Dihydropyrimidine Dehydrogenase Deficiency

A number sign (#) is used with this entry because dihydropyrimidine dehydrogenase (DPD) deficiency is caused by homozygous or compound heterozygous mutation in the DPYD gene (612779) on chromosome 1p21.

Description

Dihyropyrimidine dehydrogenase deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation in homozygous patients. In addition, homozygous and heterozygous mutation carriers can develop severe toxicity after the administration of the antineoplastic drug 5-fluorouracil (5FU), which is also catabolized by the DPYD enzyme. This is an example of a pharmacogenetic disorder (Van Kuilenburg et al., 1999).

Since there is no correlation between genotype and phenotype in DPD deficiency, it appears that the deficiency is a necessary, but not sufficient, prerequisite for the development of clinical abnormalities (Van Kuilenburg et al., 1999; Enns et al., 2004).

Clinical Features

Berger et al. (1984) presented findings in 3 unrelated patients (2 boys and 1 girl) with a nonspecific clinical picture of cerebral dysfunction and persistent urinary excretion of excessive amounts of uracil, thymine, and 5-hydroxymethyluracil. The excretory pattern suggested deficiency of DPD. The parents of 1 patient were first cousins, suggesting autosomal recessive inheritance.

Wadman et al. (1984) postulated deficiency of DPD as the cause of the thymine-uraciluria they observed in a child with autism.

Brockstedt et al. (1990) commented that 7 of the 8 previously reported pediatric patients were Dutch. They reported a ninth pediatric patient who had developmental retardation, epilepsy, and muscular hypertonia.

Van Gennip et al. (1994) described a Dutch patient with a severe form of DPD deficiency. At age 25 months, the patient had bilateral microphthalmia, coloboma of the iris and choroid, nystagmus, and gradually increasing psychomotor retardation.

Vreken et al. (1997) reported a child with DPD deficiency who showed febrile convulsions, severe neuromotor retardation, and spastic tetraplegia at age 9 months. Cerebral MRI showed ventriculomegaly with white matter hypodensity. At the age of 6 years, thymine-uraciluria was noted and DPD deficiency was demonstrated in fibroblasts. An earlier-born child had died before her first birthday with severe neuromotor retardation and febrile convulsions. Genetic analysis identified a homozygous truncating mutation in the DPYD gene (611779.0005).

Enns et al. (2004) reported a 17-month-old girl, born to consanguineous Pakistani parents, who had a history of failure to thrive, developmental delay, and encephalopathy with prolonged hypoventilation. Other features included microcephaly, strabismus, nystagmus, hypotonia, and mild hepatomegaly. Brain MRI showed prominent sulci and abnormal signals in the cerebral white matter and brainstem. Urinary profile showed increased uracil and thymine consistent with DPD deficiency. She developed seizures at age 22 months, and died at age 31 months of recurrent aspiration pneumonia.

5-Fluorouracil Toxicity

Tuchman et al. (1985) described a 27-year-old woman who had an unusually severe reaction to 5-FU given in limited dosage on a weekly schedule. Symptoms included stomatitis, leukopenia, thrombocytopenia, hair loss, diarrhea, fever, marked weight loss, cerebellar ataxia, and neurologic symptoms, progressing to semicoma. High levels of uracil and thymine were found in the urine of the patient and of 1 brother; both had very high plasma and urinary concentrations of pyrimidine bases. Serum levels and urinary excretion of uric acid were normal in all members of the family, and the patient's white cell thymidine kinase (TK; 188300) was normal. The mother's urine showed a small amount of uracil but no thymine. A second brother and a sister showed none of the abnormalities. The authors suggested that the defect may be in dihydropyrimidine dehydrogenase, which is involved in pyrimidine base degradation. The defect would not be expected to be apparent clinically unless the subject was given a pyrimidine-base analog.

Diasio et al. (1988) reported a previously healthy 40-year-old woman who suffered severe neurotoxicity due to 5-fluorouracil given for breast cancer. After administration of a 'test' dose of 5-fluorouracil, the patient showed a markedly prolonged elimination half-life (159 min), with no evidence of catabolites of the drug in plasma or cerebrospinal fluid, and 89.7% of the administered dose was excreted into the urine as unchanged drug. Partial deficiency of the enzyme was found also in the patient's father; the mother was deceased. The enzyme was assayed in peripheral blood mononuclear cells.

In an adult patient with asymptomatic DPD deficiency from a family studied by (Sumi et al., 1996), Hayashi et al. (1996) demonstrated metabolic changes predicting a risk of severe 5-fluorouracil toxicity. On restudy of the family of this patient, a sister of the proband was found to excrete large amounts of dihydrouracil and dihydrothymine. The parents and the child of the propositus showed slight increases of dihydrouracil and dihydrothymine. This was the first reported instance of a family with 2 cases of DPD deficiency. A uracil loading test performed on the parents showed increased urinary dihydrouracil concentrations consistent with heterozygosity. Hayashi et al. (1996) noted that individuals with decreased DPYD activity may show increased adverse effects of 5FU treatment.

