title: Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?
abstract: Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of pyrimidine metabolism that impairs the first step of uracil und thymine degradation. The spectrum of clinical presentations in subjects with the full biochemical phenotype of DPD deficiency ranges from asymptomatic individuals to severely affected patients suffering from seizures, microcephaly, muscular hypotonia, developmental delay and eye abnormalities.We report on a boy with intellectual disability, significant impairment of speech development, highly active epileptiform discharges on EEG, microcephaly and impaired gross-motor development. This clinical presentation triggered metabolic workup that demonstrated the biochemical phenotype of DPD deficiency, which was confirmed by enzymatic and molecular genetic studies. The patient proved to be homozygous for a novel c.2059-22T>G mutation which resulted in an in-frame insertion of 21 base pairs (c.2059-21_c.2059-1) of intron 16 of DPYD. Family investigation showed that the asymptomatic father was also homozygous for the same mutation and enzymatic and biochemical findings were similar to his severely affected son. When the child deteriorated clinically, exome sequencing was initiated under the hypothesis that DPD deficiency did not explain the phenotype completely. A deletion of the maternal allele on chromosome 15q11.2-13-1 was identified allowing the diagnosis of Angelman syndrome (AS). This diagnosis explains the patient's clinical presentation sufficiently; the influence of DPD deficiency on the phenotype, however, remains uncertain.
authors.affiliation: Department of Paediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Straße 2, 6900, Bregenz, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Fleger
authors.affiliation: Department of Paediatrics, Krankenhaus Dornbirn, Dornbirn, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Willomitzer
authors.affiliation: Departments of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Meinsma
authors.affiliation: Departments of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Alders
authors.affiliation: Departments of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Meijer
authors.affiliation: Departments of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: R C M
authors.initials: RCM
authors.lastname: Hennekam
authors.affiliation: Department of Paediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Straße 2, 6900, Bregenz, Austria. martina.huemer@lkhb.at.|Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. martina.huemer@lkhb.at.
authors.forename: M
authors.initials: M
authors.lastname: Huemer
authors.affiliation: Departments of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: A B P
authors.initials: ABP
authors.lastname: van Kuilenburg