Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings

Abstract

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).

Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1

“…The phenotype in the patient, i.e., cognitive impairment, language delay, and seizures, is similar to the phenotype typically observed in clinically affected patients with DPD deficiency (van Kuilenburg et al 1999(van Kuilenburg et al , 2002a(van Kuilenburg et al , 2009. The MRI findings in the present patient are nonspecific and have been reported infrequently in DPDdeficient patients (Chen et al 2014;Enns et al 2004). Chromosome 1 is not known to contain imprinted areas or imprinted genes, so UPD of chromosome 1 is not expected to cause a phenotype by a disturbed methylation.…”

“…Therefore, a DPD deficiency is probably a necessary, but not a sole prerequisite for the onset of a clinical phenotype (Fleger et al 2017;van Kuilenburg et al 1999). Delayed cognitive and motor development and convulsive disorders are relatively frequent manifestations, whereas growth retardation, microcephaly, dysmorphia, autism, hypotonia, and ocular abnormalities are less frequently observed (Chen et al 2014;Enns et al 2004;van Kuilenburg et al 1999van Kuilenburg et al , 2002avan Kuilenburg et al , 2009. In addition, patients with a DPD deficiency have a strongly reduced capacity to degrade the widely used chemotherapeutic drug 5-fluorouracil and, therefore, an increased likelihood of suffering from severe and sometimes fatal multi-organ toxicity (Johnson and Diasio 2001;van Kuilenburg 2004).…”

Novel two-step derivation method for the synchronous analysis of inherited metabolic disorders using urine

“…There are three defects associated with pyrimidines, namely dihydropyrimidine dehydrogenase, dihydropyrimidinase and 3-ureidopropionase deficiencies (42,43). There are numerous purine-associated disorders, including orotic aciduria (44,45).…”

Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G>A and a large intragenic inversion in DPYD spanning intron 8 to intron 12

“…Cognitive impairment is one of the most frequently encountered clinical presentations of DPD‐deficient patients, but both mother and daughter in this family were of normal intelligence with college educations (van Kuilenburg et al., ). Brain malformations on neuroimaging have only occasionally been reported in DPD‐deficient patients (Brussel, van Kuilenburg, & Janssens, ; Chen et al., ; Enns et al., ). Delayed myelination is not a malformation and overall an unspecific feature.…”