Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patient s and has been associated with a variable clinical phenotype. In order to u nderstand the genetic and phenotypic basis for DPD deficiency, we have revi ewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, includ ing 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1 G>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 tha t 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 obs erved. A large phenotypic variability has been observed, with convulsive di sorders, motor retardation and mental retardation being the most abundant m anifestations. A clear correlation between the genotype and phenotype has n ot been established. An altered beta-alanine, uracil and thymine homeostasi s might underlie the various clinical abnormalities encountered in patients with DPD deficiency.