Diagnosis of dihydropyrimidine dehydrogenase deficiency in a neonate with thymine-uraciluria

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Dihydropyrimidine dehydrogenase (DPD) deficiency is an inherited metabolic disorder affecting pyrimidine breakdown.
• It is characterized by thymine-uraciluria, neurological issues in children, and severe toxicity from 5-fluorouracil chemotherapy.
• This condition poses a significant clinical challenge due to its variable presentation and treatment implications.

Observation:

• A 2-day-old male neonate of Pakistani origin presented with convulsions, prompting investigation.
• The patient was diagnosed with DPD deficiency in Hong Kong, marking the first reported case in the region.
• Clinical assessment revealed thymine-uraciluria, a key biomarker for DPD deficiency.

Findings:

• Gas chromatographic-mass spectrometry confirmed thymine-uraciluria.
• Molecular analysis identified a specific G to A point mutation in a 5'-splicing site of the DPYD gene.
• This mutation resulted in the skipping of exon 14, leading to deficient dihydropyrimidine dehydrogenase enzyme activity. The patient and his mother were homozygous, while the father was heterozygous for this mutation. Notably, the mother, despite having thymine-uraciluria, was asymptomatic.

Implications:

• This case highlights the importance of early diagnosis of DPD deficiency in neonates presenting with neurological symptoms.
• Genetic screening for DPYD mutations can identify individuals at risk for 5-fluorouracil toxicity.
• Understanding the genetic basis and variable clinical expressivity, as seen in the asymptomatic mother, is crucial for patient management and genetic counseling.