Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency

A. B P Van Kuilenburg, P. Vreken, N. G G M Abeling, H. D. Bakker, R. Meinsma, H. Van Lenthe, R. A. De Abreu, J. A M Smeitink, H. Kayserili, M. Y. Apak, E. Christensen, I. Holopainen, K. Pulkki, D. Riva, G. Botteon, E. Holme, M. Tulinius, W. J. Kleijer, F. A. Beemer, M. DuranK. E. Niezen-Koning, G. P A Smit, C. Jakobs, L. M E Smit, U. Moog, L. J M Spaapen, A. H. Van Gennip

Research output: Contribution to journalArticle

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G→A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered β-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalHuman Genetics
Volume104
Issue number1
Publication statusPublished - 1999

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Dihydropyrimidine Dehydrogenase Deficiency
Genotype
Phenotype
Mutation
Thymine
Dihydrouracil Dehydrogenase (NADP)
RNA Splice Sites
Uracil
Genetic Association Studies
Missense Mutation
Point Mutation
Intellectual Disability
Alanine
Homeostasis

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Van Kuilenburg, A. B. P., Vreken, P., Abeling, N. G. G. M., Bakker, H. D., Meinsma, R., Van Lenthe, H., ... Van Gennip, A. H. (1999). Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Human Genetics, 104(1), 1-9.

Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. / Van Kuilenburg, A. B P; Vreken, P.; Abeling, N. G G M; Bakker, H. D.; Meinsma, R.; Van Lenthe, H.; De Abreu, R. A.; Smeitink, J. A M; Kayserili, H.; Apak, M. Y.; Christensen, E.; Holopainen, I.; Pulkki, K.; Riva, D.; Botteon, G.; Holme, E.; Tulinius, M.; Kleijer, W. J.; Beemer, F. A.; Duran, M.; Niezen-Koning, K. E.; Smit, G. P A; Jakobs, C.; Smit, L. M E; Moog, U.; Spaapen, L. J M; Van Gennip, A. H.

In: Human Genetics, Vol. 104, No. 1, 1999, p. 1-9.

Research output: Contribution to journalArticle

Van Kuilenburg, ABP, Vreken, P, Abeling, NGGM, Bakker, HD, Meinsma, R, Van Lenthe, H, De Abreu, RA, Smeitink, JAM, Kayserili, H, Apak, MY, Christensen, E, Holopainen, I, Pulkki, K, Riva, D, Botteon, G, Holme, E, Tulinius, M, Kleijer, WJ, Beemer, FA, Duran, M, Niezen-Koning, KE, Smit, GPA, Jakobs, C, Smit, LME, Moog, U, Spaapen, LJM & Van Gennip, AH 1999, 'Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency', Human Genetics, vol. 104, no. 1, pp. 1-9.
Van Kuilenburg ABP, Vreken P, Abeling NGGM, Bakker HD, Meinsma R, Van Lenthe H et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Human Genetics. 1999;104(1):1-9.
Van Kuilenburg, A. B P ; Vreken, P. ; Abeling, N. G G M ; Bakker, H. D. ; Meinsma, R. ; Van Lenthe, H. ; De Abreu, R. A. ; Smeitink, J. A M ; Kayserili, H. ; Apak, M. Y. ; Christensen, E. ; Holopainen, I. ; Pulkki, K. ; Riva, D. ; Botteon, G. ; Holme, E. ; Tulinius, M. ; Kleijer, W. J. ; Beemer, F. A. ; Duran, M. ; Niezen-Koning, K. E. ; Smit, G. P A ; Jakobs, C. ; Smit, L. M E ; Moog, U. ; Spaapen, L. J M ; Van Gennip, A. H. / Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. In: Human Genetics. 1999 ; Vol. 104, No. 1. pp. 1-9.
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AU - Van Kuilenburg, A. B P

AU - Vreken, P.

AU - Abeling, N. G G M

AU - Bakker, H. D.

AU - Meinsma, R.

AU - Van Lenthe, H.

AU - De Abreu, R. A.

AU - Smeitink, J. A M

AU - Kayserili, H.

AU - Apak, M. Y.

AU - Christensen, E.

AU - Holopainen, I.

AU - Pulkki, K.

AU - Riva, D.

AU - Botteon, G.

AU - Holme, E.

AU - Tulinius, M.

AU - Kleijer, W. J.

AU - Beemer, F. A.

AU - Duran, M.

AU - Niezen-Koning, K. E.

AU - Smit, G. P A

AU - Jakobs, C.

AU - Smit, L. M E

AU - Moog, U.

AU - Spaapen, L. J M

AU - Van Gennip, A. H.

PY - 1999

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N2 - Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G→A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered β-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

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