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Disease Profile

Dihydropyrimidine dehydrogenase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

All ages

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ICD-10

E79.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

DPD deficiency; Hereditary thymine-uraciluria; Familial pyrimidinemia

Categories

Congenital and Genetic Diseases; Metabolic disorders; Musculoskeletal Diseases

Summary

Dihydropyrimidine dehydrogenase (DPD) deficiency is a condition in which the body cannot break down the nucleotides, thymine and uracil. DPD deficiency can have a has a wide range of severity. Most people have no obvious signs or symptoms, but some develop serious neurological problems as infants. In infants with severe DPD deficiency, the signs and symptoms may include seizures, intellectual disability, microcephaly, increased muscle tone (hypertonia), delayed motor skills, and autistic behavior.[1] It is not clear why some individuals with DPD deficiency have symptoms and others don't.[2] 

DPD deficiency is caused by mutations in the DPYD gene and is inherited in an autosomal recessive manner.[1] Babies with the severe form of DPD deficiency may be diagnosed based on the symptoms, and additional laboratory testing.[3] Treatment for the severe form is based on the symptoms.

All individuals with the DPD deficiency, regardless of the presence or severity of symptoms, are at risk for severe, toxic reactions to drugs called fluoropyrimidines which are used to treat cancer.[1] Individuals with no symptoms may be diagnosed only by laboratory testing or after exposure to fluoropyrimidines.

Symptoms

All patients, including infants and children, with Dihydropyrimidine dehydrogenase (DPD) deficiency have complete or partial absence of dihydropyrimidine dehydrogenase (DPD) enzyme activity. However, most people do not have obvious symptoms. 

Infants with the severe form of DPD deficiency may have the following symptoms. However, these symptoms can vary greatly from person to person.

  • seizures
  • intellectual disability
  • growth retardation
  • unusual physical features
  • microcephaly
  • motor delay
  • increased muscle tone
  • autism
  • hyperreflexia (exaggerated reflexes)

Some documented cases have also presented with other findings such as enlarged liver and spleen (hepatosplenomegaly) and abnormal eye findings; however, these symptoms appear to be rarer.[1]

Everyone with DPD deficiency, regardless of whether or not they show any symptoms, is at risk to have a severe, toxic reaction to drugs known as fluoropyrimidines, the most common of which is 5-FU used to treat cancer.[3]

 

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
5%-29% of people have these symptoms
Agenesis of corpus callosum
0001274
Percent of people who have these symptoms is not available through HPO
Autism
0000717
Autosomal recessive inheritance
0000007
Cerebral atrophy
Degeneration of cerebrum
0002059
Coloboma
Notched pupil
0000589
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Hyperactivity
More active than typical
0000752
Hypertonia
0001276
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Lethargy
0001254
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Microphthalmia
Abnormally small eyeball
0000568
Motor delay
0001270
Muscular hypotonia
Low or weak muscle tone
0001252
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Optic atrophy
0000648
Reduced dihydropyrimidine dehydrogenase level
0003654
Seizure
0001250
Tetraplegia
Paralysis of all four limbs
0002445
Uraciluria
High urine uracil levels
0012127

Cause

DPD deficiency is caused by mutations in the DPYD gene. This gene provides instructions for making an enzyme called dihydropyrimidine dehydrogenase (DPD), which is involved in the breakdown of molecules called uracil and thymine. Uracil and thymine are building blocks of DNA, RNA, and molecules that serve as energy sources in cells.

Mutations in the DPYD gene result in reduced amounts of working DPD enzyme, interfering with the breakdown of uracil and thymine in cells. This results in excessive amounts of uracil and thymine in the blood, urine, and the fluid that surrounds the brain and spinal cord. It is currently poorly understood exactly how this cascade of events causes the signs and symptoms of the condition, or why only some infants with DPYD gene mutations have symptoms.[1]

Diagnosis

DPD deficiency may be diagnosed in various ways. In infants with early neurological symptoms such as seizures or microcephaly, or people who are suspected to have DPYD gene mutations, specific types of laboratory testing can detect elevated levels of uracil and/or thymine in plasma or urine.[3] In addition, testing is available to look for the levels of the DPD enzyme. Genetic testing can also be helpful for diagnosis.

There is a breath test available that can measure DPD enzyme activity.[4] In addition, there is evidence that genetic testing can identify many people with DPYD gene mutations. This may be important for screening people prior to receiving 5-FU chemotherapy.[5]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    Currently, no specific treatment exists for the severe form of dihydropyrimidine dehydrogenase deficiency. Treatment is aimed at managing the symptoms. Symptoms usually remain the same throughout the person's life.[1]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • MedlinePlus Genetics contains information on Dihydropyrimidine dehydrogenase deficiency. This website is maintained by the National Library of Medicine.

        In-Depth Information

        • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Dihydropyrimidine dehydrogenase deficiency. Click on the link to view a sample search on this topic.

          References

          1. Dihydropyrimidine dehydrogenase deficiency. Genetics Home Reference. Updated Sept 2015; https://ghr.nlm.nih.gov/condition/dihydropyrimidine-dehydrogenase-deficiency.
          2. Dihydropyrimidine dehydrogenase deficiency. Online Mendelian Inheritance in Man (OMIM). Updated 2012; https://www.omim.org/entry/274270.
          3. Fleger M Willomitzer J, Meinsma R, Alders M, Meijer J et al. Dihydropyrimidine dehydrogenase deficiency: Metabolic disease or biochemical phenotype?. JIMD Rep. Feb 2017; 37:49-54. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740048/.
          4. Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer. September 2004; 4(3):181-189.
          5. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M.. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther. Dec 2013; 94(6):640-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831181/.
          6. Mir, Fazia. Fluorouracil Toxicity and DPYD. Medscape Reference. Updated Jan 5, 2016; https://emedicine.medscape.com/article/1746057-overview.

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