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Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1

  • André B. P. van KuilenburgEmail author
  • Judith Meijer
  • Rutger Meinsma
  • Belén Pérez-Dueñas
  • Marielle Alders
  • Zahurul A. Bhuiyan
  • Rafael Artuch
  • Raoul C. M. Hennekam
Research Report
Part of the JIMD Reports book series (JIMD, volume 45)

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.

Keywords

Dihydropyrimidine dehydrogenase DPYD Pyrimidines Uniparental isodisomy 

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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • André B. P. van Kuilenburg
    • 1
    Email author
  • Judith Meijer
    • 1
  • Rutger Meinsma
    • 1
  • Belén Pérez-Dueñas
    • 2
    • 3
  • Marielle Alders
    • 1
  • Zahurul A. Bhuiyan
    • 4
  • Rafael Artuch
    • 2
  • Raoul C. M. Hennekam
    • 1
  1. 1.Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry, Genetics and Pediatrics, Amsterdam Gastroenterology & MetabolismAmsterdamThe Netherlands
  2. 2.Departments of Neuropediatrics and Clinical BiochemistryInstitut de Recerca Sant Joan de Déu, CIBERER-ISCIIIBarcelonaSpain
  3. 3.Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de BarcelonaBarcelonaSpain
  4. 4.Service de Médecine Génétique, Laboratoires de Médecine GénétiqueCentre Hospitalier Universitaire VaudoisLausanneSwitzerland

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