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.
“M. Huemer” and “A. B. P. Kuilenburg” are contributed equally to this work.
This is a preview of subscription content, log in via an institution to check access.
References
Angelman H (1965) ‘Puppet’ children. A report of three cases. Dev Med Child Neurol 7:681–688
Bakker HD, Rubio Gozalbo ME, Van Gennip AH (1994) Dihydropyrimidine dehydrogenase deficiency presenting with psychomotor retardation and ocular abnormalities. J Inherit Metab Dis 17:640–641
Bakkeren JAJM, De Abreu RA, Sengers RCA, Gabreëls FJM, Maas JM, Reinier WO (1984) Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydropyrimidine dehydrogenase deficiency. Clin Chim Acta 140:247–256
Boyd SG, Harden A, Patton MA (1988) The EEG in early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr 147:508–513
Braakhekke JP, Renier WO, Gabreëls FJ, De Abreu RA, Bakkeren JA, Sengers RC (1987) Dihydropyrimidine dehydrogenase deficiency. Neurological aspects. J Neurol Sci 78:71–77
Buiting K, Williams C, Horsthemke B (2016) Angelman syndrome – insights into a rare neurogenetic disorder. Nat Rev Neurol 12:584–593
Enns GM, Barkovich AJ, van Kuilenburg ABP (2004) Head imaging abnormalities in dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis 27:513–522
Fiumara A, van Kuilenburg ABP, Caruso U et al (2003) Dihydropyrimidine dehydrogenase deficiency and acute neurological presentation. J Inherit Metab Dis 26:407–409
Van Gennip AH, van Bree-Blom EJ, Wadman SK, De Bree PK, Duran M, Beemer FA (1981) Liquid chromatography of urinary pyrimidines for the evaluation of primary and secondary abnormalities of pyrimidine metabolism. In: Hawk GL, Champlin PB, Hutton RF, Mol C (eds) Biological/biomedical applications of liquid chromatography III, Chromatographic sciences series, vol 18. Marcel Dekker, New York and Basel, pp 285–296
Van Gennip AH, Abeling NGGM, Stroomer AEM, van Lenthe H, Bakker HD (1994) Clinical and biochemical findings in six patients with pyrimidine degradation defects. J Inherit Metab Dis 17:130–132
van Kuilenburg ABP, Vreken P, Abeling NGGM et al (1999) Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 104:1–9
van Kuilenburg ABP, Haasjes J, Richel DJ et al (2000a) Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 6:4705–4712
van Kuilenburg ABP, van Lenthe H, Tromp A, Veltman PCJ, van Gennip AH (2000b) Pitfalls in the diagnosis of patients with a partial dihydropyrimidine dehydrogenase deficiency. Clin Chem 46:9–17
van Kuilenburg ABP, Meinsma R, Zoetekouw L, Van Gennip AH (2002) Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation. Int J Cancer 101:253–258
van Kuilenburg ABP, Stroomer AEM, van Lenthe H, Abeling NGGM, van Gennip AH (2004a) New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid? Biochem J 379:119–124
van Kuilenburg ABP, Meinsma R, Beke E et al (2004b) Beta-ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities. Hum Mol Genet 13:2793–2801
van Kuilenburg ABP, Stroomer AEM, Abeling NGGM, van Gennip AH (2006) A pivotal role for beta-aminoisobutyric acid and oxidative stress in dihydropyrimidine dehydrogenase deficiency? Nucleosides Nucleotides Nucleic Acids 25:1103–1106
van Lenthe H, van Kuilenburg ABP, Ito T et al (2000) Defects in pyrimidine degradation identified by HPLC-electrospray tandem mass spectrometry of urine specimens or urine-soaked filter paper strips. Clin Chem 46:1916–1922
Yau EK, Shek CC, Chan KY, Chan AY (2004) Dihydropyrimidine dehydrogenase deficiency: a baby boy with ocular abnormalities, neonatal seizure and global developmental delay. HK J Paediatr 9:167–170
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Verena Peters
Compliance with Ethical Guidelines
Compliance with Ethical Guidelines
All procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000.
Conflict of Interest
M. Fleger, J. Willomitzer, R. Meinsma, M. Alders, J. Meijer, R. C. M. Hennekam, A. B. P. van Kuilenburg and M. Huemer declare that they have no relevant conflict of interest.
Details of the Contributions of Individual Authors
M. Fleger, M. Huemer and A. B. P. van Kuilenburg designed the research and drafted the manuscript. R. Meinsma, M. Alders, J. Meijer and R. C. M. Hennekam performed the experiments and critically revised the manuscript. J. Willomitzer provided clinical data and revised the manuscript.
Rights and permissions
Copyright information
© 2017 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Fleger, M. et al. (2017). Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 37. JIMD Reports, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_14
Download citation
DOI: https://doi.org/10.1007/8904_2017_14
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-56358-8
Online ISBN: 978-3-662-56359-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)