in human patients.
- name: Osteopenia
  description: >
    Osteopenia is named among the human bone abnormalities investigated in a
    12-patient series. The review does not provide a per-feature numerator, so no
    frequency band is asserted.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, 12 patients were previously investigated by Besio et al. in the
      light of bone abnormalities, namely short stature, microcephaly, osteopenia
      and genu valgum
    explanation: Documents osteopenia among bone abnormalities evaluated in human patients.
- name: Genu valgum
  description: >
    Genu valgum is named among the human bone abnormalities investigated in a
    12-patient series. The review does not provide a per-feature numerator, so no
    frequency band is asserted.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, 12 patients were previously investigated by Besio et al. in the
      light of bone abnormalities, namely short stature, microcephaly, osteopenia
      and genu valgum
    explanation: Documents genu valgum among bone abnormalities evaluated in human patients.
histopathology:
- name: Diffuse alveolar fibrosis with excessive collagen deposition
  finding_term:
    preferred_term: Fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  description: >-
    Lung biopsy in a reported patient with prolidase deficiency and systemic
    lupus erythematosus showed diffuse alveolar fibrosis, excessive collagen
    deposition, architectural distortion, and alveolar cysts.
  context: Lung biopsy
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His videothoracoscopic lung biopsy showed diffuse alveolar fibrosis with
      excessive collagen deposition, architectural distortion and alveolar cysts
      [48].
    explanation: >-
      Directly reports the pulmonary histopathology and collagen-deposition
      finding in a human case.
biochemical:
- name: Urinary imidodipeptides (imidodipeptiduria)
  presence: INCREASED
  context: >
    Massive urinary excretion of imidodipeptides bearing C-terminal proline or
    hydroxyproline - principally proline-glycine and proline-hydroxyproline - is
    the essential biochemical marker of the disorder, because healthy individuals
    excrete negligible amounts. The dipeptides also accumulate in fibroblasts and
    blood, at lower levels in serum than in urine. Standard urine amino-acid
    quantification may require prior hydrolysis (boiling) to reveal the markedly
    elevated proline.
  biomarker_term:
    preferred_term: imidodipeptide (C-terminal proline/hydroxyproline dipeptide)
    term:
      id: CHEBI:46761
      label: dipeptide
  readouts:
  - target: Imidodipeptide Accumulation and Imidodipeptiduria
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Urinary imidodipeptide excretion directly reports the accumulation of the
      substrates prolidase can no longer hydrolyse.
  specificity: >
    Highly specific: imidodipeptide excretion is negligible in healthy
    individuals. Levels do not correlate with disease severity, so the marker is
    diagnostic but not prognostic.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imidopeptiduria is therefore an essential biochemical marker for the diagnosis"
    explanation: Establishes imidodipeptiduria as the essential diagnostic biochemical marker.
  - reference: PMID:36757671
    reference_title: "Prolidase deficiency: A novel PEPD missense variant in exon 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "quantitative urine \namino acids demonstrated a markedly elevated proline level, confirming the \ndiagnosis"
    explanation: Shows urine amino-acid quantification (after hydrolysis) confirming the diagnosis.
- name: Erythrocyte and fibroblast prolidase activity
  presence: DECREASED
  context: >
    Prolidase activity measured in erythrocyte haemolysates or cultured dermal
    fibroblasts is deficient, especially against glycyl-proline. On FPLC
    separation, activity of the major isoform (I) is markedly reduced while the
    minor isoform (II) is unaltered. Residual activity does not predict clinical
    severity.
  readouts:
  - target: PEPD Prolidase Catalytic Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Measured enzyme activity is the direct functional readout of the PEPD
      molecular defect.
  evidence:
  - reference: PMID:15378943
    reference_title: "Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prolidase activity was found to be deficient, especially against gly-pro."
    explanation: Documents deficient erythrocyte and fibroblast prolidase activity, notably against Gly-Pro.
