Dihydropyrimidinase Deficiency

Mendelian MONDO:0009111 Pathograph 21 Show in embeddings browser Inborn Error of Pyrimidine Metabolism

Autosomal recessive inborn error of pyrimidine catabolism caused by biallelic DPYS variants that abolish dihydropyrimidinase (DHP), the second of the three enzymes that break down uracil and thymine. DHP opens the ring of 5,6-dihydrouracil and 5,6-dihydrothymine, so its loss makes these two intermediates accumulate in urine, plasma and cerebrospinal fluid, which is the biochemical signature of the disease. Downstream, beta-aminoisobutyric acid, the product of thymine breakdown, is strongly reduced while beta-alanine stays normal. The clinical picture is unusually variable. Reported patients have developmental delay, seizures including infantile spasms, white-matter abnormalities and brain atrophy, microcephaly, autistic features and gastrointestinal problems, while others with the same biochemical findings, including affected siblings, have no symptoms at all. How the metabolite changes would cause neurological disease is not known, and this entry records that link as a hypothesis rather than an established chain. DHP also catalyses the second step in the breakdown of 5-fluorouracil, so DHP deficiency is a candidate pharmacogenetic risk factor for fluoropyrimidine toxicity, by analogy with the upstream enzyme dihydropyrimidine dehydrogenase. The evidence for that arm is much weaker than for DPD deficiency: one reported case of severe toxicity in a partially deficient heterozygote, and cohort studies of DPYS variants that disagree with each other.

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1
Inheritance
5
Pathophys.
14
Phenotypes
1
Hypotheses
21
Pathograph
1
Genes
1
Variants
2
Medical Actions
2
Differentials
1
Models
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
The metabolic disease requires biallelic DPYS variants. A single deleterious allele does not cause the inborn error but may reduce DHP activity enough to matter if a fluoropyrimidine is given.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS"
States the mode of inheritance.
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Mechanistic Hypotheses

1
Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
dihydropyrimidine_accumulation_neurotoxicity EMERGING
Evidence balance 3 refute 2 no evidence
Holds that the accumulated dihydropyrimidines, or the shortage of beta-aminoisobutyric acid, disturb the developing nervous system and so account for the seizures, developmental delay and white-matter change seen in some patients. Nothing stronger than coherence supports it. The decisive objection is the same as in the upstream DPD deficiency: siblings with identical complete enzyme deficiency and identical metabolite profiles differ in whether they have any symptoms at all, so the metabolite disturbance cannot be sufficient.
Kept as a hypothesis rather than a pathophysiology chain. Any complete account has to explain the asymptomatic patients as well as the affected ones, and none currently does. The size of that problem is nine of the 35 published patients asymptomatic at diagnosis, which is the closest thing to a penetrance figure this disease has.
Pathograph links
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Intellectual disability INDIRECT UNKNOWN INTERMEDIATES Proposed route to the cognitive phenotype. Not asserted: the intermediates are unknown, and biochemically identical siblings differ in whether they are affected. See the hypothesis of the same name.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Global developmental delay INDIRECT UNKNOWN INTERMEDIATES Same proposed route, same reservation.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Seizure INDIRECT UNKNOWN INTERMEDIATES Same proposed route, same reservation.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Hypotonia INDIRECT UNKNOWN INTERMEDIATES Same proposed route, same reservation.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Abnormal cerebral white matter morphology INDIRECT UNKNOWN INTERMEDIATES Same proposed route. The authors who described the imaging phenotype in the upstream disease state that its mechanism is unknown, which is the same reservation.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Autistic behavior INDIRECT UNKNOWN INTERMEDIATES Same proposed route, same reservation.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion -> Microcephaly INDIRECT UNKNOWN INTERMEDIATES Same proposed route, same reservation.
Show evidence (5 references)
PMID:18600547 NO_EVIDENCE Human Clinical
"the relevance of the shortage of beta-aminoisobutyric acid for the onset of a clinical phenotype in patients with DHP deficiency remains to be established."
The authors who measured the depletion state that its relevance to the clinical phenotype is unestablished. Graded NO_EVIDENCE rather than SUPPORT because a sentence saying a question is open does not support either answer to it; it is cited to record that the question is open.
PMID:18600547 REFUTE Human Clinical
"No major differences were observed for the concentrations of the beta-amino acids in plasma and urine between the symptomatic and asymptomatic sibling."
The discordant sibling pair, which is direct evidence against the metabolite level determining the phenotype.
PMID:38199782 REFUTE REVIEW SYNTHESIS Human Clinical
"Among the 35 patients, nine patients were asymptomatic at the time of diagnosis"
Roughly a quarter of published patients had no symptoms at diagnosis despite the biochemical defect, which is the scale of what any metabolite-driven account of the phenotype has to explain. REFUTE because it counts against the metabolite disturbance being sufficient, not because it bears on whether it contributes.
+ 2 more references
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Pathophysiology

5
Biallelic DPYS Loss of Function
Missense, nonsense, splice-site and deletion variants in DPYS. Most missense variants leave no measurable activity when expressed; structural mapping places them at the tetramer interface, near the di-zinc catalytic centre and substrate site, or in regions where they destabilise folding. Many inactive variants are degraded by the proteasome and fail to form the large oligomers the active enzyme needs.
DPYS hgnc:3013 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DPYS (hgnc:3013). hgnc:3013 is a gene from the HUGO Gene Nomenclature Committee.
dihydropyrimidinase activity GO:0004157 ⇓ LOSS OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dihydropyrimidinase activity (GO:0004157), qualified as loss of function. GO:0004157 is a molecular function from the Gene Ontology.
Downstream
Block of Dihydropyrimidine Ring Opening Without DHP activity the second step of pyrimidine catabolism stops.
Impaired Fluoropyrimidine Catabolism The same enzyme opens the ring of dihydro-5-fluorouracil, so the deficit is also a drug-clearance deficit. Latent until a fluoropyrimidine is given.
Show evidence (5 references)
PMID:20362666 SUPPORT In Vitro
"Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity."
Patient variants abolish enzyme activity when expressed.
PMID:20362666 SUPPORT Computational
"The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme."
Structural mapping of patient missense variants to the oligomer interface.
PMID:28642038 SUPPORT In Vitro
"9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation."
Protein instability and proteasomal degradation as a loss-of-function route.
+ 2 more references
Block of Dihydropyrimidine Ring Opening
The committed hydrolytic step of pyrimidine degradation is lost, so 5,6-dihydrouracil and 5,6-dihydrothymine are not converted to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid.
pyrimidine nucleobase catabolic process GO:0006208 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pyrimidine nucleobase catabolic process (GO:0006208). GO:0006208 is a biological process from the Gene Ontology.
Downstream
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion Substrates build up and the downstream thymine product is not made.
Show evidence (1 reference)
PMID:17383919 SUPPORT BACKGROUND In Vitro
"Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and it catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid"
Names the reaction that is lost and both of its products.
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion
5,6-dihydrouracil and 5,6-dihydrothymine accumulate in urine, plasma and cerebrospinal fluid. Beta-aminoisobutyric acid is strongly reduced, while beta-alanine is normal, which distinguishes this block from the upstream DPD deficiency where beta-alanine itself is depleted. Both the symptomatic and the asymptomatic sibling in one family had the same metabolite profile, so the profile alone does not predict whether anyone will be ill.
Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Animal models
Feline dihydropyrimidinase deficiency (DPYS p.G435R homozygous cat) Cat recapitulates Reproduces the metabolite accumulation at the same enzymatic step, by a variant at a residue mutated in human disease.
Downstream
Elevated urinary dihydrouracil level The accumulating intermediate is excreted, giving dihydropyrimidinuria.
Elevated urinary dihydrothymine level The thymine-derived intermediate is excreted in the same way.
Intellectual disability Proposed route to the cognitive phenotype. Not asserted: the intermediates are unknown, and biochemically identical siblings differ in whether they are affected. See the hypothesis of the same name. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Global developmental delay Same proposed route, same reservation. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Seizure Same proposed route, same reservation. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Hypotonia Same proposed route, same reservation. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Abnormal cerebral white matter morphology Same proposed route. The authors who described the imaging phenotype in the upstream disease state that its mechanism is unknown, which is the same reservation. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Autistic behavior Same proposed route, same reservation. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Microcephaly Same proposed route, same reservation. Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
Show evidence (2 references)
PMID:20362666 SUPPORT Human Clinical
"Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine."
The accumulating metabolites and the compartments they are measured in.
PMID:18600547 SUPPORT Human Clinical
"In two siblings with a complete DHP deficiency and a variable clinical presentation, a normal concentration of beta-alanine and strongly decreased levels of beta-aminoisobutyric acid were observed in plasma, urine and CSF."
The downstream half of the profile, and the reason beta-alanine is recorded as normal rather than depleted here.
Impaired Fluoropyrimidine Catabolism
Reduced capacity to degrade 5-fluorouracil and its prodrugs at the second catabolic step. This node is inert without drug exposure, which is why the exposure is modelled separately below. The strength of this arm is deliberately not overstated: it rests on a single patient in whom severe toxicity was attributed to partial DHP deficiency, plus cohort evidence that is inconsistent.
pyrimidine nucleobase catabolic process GO:0006208 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pyrimidine nucleobase catabolic process (GO:0006208). GO:0006208 is a biological process from the Gene Ontology.
Downstream
Fluoropyrimidine Cytotoxicity The proposed route runs through accumulated 5,6-dihydro-5-fluorouracil, which dihydropyrimidine dehydrogenase can convert back to 5-fluorouracil. The intermediate is named in the literature, which is why the edge is INDIRECT_KNOWN_INTERMEDIATES rather than direct, but no pharmacokinetic measurement in a DHP-deficient patient was found.
Show evidence (2 references)
PMID:14555507 SUPPORT Human Clinical
"we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP."
The originating observation for this arm, and the reason it is a single case rather than a cohort finding.
PMID:14555507 SUPPORT Human Clinical
"Our results show that a partial DHP deficiency is a novel pharmacogenetic disorder associated with severe 5FU toxicity."
The authors' own framing of partial deficiency as a pharmacogenetic risk.
Fluoropyrimidine Cytotoxicity
Severe fluoropyrimidine-associated toxicity. In the only cohort that found a signal, carrying at least one rare DPYS variant was associated with about a fourfold higher risk of severe cumulative toxicity; a second cohort genotyping common DPYS variants found no association, so this node is carried as a contested claim and both results are cited.
Show evidence (2 references)
PMID:37946254 SUPPORT Human Clinical
"Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity."
The strongest cohort evidence for this arm. Note the acute-toxicity association did not reach significance in the same analysis.
PMID:38215018 REFUTE Human Clinical
"in our cohort of mostly Caucasian Canadians, genetic variations in DPYS do not appear to be a significant contributor to severe fluoropyrimidine-associated toxicity."
The contradicting cohort. It genotyped three common DPYS variants rather than sequencing for rare ones, so it does not test the same claim as the rare-variant-burden study; it does refute a common-variant effect.
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Pathograph

