beta-ureidopropionase deficiency

Beta-ureidopropionase deficiency is an inborn error of pyrimidine metabolism that affects how the body breaks down the nucleic acid building blocks uracil and thymine. Variants in the UPB1 gene reduce or eliminate the activity of the beta-ureidopropionase enzyme, causing certain intermediary metabolites to accumulate in blood and urine. Fewer than one in a million people are thought to be affected worldwide, and fewer than ten individuals have been described in the medical literature to date. Reported ages of diagnosis range from infancy to adulthood, reflecting a clinical spectrum that spans from completely asymptomatic findings on metabolic screening to significant neurological and developmental concerns. Both males and females can be affected because the condition follows an autosomal recessive inheritance pattern.

The clinical picture is highly variable, and not all individuals experience all features. Biochemical hallmarks, present in every reported case, include markedly elevated levels of N-carbamyl-beta-aminoisobutyric acid and ureidopropionic acid in blood or urine, along with reduced beta-ureidopropionase activity when the enzyme is measured directly. Many affected children first come to medical attention because of neurological signs such as seizures, status epilepticus, or global developmental delay. Intellectual or other cognitive difficulties, hypotonia, and motor delay have also been observed. Some individuals develop episodes of metabolic acidosis or transient increases in blood lactate during illness, reflecting underlying metabolic stress. Less commonly reported findings include dystonia, scoliosis, or loss of consciousness during acute metabolic crises. Because severity and symptoms vary widely between individuals, two people with the same biochemical abnormality can have very different day-to-day experiences.

Beta-ureidopropionase deficiency is caused by pathogenic variants in the UPB1 gene. UPB1 provides instructions for making beta-ureidopropionase, the last enzyme in the pathway that converts uracil and thymine into beta-alanine and beta-aminoisobutyric acid for excretion. When both copies of the gene carry a non-working variant, the pathway stalls, and intermediary compounds build up. The condition is inherited in an autosomal recessive manner, meaning a child must receive one altered gene from each parent to be affected. Parents who each carry a single UPB1 variant (carriers) are typically healthy but have a 25 percent chance with each pregnancy of having a child with the condition. Because beta-ureidopropionase deficiency is extremely rare, it may be more common when parents share a common ancestor, as this increases the likelihood that both carry the same rare genetic change. Genetic counseling can help families understand carrier testing options and discuss reproductive planning.

Currently, management focuses on supportive care and symptom control because no disease-specific therapies have been approved. A multidisciplinary team, often including neurologists, metabolic specialists, dietitians, and rehabilitation therapists, tailors treatment to each person’s needs. Seizure control with standard antiepileptic medications and physical or occupational therapy for hypotonia or motor delay are common interventions. During intercurrent illnesses, careful metabolic monitoring can help prevent or manage episodes of acidosis. Regular surveillance is an essential part of long-term care, with periodic neurological assessments and metabolic laboratory testing to detect emerging complications early. Families are encouraged to discuss individualized care plans and emergency protocols with their healthcare team.

Because so few individuals have been described, long-term outcomes are not yet well characterized. Some people remain asymptomatic throughout life, while others have persistent neurological challenges or metabolically triggered crises. Outcomes depend on many factors, including the severity of enzyme deficiency, age at diagnosis, and access to specialized care. With attentive monitoring, prompt treatment of metabolic stress, and appropriate developmental supports, many individuals can achieve improved quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with metabolic specialists familiar with this condition and to engage with genetic counseling services for ongoing guidance.

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