Of 53 cases of DPD deficiency associated with 5FU-related toxicity reviewed by Milano et al. (1999), 19 cases had moderate or marked DPD deficiency, with less than 70% of the mean population value. More of the cases occurred in women (15 of 19), which was in accord with several previous reports (e.g., Milano et al., 1992). The toxicity score was significantly higher in patients with markedly low DPD activity. Neurotoxicity was the predominant manifestation; cardiotoxicity was observed in only 1 case. None of the reported cases had complete DPD deficiency, even in the 2 patients that died.

Biochemical Features

Berglund et al. (1979) observed urinary excretion of thymine and uracil in a child with medulloblastoma. The activity of DPYD in patient fibroblasts was somewhat lower than in controls. The tumor was considered to be the likely cause of the increased excretion of pyrimidines, but an impaired degradation of pyrimidines in the liver could not be ruled out.

Bakkeren et al. (1984) found increased urinary levels of uracil and thymine in a child with unexplained convulsions. Quantitation of the urinary excretion by means of a sensitive high-performance liquid chromatographic (HPLC) method revealed a 1000-fold elevation compared to normal. Serum and cerebrospinal fluid levels of the 2 pyrimidine bases were about a hundred times higher than normal. Patient fibroblasts showed a complete deficiency of dihydrothymine dehydrogenase activity. Bakkeren et al. (1984) stated that this was the first case described with such a proven enzyme deficiency.

Vreken et al. (1997) stated that about 50% of patients with a nearly complete enzyme defect show convulsive disorders, whereas those experiencing acute 5-fluorouracil toxicity usually show DPD enzymatic activities in the heterozygous range.

Van Kuilenburg et al. (1999) suggested that altered homeostasis of uracil, thymine, and beta-alanine may underlie the various clinical abnormalities in DPD deficiency. Beta-alanine is a structural analog of gamma-aminobutyric acid (GABA) and glycine, which are major inhibitory neurotransmitters in the central nervous system.

Inheritance

Diasio et al. (1988) established autosomal recessive inheritance by describing consanguinity in the parents of a homozygote and partial deficiency of DPD in both of her children. The proband, a previously completely healthy 40-year-old woman, suffered severe neurotoxicity due to 5-fluorouracil given for breast cancer.

Sumi et al. (1998) concluded that dihydropyrimidinuria is an autosomal recessive condition, and suggested that homozygotes may have a high risk of 5FU toxicity, while the risk may be lower in heterozygotes.

Molecular Genetics

In a Dutch patient with dihydropyrimidine dehydrogenase deficiency reported by Van Gennip et al. (1994), Meinsma et al. (1995) identified a homozygous truncating mutation in the DPYD gene (IVS14+1G-A; 612779.0001). Both unaffected parents and 1 unaffected sib were heterozygous for the mutation.

Vreken et al. (1997) found a 4-bp deletion in the DPYD gene (612779.0003) in affected members of a Dutch consanguineous family with DPD deficiency.

Among a group of 22 patients from 17 families with complete DPD deficiency, Van Kuilenburg et al. (1999) identified 7 different mutations in the DPYD gene. The most common mutation by far, accounting for 52% of mutant alleles, was the splice site mutation IVS14+1G-A. There were no genotype/phenotype correlations.

Van Kuilenburg et al. (2009) identified intragenic deletions of the DPYD gene in 4 patients with severe DPD deficiency in whom no point mutations were found. Three patients had a homozygous 13.8-kb deletion of exon 12, and 1 had a homozygous 122-kb deletion of exons 14 through 16 of the DPYD gene. All of these patients were born of consanguineous parents. A fifth patient was compound heterozygous for a 4-bp deletion (612779.0003) in the DPYD gene and a de novo 14-Mb deletion of chromosome 1p21.3-p13.3, including DPYD and several other genes, which likely contributed to severe psychomotor retardation and unusual craniofacial features in this patient. Overall, the study found genomic deletions affecting the DPYD gene in 7% (5 of 72) of DPD-deficient patients. These patients had a severe form of the disorder, with psychomotor retardation, epilepsy, hypotonia, and dysmorphic features, suggesting that gross deletions have a particularly detrimental effect.

Population Genetics

Sumi et al. (1998) identified asymptomatic dihydropyrimidinuria in 2 of 21,200 healthy Japanese urine samples, yielding a prevalence of approximately 1 in 10,000 births.