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

14
Cardiovascular 1
Atrioventricular canal defect Complete atrioventricular canal defect HP:0001674 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Complete atrioventricular septal defect, annotated with Complete atrioventricular canal defect (HP:0001674). HP:0001674 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38958169 SUPPORT Human Clinical
"This is the second report of congenital heart disease in dihydropyrimidinase deficiency, following a single patient with a ventricular septal defect."
Places this phenotype as the second such report, which is why it is carried without a frequency.
Digestive 2
Feeding difficulties OCCASIONAL HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding problems, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Feeding problem | Y | 8/35 (23%) |"
The pooled count behind the OCCASIONAL band.
Vomiting OCCASIONAL HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Vomiting | Y | 3/35 (9%) |"
The pooled count for vomiting specifically, which is what this phenotype claims, and the basis for the OCCASIONAL band.
PMID:20362666 SUPPORT INDIRECT Human Clinical
"Patients presented mainly with neurological and gastrointestinal abnormalities"
Gastrointestinal involvement as one of the two main presenting categories. INDIRECT because it does not name vomiting; the pooled row above is the direct support.
Genitourinary 2
Elevated urinary dihydrouracil level VERY_FREQUENT HP:6000118 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urinary dihydrouracil level (HP:6000118). HP:6000118 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples."
The biochemical hallmark and the basis of diagnosis.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"All patients exhibited characteristic biochemical findings of increased UR, DHU, THY, and DHT levels in bodily fluids."
The all-patients statement behind the VERY_FREQUENT band, pooled over the 35 published patients.
Elevated urinary dihydrothymine level VERY_FREQUENT HP:6000119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urinary dihydrothymine level (HP:6000119). HP:6000119 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23732435 SUPPORT Human Clinical
"Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine"
Both metabolites measured in urine in a diagnosed patient.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"All patients exhibited characteristic biochemical findings of increased UR, DHU, THY, and DHT levels in bodily fluids."
The all-patients statement behind the VERY_FREQUENT band, pooled over the 35 published patients.
Head and Neck 1
Microcephaly OCCASIONAL 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 (2 references)
PMID:38958169 SUPPORT Human Clinical
"Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits."
Microcephaly among the suggestive features.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Microcephaly | N | 3/35 (9%) |"
The pooled count behind the OCCASIONAL band.
Musculoskeletal 1
Hypotonia OCCASIONAL HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Hypotonia | N | 9/35 (26%) |"
The pooled count behind the OCCASIONAL band. The same publication's narrative says 10 of 35, so the two figures in one paper disagree by one patient; the table is cited as the more specific statement.
Nervous System 6
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:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Intellectual disability | Y | 16/35 (46%) |"
The pooled count behind the FREQUENT band.
Global developmental delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:38958169 SUPPORT BACKGROUND Human Clinical
"Global developmental delay and increased susceptibility to 5-fluorouracil are commonly reported."
Names developmental delay as a commonly reported feature.
PMID:23732435 SUPPORT Human Clinical
"The patient was a 32-month-old boy who presented with language development delay."
A patient presenting with delay at the milder end.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| DD | Y | 8/35 (23%) |"
The pooled count for unspecified developmental delay behind the OCCASIONAL band.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29054612 SUPPORT Human Clinical
"a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy."
Reports infantile spasms at the severe end of the spectrum.
PMID:38958169 SUPPORT Human Clinical
"A four-year-old male with global developmental delay, dysmorphic facies, autistic features and a history of seizures was diagnosed with dihydropyrimidinase deficiency"
Seizures in a molecularly confirmed patient.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| EEG finding/seizure | Y | 12/35 (34%) |"
The pooled count behind the FREQUENT band, from the 35-patient literature review table.
Abnormal cerebral white matter morphology OCCASIONAL HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced cerebral white matter, annotated with Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29054612 SUPPORT Human Clinical
"a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy."
White-matter reduction and atrophy in the severe patients.
PMID:17383919 SUPPORT Human Clinical
"One of the siblings had a severe delay in speech development and white matter abnormalities, whereas the other one was free of symptoms."
White-matter abnormality in one sibling, with the discordant sibling in the same sentence.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| MRI abnormalities | Y | 5/35 (14%) |"
The pooled count behind the OCCASIONAL band.
Autistic behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic features, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38958169 SUPPORT Human Clinical
"Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits."
Autistic traits among the features the authors flag for suspicion.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Autism | N | 3/35 (9%) |"
The pooled count behind the OCCASIONAL band.
Parkinsonism Parkinsonism with favorable response to dopaminergic medication HP:0002548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Levodopa-responsive juvenile parkinsonism, annotated with Parkinsonism with favorable response to dopaminergic medication (HP:0002548). HP:0002548 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39558747 SUPPORT Human Clinical
"We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant."
The single reported case.
Growth 1
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation and failure to thrive, annotated with Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Growth retardation/FTT | N | 6/35 (17%) |"
The pooled count behind the OCCASIONAL band.
🧬

Genetic Associations

1
DPYS
Gene: DPYS hgnc:3013 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DPYS (hgnc:3013). hgnc:3013 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (3 references)
PMID:20362666 SUPPORT Human Clinical
"Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence."
The exonic clustering described in the notes.
PMID:20362666 SUPPORT Human Clinical
"Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated."
Recurrent alleles across unrelated patients.
PMID:29054612 SUPPORT In Vitro
"Functional analysis of recombinantly expressed DHP mutants carrying the p.M250I, p.H295R, p.Q334R, p.T418I and the p.R490H variant showed residual DHP activities of 2.0%, 9.8%, 9.7%, 64% and 0.3%, respectively."
The range of residual activity across alleles, which is the basis for the statement that activity varies widely.
Variants (1)
p.R302Q Pathogenic
Recurrent missense variant seen in unrelated patients including Chinese and other East Asian cases, with low residual activity on expression.
Show evidence (2 references)
PMID:20362666 SUPPORT In Vitro
"Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively."
Residual activity measured for this allele.
PMID:23732435 SUPPORT Human Clinical
"DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K)."
The same allele in a patient from a different population.
💊

Medical Actions

2
Fluoropyrimidine Avoidance or Dose Reduction
Platform: Other
The one actionable intervention in this disease, and it is preventive rather than therapeutic: knowing the diagnosis before a fluoropyrimidine is prescribed. The published argument for it is that severe toxicity has been reported in patients and in carriers of congenital pyrimidine metabolic disorders, so identifying affected people, including the asymptomatic ones, is worthwhile before 5-fluorouracil is given. Note this is a published recommendation rather than a guideline: no dosing algorithm for DPYS exists, unlike DPYD, and the cohort evidence on DPYS variants and toxicity is contested (see the Fluoropyrimidine Cytotoxicity node).
Mechanism Target:
INHIBITS Impaired Fluoropyrimidine Catabolism — Withholding or reducing the drug removes the substrate the deficient enzyme cannot process, which is the only point in this arm that can be acted on; the enzyme deficit itself is not treatable.
Show evidence (1 reference)
PMID:30384990 SUPPORT Human Clinical
"As severe 5-fluorouracil-associated toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders, urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment."
The published rationale for identifying affected people before the drug is given, which is what this intervention acts on.
Show evidence (1 reference)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"Identifying patients with DHP deficiency, even when they are asymptomatic, is warranted to prevent neurotoxicity while administering pyrimidine analog drugs, such as 5-fluorouracil (5-FU), to patients with cancer."
States the case for pre-treatment identification including of asymptomatic individuals, which is what makes this a preventive intervention rather than a therapy.
Levodopa for the Parkinsonian Presentation
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: levodopa NCIT:C611 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses levodopa (NCIT:C611). NCIT:C611 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
In the single reported patient with levodopa-responsive juvenile parkinsonism, levodopa relieved the motor symptoms. One patient, so this is a lead rather than established management, but it is recorded because the presentation is treatable and would not otherwise be looked for in a pyrimidine disorder.
Mechanism Target:
MODULATES Parkinsonism — Symptomatic dopaminergic replacement. It acts on the parkinsonian phenotype, not on the metabolic lesion, and nothing is known about why this patient was dopamine-responsive.
Show evidence (1 reference)
PMID:39558747 SUPPORT Human Clinical
"Levodopa treatment effectively relieved the patient's motor symptoms."
The reported response in the single treated patient.
Show evidence (1 reference)
PMID:39558747 SUPPORT Human Clinical
"This report identifies DPYS as a novel genetic cause of juvenile parkinsonism and underscores the potential efficacy of levodopa therapy in managing motor dysfunction in DYPS-related parkinsonism."
The authors' own framing, as potential efficacy from one case rather than established treatment.
🌍

Environmental Factors

1
Fluoropyrimidine chemotherapy administration
Administration of 5-fluorouracil or a prodrug such as capecitabine. The toxicity arm of this entry is inert without it. It is included because the enzyme that is missing is also the second enzyme of fluoropyrimidine catabolism, and because partial deficiency has been reported as the cause of severe toxicity in a patient.
Show evidence (1 reference)
PMID:14555507 SUPPORT BACKGROUND Human Clinical
"it has been suggested that patients with a deficiency of this enzyme are at risk from developing severe 5FU-associated toxicity."
The prior suggestion that this paper set out to test, in its own hedged wording. BACKGROUND because the sentence restates somebody else's hypothesis; it establishes that deficient patients are at risk, not the exposure-dependence, which the paper's own result below carries.
Mechanism Target:
TRIGGERS Impaired Fluoropyrimidine Catabolism — Supplies the substrate the deficient enzyme cannot process. With no administration there is nothing to clear and no toxicity, however low the activity.
Show evidence (1 reference)
PMID:14555507 SUPPORT Human Clinical
"we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP."
Toxicity followed drug administration in a patient with reduced enzyme activity, which is the exposure-dependence this link asserts.
🔬

Biochemical Markers

2
Urinary dihydrouracil and dihydrothymine (INCREASED)
Show evidence (2 references)
PMID:39558747 SUPPORT Human Clinical
"Further urinary metabolome analysis demonstrated markedly elevated dihydrouracil and dihydrothymine levels, confirming impaired pyrimidine metabolism."
Urine metabolite measurement used to confirm the diagnosis.
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"All patients exhibited characteristic biochemical findings of increased UR, DHU, THY, and DHT levels in bodily fluids."
The all-patients statement behind the VERY_FREQUENT band, pooled over the 35 published patients.
Plasma beta-aminoisobutyric acid (DECREASED)
Show evidence (1 reference)
PMID:18600547 SUPPORT Human Clinical
"a normal concentration of beta-alanine and strongly decreased levels of beta-aminoisobutyric acid were observed in plasma, urine and CSF."
The measured direction for both beta-amino acids.
🔬

Diagnosis

2
Urine pyrimidine analysis
Quantification of dihydrouracil and dihydrothymine in urine, by tandem mass spectrometry or gas chromatography-mass spectrometry. This is what makes the biochemical diagnosis; DPYS sequencing then confirms it and allows family testing.
Show evidence (2 references)
PMID:38199782 SUPPORT REVIEW SYNTHESIS Human Clinical
"Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies."
The confirmatory role of sequencing after the biochemical finding.
PMID:30384990 SUPPORT Human Clinical
"Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry."
The two-assay sequence in a patient found incidentally, which is how several reported patients came to attention.
Urinary pyrimidine analysis before fluoropyrimidine treatment
Proposed as a pre-treatment screen for patients about to receive 5-fluorouracil, on the grounds that severe toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders. This is a published suggestion rather than established practice; no guideline endorsing it was identified.
Show evidence (1 reference)
PMID:30384990 SUPPORT Human Clinical
"urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment."
The authors' proposal, in their own words.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
Fewer than 40 published patients by 2024. Recurrent variants found in unrelated patients, and variants enriched in Japanese population data, have led authors to suggest the disease is under-diagnosed.
Show evidence (2 references)
PMID:38958169 SUPPORT BACKGROUND Human Clinical
"Dihydropyrimidinase deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway, with fewer than 40 patients published."
Published case count as of 2024.
PMID:29054612 SUPPORT Human Clinical
"The observation that the identified mutations were more prevalent in East Asians and the Japanese population indicates that DHP deficiency may be more common than anticipated in these ethnic groups."
Suggests under-ascertainment in East Asian populations.
Worldwide, biochemically defined
Unknown 10.0 per 100,000 1–9 per 10,000
An estimate of 2 in 20,000, i.e. 10 per 100,000, quoted in a case report arguing that the disease is under-diagnosed. Recorded separately from the published case count above because the two are not the same quantity and are in open tension: fewer than 40 patients have been described, orders of magnitude fewer than this estimate implies. The reconciliation the authors propose is that most biochemically affected people are asymptomatic or have non-specific findings and are never tested. Do not quote the two figures as one number. The source gives only "an estimated prevalence of 2/20,000" without saying whether it is a point or a lifetime prevalence, which is why measure_type is UNKNOWN.
Show evidence (1 reference)
PMID:30384990 SUPPORT Human Clinical
"Dihydropyrimidinase deficiency is probably underdiagnosed, considering its wide phenotypical variability, nonspecific neurological presentations, and an estimated prevalence of 2/20,000."
The estimate, and the authors' own argument for why it exceeds the reported case count.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Dihydropyrimidinase Deficiency:

Dihydropyrimidine dehydrogenase deficiency
Overlapping Features Deficiency of DPYD, the first and rate-limiting enzyme of the same pathway. It shares the variable neurological presentation and the fluoropyrimidine-toxicity implication, but the block sits one step earlier, so uracil and thymine accumulate rather than their dihydro forms, and beta-alanine is depleted rather than normal. Curated as Dihydropyrimidine_Dehydrogenase_Deficiency.
Beta-ureidopropionase deficiency
Overlapping Features Deficiency of UPB1, the third and final enzyme of pyrimidine catabolism. The N-carbamyl compounds that DHP produces accumulate instead, which is what separates it on urine analysis.
🐁

Animal Models

1
Feline dihydropyrimidinase deficiency (DPYS p.G435R homozygous cat)
A naturally occurring case rather than an engineered model: a cat homozygous for a DPYS missense variant at a residue also mutated in a human patient, with dihydrouracil and dihydrothymine in urine. It presented with malnutrition, depression, vomiting and hyperammonaemia. Screening 1,000 cats found no other carrier.
Species
Cat
Genotype
DPYS c.1303G>A (p.G435R) homozygous
Publication
PMID:23430934
Pathograph links
Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion recapitulates fidelity: moderate observes: organism Reproduces the metabolite accumulation at the same enzymatic step, by a variant at a residue mutated in human disease.
Limitations: A single animal, and its hyperammonaemia is not a reported feature of the human disease, so the presentation is not a match even though the biochemistry is. Beta-aminoisobutyrate was not measured.
Readouts
Urinary dihydrouracil and dihydrothymine
Direction: INCREASED
Interpretation: The same metabolite accumulation as in human patients.
Show evidence (1 reference)
PMID:23430934 SUPPORT Model Organism
"A gas chromatographic-mass spectrometric analysis of urinary metabolic substances showed the presence of large amounts of dihydrouracil and dihydrothymine and moderate amounts of uracil and thymine, suggesting DHP deficiency."
The metabolite measurement in the affected cat.
Show evidence (1 reference)
PMID:23430934 SUPPORT Model Organism
"Analysis of the feline DPYS gene encoding DHP demonstrated that the cat was homozygous for the missense mutation c.1303G>A (p.G435R) in exon 8, which corresponds to a known mutation in a human patient with DHP deficiency."
The variant corresponds to a human patient allele, which is what makes this animal informative for the human mechanism.
{ }

Source YAML

click to show 
name: Dihydropyrimidinase Deficiency
creation_date: "2026-10-15T07:30:00Z"
category: Mendelian
parents:
- Inborn Error of Pyrimidine Metabolism
disease_term:
  preferred_term: dihydropyrimidinase deficiency
  term:
    id: MONDO:0009111
    label: dihydropyrimidinuria
synonyms:
- dihydropyrimidinuria
- DHP deficiency
- DPYS deficiency
description: >-
  Autosomal recessive inborn error of pyrimidine catabolism caused by biallelic
  DPYS variants that abolish dihydropyrimidinase (DHP), the second of the three
  enzymes that break down uracil and thymine. DHP opens the ring of
  5,6-dihydrouracil and 5,6-dihydrothymine, so its loss makes these two
  intermediates accumulate in urine, plasma and cerebrospinal fluid, which is
  the biochemical signature of the disease. Downstream, beta-aminoisobutyric
  acid, the product of thymine breakdown, is strongly reduced while
  beta-alanine stays normal.

  The clinical picture is unusually variable. Reported patients have
  developmental delay, seizures including infantile spasms, white-matter
  abnormalities and brain atrophy, microcephaly, autistic features and
  gastrointestinal problems, while others with the same biochemical findings,
  including affected siblings, have no symptoms at all. How the metabolite
  changes would cause neurological disease is not known, and this entry records
  that link as a hypothesis rather than an established chain.

  DHP also catalyses the second step in the breakdown of 5-fluorouracil, so DHP
  deficiency is a candidate pharmacogenetic risk factor for fluoropyrimidine
  toxicity, by analogy with the upstream enzyme dihydropyrimidine
  dehydrogenase. The evidence for that arm is much weaker than for DPD
  deficiency: one reported case of severe toxicity in a partially deficient
  heterozygote, and cohort studies of DPYS variants that disagree with each
  other.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 40 published patients by 2024. Recurrent variants found in
    unrelated patients, and variants enriched in Japanese population data, have
    led authors to suggest the disease is under-diagnosed.
  evidence:
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Dihydropyrimidinase deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway, with fewer than 40 patients published."
    explanation: Published case count as of 2024.
  - reference: PMID:29054612
    reference_title: Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observation that the identified mutations were more prevalent in East Asians and the Japanese population indicates that DHP deficiency may be more common than anticipated in these ethnic groups."
    explanation: Suggests under-ascertainment in East Asian populations.
- population: Worldwide, biochemically defined
  measure_type: UNKNOWN
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 10.0
  rate_denominator: POPULATION
  notes: >-
    An estimate of 2 in 20,000, i.e. 10 per 100,000, quoted in a case report
    arguing that the disease is under-diagnosed. Recorded separately from the
    published case count above because the two are not the same quantity and
    are in open tension: fewer than 40 patients have been described, orders of
    magnitude fewer than this estimate implies. The reconciliation the authors
    propose is that most biochemically affected people are asymptomatic or
    have non-specific findings and are never tested. Do not quote the two
    figures as one number.