  - reference: PMID:15378943
    reference_title: "Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We were unable to find any correlation between degree of enzyme \nactivity loss and severity of symptoms"
    explanation: Establishes the absence of an enzyme-activity/severity correlation.
diagnosis:
- name: Urinary amino acid and imidodipeptide analysis
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  description: >
    Quantitative urinary amino acid analysis, with hydrolysis of the sample where
    needed, detects the massive imidodipeptide excretion (proline-glycine,
    proline-hydroxyproline) that is the disorder's biochemical signature.
  results: >
    Markedly elevated urinary imidodipeptides / proline; negligible excretion in
    unaffected individuals.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of urinary amino acids in all tested patients revealed a massive excretion of imidodipeptides such as proline-glycine or proline-hydroxyproline"
    explanation: Describes the diagnostic urinary finding across all tested patients.
- name: PEPD molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >
    Identification of biallelic pathogenic PEPD variants establishes the
    diagnosis; missense, splice, deletion, and duplication alleles have all been
    reported, and copy-number variation may be missed by sequencing alone.
  results: Biallelic pathogenic or likely pathogenic PEPD variants.
  evidence:
  - reference: PMID:36757671
    reference_title: "Prolidase deficiency: A novel PEPD missense variant in exon 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is dependent on the detection of a pathologic gene variant."
    explanation: States that diagnosis rests on detecting a pathogenic PEPD variant.
treatments:
- name: Topical glycine-proline ointment for recalcitrant ulcers
  description: >
    Topical application of a proline 5% / glycine 5% water-emulsive ointment is a
    mechanism-motivated local therapy: it supplies the amino acids that the
    blocked proline salvage loop fails to deliver to healing skin. It is used for
    ulcers refractory to conventional topical treatment and skin grafting, and the
    reported response is variable - partial improvement with fewer admissions for
    superinfection in the published case.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: wound care management
    term:
      id: NCIT:C116681
      label: Wound Care Management
    therapeutic_agent:
    - preferred_term: L-proline
      term:
        id: CHEBI:17203
        label: L-proline
    - preferred_term: glycine
      term:
        id: CHEBI:15428
        label: glycine
  target_mechanisms:
  - target: Impaired Proline Recycling for Collagen Resynthesis
    treatment_effect: BYPASSES
    description: >
      Exogenous topical proline and glycine bypass the blocked salvage step by
      supplying its products directly to healing skin, rather than restoring
      prolidase activity.
    evidence:
    - reference: PMID:17166065
      reference_title: "[Effective therapy with a glycine-proline ointment in a patient with recurrent ulcers from prolidase deficiency]."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pharmacy service draws up an elaboration guide and a patient information leaflet of a proline 5%-glycine 5% water emulsive ointment"
      explanation: Documents the amino-acid composition of the ointment, which is the basis of the bypass rationale.
  target_phenotypes:
  - preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:17166065
    reference_title: "[Effective therapy with a glycine-proline ointment in a patient with recurrent ulcers from prolidase deficiency]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical application of a glycine-proline ointment is an alternative \nfor the treatment of recalcitrant ulcerations and it has resulted in variable \nresponse"
    explanation: Single-patient report; the authors themselves describe the response as variable.
- name: Rituximab for refractory autoimmune manifestations
  description: >
    There is no consensus treatment for the autoimmune manifestations of prolidase
    deficiency, and steroids plus conventional synthetic DMARDs may fail while
    causing infectious complications. B-cell depletion with rituximab produced
    sustained recession of mucocutaneous ulceration in one patient with
    PD-associated vasculitis and undifferentiated connective tissue disease,
    allowing steroid tapering - implying a role for CD20-positive B cells in the
    immunopathogenesis.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Systemic Autoimmunity
    treatment_effect: INHIBITS
    description: >
      B-cell depletion suppresses the autoimmune arm of the disorder; it does not
      address the underlying enzyme deficiency.
    evidence:
    - reference: PMID:38088248
      reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD"
      explanation: Links the therapeutic effect to B-cell-mediated autoimmune pathogenesis.
  target_phenotypes:
  - preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Introduction of \nrituximab (RTX) treatment in this patient led to sustained recession of \nmucocutaneous ulceration, enabling tapering of steroids"
    explanation: Single-patient evidence of rituximab efficacy for the autoimmune/mucocutaneous manifestations.
