Dihydropyrimidine Dehydrogenase Deficiency Found in Boy Later Diagnosed with Angelman, Case Study Reports

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Angelman syndrome can occur alongside a condition called dihydropyrimidine dehydrogenase (DPD) deficiency, which has varying degrees of severity and elusive disease mechanisms, a case report suggests. A connection between the two disorders, however, was not established and may be coincidence.

The study, “Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?” was published in JIMD Reports.

DPD deficiency is a disorder caused by a genetic mutation in the DPYD gene, which provides the instructions for the production of an enzyme called dihydropyrimidine dehydrogenase. This enzyme is involved in the breakdown of two types of pyrimidines — a type of nucleotide, the building blocks of DNA and RNA in cells — called uracil and thymine.

The disorder can manifest in different ways, ranging from individuals with no symptoms at all to severely affected patients experiencing seizures, microcephaly (smaller-than-normal head circumference), muscular hypotonia (lack of muscle strength), developmental delay, and eye abnormalities.

In this case report, researchers described the clinical case of a boy with microcephaly, intellectual disability, and impaired motor and speech development. After performing an extensive metabolic workup, they found excessive levels of uracil and thymine, a biochemical hallmark of DPD deficiency, which was then confirmed by subsequent enzymatic and molecular genetic studies.

Further analyses revealed the patient was carrying a novel mutation causing the insertion of a DNA fragment in a sequence of the DPYD gene. Family analysis showed the boy’s father, who did not have any symptoms, was also carrying the same DPYD mutation, which was confirmed by enzymatic and biochemical test results identical to those of his son.

When the child’s clinical state began to deteriorate, researchers decided to perform genetic sequencing to fully decode all protein-producing genes in the boy’s genome, under the assumption that DPD deficiency could not explain the number and severity of symptoms displayed by the child.

Sequencing data revealed the boy suffered from a deletion of a maternal allele (one of the two copies of a gene) located on chromosome 15q11.2-13-1. This confirmed a diagnosis of Angelman syndrome. Although this diagnosis  was able to explain the number and severity of symptoms experienced by the boy, the impact of DPD deficiency on the child’s clinical state remained unclear.

“This broad spectrum [of symptoms] indicates [multiple degrees of severity] of DPD deficiency. Additional factors such as other metabolites in pyrimidine catabolism, and oxidative stress or febrile infections as triggers may be involved in the development of the clinical phenotype [symptoms presented] and may even lead to sudden, eventually devastating neurologic disease in formerly asymptomatic individuals,” the authors wrote.

“We conclude that more investigations are necessary to elucidate possible pathogenic mechanisms behind the variable [symptoms] of DPD. We recommend thorough diagnostic workup of patients with the DPD biochemical phenotype beyond DPD in case the clinical course is suggestive of another disease or not consistent with clinical observations in DPD deficiency,” they said.