    The source gives only "an estimated prevalence of 2/20,000" without
    saying whether it is a point or a lifetime prevalence, which is why
    measure_type is UNKNOWN.
  evidence:
  - reference: PMID:30384990
    reference_title: A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dihydropyrimidinase deficiency is probably underdiagnosed, considering its wide phenotypical variability, nonspecific neurological presentations, and an estimated prevalence of 2/20,000."
    explanation: >-
      The estimate, and the authors' own argument for why it exceeds the
      reported case count.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The metabolic disease requires biallelic DPYS variants. A single
    deleterious allele does not cause the inborn error but may reduce DHP
    activity enough to matter if a fluoropyrimidine is given.
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS"
    explanation: States the mode of inheritance.
pathophysiology:
- name: Biallelic DPYS Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Missense, nonsense, splice-site and deletion variants in DPYS. Most
    missense variants leave no measurable activity when expressed; structural
    mapping places them at the tetramer interface, near the di-zinc catalytic
    centre and substrate site, or in regions where they destabilise folding.
    Many inactive variants are degraded by the proteasome and fail to form the
    large oligomers the active enzyme needs.
  genes:
  - preferred_term: DPYS
    term:
      id: hgnc:3013
      label: DPYS
  molecular_functions:
  - preferred_term: dihydropyrimidinase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004157
      label: dihydropyrimidinase activity
  evidence:
  - reference: PMID:20362666
    reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity."
    explanation: Patient variants abolish enzyme activity when expressed.
  - reference: PMID:20362666
    reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme."
    explanation: Structural mapping of patient missense variants to the oligomer interface.
  - reference: PMID:28642038
    reference_title: Functional characterization of 21 allelic variants of dihydropyrimidinase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation."
    explanation: Protein instability and proteasomal degradation as a loss-of-function route.
  - reference: PMID:35961217
    reference_title: Structural investigation of pathogenic variants in dihydropyrimidinase using molecular dynamics simulations.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In the T68R, D81G, G278D, and L337P variants, the flexibilities of structures related to the interaction for oligomer formation increased in comparison with those of the wild type."
    explanation: >-
      Simulation evidence that one class of patient variant acts by
      destabilising the oligomerisation interface, consistent with the
      crystal-structure mapping above.
  - reference: PMID:9718352
    reference_title: "Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using a eukaryotic expression system, we showed that all mutations reduced enzyme activity significantly, indicating that these are crucial DHP deficiency-causing mutations."
    explanation: >-
      The first demonstration that the identified DPYS variants reduce enzyme
      activity, in the paper that characterised the gene.
  downstream:
  - target: Block of Dihydropyrimidine Ring Opening
    causal_link_type: DIRECT
    description: Without DHP activity the second step of pyrimidine catabolism stops.
  - target: Impaired Fluoropyrimidine Catabolism
    causal_link_type: DIRECT
    description: >-
      The same enzyme opens the ring of dihydro-5-fluorouracil, so the deficit
      is also a drug-clearance deficit. Latent until a fluoropyrimidine is
      given.
    evidence:
    - reference: PMID:28642038
      reference_title: Functional characterization of 21 allelic variants of dihydropyrimidinase.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil."
      explanation: >-
        The enzyme acts on the fluoropyrimidine intermediate as well as the
        natural one. BACKGROUND because it is the paper's framing of
        established enzymology rather than its own result.
- name: Block of Dihydropyrimidine Ring Opening
  biological_scale: MOLECULAR
  description: >-
    The committed hydrolytic step of pyrimidine degradation is lost, so
    5,6-dihydrouracil and 5,6-dihydrothymine are not converted to
    N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid.
  biological_processes:
  - preferred_term: pyrimidine nucleobase catabolic process
    modifier: DECREASED
    term:
      id: GO:0006208
      label: pyrimidine nucleobase catabolic process
  evidence:
  - reference: PMID:17383919
    reference_title: Clinical, biochemical and genetic findings in two siblings with a dihydropyrimidinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and it catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid"
    explanation: Names the reaction that is lost and both of its products.
  downstream:
  - target: Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion
    causal_link_type: DIRECT
    description: Substrates build up and the downstream thymine product is not made.
- name: Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion
  biological_scale: ORGANISM
  description: >-
    5,6-dihydrouracil and 5,6-dihydrothymine accumulate in urine, plasma and
    cerebrospinal fluid. Beta-aminoisobutyric acid is strongly reduced, while
    beta-alanine is normal, which distinguishes this block from the upstream
    DPD deficiency where beta-alanine itself is depleted. Both the symptomatic
    and the asymptomatic sibling in one family had the same metabolite profile,
    so the profile alone does not predict whether anyone will be ill.
  chemical_entities:
  - preferred_term: 3-aminoisobutyric acid
    modifier: DECREASED
    term:
      id: CHEBI:27389
      label: 3-aminoisobutyric acid
  evidence:
  - reference: PMID:20362666
    reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine."
    explanation: The accumulating metabolites and the compartments they are measured in.
  - reference: PMID:18600547
    reference_title: Beta-alanine and beta-aminoisobutyric acid levels in two siblings with dihydropyrimidinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two siblings with a complete DHP deficiency and a variable clinical presentation, a normal concentration of beta-alanine and strongly decreased levels of beta-aminoisobutyric acid were observed in plasma, urine and CSF."
    explanation: >-
      The downstream half of the profile, and the reason beta-alanine is
      recorded as normal rather than depleted here.
  downstream:
  - target: Elevated urinary dihydrouracil level
    causal_link_type: DIRECT
    description: The accumulating intermediate is excreted, giving dihydropyrimidinuria.
  - target: Elevated urinary dihydrothymine level
    causal_link_type: DIRECT
    description: The thymine-derived intermediate is excreted in the same way.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: >-
      Proposed route to the cognitive phenotype. Not asserted: the
      intermediates are unknown, and biochemically identical siblings differ
      in whether they are affected. See the hypothesis of the same name.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: Same proposed route, same reservation.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: Same proposed route, same reservation.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: Same proposed route, same reservation.
  - target: Abnormal cerebral white matter morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: >-
      Same proposed route. The authors who described the imaging phenotype in
      the upstream disease state that its mechanism is unknown, which is the
      same reservation.
  - target: Autistic behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: Same proposed route, same reservation.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dihydropyrimidine_accumulation_neurotoxicity
    description: Same proposed route, same reservation.
- name: Impaired Fluoropyrimidine Catabolism
  biological_scale: ORGANISM
  description: >-
    Reduced capacity to degrade 5-fluorouracil and its prodrugs at the second
    catabolic step. This node is inert without drug exposure, which is why the
    exposure is modelled separately below. The strength of this arm is
    deliberately not overstated: it rests on a single patient in whom severe
    toxicity was attributed to partial DHP deficiency, plus cohort evidence
    that is inconsistent.
  biological_processes:
  - preferred_term: pyrimidine nucleobase catabolic process
    modifier: DECREASED
    term:
      id: GO:0006208
      label: pyrimidine nucleobase catabolic process
  evidence:
  - reference: PMID:14555507
    reference_title: Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP."
    explanation: >-
      The originating observation for this arm, and the reason it is a single
      case rather than a cohort finding.
  - reference: PMID:14555507
    reference_title: Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results show that a partial DHP deficiency is a novel pharmacogenetic disorder associated with severe 5FU toxicity."
    explanation: The authors' own framing of partial deficiency as a pharmacogenetic risk.
  downstream:
  - target: Fluoropyrimidine Cytotoxicity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The proposed route runs through accumulated 5,6-dihydro-5-fluorouracil,
      which dihydropyrimidine dehydrogenase can convert back to
      5-fluorouracil. The intermediate is named in the literature, which is
      why the edge is INDIRECT_KNOWN_INTERMEDIATES rather than direct, but no
      pharmacokinetic measurement in a DHP-deficient patient was found.
    evidence:
    - reference: PMID:38199782
      reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Patients with DHP deficiency are prone to accumulating 5,6-dihydro-5-FU in the plasma. DPD can convert this back to 5-FU, reaching toxic levels rapidly"
      explanation: >-
        Names the accumulating intermediate and the back-conversion that is
        the proposed route to toxicity. BACKGROUND because the review is
        restating the mechanism from earlier work rather than measuring it.
- name: Fluoropyrimidine Cytotoxicity
  biological_scale: ORGANISM
  description: >-
    Severe fluoropyrimidine-associated toxicity. In the only cohort that found a
    signal, carrying at least one rare DPYS variant was associated with about a
    fourfold higher risk of severe cumulative toxicity; a second cohort
    genotyping common DPYS variants found no association, so this node is
    carried as a contested claim and both results are cited.
  evidence:
  - reference: PMID:37946254
    reference_title: The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity."
    explanation: >-
      The strongest cohort evidence for this arm. Note the acute-toxicity
      association did not reach significance in the same analysis.
  - reference: PMID:38215018
    reference_title: Common dihydropyrimidinase ( DPYS ) genetic variations do not predict fluoropyrimidine-related chemotherapy toxicity in a Canadian cohort.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "in our cohort of mostly Caucasian Canadians, genetic variations in DPYS do not appear to be a significant contributor to severe fluoropyrimidine-associated toxicity."
    explanation: >-
      The contradicting cohort. It genotyped three common DPYS variants rather
      than sequencing for rare ones, so it does not test the same claim as the
      rare-variant-burden study; it does refute a common-variant effect.
mechanistic_hypotheses:
- hypothesis_group_id: dihydropyrimidine_accumulation_neurotoxicity
  hypothesis_label: Accumulated dihydropyrimidines or depleted beta-aminoisobutyrate cause the neurological phenotype
  status: EMERGING
  description: >-
    Holds that the accumulated dihydropyrimidines, or the shortage of
    beta-aminoisobutyric acid, disturb the developing nervous system and so
    account for the seizures, developmental delay and white-matter change seen
    in some patients. Nothing stronger than coherence supports it. The decisive
    objection is the same as in the upstream DPD deficiency: siblings with
    identical complete enzyme deficiency and identical metabolite profiles
    differ in whether they have any symptoms at all, so the metabolite
    disturbance cannot be sufficient.
  evidence:
  - reference: PMID:18600547
    reference_title: Beta-alanine and beta-aminoisobutyric acid levels in two siblings with dihydropyrimidinase deficiency.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "the relevance of the shortage of beta-aminoisobutyric acid for the onset of a clinical phenotype in patients with DHP deficiency remains to be established."
    explanation: >-
      The authors who measured the depletion state that its relevance to the
      clinical phenotype is unestablished. Graded NO_EVIDENCE rather than
      SUPPORT because a sentence saying a question is open does not support
      either answer to it; it is cited to record that the question is open.
  - reference: PMID:18600547
    reference_title: Beta-alanine and beta-aminoisobutyric acid levels in two siblings with dihydropyrimidinase deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No major differences were observed for the concentrations of the beta-amino acids in plasma and urine between the symptomatic and asymptomatic sibling."
    explanation: >-
      The discordant sibling pair, which is direct evidence against the
      metabolite level determining the phenotype.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Among the 35 patients, nine patients were asymptomatic at the time of diagnosis"
    explanation: >-
      Roughly a quarter of published patients had no symptoms at diagnosis
      despite the biochemical defect, which is the scale of what any
      metabolite-driven account of the phenotype has to explain. REFUTE
      because it counts against the metabolite disturbance being sufficient,
      not because it bears on whether it contributes.
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The mechanism of neurological and other systemic findings is unclear."
    explanation: >-
      An independent statement that the mechanism remains unknown, from a case
      report's framing of established knowledge. NO_EVIDENCE for the same
      reason as the item above: it records that the question is open rather
      than bearing on the answer.
  - reference: PMID:9718352
    reference_title: "Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "There was no significant difference, in residual activity, between mutations observed in the symptomatic and those observed in the asymptomatic individuals."
    explanation: >-
      Residual activity did not separate the symptomatic from the asymptomatic
      individuals, which cuts against the enzyme deficit determining the
      phenotype. INDIRECT because the inference runs from residual activity
      through metabolite level to phenotype and the sentence speaks only to
      the first step, and IN_VITRO because the activities were measured in a
      eukaryotic expression system. Note the comparison is one symptomatic
      against five asymptomatic individuals, so it bounds rather than
      excludes an effect; the discordant sibling pair above is the stronger
      argument.
  notes: >-
    Kept as a hypothesis rather than a pathophysiology chain. Any complete
    account has to explain the asymptomatic patients as well as the affected
    ones, and none currently does. The size of that problem is nine of the 35
    published patients asymptomatic at diagnosis, which is the closest thing
    to a penetrance figure this disease has.
environmental:
- name: Fluoropyrimidine chemotherapy administration
  description: >-
    Administration of 5-fluorouracil or a prodrug such as capecitabine. The
    toxicity arm of this entry is inert without it. It is included because the
    enzyme that is missing is also the second enzyme of fluoropyrimidine
    catabolism, and because partial deficiency has been reported as the cause
    of severe toxicity in a patient.
  evidence:
  - reference: PMID:14555507
    reference_title: Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "it has been suggested that patients with a deficiency of this enzyme are at risk from developing severe 5FU-associated toxicity."
    explanation: >-
      The prior suggestion that this paper set out to test, in its own hedged
      wording. BACKGROUND because the sentence restates somebody else's
      hypothesis; it establishes that deficient patients are at risk, not the
      exposure-dependence, which the paper's own result below carries.
  influences_mechanisms:
  - target: Impaired Fluoropyrimidine Catabolism
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Supplies the substrate the deficient enzyme cannot process. With no
      administration there is nothing to clear and no toxicity, however low the
      activity.
    evidence:
    - reference: PMID:14555507
      reference_title: Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP."
      explanation: >-
        Toxicity followed drug administration in a patient with reduced
        enzyme activity, which is the exposure-dependence this link asserts.
phenotypes:
- name: Intellectual disability
  category: Neurological
  description: >-
    The commonest reported feature, in 16 of 35 published patients. Counted
    separately from unspecified developmental delay in the pooled table.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Intellectual disability | Y | 16/35 (46%) |"
    explanation: >-
      The pooled count behind the FREQUENT band.
- name: Hypotonia
  category: Neurological
  description: >-
    Reported in 9 of 35 patients in the pooled table. The same paper's prose
    gives 10 of 35 (29%) for hypotonia; the table row is cited here and the
    discrepancy is noted rather than averaged.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Hypotonia | N | 9/35 (26%) |"
    explanation: >-
      The pooled count behind the OCCASIONAL band. The same publication's
      narrative says 10 of 35, so the two figures in one paper disagree by
      one patient; the table is cited as the more specific statement.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Feeding problems, the commonest gastrointestinal feature, reported in 8 of
    35 patients and in one case requiring gastrostomy in early adulthood.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Feeding problems
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Feeding problem | Y | 8/35 (23%) |"
    explanation: >-
      The pooled count behind the OCCASIONAL band.
- name: Failure to thrive
  category: Growth
  description: Growth retardation or failure to thrive, in 6 of 35 patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Growth retardation and failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Growth retardation/FTT | N | 6/35 (17%) |"
    explanation: >-
      The pooled count behind the OCCASIONAL band.
- name: Elevated urinary dihydrouracil level
  category: Biochemical
  description: >-
    Dihydropyrimidinuria. Present in every reported patient, including the
    asymptomatic ones, and the finding the disease is named for.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated urinary dihydrouracil level
    term:
      id: HP:6000118
      label: Elevated urinary dihydrouracil level
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples."
    explanation: The biochemical hallmark and the basis of diagnosis.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients exhibited characteristic biochemical findings of increased UR, DHU, THY, and DHT levels in bodily fluids."
    explanation: >-
      The all-patients statement behind the VERY_FREQUENT band, pooled over
      the 35 published patients.
- name: Elevated urinary dihydrothymine level
  category: Biochemical
  description: The thymine-derived counterpart, measured alongside dihydrouracil.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated urinary dihydrothymine level
    term:
      id: HP:6000119
      label: Elevated urinary dihydrothymine level