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, there is no consensus regarding treatment of PD and its autoimmune manifestations."
    explanation: Documents the absence of a consensus treatment standard, which frames rituximab as an off-label option.
- name: Genetic counseling
  description: >
    Counseling and carrier testing are offered to families based on autosomal
    recessive inheritance. Founder enrichment in some populations (Druze and Arab
    Muslim minority populations in Israel) raises the value of targeted testing
    there.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but is more frequent in some populations, as the Druze and Arab Muslim minority in Israel"
    explanation: Population enrichment is the counseling-relevant fact supporting targeted carrier testing.
inheritance:
- name: Autosomal recessive
  description: >
    Prolidase deficiency is inherited in an autosomal recessive manner, requiring
    biallelic homozygous or compound heterozygous loss-of-function PEPD variants.
    Expressivity is markedly variable, including within families: reported
    phenotypes range from essentially asymptomatic to very severe, with onset from
    age 3 to the third decade, and neither residual enzyme activity nor
    accumulated dipeptide level predicts severity.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rare autosomal recessive inborn error of immunity \ncaused by biallelic homozygous or compound heterozygous loss-of-function \nmutations in PEPD"
    explanation: States the autosomal recessive, biallelic loss-of-function inheritance mechanism.
  - reference: PMID:15378943
    reference_title: "Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was considerable heterogeneity in age at onset of symptoms (varying from 3-17 years), mental retardation and clinical manifestations (asymptomless to very severe)."
    explanation: Documents the wide phenotypic range underlying the VARIABLE expressivity assignment.
genetic:
- name: PEPD
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PEPD
    term:
      id: hgnc:8840
      label: PEPD
  features: >
    PEPD encodes prolidase (peptidase D) and is the single causative locus, acting
    through autosomal recessive biallelic loss of function. Reported disease
    alleles include single amino-acid substitutions, exon-splicing variants,
    deletions, and a duplication, mainly affecting residues that are highly
    conserved across species; intragenic copy-number variation has also been
    reported and may escape sequencing-only testing. Fewer than one hundred
    molecularly confirmed patients had been reported as of 2020.
  evidence:
  - reference: PMID:18340504
    reference_title: "Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Single amino acid substitutions, exon splicing, deletions and a \nduplication were described as causative for the disease and are mainly located \nat highly conserved amino acids"
    explanation: Summarises the reported PEPD variant classes and their location at conserved residues.
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel homozygous intragenic deletion in PEPD"
    explanation: Documents intragenic copy-number variation as a disease mechanism at this locus.
discussions:
- discussion_id: pd_pathophysiology_unresolved
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what route does loss of a single cytosolic dipeptidase produce a phenotype
    spanning skin, immune, neurodevelopmental, skeletal, and pulmonary systems,
    and why is severity uncoupled from residual enzyme activity and from
    accumulated dipeptide levels?
  attaches_to:
  - pathophysiology#PEPD Prolidase Catalytic Deficiency
  - pathophysiology#Imidodipeptide Accumulation and Imidodipeptiduria
  - pathophysiology#Impaired Host Defense and Recurrent Infection
  rationale: >-
    The collagen-recycling model accounts convincingly for impaired wound healing
    and ulceration, but not for the neurodevelopmental, immunological, or
    haematological burden. Two independent reviews state explicitly that the
    pathophysiology is unresolved, and the absence of any correlation between
    either residual enzyme activity or accumulated dipeptide level and clinical
    severity argues that substrate accumulation is not the proximate injurious
    mechanism. A non-enzymatic role of prolidase in cell regulation has been
    proposed as an additional axis.
  proposed_experiments:
  - experiment_id: pd_genotype_stratified_phenotyping
    name: Genotype-stratified deep phenotyping of a multi-centre cohort
    description: >-
      Assemble a multi-centre prolidase deficiency cohort with paired genotype,
      residual erythrocyte/fibroblast enzyme activity, urinary imidodipeptide
      quantification, and systematic organ-by-organ phenotyping.
