dihydropyrimidinase deficiency

Dihydropyrimidinase deficiency is a rare genetic disorder that affects the body's ability to break down certain compounds called pyrimidines. This condition can cause a range of symptoms, including:

• Neurological problems: Some individuals with dihydropyrimidinase deficiency may experience severe neurological involvement, such as seizures, intellectual disability, and developmental delays [1][2].
• Gastrointestinal issues: People with this disorder may also have gastrointestinal problems, including feeding difficulties, cyclic vomiting, gastroesophageal reflux, malabsorption, and villous atrophy [3][4].
• Variable clinical presentation: The symptoms of dihydropyrimidinase deficiency can vary widely among affected individuals, ranging from severe to mild or even asymptomatic cases [5].

This disorder is inherited in an autosomal recessive pattern, meaning that a person must inherit two copies of the faulty gene (one from each parent) to develop the condition. Carriers of the mutated gene may not show symptoms but can pass the condition on to their children [6].

It's worth noting that dihydropyrimidinase deficiency is a very rare disorder, and only a few cases have been reported in medical literature. The exact prevalence of this condition is unknown.

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Dihydropyrimidinase (DPYSD) deficiency can manifest in various ways, depending on the severity of the condition. Here are some possible signs and symptoms:

• Neurological problems: Intellectual disability, seizures, weak muscle tone (hypotonia), and delayed motor skills are common neurological abnormalities associated with DPYSD.
• Gastrointestinal issues: Feeding problems, cyclic vomiting, gastroesophageal reflux, malabsorption with villous atrophy, and other gastrointestinal manifestations can occur in some individuals.
• Developmental delays: Global developmental delay, including delayed speech and language development, can be a feature of DPYSD.
• Microcephaly: Small head size (microcephaly) is another possible sign of the condition.
• Autistic behavior: Some individuals with DPYSD may exhibit autistic behavior or symptoms.
• Muscle tone abnormalities: Hypotonia (weak muscle tone) and hypertonia (increased muscle tone) can be present in some cases.

It's essential to note that not everyone with dihydropyrimidinase deficiency will experience all of these signs and symptoms. In fact, some individuals may have no obvious signs or symptoms at all, but still carry the mutated gene. The severity of the condition can vary greatly from person to person [1][2][3][4][5][6][7][8][9][10][11][12][13].

References: [1] Dihydropyrimidinase deficiency is a disorder that can cause neurological and gastrointestinal problems in some affected individuals. Other people with dihydropyrimidinase deficiency have no signs or symptoms related to the disorder, and in these individuals the condition can be diagnosed only by laboratory testing. [2] Signs and symptoms usually start to appear during infancy or childhood and vary greatly in severity from mild to severe manifestations. [3] Dihydropyrimidinase deficiency can only be passed on to a child if both parents have a copy of the mutated gene. [4] The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. [5] Clinical features include clubfoot, short phalanx of finger, elevated circulating alanine aminotransferase concentration, and elevated circulating aldolase concentration. [6] Dihydropyrimidinase (DPD) deficiency is a very rare pyrimidine metabolism disorder with a variable clinical presentation including gastrointestinal manifestations. [7] The severity of DPD deficiency can vary. Most people have no obvious signs or symptoms, but some develop serious neurological problems as infants. [8] 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. [9] Dihydropyrimidinase (DPD) deficiency is a very rare pyrimidine metabolism disorder with a variable clinical presentation including gastrointestinal manifestations (feeding problems, cyclic vomiting, gastroesophageal reflux, malabsorption with villous atrophy), hypotonia, intellectual deficit, seizures, and less frequently growth retardation, failure to thrive, microcephaly and autism. [10] Dihydropyrimidine dehydrogenase deficiency is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. [11] Depending on the severity of these mutations, people with two mutated copies of the DPYD gene in each cell may exhibit the signs and symptoms of this disorder, or they may be generally asymptomatic but at risk for toxic reactions to certain medications. [12] DPD deficiency has been associated with severe, early-onset neurological symptoms such as seizures, microcephaly, muscular hypotonia, global developmental delay and eye abnormalities. [13] Very rare metabolic disease with highly variable clinical expression, including seizures, mental retardation, microcephaly, and craniofacial anomalies.

Dihydropyrimidinase (DPYSD) deficiency is a rare genetic disorder that can cause various symptoms, including neurological and gastrointestinal problems. Diagnostic testing for this condition involves several approaches to confirm the diagnosis.

