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Robert B. Diasio - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine Dehydrogenase Deficiency (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS
Pakistan journal of medical sciences, 2007Co-Authors: Muhammad Wasif Saif, Lori K. Mattison, Kostas N. Syrigos, Ranee Mehra, Robert B. DiasioAbstract:Objectives 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its Deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome.
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Increased Prevalence of Dihydropyrimidine Dehydrogenase Deficiency in African-Americans Compared with Caucasians
Clinical Cancer Research, 2006Co-Authors: Lori K. Mattison, Muhammad Wasif Saif, Jeanne Fourie, Renee A. Desmond, Anil S. Modak, Robert B. DiasioAbstract:Purpose: African-American patients with colorectal cancer were observed to have increased 5-fluorouracil (5-FU)–associated toxicity (leukopenia and anemia) and decreased overall survival compared with Caucasian patients. One potential source for this disparity may be differences in 5-FU metabolism. Dihydropyrimidine Dehydrogenase (DPD), the initial and rate-limiting enzyme of 5-FU catabolism, has previously been shown to have significant interpatient variability in activity. Several studies have linked reduced DPD activity to the development of 5-FU toxicity. Although the distribution of DPD enzyme activity and the frequency of DPD Deficiency have been well characterized in the Caucasian population, the distribution of DPD enzyme activity and the frequency of DPD Deficiency in the African-American population are unknown. Experimental Design: Healthy African-American ( n = 149) and Caucasian ( n = 109) volunteers were evaluated for DPD Deficiency using both the [2- 13 C]uracil breath test and peripheral blood mononuclear cell DPD radioassay. Results: African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26 ± 0.07 and 0.29 ± 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD Deficiency was 3-fold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P = 0.07). African-American women showed the highest prevalence of DPD Deficiency compared with African-American men, Caucasian women, and Caucasian men (12.3%, 4.0%, 3.5%, and 1.9%, respectively). Conclusion: These results indicate that African-Americans, particularly African-American women, have significantly reduced DPD enzyme activity compared with Caucasians, which may predispose this population to more 5-FU toxicity.
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Dihydropyrimidine Dehydrogenase Deficiency (DPD) in GI malignancies: Experience of 4 years
Journal of Clinical Oncology, 2006Co-Authors: Ranee Mehra, Lori K. Mattison, Hany Ezzeldin, Robert B. Diasio, Leslie Ledbetter, Muhammad Wasif SaifAbstract:2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its Deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD Deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD Deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treate...
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Dihydropyrimidine Dehydrogenase Deficiency in an Indian population
Cancer Chemotherapy and Pharmacology, 2006Co-Authors: Muhammad Wasif Saif, Lori K. Mattison, Tom Carollo, Hany Ezzeldin, Robert B. DiasioAbstract:Background: Dihydropyrimidine Dehydrogenase (DPD) Deficiency is prevalent in 3–5% of the Caucasian population; however, the frequency of this pharmacogenetic syndrome in the Indian population and other racial and ethnic groups remains to be elucidated. Patients and methods: We describe an Indian patient who presented to clinic for the treatment of gastric adenocarcinoma with 5-flurouracil (5-FU) therapy who subsequently was diagnosed with DPD Deficiency by using the peripheral blood mononuclear cell (PBMC) DPD radioassay. This observation prompted us to examine the data generated from healthy (cancer-free) Indian subjects who were enrolled in a large population study to determine the sensitivity and specificity of the uracil breath test (UraBT) in the detection of DPD Deficiency. Thirteen Indian subjects performed the UraBT. UraBT results were confirmed by PBMC DPD radioassay. Results: The Indian cancer patient demonstrated reduced DPD activity (0.11 nmol/min/mg protein) and severe 5-FU toxicities commonly associated with DPD Deficiency. Of the 13 Indian subjects [ten men and three women; mean age, 26 years (range: 21–31 years)] enrolled in the UraBT, 12 Indian subjects demonstrated UraBT breath profiles and PBMC DPD activity within the normal range; one Indian subject demonstrated a reduced breath profile and partial DPD Deficiency. Conclusions: DPD Deficiency is a pharmacogenetic syndrome which is also present in the Indian population. If undiagnosed, the DPD Deficiency can lead to death. Future epidemiological studies would be helpful to determine the prevalence of DPD Deficiency among racial and ethnic groups, allowing for the optimization of 5-FU chemotherapy.