    would_support:
    - pathophysiology#Imidodipeptide Accumulation and Imidodipeptiduria
    supporting_outcome:
    - An allele class, residual-activity band, or metabolite level that predicts organ involvement would support substrate accumulation or enzyme dosage as the proximate mechanism.
    would_refute:
    - pathophysiology#Imidodipeptide Accumulation and Imidodipeptiduria
    refuting_outcome:
    - Continued absence of any genotype-, activity-, or metabolite-to-phenotype relation would refute dose-dependent substrate toxicity and redirect attention to modifier or non-enzymatic mechanisms.
  - experiment_id: pd_tissue_resolved_omics
    name: Tissue-resolved omics of PEPD-null human cells
    description: >-
      Transcriptomic and proteomic profiling of isogenic PEPD-null human
      fibroblasts, keratinocytes, monocytes, and neural cells.
    would_support:
    - pathophysiology#PEPD Prolidase Catalytic Deficiency
    supporting_outcome:
    - A shared downstream programme across all four lineages would support a single unifying mechanism for the multisystem phenotype.
    would_refute:
    - pathophysiology#PEPD Prolidase Catalytic Deficiency
    refuting_outcome:
    - Wholly lineage-specific programmes would refute a single unifying mechanism and favour tissue-specific consequences of the same enzyme block.
  - experiment_id: pd_allele_panel_abundance_stability_catalysis
    name: Decomposition of residual prolidase activity across a patient allele panel
    description: >-
      Express a panel of reported PEPD missense alleles alongside wild-type and a
      catalytically dead control in a cell-free transcription-translation system,
      and measure three quantities separately for each allele: how much protein
      accumulates, whether it is folded, and whether it turns over an
      imidodipeptide substrate. Clinical "residual prolidase activity" is assayed
      as one number in erythrocyte or fibroblast lysate, where low abundance of a
      normally catalytic enzyme and normal abundance of a dead one are
      indistinguishable. Separating them gives a per-allele measure to test
      against severity in place of the composite.
    model_systems:
    - name: Cell-free expressed PEPD allele panel
      description: >-
        Each reported PEPD missense allele, wild type, and a catalytically dead
        control expressed from a linear DNA template in a reconstituted
        transcription-translation system, giving the isolated human enzyme in a
        defined reaction rather than in a patient cell.
      experimental_model_type: OTHER
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      culture_system: >-
        Reconstituted Escherichia coli cell-free transcription-translation
        reaction, 96-well format, no intact cells
      modeled_mechanisms:
      - target: PEPD Prolidase Catalytic Deficiency
        relationship: MEASURES
        fidelity: MODERATE
        model_scale: MOLECULAR
        description: >-
          Reports abundance, folding, and imidodipeptide turnover for each allele
          as three separately measured quantities, which is the decomposition the
          clinical lysate assay cannot make.
        limitations: >-
          A bacterial cell-free system supplies neither the human chaperone
          complement nor the cytosolic milieu, so a folding result is a property
          of the allele in this reaction and not a prediction of its stability in
          a patient cell.
        divergences:
        - divergence_type: BOUNDARY_OMISSION
          materiality: QUALIFYING
          description: >-
            The cytosol in which prolidase is proposed to act non-enzymatically
            lies outside the reaction boundary: there are no intact cells, no
            binding partners, and no signalling context. The model therefore
            constrains the enzymatic arm of the gap and is silent on the
            separation-of-function question, which needs a cellular system.
        - divergence_type: BOUNDARY_OMISSION
          materiality: QUALIFYING
          description: >-
            Human chaperones and post-translational modification machinery are
            absent from a bacterial extract, so misfolding seen here may be an
            artefact of the expression host rather than a property of the allele.
            Bears on the folding readout specifically, which is why it is recorded
            separately from the cytosolic omission above.
    readouts:
    - name: Accumulated PEPD protein per allele
      target: pathophysiology#PEPD Prolidase Catalytic Deficiency
      direction: ALTERED
      interpretation: >-
        Separates an allele that fails to accumulate from one that is present and
        inactive, which a single lysate activity figure cannot distinguish.
