DPYS – Dihydropyrimidinuria

Dihydropyrimidinase deficiency is a rare autosomal recessive disorder of pyrimidine degradation caused by biallelic variants in the DPYS gene. Patients have markedly elevated dihydrouracil and dihydrothymine in urine, blood, and cerebrospinal fluid, and only ~30 cases have been reported to date (PMID:30384990). The clinical spectrum ranges from asymptomatic biochemically positive individuals to severe neurological and gastrointestinal involvement.

Genetic studies describe at least 31 unrelated probands: six individuals in the initial cohort (PMID:9718352), 17 newly identified patients (PMID:20362666), and eight additional case reports (PMID:30384990; PMID:38958169; PMID:38199782; PMID:29054612). Segregation analysis demonstrated homozygosity for p.Gln334Arg in two affected siblings, confirming autosomal recessive inheritance (PMID:9718352).

The DPYS variant spectrum comprises >20 missense mutations, multiple nonsense and frameshift alleles, a splice-site change (c.1443+5G>A), and small deletions. Recurrent alleles include p.Gln334Arg in Japanese subjects and p.Arg490His in East Asian cohorts (PMID:9718352; PMID:29054612). An exemplar pathogenic change is c.1469G>A (p.Arg490His).

Clinically, patients present with seizures (HP:0001250), global developmental delay (HP:0001263), dysmorphic facial features (HP:0001999), and occasional congenital heart defects; asymptomatic individuals underscore the variable expressivity. Estimated prevalence is ~1/10 000 (PMID:30384990).

Functional assays—including heterologous expression in Escherichia coli and HEK293 minigene splicing—show that most DPYS variants abolish enzyme activity (PMID:28642038; PMID:26771602). Structural modelling of human DHP confirms disruption of the di-zinc catalytic core for key mutations (PMID:20362666).

Overall, genetic and experimental evidence support a loss-of-function mechanism underlying autosomal recessive Dihydropyrimidinuria. Urinary pyrimidine analysis combined with DPYS genotyping enables definitive diagnosis and guides fluoropyrimidine dosing to avoid severe 5-FU toxicity.

Key Take-home: DPYS variant and metabolite screening facilitate accurate diagnosis of dihydropyrimidinuria and inform safe use of 5-fluorouracil.

References

• American journal of human genetics • 1998 • Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene. PMID:9718352
• Biochimica et biophysica acta • 2010 • Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. PMID:20362666
• Brain & development • 2019 • A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. PMID:30384990
• Journal of pediatric endocrinology & metabolism • 2024 • Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report. PMID:38958169
• Cold Spring Harbor molecular case studies • 2023 • The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature. PMID:38199782
• Molecular genetics and metabolism • 2017 • Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity. PMID:29054612
• International journal of molecular sciences • 2016 • Altered Pre-mRNA Splicing Caused by a Novel Intronic Mutation c.1443+5G>A in the Dihydropyrimidinase (DPYS) Gene. PMID:26771602
• Biochemical pharmacology • 2017 • Functional characterization of 21 allelic variants of dihydropyrimidinase. PMID:28642038

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