Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).

Keywords:
Dihydropyrimidine dehydrogenase deficiency, MRI abnormality, Protein folding
1.
Bakkeren JA, De Abreu RA, Sengers RC, Gabreëls FJ, Maas JM, Renier WO: Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta 140:247-256 (1984).
2.
Braakhekke JP, Renier WO, Gabreëls FJ, De Abreu RA, Bakkeren JA, Sengers RC: Dihydropyrimidine dehydrogenase deficiency. Neurological aspects. J Neurol Sci 78:71-77 (1987).
3.
Chen BC, Thong MK, Yunus Z: Biochemical profiling of inborn errors of purine and pyrimidine metabolism by high performance liquid chromatography - a strategy to improve childhood mortality and morbidity in Malaysian children. Hamdan Medical Journal 5:363-371 (2012).
4.
Enns GM, Barkovich AJ, van Kuilenburg AB, Manning M, Sanger T, et al: Head imaging abnormalities in dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis 27:513-522 (2004).
5.
Fiumara A, van Kuilenburg AB, Caruso U, Nucifora C, Marzullo E, et al: Dihydropyrimidine dehydrogenase deficiency and acute neurological presentation. J Inherit Metab Dis 26:407-409 (2003).
6.
Krokan HE, Drabløs F, Slupphaug G: Uracil in DNA - occurrence, consequences and repair. Oncogene 21:8935-8948 (2002).
7.
Raida M, Schwabe W, Häusler P, van Kuilenburg AB, van Gennip AH, et al: Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil - related toxicity compared with controls. Clin Cancer Res 7:2832-2839 (2001).
8.
Sweetman L: Organic acid analysis, in Hommes FA (ed): Techniques in Diagnostic Human Biochemical Genetics, pp 143-176 (Wiley-Liss, New York 1991).
9.
van Gennip AH, van Bree-Blom EJ, Wadman SK, Bree PK, Duran M, Beemer FA: Liquid chromatography of urinary pyrimidine for the evaluation of primary and secondary abnormalities of pyrimidine metabolism, in Hawk GL, Champlin PB, Hutton RF, Mol C (eds): Biological/Biomedical Application of Liquid Chromatography III. Chromatographic Science Series, pp 285-296 (Dekker, New York 1981).
10.
van Gennip AH, Abeling NG, Stroomer AE, van Lenthe H, Bakker HD: Clinical and biochemical findings in six patients with pyrimidine degradation defects. J Inherit Metab Dis 17:130-132 (1994).
11.
van Gennip AH, Abeling NG, Vreken P, van Kuilenburg AB: Inborn errors of pyrimidine degradation: clinical, biochemical and molecular aspects. J Inherit Metab Dis 20:203-213 (1997).
12.
van Kuilenburg AB, Vreken P, Abeling NG, Bakker HD, Meinsma R, et al: Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 104:1-9 (1999).
13.
van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, van Lenthe H, et al: 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 (2000).
14.
van Kuilenburg AB, Meinsma R, Beke E, Bobba B, Boffi P, et al: Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function. Biol Chem 386:319-324 (2005).
15.
van Kuilenburg AB, Stroomer AE, Abeling NG, van Gennip AH: A pivotal role for beta-aminoisobutyric acid and oxidative stress in dihydropyrimidine dehydrogenase deficiency? Nucleosides Nucleotides Nucleic Acids 25:1103-1106 (2006).
16.
van Kuilenburg AB, Meijer J, Mul AN, Hennekam RC, Hoovers JM, et al: Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3-21.3). Hum Genet 125:581-590 (2009).
17.
van Kuilenburg AB, Dobritzsch D, Meijer J, Krumpel M, Selim LA, et al: β-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients. Biochim Biophys Acta 1822:1096-1108 (2012).
18.
van Lenthe H, van Kuilenburg AB, Ito T, Bootsma AH, van Cruchten A, et al: 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 (2000).
19.
Webster DR, Becroft DO, van Gennip AH, van Kuilenberg AB: Hereditary orotic aciduria and other disorders of pyrimidine metabolism, in Scriver CR, Beaudet AL, Sly WS, et al. (eds): The Metabolic and Molecular Bases of Inherited Diseases, ed 8, pp 2663-2702 (McGraw-Hill, New York 2001).
20.
Wei X, Elizondo G, Sapone A, McLeod HL, Raunio H, et al: Characterization of the human dihydropyrimidine dehydrogenase gene. Genomics 51:391-400 (1998).
21.
Yau EK, Shek CC, Chan KY, Chan AY: Dihydropyrimidine dehydrogenase deficiency: a baby boy with ocular abnormalities, neonatal seizure and global developmental delay. HK J Paediatr 9:167-170 (2004).
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2014
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