dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine Dehydrogenase Deficiency: A Rare Genetic Disorder

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder that affects the body's ability to break down certain nucleotides, specifically thymine and uracil. This condition is caused by genetic mutations in the DPYD gene, which codes for the DPD enzyme.

Symptoms and Severity

The severity of DPD deficiency can vary greatly among individuals, ranging from asymptomatic to severe neurological involvement. Some people may experience developmental delays, seizures, and other symptoms, while others may not show any signs or symptoms at all [1][2]. In severe cases, the disorder can become apparent in infancy.

Phenotypic Variation

The phenotype of DPD deficiency is highly variable, with some individuals experiencing no symptoms, while others may develop life-threatening toxicity following exposure to certain chemotherapy drugs, such as 5-fluorouracil (5-FU) [3][4]. The disorder can also be associated with convulsive disorders and mental and motor retardation.

Causes and Genetics

DPD deficiency is caused by genetic mutations in the DPYD gene, which codes for the DPD enzyme. These mutations can lead to a range of symptoms, depending on their severity and location within the gene [5][6].

References:

[1] Description. Dihydropyrimidine dehydrogenase deficiency is a disorder characterized by a wide range of severity, with neurological problems in some individuals and no signs or symptoms in others.

[2] A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. ... Dihydropyrimidine dehydrogenase deficiency is caused by genetic mutations in the DPYD gene.

[3] Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.

[4] Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder that was first described in the 1980s (van Gennip et al. 1981; Bakkeren et al. 1984).

[5] Dihydropyrimidine dehydrogenase (DPD) deficiency is an extremely rare autosomal recessive condition that was initially identified in the 1980s (Van Gennip et al. 1981).DPD is an enzyme that plays a role in the metabolism of pyrimidines, specifically the breakdown of thymine and uracil.

[6] Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder that has been associated with a variety of clinical phenotypes, including convulsive disorders and mental and motor retardation.

Dihydropyrimidine dehydrogenase (DPD) deficiency can manifest in various ways, depending on the severity of the condition.

Common Signs and Symptoms:

• Severe neurological problems, such as seizures [2], microcephaly [3], muscular hypotonia [7], global developmental delay [7]
• Intellectual disability or delayed development [14]
• Autistic behavior [4]
• Ocular abnormalities, including microphthalmia, nystagmus, and strabismus [4]

Less Common Signs and Symptoms:

• Hypotonia (low muscle tone) [4]
• Microcephaly (small head size) [3]
• Delayed development or intellectual disability [14]

Asymptomatic Cases:

• Some individuals with DPD deficiency may not exhibit any signs or symptoms, especially if the condition is mild [6]. However, they may still be at risk of suffering from severe toxicity when exposed to certain medications, such as 5-fluorouracil (5-FU) [8].

It's essential to note that the severity and presentation of DPD deficiency can vary widely among individuals. In some cases, symptoms may not become apparent until infancy or early childhood.

References: [1] - Not applicable [2] - Search result 7 [3] - Search result 4 [4] - Search result 4 [6] - Search result 6 [7] - Search result 7 [8] - Search result 8 [14] - Search result 14

Diagnostic Tests for Dihydropyrimidine Dehydrogenase (DPD) Deficiency

Dihydropyrimidine dehydrogenase (DPD) deficiency is a genetic disorder that affects the body's ability to break down certain medications, such as 5-fluorouracil and capecitabine. Diagnostic tests for DPD deficiency are essential to identify individuals who may be at risk of severe side effects from these medications.

Types of Diagnostic Tests

Several diagnostic tests can detect DPD deficiency:

• Genetic testing: This involves analyzing the DPYD gene to identify variants that may lead to DPD deficiency. Genetic testing can be done through full gene sequencing or targeted assays (1, 5).
• Uracil measurement: Measuring the level of uracil in the blood can also detect DPD deficiency. Uracil is a substance broken down by DPD, and low levels may indicate enzyme deficiency (7).
• Clinical evaluation: A clinical evaluation involves assessing an individual's medical history, symptoms, and physical examination to determine if they have DPD deficiency (8).

Importance of Diagnostic Tests

Diagnostic tests for DPD deficiency are crucial to prevent severe side effects from medications like 5-fluorouracil and capecitabine. Individuals with DPD deficiency may experience severe toxicity, including convulsive disorders, motor disabilities, and intellectual disabilities (8). Early detection through diagnostic testing can help identify individuals who require alternative treatment plans or closer monitoring.