    - name: Thermal unfolding midpoint of purified PEPD per allele
      target: pathophysiology#PEPD Prolidase Catalytic Deficiency
      direction: ALTERED
      interpretation: >-
        A reduced midpoint relative to wild type marks a destabilising allele, as
        against one that folds normally and cannot catalyse. Reports on the
        subunit rather than the assembled homodimer.
    - name: Imidodipeptide turnover per allele
      target: pathophysiology#PEPD Prolidase Catalytic Deficiency
      direction: ALTERED
      interpretation: >-
        Substrate depletion or product formation gives catalytic competence
        independently of how much protein is present, which is the quantity the
        clinical assay conflates with abundance.
    decision_criterion: >-
      The three measurements are read together per allele. Pathogenic alleles
      falling into more than one class — reduced accumulation with retained
      turnover, normal accumulation with abolished turnover, or loss of folding —
      establish that the clinical residual-activity figure is a composite.
      Pathogenic alleles all behaving alike establish that it is not.
    would_support:
    - pathophysiology#PEPD Prolidase Catalytic Deficiency
    supporting_outcome:
    - >-
      Alleles separating into distinct classes — reduced accumulation with
      retained specific activity, normal accumulation with abolished catalysis,
      or loss of folding — would show that the single residual-activity figure
      conflates three quantities, and would supply the per-allele measures the
      genotype-severity comparison has so far lacked.
    would_refute:
    - pathophysiology#PEPD Prolidase Catalytic Deficiency
    refuting_outcome:
    - >-
      Every pathogenic allele behaving alike, with accumulation and catalysis
      lost together, would show residual activity is already an adequate summary
      of the enzymatic lesion, and would place the source of the severity
      uncoupling outside the enzyme — in modifiers, or in the proposed
      non-enzymatic axis.
    executable_protocols:
    - name: Cell Free Protein Expression with HiBiT Quantification
      provider: Ginkgo Cloud Lab
      venue_type: COMMERCIAL_CLOUD_LAB
      protocol_id: cell-free-protein-expression-validation-hibit
      protocol_url: https://cloud.ginkgo.bio/protocols/cell-free-protein-expression-validation-hibit
      description: >-
        Supplies the abundance term: how much protein each allele accumulates,
        quantified by luminescence from the crude reaction without purification,
        so an allele that is simply unstable in the lysate is distinguished from
        one that is expressed and inactive.
      measures:
      - pathophysiology#PEPD Prolidase Catalytic Deficiency
      inputs_required: Coding sequences for each allele, submitted as linear DNA templates
      retrieved_date: '2026-10-01'
    - name: Protein Expression and Thermal Shift Assay
      provider: Ginkgo Cloud Lab
      venue_type: COMMERCIAL_CLOUD_LAB
      protocol_id: protein-expression-and-thermal-shift-assay
      protocol_url: https://cloud.ginkgo.bio/protocols/protein-expression-and-thermal-shift-assay
      description: >-
        Supplies the folding term: expression, Strep-II purification and a SYPRO
        Orange thermal unfolding curve, so a destabilising allele is separated
        from one that folds normally and cannot catalyse.
      measures:
      - pathophysiology#PEPD Prolidase Catalytic Deficiency
      inputs_required: Coding sequences carrying a Strep-II tag, as a DNA template plate
      retrieved_date: '2026-10-01'
      notes: >-
        Prolidase is a homodimeric metallopeptidase, so a thermal unfolding
        curve from the purified monomer reports on the subunit and not
        necessarily on the assembled holoenzyme.
