Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

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.

Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase <em>(DPYD)</em> gene

“…Other DPYD variants affecting donor splicing sites have also demonstrated skipping of the corresponding exon 12 , 14 or generation of an in-frame insertion of small fragments causing severe and occasionally fatal adverse reactions to fluoropyrimidine. 15 …”

A Robust Bayesian Approach to Bulk Gene Expression Deconvolution with Noisy Reference Signatures

“…Dihydropyridine dehydrogenase (DPD) deficiency is caused by deleterious germline variants within the DPYD gene and typically presents as a pharmacogenomic condition, in which patients are at significantly higher risk of severe adverse events when treated with the commonly used chemotherapeutic 5-fluorouracil (5-FU) (23). DPD deficiency has also been linked to rare inborn error of metabolism that is accompanied by neurological disorders of varying degrees of severity in children (24,25). The penetrance of the pediatric condition within individuals with DPD deficiency is very low.…”

The Evaluation of Dihydropyrimidine Dehydrogenase Enzyme Level in the Serum of Colorectal Cancer Iraqi Males on Fluoropyrimidine-Based Chemotherapy (Capecitabine)

“…The deficit of DPD is inherited in an autosomal recessive manner [ 16 ]. Individuals who possess two copies of mutant alleles are classified as homozygous for DPD deficiency [ 17 ].…”