  evidence:
  - reference: PMID:23732435
    reference_title: Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine"
    explanation: Both metabolites measured in urine in a diagnosed patient.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients exhibited characteristic biochemical findings of increased UR, DHU, THY, and DHT levels in bodily fluids."
    explanation: >-
      The all-patients statement behind the VERY_FREQUENT band, pooled over
      the 35 published patients.
- name: Global developmental delay
  category: Neurological
  description: >-
    Severity ranges from isolated speech delay to global delay with
    regression, and some biochemically affected individuals have none. The
    pooled table counts unspecified developmental delay separately from
    intellectual disability, which is the commoner of the two.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Global developmental delay and increased susceptibility to 5-fluorouracil are commonly reported."
    explanation: Names developmental delay as a commonly reported feature.
  - reference: PMID:23732435
    reference_title: Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was a 32-month-old boy who presented with language development delay."
    explanation: A patient presenting with delay at the milder end.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| DD | Y | 8/35 (23%) |"
    explanation: >-
      The pooled count for unspecified developmental delay behind the
      OCCASIONAL band.
- name: Seizure
  category: Neurological
  description: >-
    Seizures are reported across the series, including infantile spasms in one
    East Asian patient. Banded from the pooled figure of 12 of 35 published
    patients, which is subject to ascertainment bias: patients come to
    attention through neurological presentations, so a literature pool
    over-represents them relative to all biochemically affected people.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29054612
    reference_title: Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy."
    explanation: Reports infantile spasms at the severe end of the spectrum.
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A four-year-old male with global developmental delay, dysmorphic facies, autistic features and a history of seizures was diagnosed with dihydropyrimidinase deficiency"
    explanation: Seizures in a molecularly confirmed patient.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| EEG finding/seizure | Y | 12/35 (34%) |"
    explanation: >-
      The pooled count behind the FREQUENT band, from the 35-patient
      literature review table.
- name: Abnormal cerebral white matter morphology
  category: Neurological
  description: >-
    Reduced white matter and brain atrophy on imaging, reported in a minority
    of patients. The pooled table counts MRI abnormalities as a single row, of
    which white-matter volume loss was the commonest finding.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Reduced cerebral white matter
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:29054612
    reference_title: Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy."
    explanation: White-matter reduction and atrophy in the severe patients.
  - reference: PMID:17383919
    reference_title: Clinical, biochemical and genetic findings in two siblings with a dihydropyrimidinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the siblings had a severe delay in speech development and white matter abnormalities, whereas the other one was free of symptoms."
    explanation: >-
      White-matter abnormality in one sibling, with the discordant sibling in
      the same sentence.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| MRI abnormalities | Y | 5/35 (14%) |"
    explanation: >-
      The pooled count behind the OCCASIONAL band.
- name: Autistic behavior
  category: Neurological
  description: Autistic features, reported with developmental delay and seizures.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autistic features
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits."
    explanation: Autistic traits among the features the authors flag for suspicion.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Autism | N | 3/35 (9%) |"
    explanation: >-
      The pooled count behind the OCCASIONAL band.
- name: Microcephaly
  category: Neurological
  description: Reported among the features that should raise suspicion of the disease.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits."
    explanation: Microcephaly among the suggestive features.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Microcephaly | N | 3/35 (9%) |"
    explanation: >-
      The pooled count behind the OCCASIONAL band.
- name: Parkinsonism
  category: Neurological
  description: >-
    Levodopa-responsive juvenile parkinsonism, reported once, in a 13-year-old
    with compound heterozygous DPYS variants. A single case; recorded because
    it is treatable and would otherwise not be looked for.
  phenotype_term:
    preferred_term: Levodopa-responsive juvenile parkinsonism
    term:
      id: HP:0002548
      label: Parkinsonism with favorable response to dopaminergic medication
  evidence:
  - reference: PMID:39558747
    reference_title: Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant."
    explanation: The single reported case.
- name: Atrioventricular canal defect
  category: Cardiovascular
  description: >-
    Complete atrioventricular septal defect, corrected surgically in infancy,
    in one patient. The second report of congenital heart disease in the
    disease; the authors propose it as a rare feature rather than an
    established one.
  phenotype_term:
    preferred_term: Complete atrioventricular septal defect
    term:
      id: HP:0001674
      label: Complete atrioventricular canal defect
  evidence:
  - reference: PMID:38958169
    reference_title: "Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the second report of congenital heart disease in dihydropyrimidinase deficiency, following a single patient with a ventricular septal defect."
    explanation: >-
      Places this phenotype as the second such report, which is why it is
      carried without a frequency.
- name: Vomiting
  category: Gastrointestinal
  description: >-
    Gastrointestinal features are one of the two main presenting categories in
    the largest series. Vomiting is the specific sign reported in the feline
    model and in patients.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "| Vomiting | Y | 3/35 (9%) |"
    explanation: >-
      The pooled count for vomiting specifically, which is what this
      phenotype claims, and the basis for the OCCASIONAL band.
  - reference: PMID:20362666
    reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presented mainly with neurological and gastrointestinal abnormalities"
    explanation: >-
      Gastrointestinal involvement as one of the two main presenting
      categories. INDIRECT because it does not name vomiting; the pooled row
      above is the direct support.
biochemical:
- name: Urinary dihydrouracil and dihydrothymine
  presence: INCREASED
  frequency: VERY_FREQUENT
  notes: >-
    The diagnostic measurement, by urine pyrimidine analysis or metabolome
    screening. One patient was found incidentally on untargeted urine
    metabolome analysis, so the finding can precede any clinical suspicion.
  evidence:
  - reference: PMID:39558747
    reference_title: Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further urinary metabolome analysis demonstrated markedly elevated dihydrouracil and dihydrothymine levels, confirming impaired pyrimidine metabolism."
    explanation: Urine metabolite measurement used to confirm the diagnosis.
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients exhibited characteristic biochemical findings of increased UR, DHU, THY, and DHT levels in bodily fluids."
    explanation: >-
      The all-patients statement behind the VERY_FREQUENT band, pooled over
      the 35 published patients.
- name: Plasma beta-aminoisobutyric acid
  presence: DECREASED
  notes: >-
    Reduced because the thymine arm of the pathway is blocked upstream of it.
    Beta-alanine, by contrast, is normal, which separates this disease
    biochemically from dihydropyrimidine dehydrogenase deficiency. Measured in
    two siblings only; whether the depletion matters clinically is unresolved.
  evidence:
  - reference: PMID:18600547
    reference_title: Beta-alanine and beta-aminoisobutyric acid levels in two siblings with dihydropyrimidinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a normal concentration of beta-alanine and strongly decreased levels of beta-aminoisobutyric acid were observed in plasma, urine and CSF."
    explanation: The measured direction for both beta-amino acids.
genetic:
- name: DPYS
  gene_term:
    preferred_term: DPYS
    term:
      id: hgnc:3013
      label: DPYS
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    DPYS encodes dihydropyrimidinase, a zinc-dependent cyclic amidohydrolase
    that works as a tetramer. Reported variants cluster in exons 5 to 8, which
    carry about 41 per cent of the coding sequence but 71 per cent of the
    variants in the largest series. Residual activity varies widely between
    alleles, from none to about half of wild type, but it does not explain the
    clinical variability: the paper that first characterised the gene found no
    significant difference in residual activity between the variants carried
    by symptomatic and by asymptomatic individuals.
    Four variants recurred in unrelated patients in that series, and p.R302Q
    has since been seen in Chinese and other East Asian patients.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20362666
    reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence."
    explanation: The exonic clustering described in the notes.
  - reference: PMID:20362666
    reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated."
    explanation: Recurrent alleles across unrelated patients.
  - reference: PMID:29054612
    reference_title: Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional analysis of recombinantly expressed DHP mutants carrying the p.M250I, p.H295R, p.Q334R, p.T418I and the p.R490H variant showed residual DHP activities of 2.0%, 9.8%, 9.7%, 64% and 0.3%, respectively."
    explanation: >-
      The range of residual activity across alleles, which is the basis for
      the statement that activity varies widely.
  variants:
  - name: p.R302Q
    description: >-
      Recurrent missense variant seen in unrelated patients including Chinese
      and other East Asian cases, with low residual activity on expression.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:20362666
      reference_title: "Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively."
      explanation: Residual activity measured for this allele.
    - reference: PMID:23732435
      reference_title: Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K)."
      explanation: The same allele in a patient from a different population.
treatments:
- name: Fluoropyrimidine Avoidance or Dose Reduction
  description: >-
    The one actionable intervention in this disease, and it is preventive
    rather than therapeutic: knowing the diagnosis before a fluoropyrimidine
    is prescribed. The published argument for it is that severe toxicity has
    been reported in patients and in carriers of congenital pyrimidine
    metabolic disorders, so identifying affected people, including the
    asymptomatic ones, is worthwhile before 5-fluorouracil is given. Note
    this is a published recommendation rather than a guideline: no dosing
    algorithm for DPYS exists, unlike DPYD, and the cohort evidence on DPYS
    variants and toxicity is contested (see the Fluoropyrimidine Cytotoxicity
    node).
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Drug avoidance in a susceptible patient
  notes: >-
    No ontology term is bound, because this treatment consists of not
    administering a drug and NCIT appears to have no clinical-action term for
    that. Searched `ols:ncit` for l~drug avoidance, l~drug withholding,
    l~dose reduction, l~drug discontinuation (all returned nothing),
    l~avoidance (returns NCIT:C54264 Avoidance, a behavioural concept, plus
    questionnaire items), l~contraindication (returns NCIT:C50646 Medical
    Contraindication and NCIT:C37933 Contraindicated, which are a finding and
    a qualifier rather than actions) and l~treatment modification (returns
    protocol-administration items only). The entry previously bound
    NCIT:C15986 Pharmacotherapy here, which asserts the opposite of what this
    record means, so it was removed rather than replaced.
    therapeutic_modality is OTHER rather than BEHAVIORAL because a
    prescribing decision is not the behavioural, physical or dietary
    intervention that value describes.
  target_mechanisms:
  - target: Impaired Fluoropyrimidine Catabolism
    treatment_effect: INHIBITS
    description: >-
      Withholding or reducing the drug removes the substrate the deficient
      enzyme cannot process, which is the only point in this arm that can be
      acted on; the enzyme deficit itself is not treatable.
    evidence:
    - reference: PMID:30384990
      reference_title: A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As severe 5-fluorouracil-associated toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders, urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment."
      explanation: >-
        The published rationale for identifying affected people before the
        drug is given, which is what this intervention acts on.
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Identifying patients with DHP deficiency, even when they are asymptomatic, is warranted to prevent neurotoxicity while administering pyrimidine analog drugs, such as 5-fluorouracil (5-FU), to patients with cancer."
    explanation: >-
      States the case for pre-treatment identification including of
      asymptomatic individuals, which is what makes this a preventive
      intervention rather than a therapy.
- name: Levodopa for the Parkinsonian Presentation
  description: >-
    In the single reported patient with levodopa-responsive juvenile
    parkinsonism, levodopa relieved the motor symptoms. One patient, so this
    is a lead rather than established management, but it is recorded because
    the presentation is treatable and would not otherwise be looked for in a
    pyrimidine disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: NCIT:C611
        label: Levodopa
  target_mechanisms:
  - target: Parkinsonism
    treatment_effect: MODULATES
    description: >-
      Symptomatic dopaminergic replacement. It acts on the parkinsonian
      phenotype, not on the metabolic lesion, and nothing is known about why
      this patient was dopamine-responsive.
    evidence:
    - reference: PMID:39558747
      reference_title: Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Levodopa treatment effectively relieved the patient's motor symptoms."
      explanation: The reported response in the single treated patient.
  evidence:
  - reference: PMID:39558747
    reference_title: Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report identifies DPYS as a novel genetic cause of juvenile parkinsonism and underscores the potential efficacy of levodopa therapy in managing motor dysfunction in DYPS-related parkinsonism."
    explanation: >-
      The authors' own framing, as potential efficacy from one case rather
      than established treatment.
diagnosis:
- name: Urine pyrimidine analysis
  description: >-
    Quantification of dihydrouracil and dihydrothymine in urine, by tandem
    mass spectrometry or gas chromatography-mass spectrometry. This is what
    makes the biochemical diagnosis; DPYS sequencing then confirms it and
    allows family testing.
  evidence:
  - reference: PMID:38199782
    reference_title: "The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies."
    explanation: The confirmatory role of sequencing after the biochemical finding.
  - reference: PMID:30384990
    reference_title: A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry."
    explanation: >-
      The two-assay sequence in a patient found incidentally, which is how
      several reported patients came to attention.
- name: Urinary pyrimidine analysis before fluoropyrimidine treatment
  description: >-
    Proposed as a pre-treatment screen for patients about to receive
    5-fluorouracil, on the grounds that severe toxicity has been reported in
    patients and carriers of congenital pyrimidine metabolic disorders. This is
    a published suggestion rather than established practice; no guideline
    endorsing it was identified.
  evidence:
  - reference: PMID:30384990
    reference_title: A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment."
    explanation: The authors' proposal, in their own words.
animal_models:
- name: Feline dihydropyrimidinase deficiency (DPYS p.G435R homozygous cat)
  species: Cat
  genotype: DPYS c.1303G>A (p.G435R) homozygous
  publication: PMID:23430934
  description: >-
    A naturally occurring case rather than an engineered model: a cat
    homozygous for a DPYS missense variant at a residue also mutated in a human
    patient, with dihydrouracil and dihydrothymine in urine. It presented with
    malnutrition, depression, vomiting and hyperammonaemia. Screening 1,000
    cats found no other carrier.
  modeled_mechanisms:
  - target: Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the metabolite accumulation at the same enzymatic step, by a
      variant at a residue mutated in human disease.
    limitations: >-
      A single animal, and its hyperammonaemia is not a reported feature of
      the human disease, so the presentation is not a match even though the
      biochemistry is. Beta-aminoisobutyrate was not measured.
    evidence:
    - reference: PMID:23430934
      reference_title: "Dihydropyrimidinase deficiency: the first feline case of dihydropyrimidinuria with clinical and molecular findings."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Analysis of the feline DPYS gene encoding DHP demonstrated that the cat was homozygous for the missense mutation c.1303G>A (p.G435R) in exon 8, which corresponds to a known mutation in a human patient with DHP deficiency."
      explanation: >-
        The variant corresponds to a human patient allele, which is what makes
        this animal informative for the human mechanism.
    readouts:
    - name: Urinary dihydrouracil and dihydrothymine
      target: Dihydropyrimidine Accumulation with Beta-Aminoisobutyrate Depletion
      direction: INCREASED
      interpretation: The same metabolite accumulation as in human patients.
      evidence:
      - reference: PMID:23430934
        reference_title: "Dihydropyrimidinase deficiency: the first feline case of dihydropyrimidinuria with clinical and molecular findings."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "A gas chromatographic-mass spectrometric analysis of urinary metabolic substances showed the presence of large amounts of dihydrouracil and dihydrothymine and moderate amounts of uracil and thymine, suggesting DHP deficiency."
        explanation: The metabolite measurement in the affected cat.
differential_diagnoses:
- name: Dihydropyrimidine dehydrogenase deficiency
  description: >-
    Deficiency of DPYD, the first and rate-limiting enzyme of the same
    pathway. It shares the variable neurological presentation and the
    fluoropyrimidine-toxicity implication, but the block sits one step
    earlier, so uracil and thymine accumulate rather than their dihydro
    forms, and beta-alanine is depleted rather than normal. Curated as
    Dihydropyrimidine_Dehydrogenase_Deficiency.
- name: Beta-ureidopropionase deficiency
  description: >-
    Deficiency of UPB1, the third and final enzyme of pyrimidine catabolism.
    The N-carbamyl compounds that DHP produces accumulate instead, which is
    what separates it on urine analysis.
notes: >-
  Lump/split decision: DISEASE. One gene, one enzymatic step, and one
  conserved biochemical chain from biallelic DPYS loss of function to
  dihydropyrimidinuria. MONDO records no descendants for MONDO:0009111.