    - name: Echo-MS Detection of Molecules from an Enzymatic Reaction in Cell Free Expression System
      provider: Ginkgo Cloud Lab
      venue_type: COMMERCIAL_CLOUD_LAB
      protocol_id: echo-ms-detection-of-molecules-from-an-enzymatic-reaction-in-cell-free-expression-system
      protocol_url: https://cloud.ginkgo.bio/protocols/echo-ms-detection-of-molecules-from-an-enzymatic-reaction-in-cell-free-expression-system
      description: >-
        Supplies the catalysis term: substrate depletion or product formation
        measured by acoustic ejection mass spectrometry on the expressed enzyme,
        giving turnover per allele independently of how much protein is present.
      measures:
      - pathophysiology#PEPD Prolidase Catalytic Deficiency
      inputs_required: >-
        Coding sequences as linear DNA templates, plus an imidodipeptide substrate
        and a proline product standard for the mass-spectrometry method
      retrieved_date: '2026-10-01'
      notes: >-
        The provider's catalogue does not record whether this method is
        validated for an imidodipeptide substrate and free proline, and lists a
        separate Echo-MS method onboarding service, so method development should
        be assumed to be required.
    notes: >-
      The amount-versus-activity distinction this experiment turns on is the axis
      deferred in design decisions section 12 (Quantity kind: analyte amount vs
      catalytic activity), which names the residual-enzyme-activity
      genotype-severity question as one of its motivating cases; nothing here
      settles that decision. The limits of the cell-free system are recorded as
      typed divergences on the model system above rather than restated here.
  - experiment_id: pd_separation_of_function_alleles
    name: Separation-of-function PEPD alleles
    description: >-
      Engineer PEPD alleles that retain protein expression and any scaffolding role
      but abolish catalysis, and compare them with a full null.
    would_support:
    - pathophysiology#PEPD Prolidase Catalytic Deficiency
    supporting_outcome:
    - A phenotypic difference between catalytically dead and null alleles would support a distinct non-enzymatic contribution of prolidase.
    would_refute:
    - pathophysiology#PEPD Prolidase Catalytic Deficiency
    refuting_outcome:
    - Indistinguishable phenotypes between catalytically dead and null alleles would refute a separable non-enzymatic role.
  evidence:
  - reference: PMID:32455636
    reference_title: "Clinical Genetics of Prolidase Deficiency: An Updated Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physiopathology of PD is not clearly understood, as there is marked phenotypic variability among affected individuals"
    explanation: Review states the pathophysiology is unresolved and links this to phenotypic variability.
  - reference: PMID:18340504
    reference_title: "Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathophysiology of PD is still poorly understood"
    explanation: Independent review confirms the pathophysiology gap.
  - reference: PMID:15378943
    reference_title: "Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We were unable to find any correlation between degree of enzyme \nactivity loss and severity of symptoms"
    explanation: Absence of an activity-severity correlation is direct evidence for the gap.
- discussion_id: pd_mouse_autoimmunity_translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the cell-intrinsic T-cell activation defect that drives lupus-like
    autoimmunity in Pepd-null mice also operate in human prolidase deficiency, or
    is the human autoimmunity primarily innate/B-cell driven?
  attaches_to:
  - pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
  - pathophysiology#Enhanced Inflammasome Activation
  - pathophysiology#Systemic Autoimmunity
  rationale: >-
    The mechanistic case for T-cell-intrinsic loss of self-tolerance rests on the
    mouse null model, and even there the autoimmune phenotype is absent in mixed
    chimeras, implying a required contribution from outside the haematopoietic
    system. The available human mechanistic data point in a partly different
    direction - monocyte IL-1beta overproduction with serum IL-1beta and IL-18
    (innate/inflammasome), and therapeutic response to B-cell depletion
    (CD20-positive B cells) - so the dominant human effector arm is not settled.
    This is a translational-validity question rather than an absence of evidence:
    evidence exists in the model, and its fidelity to human disease is the open
    issue.
  proposed_experiments:
  - experiment_id: pd_patient_deep_immunophenotyping
    name: Deep immunophenotyping of a patient cohort
    description: >-
      T-cell activation/exhaustion panels, TCR repertoire sequencing, and
      autoantibody profiling in prolidase deficiency patients versus matched
      controls.
    would_support:
    - pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
    - mechanistic_hypotheses#immune_dysregulation_arm
    supporting_outcome:
    - Antigen-independent effector T-cell expansion with a polyclonal repertoire in patients would support translation of the mouse mechanism to humans.
    would_refute:
    - pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
    refuting_outcome:
    - A normal T-cell activation state with an oligoclonal, antigen-driven repertoire would refute the mouse-predicted cell-intrinsic mechanism in humans.
