dihydropyrimidinuria

Dihydropyrimidinuria is a very rare disorder of pyrimidine metabolism that affects multiple body systems, including the gastrointestinal tract and central nervous system. It is caused by pathogenic variants in the DPYS gene, which impair the normal breakdown of pyrimidines in the body. Affected individuals may present in early childhood with a variety of symptoms, although some cases remain asymptomatic. In plain language, the condition occurs in fewer than 1 in 1,000,000 people.

The clinical presentation of dihydropyrimidinuria is variable. Characteristic laboratory findings include reduced dihydropyrimidine dehydrogenase levels, elevated concentrations of thymine, aldolase, aspartate aminotransferase, alanine aminotransferase, and increased levels of dihydrouracil in both the cerebrospinal fluid and urine, all of which are consistently observed. Many affected individuals also experience neurodevelopmental issues such as delayed speech and language development, intellectual disability, seizures, and hyperactivity, alongside gastrointestinal challenges including feeding difficulties, cyclic vomiting, gastroesophageal reflux, and malabsorption with villous atrophy. Less common features may include growth delay, failure to thrive, microcephaly, and autism. Not all individuals experience all features, and severity varies considerably.

Dihydropyrimidinuria results from pathogenic variants in the DPYS gene, which plays a crucial role in the pyrimidine metabolism pathway. The deficiency in the enzyme dihydropyrimidinase disrupts the normal processing of pyrimidines, leading to the accumulation of metabolites that contribute to the varied clinical features observed. This condition is inherited in an autosomal recessive manner, meaning that an affected individual has inherited two copies of the altered gene, one from each parent. It is more commonly seen in cases where both parents share a common ancestor, as the likelihood of both carrying the same rare variant is increased. Genetic counseling is recommended for family planning and to help clarify recurrence risks.

Currently, management of dihydropyrimidinuria focuses on supportive care and symptomatic treatment, as no specific or approved treatments exist for this condition. Therapy is tailored to the individual and often involves a multidisciplinary team to address both neurological and gastrointestinal manifestations. Regular surveillance is an essential part of long-term care, helping to identify potential complications early and allow for prompt intervention. Genetic counseling is advised for affected families, and patients should discuss treatment options with their healthcare team to determine the most appropriate approach based on their specific situation.

The clinical course of dihydropyrimidinuria is highly variable, with outcomes that depend on the severity and range of symptoms as well as the age at diagnosis and access to specialized care. With current standards of care, many individuals manage their symptoms successfully and live into adulthood, though some may experience ongoing challenges related to neurodevelopment and gastrointestinal function. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists experienced in metabolic disorders and genetic counseling to gain further guidance on long-term management.

A clinical trial is currently underway exploring new treatment approaches for dihydropyrimidinuria. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility and emerging therapies.