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Is capecitabine safe in patients with gastrointestinal cancer and Dihydropyrimidine Dehydrogenase Deficiency
Clinical Colorectal Cancer, 2006Co-Authors: M. Wasif Saif, Robert B. DiasioAbstract:Patients with cancer with Dihydropyrimidine Dehydrogenase (DPD) Deficiency are at significant risk for severe 5-fluorouracil (5-FU) toxicity, including the risk of death. Data regarding the toxicity of capecitabine, an oral fluoropyrimidine, in patients with DPD Deficiency are scarce. From 2004 to 2005, 2 patients with gastrointestinal (GI) malignancies (of the pancreas and liver) experienced severe to even life-threatening toxicities during capecitabine therapy, which resulted in death for 1 patient. A DPD enzyme assay was performed as previously defined in our laboratory. Both patients were DPD deficient upon evaluation for toxicity. Capecitabine can lead to severe and sometimes life-threatening toxicities akin to toxicities caused by 5-FU in patients with DPD Deficiency. In cases of unexpected severe toxicity during capecitabine treatment, DPD Deficiency should be considered. We suggest that capecitabine should not be used in patients with DPD Deficiency. Screening should be considered in view of the widespread use of capecitabine and 5-FU, the severe toxicity that can develop in patients with low DPD activity, and the prevalence of the mutation.
André B.p. Van Kuilenburg - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1
JIMD Reports, 2018Co-Authors: André B.p. Van Kuilenburg, Judith Meijer, Rutger Meinsma, Marielle Alders, Belén Pérez-dueñas, Zahurul A. Bhuiyan, Rafael Artuch, Raoul C.m. HennekamAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD Deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD Deficiency.
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Genome sequencing reveals a novel genetic mechanism underlying Dihydropyrimidine Dehydrogenase Deficiency: a large intragenic inversion in DPYD spanning intron 8 to intron 12
2018Co-Authors: André B.p. Van Kuilenburg, Maja Tarailo-graovac, Judith Meijer, Britt I. Drögemöller, Gerard Vockley, Dirk Maurer, Doreen Dobritzsch, Colin J. Ross, Wyeth W. Wasserman, Rutger MeinsmaAbstract:Genome sequencing reveals a novel genetic mechanism underlying Dihydropyrimidine Dehydrogenase Deficiency: a large intragenic inversion in DPYD spanning intron 8 to intron 12
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Capecitabine-based treatment of a patient with a novel DPYD genotype and complete Dihydropyrimidine Dehydrogenase Deficiency.
International Journal of Cancer, 2017Co-Authors: Linda M. Henricks, Judith Meijer, Lida Zoetekouw, Ester J.m. Siemerink, Hilde Rosing, Susan M. I. Goorden, Abeltje M. Polstra, Annemieke Cats, Jan H.m. Schellens, André B.p. Van KuilenburgAbstract:Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of Dihydropyrimidine Dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD Deficiency and dose reduction in patients with partial DPD Deficiency is recommended and improves patient safety. For patients with complete DPD Deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year-old patient with a sigmoid adenocarcinoma who proved to have a complete DPD Deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m2 . When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients.
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Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings
Molecular Syndromology, 2014Co-Authors: Bee Chin Chen, Judith Meijer, Rutger Meinsma, Raoul C.m. Hennekam, Rowani Mohd Rawi, André B.p. Van KuilenburgAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a Deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD Deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).
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Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients
Pharmacogenomics, 2013Co-Authors: André B.p. Van Kuilenburg, J G MaringAbstract:5-fluorouracil (5-FU) remains the cornerstone of all currently applied regimens for the treatment of patients with cancers of the gastrointestinal tract, breast, and head and neck. Unfortunately, a large variation in the clearance of 5-FU has been observed between patients, suggesting that some patients might receive nonoptimal 5-FU doses. However, therapeutic drug monitoring of 5-FU has been shown to result in reduced intra- and inter-individual variability in 5-FU plasma levels and pharmacokinetically guided dose adjustments of 5-FU-containing therapy results in a significantly improved efficacy and tolerability. To date, compartmental Michaelis-Menten elimination-based modeling has proven to be a sensitive and accurate tool for analyzing the pharmacokinetics of 5-FU and to identify patients with a Dihydropyrimidine Dehydrogenase Deficiency. These Michaelis-Menten models also allow the use of a limited sampling strategy and offer the opportunity to predict a priori the 5-FU plasma concentrations in patients receiving adapted doses of 5-FU.