  - experiment_id: pd_serial_inflammasome_readouts
    name: Serial inflammasome readouts across multiple patients
    description: >-
      Repeated serum IL-1beta and IL-18 measurement plus ex vivo monocyte
      stimulation assays in an unselected patient series.
    would_support:
    - pathophysiology#Enhanced Inflammasome Activation
    supporting_outcome:
    - Reproducible elevation across multiple patients would establish inflammasome activation as a general feature rather than a single-patient observation.
    would_refute:
    - pathophysiology#Enhanced Inflammasome Activation
    refuting_outcome:
    - Absence of elevation in other patients would confine the inflammasome finding to the index case.
  - experiment_id: pd_treatment_response_effector_arm
    name: Treatment-response discrimination of the effector arm
    description: >-
      Systematic collection of outcomes under B-cell depletion, IL-1 blockade, and
      T-cell-directed therapy in prolidase deficiency autoimmunity.
    would_support:
    - pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
    supporting_outcome:
    - Selective benefit from T-cell-directed therapy would support the T-cell arm as dominant in humans.
    would_refute:
    - pathophysiology#Spontaneous T Cell Activation and Loss of Self-Tolerance
    refuting_outcome:
    - Benefit confined to B-cell depletion or IL-1 blockade would argue that the dominant human effector arm differs from the mouse.
  evidence:
  - reference: PMID:36637239
    reference_title: "Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden."
    explanation: The authors state the human basis for autoimmunity is uncertain before offering mouse evidence.
  - reference: PMID:38088248
    reference_title: "Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD"
    explanation: Human treatment-response data implicate B cells, which the mouse T-cell model does not predict as the dominant arm.
notes: >-
  Curated as part of IEMbase metabolic work package WP-006 ("Disorders of
  glutathione metabolism; Other disorders of peptide metabolism; Disorders of
  methylamine metabolism; Disorders of polyamine metabolism", row 2.2.08.01,
  PEPD / OMIM:170100). Entered as a distinct Disease rather than a subtype: MONDO
  models prolidase deficiency as a single entity (MONDO:0008221, is_a
  MONDO:0019232 inborn disorder of peptide metabolism) with one causal gene, and
  no validated clinical subtype axis exists - severity is continuous and
  uncorrelated with residual enzyme activity, so a subtype split would not be
  defensible.

  Named Entity Confusion (NEC) preflight per CLAUDE.md was run before curation:
  the MONDO record for MONDO:0008221 carries RO:0004003 HGNC:8840 (PEPD) and
  xref OMIM:170100, both matching the WP-006 seed row, and the eponym-free
  synonym set (hyperimidodipeptiduria, imidodipeptidase deficiency) shows no
  collision with another entity. OMIM:613230, the second OMIM id on the seed row,
  is not the MONDO xref for this entity and was not used as an identity anchor.

  No `conforms_to` module reference is asserted. The disorder is not an
  intoxication-type decompensation (no catabolic-stress-triggered crises), and the
  KB currently has no module for collagen-recycling / matrix-remodelling failure;
  such a module is a reasonable follow-up if further ECM-recycling disorders are
  curated.

  Human skeletal and growth findings (failure to thrive, short stature,
  microcephaly, osteopenia, and genu valgum) are curated from the review's
  12-patient bone-abnormality series; only failure to thrive carries a pooled
  frequency because per-feature denominators were not reported. Deliberately not
  curated for want of quotable primary evidence: the reported gastrointestinal
  ulceration/pancolitis findings and enzyme-replacement therapy, which remains
  preclinical (recombinant human prolidase produced in prokaryotic and eukaryotic
  hosts as a tool toward ERT).