Dihydropyrimidinase Deficiency

A number sign (#) is used with this entry because of evidence that dihydropyrimidinase deficiency is caused by homozygous or compound heterozygous mutation in the DPYS gene (613326) on chromosome 8q22.

Description

DPYS deficiency is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017).

See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder.

Clinical Features

Duran et al. (1991) reported a Turkish male infant, the fifth child of a consanguineous couple, who was thought to have dihydropyrimidinase deficiency. The infant was well until the age of 8 weeks when he developed feeding problems following the introduction of fruits to his formula milk. He was admitted to a hospital following a convulsion and lowered consciousness associated with metabolic acidosis. At the age of 19 months, his physical and mental development appeared to be normal. The presence of dihydrouracil and dihydrothymine in bodily fluids suggested the diagnosis.

Van Gennip et al. (1997) reported an infant girl, born of consanguineous Lebanese parents, who presented at birth with low anal atresia, club foot and hip dysplasia on the right side, hypoplastic terminal phalanges and nails of fingers and toes, plagiocephaly, and facial dysmorphism. Psychomotor delay was evident by the age of 3 months. Neurologic examination showed severe retardation, convulsions, extrapyramidal dyskinesia, and pyramidal signs. Biochemical studies showed increased urinary dihydrouracil, dihydrothymine, uracil, and thymine, consistent with DPYS deficiency. The authors provided the first direct evidence at the enzyme level for deficient activity of DHP in this patient's liver.

According to van Gennip et al. (1997), 4 cases of dihydropyrimidinuria had been reported. The patients showed a variable clinical phenotype comprising seizures (3 of 4 patients), mental retardation (2 patients), growth retardation (1 patient), and dysmorphic features (1 patient). All patients excreted large amounts of dihydrouracil and dihydrothymine and moderate amounts of uracil and thymine in their urine.

Assmann et al. (1997) described a boy, born of consanguineous Turkish parents, who suffered from intractable diarrhea due to congenital microvillus atrophy (251850). He developed severe cholestasis starting at 2 weeks of age and leading to liver cirrhosis. He died of septicemia at the age of 7 months. Marked elevations of dihydrouracil and dihydrothymine, as well as markedly elevated excretion of uracil and thymine in urine, were repeatedly demonstrated, suggesting a disorder of pyrimidine degradation. An enzymatic defect of 5,6-dihydropyrimidine amidohydrolase was demonstrated in liver biopsy. Assmann et al. (1997) raised the question of whether this was 1 disorder or 2 independent recessive disorders and whether this might represent a hitherto undescribed contiguous gene syndrome.

Hamajima et al. (1998) stated that 9 cases of dihydropyrimidinuria had been reported.

Van Kuilenburg et al. (2007) reported 2 brothers, born of nonconsanguineous Moroccan parents, with DPYS deficiency. The older brother presented at age 4 years with a severe delay in speech development, but normal motor development. IQ was 93. Brain MRI showed slight widening of the lateral ventricles and thinning of the parietooccipital white matter. His brother had normal psychomotor development and an IQ of 83. Both had mildly increased urinary uracil and thymine, and strongly increased dihydrouracil and dihydrothymine. Van Kuilenburg et al. (2007) suggested that altered homeostasis of uracil, thymine, beta-alanine and beta-aminoisobutyric acid may underlie the various clinical abnormalities reported in DPYS deficiency. Beta-alanine is a structural analog of gamma-aminobutyric acid (GABA) and glycine, which are major inhibitory neurotransmitters in the central nervous system. However, additional factors besides DPYS deficiency are likely necessary for the onset of a clinical phenotype.

Nakajima et al. (2017) described 4 unrelated dihydropyrimidinase-deficient patients, 1 Chinese and 3 Japanese, who presented with highly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in urine and variable clinical presentations ranging from asymptomatic to infantile spasms with reduced white matter and brain atrophy. Nakajima et al. (2017) stated that 31 genetically confirmed patients with DPYS deficiency had been reported.

Molecular Genetics

In 1 symptomatic and 5 asymptomatic persons presenting with dihydropyrimidinuria due to DPYS deficiency, Hamajima et al. (1998) identified 1 frameshift mutation and 5 missense mutations in the DPYS gene (see, e.g., 613326.0001-613326.0003). Two unaffected Japanese adult sibs, who were identified by a screening program, were homozygous for a missense mutation (Q334R; 613326.0001). Two other unrelated asymptomatic Japanese infants were heterozygous for the same mutation, but this mutation was not common in the Japanese. The only symptomatic patient was a Lebanese girl with dysmorphic features, developmental delay and seizures (van Gennip et al., 1997) who was homozygous for a missense mutation (W360R; 613326.0003). All patients had the characteristic biochemical findings of increased uracil, dihydrouracil, thymine, and dihydrothymine in bodily fluids.

In 2 Moroccan brothers with DPYS deficiency, van Kuilenburg et al. (2007) identified compound heterozygosity for 2 mutations in the DPYS gene (W360R, 613326.0003 and R412M, 613326.0004). In vitro functional expression studies in E. coli showed no enzymatic activity for either mutation, although the mutant proteins were expressed. Structural analysis suggested that the W360R mutation would impair assembly of the tetramer, and that the R412M mutation would affect hydrogen bonding, resulting in destabilization.

Nakajima et al. (2017) identified compound heterozygous mutations in the DPYS gene, including 4 novel missense variants and 1 novel deletion, in 4 unrelated patients with DPYS deficiency.