  Two things are deliberately not asserted. The neurological phenotype is not
  placed downstream of the metabolite disturbance in the pathograph, because
  biochemically identical siblings differ in whether they are affected; that
  link is carried as an EMERGING mechanistic hypothesis instead, which is the
  same treatment the sibling DPD entry gives the same problem. And the
  fluoropyrimidine-toxicity arm is modelled but kept thin: it rests on one
  attributed case plus two cohorts that disagree, so the cohort that found no
  association is cited as REFUTE on the same node rather than left out.

  No GeneReviews chapter exists; a PubMed genereviews[book] title search for
  dihydropyrimidinase and DPYS returned nothing.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (2)

Review round 1: phenotype frequencies, treatments, hypothesis-group edges · 2026-10-15T08:03:21Z · View source

Review round 1 on PR #14301, answering the reviewer's three items and an adversarial self-review. Reviewer item 1, phenotype frequencies. PMID:38199782 is cached as full text and its Table 3 pools 35 patients, which the entry cited eight times without mining. Added intellectual disability (16/35, FREQUENT), hypotonia (9/35, OCCASIONAL), feeding difficulties (8/35) and failure to thrive (6/35), and banded the existing seizure, developmental delay, white-matter, autism, microcephaly and vomiting rows from the same table. Where the paper's table and its prose disagree on hypotonia, 9 of 35 against 10 of 35, the table row is cited and the discrepancy is stated rather than averaged. The Seizure description no longer says frequency cannot be banded; it says a pooled figure exists and is subject to ascertainment bias, which is the honest reason to read it carefully. Reviewer item 2, prevalence. prevalence_class was ABOVE_1_IN_1000 against rate_per_100000 10.0, which is two bands out: the schema puts 10 per 100,000 in BAND_1_5_PER_10000. Corrected, and measure_type moved to UNKNOWN because the source says only an estimated prevalence of 2/20,000 without saying whether it is point or lifetime. Reviewer item 3, the disconnected phenotypes. The claim in the first PR body that this entry treated the neurotoxicity link the same way as the sibling DPD entry was false: that entry keeps the link as downstream edges tagged with its hypothesis group, so its graph stays connected. This entry declared the group and drew no edge, leaving every clinical phenotype an island at 2/10 connected. Added INDIRECT_UNKNOWN_INTERMEDIATES edges from the metabolite node to the seven neurological phenotypes, each tagged dihydropyrimidine_accumulation_neurotoxicity, which keeps the link unasserted while connecting the graph. Now 9/14. The gastrointestinal, cardiac and parkinsonism phenotypes are deliberately left unwired, since no source proposes a route. Self-review findings taken. Two evidence items were graded SUPPORT for sentences saying the claim is unestablished, with explanations that admitted it; regraded NO_EVIDENCE, which is what a sentence recording an open question is. The PMID:9718352 REFUTE item keeps its direction but gains directness INDIRECT and moves to IN_VITRO, since the activities were measured in an expression system, and its explanation no longer says the metabolite disturbance cannot be what decides the phenotype, because the comparison is one symptomatic against five asymptomatic individuals. Vomiting was bound to HP:0002013 on a snippet about gastrointestinal abnormalities generally; it now cites the vomiting row and keeps the general sentence as INDIRECT. Three VERY_FREQUENT bands rested on single-patient snippets and now cite the all-patients statement from the pooled review. Two bindings were coarser than their own sources: complete atrioventricular septal defect to HP:0001674 and levodopa-responsive juvenile parkinsonism to HP:0002548. Two framing sentences gained quote_role BACKGROUND, one REVIEW_SYNTHESIS on a pure case report became BACKGROUND, and an enzymology sentence graded HUMAN_CLINICAL became IN_VITRO. An uncited organ-distribution clause was removed. The edge to fluoropyrimidine cytotoxicity was DIRECT with no evidence and asserted that no pharmacokinetic study was found; it is now INDIRECT_KNOWN_INTERMEDIATES, cites the 5,6-dihydro-5-FU back-conversion route from the cached review, and narrows the negative claim to what was actually searched. Added a treatments block: fluoropyrimidine avoidance or dose reduction, and levodopa for the parkinsonian presentation. The entry previously called parkinsonism treatable while carrying no treatment. One CURIE worth recording: the committed research report offers NCIT:C739 for levodopa, which is Phenobarbital. The lookup gave NCIT:C611, which is what is bound. That is the second wrong-CURIE catch in this run and the first to come from a deep-research report rather than from memory. Validation: just validate-disorders (66/66 snippets, 66 titles, 0 issues), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-coarse-phenotypes.

Create: Dihydropyrimidinase Deficiency · 2026-10-15T07:32:00Z · View source

Created kb/disorders/Dihydropyrimidinase_Deficiency.yaml for MONDO:0009111 (label dihydropyrimidinuria), the DPYS step of pyrimidine catabolism, as a sibling of the existing Dihydropyrimidine_Dehydrogenase_Deficiency entry which mentions DPYS only in passing. Deep research: one OpenScientist run (research/Dihydropyrimidinase_Deficiency-deep-research-openscientist.md). Its validation blocks reported 20/20 references resolved and 25/27 terms resolved with no term named as a different term. just preflight-dr returned PASS (DPYS mentioned 32 times against DPYD 4, OMIM 222748 matching MONDO's xref). Four citations were taken from the report after reading each abstract: PMID:9718352, PMID:35961217, PMID:30384990 and the recurrence of p.R302Q. The rest of the entry was built from a PubMed sweep run before the report completed. The report's most useful contribution was PMID:9718352, which reports no significant difference in residual enzyme activity between the variants carried by symptomatic and by asymptomatic individuals. That is a direct measured refutation of the obvious explanation for this disease's variability, so it is cited as REFUTE on the neurotoxicity hypothesis and the genetic notes were rewritten from 'has not been shown to predict it' to say what was actually measured. Deliberately not asserted. The neurological phenotype is not placed downstream of the metabolite disturbance in the pathograph, because biochemically identical siblings differ in whether they are affected (PMID:18600547, PMID:17383919); that link is an EMERGING mechanistic hypothesis instead, the same treatment the sibling DPD entry gives the same problem. The fluoropyrimidine-toxicity arm is modelled but kept thin: it rests on one attributed case (PMID:14555507) plus two cohorts that disagree, and the cohort finding no association (PMID:38215018) is cited as REFUTE on the same node rather than omitted, with its scope difference (common variants genotyped, not rare ones sequenced) stated in the explanation. Two prevalence records are carried because the published case count (fewer than 40) and a quoted estimate of 2 in 20,000 are different quantities in open tension; the notes say so and say not to quote them as one number. The report also offered a GTEx-based argument that DPYS is a liver and kidney enzyme not expressed in brain, implying the CNS effect is non-cell-autonomous. That is a genuinely interesting lead but it is the provider's own analysis with no citable source found for the human tissue distribution, so it was left out rather than written in unsourced. Validation: just validate, just validate-disorders (48/48 snippets, 48 titles, 0 issues), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, check-enum-values, check-genereviews (NO_CHAPTER, which the entry's notes record).

OpenScientist ▸
Key Findings
openscientist-autonomous 17 citations 2026-10-15T07:12:25.842286

Key Findings

Finding 1 — Molecular identity: an autosomal recessive defect of pyrimidine degradation (F001)

Dihydropyrimidinase deficiency is caused by biallelic mutations in DPYS, which encodes the second enzyme of the pyrimidine degradation pathway. DHP (EC 3.5.2.2) catalyzes the ring-opening (hydrolysis) of 5,6-dihydrouracil to N-carbamyl-β-alanine and of 5,6-dihydrothymine to N-carbamyl-β-aminoisobutyric acid. The pathway runs: uracil/thymine → (DPD) → dihydrouracil/dihydrothymine → (DHP/DPYS) → N-carbamyl-β-alanine/N-carbamyl-β-aminoisobutyrate → (β-ureidopropionase/UPB1) → β-alanine/β-aminoisobutyrate.

The human DHP gene spans >80 kb, consists of 10 exons, and maps to 8q22 by FISH (PMID: 9718352: "The human DHP gene spans >80 kb and consists of 10 exons. It has been assigned to 8q22, by FISH."). The enzyme reaction is defined precisely in the clinical literature (PMID: 17383919: "Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and it catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, respectively."). Inheritance is autosomal recessive — patients are homozygous or compound heterozygous, with heterozygous (carrier) parents.

Ontology anchors: MONDO:0009111; gene HGNC:3012 (DPYS); GO:0006208 (pyrimidine nucleobase catabolic process); GO:0004157 (dihydropyrimidinase activity); CHEBI 5,6-dihydrouracil, CHEBI 5,6-dihydrothymine.

Finding 2 — Biochemical hallmark: dihydropyrimidinuria across body fluids (F002)

The defining laboratory abnormality is marked accumulation of the two DHP substrates. Patients show markedly elevated 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid, and urine (PMID: 20362666: "Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine."). The defect is detectable by urine metabolomics: gas chromatography–mass spectrometry (GC-MS) screening reveals elevated dihydrouracil and dihydrothymine, confirmed by quantitative LC-MS/MS (PMID: 30384990: "Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry."). Comprehensive HPLC–electrospray ionization tandem MS panels reliably detect the entire spectrum of purine/pyrimidine disorders, including DHP deficiency, in a single run (PMID: 16613999).

Finding 3 — Highly variable, incompletely penetrant phenotype (F003)

Fewer than ~40 patients have been published. The phenotypic range spans asymptomatic → severe neurological disease. Reported features include global/developmental delay, seizures and infantile spasms, intellectual disability, dysmorphic facies, autistic features, microcephaly, white matter abnormalities, and brain atrophy, plus gastrointestinal abnormalities (feeding problems, vomiting). Congenital heart disease (atrioventricular septal defect, ventricular septal defect) has been reported as a rare feature.

Key quotes: (PMID: 38958169: "Clinical findings are variable and some patients may remain asymptomatic. Global developmental delay and increased susceptibility to 5-fluorouracil are commonly reported.") and (PMID: 29054612: "a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy"). Crucially, enzyme residual activity does not discriminate symptomatic from asymptomatic individuals (PMID: 9718352: "There was no significant difference, in residual activity, between mutations observed in the symptomatic and those observed in the asymptomatic individuals."). This poor genotype–phenotype and enzyme-activity–phenotype correlation is a central feature and strongly implies modifier genes and/or environmental triggers.

