dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine dehydrogenase deficiency is a metabolic condition in which the body is unable to break down the nucleotides thymine and uracil, leading to a range of potential neurological issues. The condition is caused by mutations in the DPYD gene, which disrupts the normal function of the enzyme responsible for pyrimidine breakdown. While some individuals may experience severe symptoms early in life, others remain asymptomatic and are only diagnosed after exposure to fluoropyrimidine drugs. The overall prevalence is currently unknown, and variability in the clinical presentation is a hallmark of the disorder.

The clinical features of dihydropyrimidine dehydrogenase deficiency can vary widely between affected individuals. Many with the condition experience neurological challenges such as seizures, intellectual disability, and cognitive or developmental delays. Other reported findings include microcephaly, increased muscle tone (hypertonia), delayed motor skills, and behavior on the autism spectrum. Not all individuals experience all features, and severity varies considerably.

Dihydropyrimidine dehydrogenase deficiency is caused by mutations in the DPYD gene, which encodes the enzyme responsible for breaking down the pyrimidines thymine and uracil. Disruption in this enzyme’s function leads to an accumulation of these substances, contributing to the neurological and developmental symptoms observed in affected individuals. The condition is inherited in an autosomal recessive manner, meaning that an individual must inherit two mutated copies of the gene to be affected. Families are encouraged to seek genetic counseling to understand recurrence risks and to discuss options for family planning, particularly in cases where parents share a common ancestor.

Currently, management focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for dihydropyrimidine dehydrogenase deficiency. Treatment is tailored to the individual and typically involves a multidisciplinary team that can include neurologists, developmental specialists, and metabolic experts. Regular monitoring and supportive therapies are important components of care. Patients should discuss treatment options with their healthcare team to determine which interventions may be most appropriate, and genetic counseling is recommended for affected families.

Outcomes for dihydropyrimidine dehydrogenase deficiency vary widely, ranging from asymptomatic individuals to those with significant neurological challenges such as cognitive impairments and seizures. With current standards of care, many individuals receive supportive therapies that help manage symptoms, and advances in modern care continue to improve long-term outcomes. Outcomes described in medical literature continue to evolve as standards of care improve, and the variability in symptom severity means that each individual’s course is unique. Families often find it helpful to connect with genetic counselors and specialists to understand the potential progression of the condition and to explore ongoing management strategies.

Clinical trials are underway exploring new treatment approaches for dihydropyrimidine dehydrogenase deficiency. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.