References

• [1] This is a pharmacogenomics test associated with 5-fluorouracil and capecitabine drug sensitivity. Biallelic variation in the DPYD gene is also associated with dihydropyrimidine dehydrogenase deficiency.
• [7] Patients can be tested for DPD deficiency by measuring the level of uracil (a substance broken down by DPD) in the blood, or by checking for the presence of specific variants in the DPYD gene.
• [8] DPD deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and intellectual disabilities.

Treatment Considerations for DPD-Deficient Patients

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at risk of experiencing severe or lethal toxicities when treated with fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine. Therefore, alternative treatment options should be considered.

• Avoidance of Fluoropyrimidines: The most critical step in managing DPD deficiency is to avoid the use of fluoropyrimidine chemotherapy agents, such as 5-FU and capecitabine, which are not broken down efficiently by individuals with this condition [6].
• Alternative Treatment Options: In cases where alternative therapy is not suitable, treatment with 5-FU (IV) may be considered in centers with expertise and therapeutic drug monitoring. However, this should be done with caution and under close supervision to minimize the risk of severe toxicity [8].
• Adaptive Dosing Strategies: Currently, no adaptive dosing strategies are incorporated into the drug labels of 5-FU and capecitabine for polymorphic metabolism of 5-FU. Therefore, individualized dosing approaches may be necessary to ensure safe treatment [11].

Important Considerations

• Genetic Testing: Genetic testing can help identify individuals with DPD deficiency, allowing for the implementation of alternative treatment strategies.
• Pharmacogenetic Approach: A pharmacogenetic approach should be considered when treating patients with DPD deficiency, taking into account their genetic profile and potential risks associated with fluoropyrimidine therapy.

References

[1] Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive condition [4]. [2] Fluorouracil, or 5-FU, is a chemotherapy drug that can be toxic to individuals with DPD deficiency [9]. [3] Capecitabine is another fluoropyrimidine drug that can cause severe toxicity in patients with DPD deficiency [10].

Differential Diagnosis of Dihydropyrimidine Dehydrogenase Deficiency

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder that can be challenging to diagnose. The differential diagnosis for this condition involves considering other metabolic disorders and genetic conditions that may present with similar symptoms.

Metabolic Disorders:

• Urea Cycle Disorders: These disorders, such as ornithine transcarbamylase (OTC) deficiency, can also lead to elevated levels of uracil and thymine in the body.
• Pyrimidine Metabolism Disorders: Other pyrimidine metabolism disorders, like dihydropyrimidinase deficiency, may present with similar symptoms.

Genetic Conditions:

• Autosomal Recessive Disorders: Other autosomal recessive disorders, such as cystic fibrosis or sickle cell disease, can also be considered in the differential diagnosis.
• Mitochondrial Disorders: Certain mitochondrial disorders, like MELAS syndrome, may present with similar symptoms.

Clinical Presentation:

The clinical presentation of DPD deficiency can vary widely, ranging from no signs or symptoms to severe neurological problems. In people with severe DPD deficiency, the disorder becomes apparent in infancy. The differential diagnosis for this condition should consider other metabolic disorders and genetic conditions that may present with similar symptoms.

• Elevated Uracil and Thymine Levels: Elevated levels of uracil and thymine in body fluids such as urine, plasma, and cerebrospinal fluid can be a key diagnostic feature.
• Neurological Problems: Severe neurological problems, including intellectual disability, motor retardation, and seizures, may also be present.

Diagnostic Tests:

The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Rapid gas chromatographic-mass spectrometric diagnosis of dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency can also be used.

Conclusion:

The differential diagnosis for DPD deficiency involves considering other metabolic disorders and genetic conditions that may present with similar symptoms. A comprehensive diagnostic approach, including biochemical tests and clinical evaluation, is essential to accurately diagnose this condition.

References:

• Rapid gas chromatographic-mass spectrometric diagnosis of dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency. J Chromatogr B 792: 107–115. 10.1016/j.jchromb.2003.09.011.
• Diagnostic teams for Dihydropyrimidine dehydrogenase deficiency may include: Genetics . Rare Disease Experts . ...