Suggested HPO terms: HP:0001263 (global developmental delay), HP:0001250 (seizures), HP:0001251 (infantile spasms → HP:0012469), HP:0001249 (intellectual disability), HP:0000729 (autistic behavior), HP:0000252 (microcephaly), HP:0002500 (cerebral white matter abnormality), HP:0002059 (cerebral atrophy), HP:0011968 (feeding difficulties), HP:0002013 (vomiting), HP:0001629 (ventricular septal defect), HP:0001674 (atrioventricular septal defect).

Finding 4 — Pharmacogenetic predisposition to severe/lethal 5-fluorouracil toxicity (F004)

This is the most clinically consequential aspect of the disorder. Partial DHP deficiency is itself a pharmacogenetic disorder associated with severe 5-FU toxicity (PMID: 15571261: "A partial dihydropyrimidinase deficiency proved to be a novel pharmacogenetic disorder associated with severe 5FU toxicity."). Because 5-FU is itself catabolized through the pyrimidine degradation pathway, DHP deficiency slows 5-FU clearance; lethal side-effects can occur even in asymptomatic patients (PMID: 19571472: "when the patients are treated with 5-fluorouracil, a pyrimidine analogue anticancer drug, lethal side-effects can be seen even in asymptomatic patients").

Quantitatively, dihydropyrimidine dehydrogenase (DPD/DPYD) deficiency accounts for ~43% of grade 3–4 5-FU toxicity (PMID: 18075467: "Dihydropyrimidine dehydrogenase (DPD) deficiency accounts for approximately 43% of grade 3-4 toxicity to 5-fluorouracil."); the residual unexplained toxicity is attributed in part to downstream DHP (DPYS) and β-ureidopropionase (UPB1) deficiencies. Additional case literature illustrates that severe 5-FU toxicity can also arise from thiamine deficiency/beriberi in the absence of a definable enzyme defect (PMID: 21941485) and that a putative "enhanced thymine absorption" phenotype may contribute (PMID: 29846282) — important differential considerations when evaluating fluoropyrimidine toxicity.

Clinical implication: urinary dihydropyrimidine screening and DPYS genotyping should be considered before fluoropyrimidine chemotherapy, alongside standard DPYD testing.

Finding 5 — Protein mechanism: a zinc-dependent amidohydrolase disrupted by diverse mutation classes (F005)

DHP is a member of the cyclic amidohydrolase family (which also includes allantoinase, dihydroorotase, hydantoinase, and imidase) and is a zinc metalloenzyme with a binuclear metal center in which two metal ions are bridged by a post-translationally carbamylated lysine; the functional unit is a homotetramer (PMID: 30268498: "Dihydropyrimidinase (DHPase) is a member of the cyclic amidohydrolase family... Almost all of these zinc metalloenzymes possess a binuclear metal center in which two metal ions are bridged by a post-translational carbamylated Lys.").

Mutation analysis in 17 patients found 9 missense, 2 nonsense, 2 deletion, and 1 splice-site mutation, with 71% localizing to exons 5–8. Most expressed mutants had no activity; p.R302Q and p.T343A retained ~3.9% and ~49% residual activity respectively. Mapping onto the crystal structure reveals distinct structural mechanisms (PMID: 20362666: "The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site."). Other variants (p.S379R, p.L7V) cause global structural destabilization. East Asian/Japanese patients carry recurrent variants (e.g., Q334R, H295R, M250I) affecting active-site loops (PMID: 29054612: "The observation that the identified mutations were more prevalent in East Asians and the Japanese population indicates that DHP deficiency may be more common than anticipated in these ethnic groups.").

Mutation class Example variants Structural/functional consequence
Oligomerization interface p.R490C, p.R302Q, p.V364M Impaired homotetramer assembly
Di-zinc center / substrate binding p.M70T, p.D81G, p.L337P, p.T343A Catalytic impairment near active site
Global destabilization p.S379R, p.L7V Misfolding / instability
Truncating p.R475, p.K501X, p.R465X, p.W117 Loss of function / NMD

Finding 6 — A naturally occurring feline model (F006)

DHP deficiency occurs spontaneously in cats, providing a comparative animal model. An affected cat presented with malnutrition, depression, vomiting, and hyperammonemia; urine GC-MS showed large amounts of dihydrouracil and dihydrothymine and moderate uracil/thymine. The cat was homozygous for the DPYS missense mutation c.1303G>A (p.G435R), which corresponds to a known human DHP-deficiency mutation (PMID: 23430934: "Analysis of the feline DPYS gene encoding DHP demonstrated that the cat was homozygous for the missense mutation c.1303G>A (p.G435R) in exon 8, which corresponds to a known mutation in a human patient with DHP deficiency."). Screening 1,000 cats found no additional carriers, indicating a very low allele frequency. The literature cites an estimated human prevalence of ~2/20,000 (PMID: 30384990: "an estimated prevalence of 2/20,000").

Taxonomy/ortholog anchors: Felis catus (NCBI Taxon:9685); feline DPYS ortholog; the p.G435R orthologous variant links feline and human disease biology directly.

Finding 7 — Population genetics: LoF-tolerant gene with East-Asian-enriched pathogenic alleles (F007)

Analysis of gnomAD v4 (GRCh38) constraint for DPYS (ENSG00000147647, chr8:104,330,324–104,467,055) confirms the recessive model: pLI ≈ 0, observed/expected LoF (o/e) = 0.775 (LOEUF 90% CI 0.60–1.01), LoF Z = 1.35, observed/expected LoF = 39/50.3 — i.e., loss-of-function is tolerated, exactly as expected for an autosomal recessive LoF disorder. Summing 87 high-confidence pLoF alleles gives a cumulative pLoF allele frequency q ≈ 8.5×10⁻⁴, implying a pLoF-only carrier frequency ≈ 2q ≈ 1/587 and homozygous-pLoF incidence q² ≈ 1/1.4M — a lower bound, because pathogenic missense alleles (which dominate the real mutation spectrum) are excluded.

Recurrent pLoF alleles include p.Arg475Ter (AF 1.3×10⁻⁴), p.Glu507MetfsTer57, p.Trp117Ter, p.Arg503GlufsTer2, and p.Arg302Ter. Known pathogenic missense alleles show marked ancestry enrichment, corroborating clinical reports of East Asian/Japanese clustering (PMID: 29054612):

Variant Population enrichment Allele frequency
p.Gln334Arg (Q334R) East Asian 0.00209 (~1/240 EAS); ~0 elsewhere
p.His295Arg (H295R) East Asian enriched
p.Arg490Cys (R490C) East Asian enriched
p.Trp360Arg (W360R) Middle Eastern enriched
p.Arg475Ter (R475*) Middle Eastern enriched
p.Met250Ile (M250I) Ashkenazi Jewish enriched

Finding 8 — ClinVar allelic heterogeneity and interpretation challenge (F008)

ClinVar harbors extensive allelic heterogeneity for DPYS: a query returned ~300 variant records — 87 Pathogenic, 27 Likely pathogenic (114 P/LP combined), 255 Uncertain significance (VUS), plus benign/likely-benign entries. Variant classes are predominantly single-nucleotide (missense/nonsense/splice) with small indels; no recurrent large structural/chromosomal abnormality is characteristic of the disease. The large VUS burden underscores the diagnostic interpretation challenge, especially given the lack of genotype–phenotype correlation.

Finding 9 — Organ localization: a liver/kidney enzyme, not a brain enzyme (F009)

A key mechanistic insight from this investigation: GTEx v8 median expression for DPYS (ENSG00000147647) is dominated by liver (132.8 TPM) and kidney cortex (39.1 TPM) (kidney medulla 12.7 TPM), while brain regions are very low (frontal cortex ~1.3, cortex ~0.8 TPM) and heart/skeletal muscle/whole blood are negligible (<0.03 TPM). This mirrors the known organ localization of pyrimidine catabolism.

The implication is important for the pathophysiological model: because the enzyme is not expressed in brain, the prominent neurological phenotype is best understood as a circulating-metabolite (non-cell-autonomous) effect — accumulated dihydropyrimidines (and/or downstream perturbations such as reduced β-alanine/β-aminoisobutyrate availability) reach the CNS through the circulation, rather than reflecting a cell-autonomous loss of DHP in neurons.

Anatomical/subcellular anchors: UBERON:0002107 (liver), UBERON:0001225 (cortex of kidney); cytoplasmic localization (GO:0005737).

Finding 10 — Phenotype expansion: levodopa-responsive juvenile parkinsonism (F010)

The phenotypic spectrum was expanded in 2024 by the first report of levodopa-responsive juvenile parkinsonism associated with DHP deficiency: a 13-year-old with rapidly progressive dysphagia, dysarthria, and loss of ambulation over 18 months, compound heterozygous for DPYS c.1393C>T (p.R465X) and c.905G>A (p.R302Q), with urinary metabolome showing markedly elevated dihydrouracil and dihydrothymine (PMID: 39558747: "We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant."). Importantly, levodopa relieved the motor symptoms (PMID: 39558747: "Levodopa treatment effectively relieved the patient's motor symptoms.") — a rare symptom-directed pharmacologic treatment opportunity.

The variant p.R302Q (c.905G>A) is recurrent — also reported homozygously in a Chinese child (PMID: 33179229). Molecular-dynamics studies of 10 DHP variants show mutation-specific effects: oligomerization-interface disruption (T68R, D81G, G278D, L337P), stereochemistry-gate loops/substrate-binding pocket perturbation (W117R, T343A, R412M), and global collapse (W360R, G435R), while a near-normal-activity variant (R181W) showed only slight changes (PMID: 35961217: "In the T68R, D81G, G278D, and L337P variants, the flexibilities of structures related to the interaction for oligomer formation increased in comparison with those of the wild type.").

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variants in DPYS (8q22) → reduce or abolish production of functional dihydropyrimidinase protein (truncating/NMD alleles) or produce misfolded/destabilized/assembly-incompetent protein (missense alleles affecting the di-zinc center, substrate-binding pocket, or homotetramer interface).
  2. Loss of DHP (EC 3.5.2.2) catalytic activity → the second step of pyrimidine degradation fails to open the ring of 5,6-dihydrouracil and 5,6-dihydrothymine (demonstrated biochemically and structurally).
  3. Metabolic block → accumulation of the substrates 5,6-dihydrouracil and 5,6-dihydrothymine, with secondary elevation of upstream uracil/thymine, in liver and kidney (principal sites of enzyme expression) and spillover into plasma, CSF, and urine → dihydropyrimidinuria (demonstrated).
  4. Systemic distribution of accumulated metabolites → because DPYS is not expressed in brain (liver/kidney enzyme), CNS exposure is driven by circulating dihydropyrimidines reaching the brain → inferred non-cell-autonomous neurotoxic/neurodevelopmental effect.
  5. Branch A — Neurodevelopmental: developmental delay, seizures/infantile spasms, intellectual disability, autistic features, white-matter abnormality, brain atrophy, and (rarely) levodopa-responsive juvenile parkinsonism. The molecular link from metabolite accumulation to neuronal dysfunction remains inferred.
  6. Branch B — Gastrointestinal/systemic: feeding problems, vomiting; in the feline model, hyperammonemia.
  7. Branch C — Pharmacogenetic 5-FU toxicity: when exogenous fluoropyrimidine (5-FU/capecitabine) is administered, the impaired degradation pathway slows 5-FU catabolism → drug/metabolite accumulation → severe or lethal systemic toxicity, even in asymptomatic individuals (demonstrated clinically).
  8. Incomplete penetrance / variable expressivity — because residual enzyme activity does not predict symptoms and identical genotypes yield discordant phenotypes, modifier genes and/or environmental factors (e.g., dietary pyrimidine load, drug exposure) determine whether branches A–B manifest (inferred).
 DPYS biallelic LoF
|
v
 Loss of dihydropyrimidinase activity (di-Zn amidohydrolase, homotetramer)
|
v
 Block of ring-opening: dihydrouracil + dihydrothymine accumulate (liver/kidney)
|
v
 Spillover -> plasma / CSF / urine  (DIHYDROPYRIMIDINURIA)
|
   -----+-----------------------------+-----------------------------+
   |                                 |                             |
   v (circulating metabolites)       v                             v (exogenous trigger)
 CNS effects (non-cell-autonomous) GI/systemic              5-FU / capecitabine
 - dev. delay, seizures            - feeding problems         -> impaired catabolism
 - autistic features, WM changes   - vomiting                 -> SEVERE/LETHAL TOXICITY
 - juvenile parkinsonism           - (feline: hyperammonemia)    (even if asymptomatic)
|
   [modifier genes / environment -> incomplete penetrance, variable expressivity]

Upstream (primary): DPYS mutation → protein dysfunction → enzymatic block → metabolite accumulation. Downstream (secondary): circulating-metabolite exposure of brain and tissues → neurodevelopmental and GI phenotypes; iatrogenic 5-FU toxicity is a conditional downstream branch requiring drug exposure.