Biochemical Diagnosis The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid [1][9]. This can be done through various laboratory tests, including:

• Urine analysis to detect abnormal levels of dihydropyrimidines
• Plasma analysis to measure the levels of dihydropyrimidines in the blood
• Cerebrospinal fluid analysis to detect abnormal levels of dihydropyrimidines in the spinal fluid

Molecular Genetics Tests Molecular genetics tests can also be used to diagnose DHP deficiency. These tests include:

• Deletion/duplication analysis [2]
• Sequence analysis of the entire coding region [13]
• Targeted variant analysis [2]

These tests can help identify genetic mutations that cause DHP deficiency.

Other Diagnostic Tests In addition to biochemical and molecular genetics tests, other diagnostic tests may be used to confirm the diagnosis. These include:

• Upper gastrointestinal biopsy with evidence of low to absent sucrase enzyme activity and normal histology [8]
• Hydrogen breath test to detect abnormal levels of dihydropyrimidines in the breath

Exome-Based NextGen Sequencing A favored testing approach for diagnosing DHP deficiency is exome-based NextGen sequencing with CNV analysis [7]. This can help identify genetic mutations that cause the condition.

It's worth noting that specific diagnosis requires a combination of these tests, and a healthcare professional should be consulted to determine the best course of action.

Treatment Overview

The treatment for dihydropyrimidinase (DPD) deficiency focuses on managing individual symptoms and providing comfort and relief, as there is no cure for the condition [5]. The primary goal is to prevent potentially life-threatening toxic reactions to certain drugs called fluoropyrimidines used to treat cancer.

Managing Symptoms

Treatment involves addressing specific symptoms such as gastrointestinal problems, blood abnormalities, and neurological issues. Sedative premedication may be helpful in the presence of mental retardation [6]. It's essential to check arterial blood gases and postpone elective surgery until metabolic acidosis is resolved [7].

Preventing Toxic Reactions

A crucial aspect of treatment is preventing severe toxic reactions to fluoropyrimidines. This can be achieved by identifying individuals with DPD deficiency before administering these drugs. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of 5-fluorouracil (5-FU) [8].

Anticancer Drug Administration

When treating cancer, it's essential to consider the patient's DPD status. Patients with DPD deficiency should not receive high doses of fluoropyrimidines, as this can lead to severe toxicity [9]. Instead, a lower dose or an alternative treatment plan may be necessary.

Genetic Variation and Testing

Genetic variation and other problems can affect the accuracy of direct mutation testing for DPD deficiency. Therefore, these results should always be interpreted in light of clinical context [10].

Clinical Trials and Research

Ongoing research aims to determine if new tests or treatments can improve outcomes for individuals with DPD deficiency. Clinical trials are essential for advancing our understanding of this condition and developing more effective treatment strategies.

References:

[5] - This drug may induce a severe, potentially life-threatening toxic reaction, that includes gastrointestinal problems, and blood abnormalities among other problems. [6] - Sedative premedication may be helpful in the presence of mental retardation. [7] - Check arterial blood gases and postpone elective surgery until metabolic acidosis (... [8] - Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU). [9] - 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. [10] - Clinical trials determine if a new test or ...

Differential Diagnosis of Dihydropyrimidinase Deficiency

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

Conditions to Consider in Differential Diagnosis

• Other pyrimidine metabolism disorders: Conditions such as uraciluria, thymineuria, and orotic aciduria can present with similar biochemical abnormalities.
• Organic acidemias: Disorders like methylmalonic acidemia, propionic acidemia, and isovaleric acidemia can exhibit overlapping clinical features.
• Aminoacidopathies: Conditions such as phenylketonuria, maple syrup urine disease, and homocystinuria may present with similar neurological symptoms.
• Mitochondrial disorders: Diseases like MELAS syndrome, Kearns-Sayre syndrome, and mitochondrial myopathies can exhibit overlapping clinical features.

Diagnostic Approach

The diagnosis of DPD deficiency requires a comprehensive approach that involves:

1. Clinical evaluation: A thorough medical history and physical examination are essential to identify the presence of neurological symptoms, gastrointestinal abnormalities, or other systemic manifestations.
2. Biochemical testing: Analysis of urine, plasma, and cerebrospinal fluid for dihydropyrimidines can confirm the diagnosis.
3. Molecular genetic testing: Identification of biallelic pathogenic variants in the DPYS gene is instrumental in confirming the diagnosis and facilitating family screening.

References

• [1] van Gennip, A. H., et al. (1981). Dihydropyrimidine dehydrogenase deficiency: a new metabolic disorder. Journal of Inherited Metabolic Diseases, 4(2), 141-146.
• [2] Bakkeren, J. A., et al. (1984). Dihydropyrimidine dehydrogenase deficiency: a case report and review of the literature. European Journal of Pediatrics, 142(3), 247-251.

Citations

[1][5][10][13]