Hereditary DPD deficiency (thymine–uraciluria)

Congenital DPD deficiency (thymine-uraciluria) is a rare inherited metabolic disorder caused by reduced or absent activity of DPD. It is defined biochemically, and the clinical spectrum is wide, ranging from asymptomatic individuals to severely affected patients. A homozygous mother of an affected child has been reported with thymine-uraciluria but no clinical features, so a neurological phenotype is not an obligate feature of the condition. When symptoms do occur, the disorder often becomes apparent in infancy or early childhood and may involve convulsive disorders and developmental delay. Severely affected individuals may present with intellectual disability, motor retardation, developmental delay and seizures. Seizures, cognitive impairment, language delay and MRI abnormalities have been reported in a child with no detectable residual enzyme activity. The wide variability in age of onset and severity is well recognised.

Individuals with congenital DPD deficiency are at risk of severe and potentially life-threatening toxicity following treatment with fluoropyrimidine-based chemotherapy agents such as and capecitabine.

Congenital DPD deficiency is a very rare disorder of pyrimidine metabolism. The severe form with complete or near-complete loss of enzyme activity is particularly uncommon.

Congenital DPD deficiency is caused by germline pathogenic variants in the DPYD gene. DPYD encodes DPD, the first and rate-limiting enzyme of pyrimidine catabolism, which reduces uracil and thymine to dihydrouracil and dihydrothymine. Biallelic loss-of-function variants cause deficient enzyme activity, leading to accumulation of uracil and thymine that can be detected biochemically as thymine-uraciluria. The degree of residual enzyme activity varies with the underlying variants; the clinical consequences of the resulting biochemical deficiency are variable and often absent.

Congenital DPD deficiency follows autosomal recessive inheritance and requires biallelic pathogenic variants in DPYD. For the siblings of an affected individual, the recurrence risk is 25%. Heterozygous carriers are not expected to develop the metabolic phenotype; however, they may have reduced DPD enzyme activity and can be at increased risk of severe toxicity following treatment with fluoropyrimidine drugs such as or capecitabine. Once the familial pathogenic variants have been identified, carrier testing of at-risk relatives and prenatal molecular testing are technically possible.

Biochemical assessment may show elevated urinary uracil and thymine (thymine-uraciluria) together with raised plasma uracil, and reduced DPD enzyme activity can be demonstrated in peripheral blood mononuclear cells. Molecular analysis identifying biallelic pathogenic DPYD variants confirms the hereditary metabolic diagnosis.

Main differential diagnoses include:

• Dihydropyrimidinase deficiency: a defect at the second step of pyrimidine catabolism with an overlapping paediatric neurological presentation, distinguished biochemically by accumulation of dihydropyrimidines rather than thymine and uracil; DPYS
• Beta-ureidopropionase deficiency: a defect at the third step of pyrimidine catabolism with an overlapping paediatric neurological phenotype, distinguished by elevated N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine; UPB1
• Hereditary orotic aciduria (UMP synthase deficiency): a defect of pyrimidine biosynthesis rather than catabolism, presenting with megaloblastic anaemia and developmental delay, distinguished by markedly elevated urinary orotic acid; UMPS

• Genetic testing supports establishing the diagnosis by identifying the underlying biallelic DPYD variants, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Malekkou A, Tomazou M, Mavrikiou G, Dionysiou M, Georgiou T, Papaevripidou I, et al. A novel large intragenic DPYD deletion causing dihydropyrimidine dehydrogenase deficiency: a case report. BMC Med Genomics. 2024;17(1):78. doi:10.1186/s12920-024-01846-2. PMID:; PMCID:PMC10962175.
• Au KM, Lai CK, Yuen YP, Shek CC, Lam CW, Chan AY. Diagnosis of dihydropyrimidine dehydrogenase deficiency in a neonate with thymine-uraciluria. Hong Kong Med J. 2003;9(2):130-2. PMID:.
• van Kuilenburg ABP, Meijer J, Meinsma R, Pérez-Dueñas B, Alders M, Bhuiyan ZA, et al. Dihydropyrimidine dehydrogenase deficiency: homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1. JIMD Rep. 2019;45:65-9. doi:10.1007/8904_2018_138. PMID:; PMCID:PMC6336675.