Cell types / processes: Primary biochemical lesion in hepatocytes (CL:0000182) and renal proximal tubule cells (kidney cortex); downstream effects in central nervous system (neurons; white matter / oligodendrocytes CL:0000128). Biological processes: pyrimidine nucleobase catabolic process (GO:0006208), dihydropyrimidinase activity (GO:0004157), cytoplasmic metabolism (GO:0005737).

Evidence Base

PMID Title (abbrev.) Supports
9718352 Gene structure, chromosomal localization, mutation analysis F001 (gene structure, 8q22, 10 exons); F003 (no residual-activity difference)
17383919 Two siblings with DHP deficiency F001 (enzyme function/reaction)
20362666 Phenotype/genotype/structure in 17 patients F002 (metabolites in plasma/CSF/urine); F005 (structure–function map)
30384990 Incidental detection by urine metabolome F002 (GC-MS/LC-MS/MS); F006 (prevalence ~2/20,000)
38958169 DHP deficiency with atrioventricular septal defect F003 (variability, asymptomatic, 5-FU susceptibility)
29054612 Four East Asian patients, novel/rare DPYS mutations F003 (phenotype range); F005/F007 (East Asian enrichment)
15571261 Pyrimidine defects and severe 5-FU toxicity F004 (partial DHP deficiency = pharmacogenetic 5-FU risk)
19571472 5-FU toxicity in pyrimidine metabolic disorders F004 (lethal toxicity in asymptomatic patients)
18075467 Genetic regulation of dihydropyrimidinase F004 (DPD ~43% of grade 3–4 toxicity)
30268498 DHPase crystal structures / amidohydrolase family F005 (zinc metalloenzyme, binuclear metal center)
23430934 First feline case of dihydropyrimidinuria F006 (feline model; orthologous p.G435R)
35961217 Molecular dynamics of pathogenic variants F005/F010 (variant-specific destabilization)
39558747 Juvenile parkinsonism with DHP deficiency F010 (levodopa-responsive parkinsonism)
33179229 Chinese child, DPYS variant analysis F010 (recurrent p.R302Q homozygous)
16613999 HPLC-ESI-MS/MS purine/pyrimidine panel F002 (comprehensive diagnostic detection)
32600357 Novel stop-gain c.1501A>T p.K501X Allelic heterogeneity; AR confirmation; liver mRNA reduction
38199782 Diagnostic odyssey case + literature review Clinical/diagnostic context
39126710 Dual diagnosis (DPYS + TBX19) in Sri Lankan boy Phenotype complexity; consanguinity
21941485 5-FU encephalopathy / beriberi differential Differential of 5-FU toxicity
29846282 "Enhanced thymine absorption" phenotype Alternative fluoropyrimidine-toxicity mechanism

Section-by-section report content (template coverage)

1. Disease Information. DHP deficiency is a rare autosomal recessive inborn error of pyrimidine degradation. Identifiers: OMIM 222748, Orphanet 35707, MONDO:0009111; ICD-10 under disorders of pyrimidine metabolism (E79.8). Synonyms: dihydropyrimidinase deficiency, DHP deficiency, DHPase deficiency, dihydropyrimidinuria, DPYS deficiency. Information derives from aggregated disease-level resources plus a small set of individual case reports (<40 patients).

2. Etiology. The sole established cause is biallelic pathogenic DPYS variants (genetic). There are no established environmental causes; however, fluoropyrimidine drug exposure is the key environmental trigger of the toxicity phenotype. Risk factors: consanguinity and East Asian/Middle Eastern/Ashkenazi ancestry (founder/enriched alleles). No protective alleles defined. Gene–environment interaction is exemplified by 5-FU: a genetic enzyme deficiency becomes life-threatening only on drug exposure.

3. Phenotypes. See Findings 3 and 10 and HPO list above. Onset typically neonatal/infantile but ranges to adult incidental detection; severity variable (asymptomatic → severe); progression usually stable but can be progressive (juvenile parkinsonism). Frequencies are qualitative given the tiny cohort; developmental delay and 5-FU susceptibility are most commonly reported.

4. Genetic/Molecular. Causal gene DPYS (HGNC:3012, OMIM 613326), 8q22, 10 exons, >80 kb. Variant spectrum: predominantly missense, with nonsense, frameshift, splice, small indels; ClinVar ~114 P/LP and ~255 VUS. Functional consequence: loss of function (catalytic, metal-center, substrate-binding, or oligomerization defects). No modifier genes formally established; no characteristic epigenetic changes or large chromosomal abnormalities. Allele frequencies: p.Q334R EAS ~1/240. Germline origin.

5. Environmental. No toxins/infectious agents cause the disease. The decisive exogenous factor is fluoropyrimidine chemotherapy (5-FU, capecitabine) precipitating severe toxicity. Dietary pyrimidine load is a plausible but unproven modifier.

6. Mechanism. See ordered causal chain above.

7. Anatomical structures. Primary biochemical organs: liver (UBERON:0002107) and kidney (UBERON:0002113 / cortex UBERON:0001225). Secondary: central nervous system / brain (UBERON:0000955), white matter (UBERON:0002316); GI tract; rarely heart. Subcellular: cytoplasm. Lateralization not characteristic.

8. Temporal development. Onset congenital/pediatric most often but variable to adulthood; pattern usually chronic/insidious, occasionally rapidly progressive (parkinsonism over 18 months). Lifelong, no spontaneous remission; the critical intervention window is avoidance of fluoropyrimidines.

9. Inheritance and population. Autosomal recessive; incomplete penetrance; variable expressivity; estimated prevalence ~2/20,000 (cited); gnomAD pLoF carrier frequency ≥~1/590 (lower bound). Consanguinity and East Asian/Middle Eastern/Ashkenazi founder effects relevant. No sex predilection established.

10. Diagnostics. First-line: urine organic acid / pyrimidine panel showing elevated dihydrouracil and dihydrothymine (GC-MS, confirmed by LC-MS/MS; comprehensive HPLC-ESI-MS/MS panel). Confirmatory: DPYS sequencing (single-gene, panels, or WES/WGS). Differential diagnosis: DPD (DPYD) deficiency, β-ureidopropionase (UPB1) deficiency, and non-genetic causes of fluoropyrimidine toxicity (thiamine deficiency/beriberi; "enhanced thymine absorption"). Screening: pre-chemotherapy pyrimidine screening; cascade family testing.

11. Outcome/Prognosis. Highly variable; many asymptomatic individuals have normal life expectancy. No disease-specific mortality data except the catastrophic risk of lethal 5-FU toxicity. Prognostic factors poorly defined; residual enzyme activity is not prognostic.

12. Treatment. No curative therapy; supportive/symptomatic management. Actionable interventions: (a) strict avoidance of fluoropyrimidines (or extreme caution/dose modification), and (b) levodopa for the parkinsonism presentation (NCIT:C739 Levodopa). Seizures, developmental, GI, and feeding issues managed supportively. No gene/cell/RNA therapy exists.

13. Prevention. Primary: carrier screening and genetic counseling in at-risk/consanguineous families; prenatal/preimplantation diagnosis feasible given known variants. Secondary: pre-chemotherapy pyrimidine/genotype screening to prevent toxicity. Tertiary: avoid fluoropyrimidines; manage complications.

14. Other species / Natural disease. Spontaneous feline disease (Felis catus, Taxon:9685) with orthologous p.G435R — the principal natural model; veterinary relevance limited but illustrative of conserved mechanism.

15. Model organisms. No widely used engineered mouse/zebrafish model is established in the reviewed literature; the naturally occurring feline case is the primary in-vivo model, supplemented by heterologous expression of mutant protein and crystallography/molecular-dynamics for structure–function.

Limitations and Knowledge Gaps

  • Tiny cohort (<40 patients) limits frequency estimates, genotype–phenotype correlation, and natural-history/prognostic data; most "frequencies" are qualitative.
  • Unexplained incomplete penetrance: the molecular basis for discordant phenotypes among identical genotypes is unknown — modifier genes, dietary pyrimidine load, and environmental triggers are hypothesized but not demonstrated.
  • CNS mechanism is inferred, not proven: the circulating-metabolite (non-cell-autonomous) model is strongly supported by DPYS tissue expression (liver/kidney, not brain) but the specific neurotoxic species and molecular target remain uncharacterized.
  • No engineered mammalian model (knockout mouse) was identified in the reviewed literature, limiting mechanistic dissection and therapeutic testing.
  • Large VUS burden (~255 ClinVar VUS) impedes clinical interpretation; functional assays are not routinely available.
  • Prevalence uncertainty: the ~2/20,000 estimate and gnomAD-derived carrier frequencies (≥~1/590) differ in scope; true prevalence (including missense alleles) is likely underestimated, especially in East Asian populations.
  • Treatment evidence is anecdotal: levodopa response is based on a single case; no trials exist.

Proposed Follow-up Experiments / Actions

  1. Establish a Dpys knockout mouse (and/or zebrafish) to test whether the neurological phenotype is reproduced and whether it is driven by circulating metabolites (parabiosis, liver-specific vs global knockout, metabolite-rescue experiments).
  2. Metabolite neurotoxicity assays: expose neuronal/organoid cultures to pathophysiological concentrations of dihydrouracil/dihydrothymine (± β-alanine/β-aminoisobutyrate depletion) to identify the toxic species and molecular target.
  3. Prospective pre-chemotherapy screening study combining DPYD + DPYS (+ UPB1) genotyping and urinary pyrimidine ratios to quantify the DPYS contribution to otherwise-unexplained fluoropyrimidine toxicity and validate predictive biomarkers (e.g., urinary THY/DHT ratio).
  4. High-throughput functional classification of VUS (saturation mutagenesis + activity/oligomerization assay) to reduce the ClinVar VUS burden and improve clinical interpretation.
  5. Modifier search: genotype–phenotype analysis across the expanding registry to identify penetrance modifiers; collect dietary/exposure data.
  6. Natural-history registry to define onset, progression, prognosis, and the real frequency of parkinsonism and cardiac sub-phenotypes; evaluate levodopa responsiveness systematically.
  7. Population carrier-frequency studies in East Asian, Middle Eastern, and Ashkenazi cohorts to refine prevalence and inform targeted carrier screening.

Report compiled from a 5-iteration autonomous investigation: 10 confirmed findings, 20 reviewed papers, integrating primary clinical literature, gnomAD/ClinVar population genetics, GTEx expression data, protein structural/computational studies, and a naturally occurring animal model.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 20
Resolved 20
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 20
On topic 16
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 27
Resolved 25
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 15
Terms named correctly 13
Terms named as a different term 0
Terms whose name is worth a second look 2

Terms whose name is worth a second look

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

  • HP:0002500 (1 mention) - the report calls it "cerebral white matter abnormality"; HP calls it Abnormal cerebral white matter morphology, and lists "Cerebral white matter abnormalities" among its other names
  • HP:0001674 (1 mention) - the report calls it "atrioventricular septal defect"; HP calls it Complete atrioventricular canal defect, and lists "Complete atrioventricular septal defect" among its other names

Prefixes with no resolver

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

25 of 27 terms resolved to a current term; the rest could not be looked up either way.