A. H. Van Gennip - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine Dehydrogenase Deficiency presenting at birth
Journal of Inherited Metabolic Disease, 2005Co-Authors: N. A. Al-sanna'a, A.b.p. Van Kuilenburg, T. M. Atrak, M. A. Abdul-jabbar, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency (McKusick 274270) is a clinically heterogeneous autosomal recessive disorder of pyrimidine metabolism. DPD is the enzyme that catalyses the first and the rate-limiting step in the catabolism of uracil, thymine and the analogue 5-fluorouracil. To date, more than 30 patients have been diagnosed with a complete enzyme Deficiency. Here, we describe the fifth case with a complete DPD Deficiency presenting at birth with severe neurological abnormalities. The patient was homozygous for the common splice-site mutation IVS14+1G > A.
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Head imaging abnormalities in Dihydropyrimidine Dehydrogenase Deficiency.
Journal of Inherited Metabolic Disease, 2004Co-Authors: Gregory M. Enns, A.b.p. Van Kuilenburg, A. J. Barkovich, Melanie A. Manning, T. Sanger, D. R. Witt, A. H. Van GennipAbstract:Summary: Dihydropyrimidine Dehydrogenase (DPD) Deficiency is a rare autosomal recessive disorder of pyrimidine metabolism. Patients may present with a wide range of neurological symptoms during the first years of life. Head imaging abnormalities have been reported only rarely and include diffuse cerebral atrophy and white-matter hyperintensity. The pathogenesis of the white-matter abnormalities is unknown, although environmental factors and altered energy metabolism may be involved. To further understanding of the spectrum of brain abnormalities associated with DPD Deficiency, we report a 17-month-old girl, born to a consanguineous Pakistani couple, who had a history of encephalopathy, prolonged hypoventilation, developmental delay and failure to thrive. Head MRI showed prominent sulci and abnormal T2 prolongation in the cerebral white matter and brainstem. Thus, DPD Deficiency may feature prominent brain abnormalities involving the cerebral white matter and brainstem. Anoxic stress may have contributed to the clinical presentation and brain findings in this case. In order to define more clearly the contribution of DPD Deficiency to the pathogenesis of these MRI abnormalities, we recommend performing detailed analysis of urine pyrimidine metabolites in patients who have such findings.
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New insights in Dihydropyrimidine Dehydrogenase Deficiency: a pivotal role for beta-aminoisobutyric acid?
Biochemical Journal, 2004Co-Authors: André B.p. Van Kuilenburg, Nico G.g.m. Abeling, Henk Van Lenthe, A. E. M. Stroomer, A. H. Van GennipAbstract:DPD (Dihydropyrimidine Dehydrogenase) constitutes the first step of the pyrimidine degradation pathway, in which the pyrimidine bases uracil and thymine are catabolized to beta-alanine and the R-enantiomer of beta-AIB (beta-aminoisobutyric acid) respectively. The S-enantiomer of beta-AIB is predominantly derived from the catabolism of valine. It has been suggested that an altered homoeostasis of beta-alanine underlies some of the clinical abnormalities encountered in patients with a DPD Deficiency. In the present study, we demonstrated that only a slightly decreased concentration of beta-alanine was present in the urine and plasma, whereas normal levels of beta-alanine were present in the cerebrospinal fluid of patients with a DPD Deficiency. Therefore the metabolism of beta-alanine-containing peptides, such as carnosine, may be an important factor involved in the homoeostasis of beta-alanine in patients with DPD Deficiency. The mean concentration of beta-AIB was approx. 2-3-fold lower in cerebrospinal fluid and urine of patients with a DPD Deficiency, when compared with controls. In contrast, strongly decreased levels (10-fold) of beta-AIB were present in the plasma of DPD patients. Our results demonstrate that, under pathological conditions, the catabolism of valine can result in the production of significant amounts of beta-AIB. Furthermore, the observation that the R-enantiomer of beta-AIB is abundantly present in the urine of DPD patients suggests that significant cross-over exists between the thymine and valine catabolic pathways.
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Rapid gas chromatographic-mass spectrometric diagnosis of Dihydropyrimidine Dehydrogenase Deficiency and dihydropyrimidinase Deficiency
Journal of Chromatography B, 2003Co-Authors: Tomiko Kuhara, Yoshiro Wada, A. H. Van Gennip, André B.p. Van Kuilenburg, Satoshi Sumi, Chie Ohdoi, Morimasa Ohse, Tetsuya Ito, Isamu MatsumotoAbstract:A rapid yet reliable chemical diagnosis for Dihydropyrimidine Dehydrogenase (DHPD) Deficiency, and possibly dihydropyrimidinase (DHP) Deficiency in cancer patients, prior to therapy with pyrimidine analogues such as 5-fluorouracil, is desired for prevention of severe side-effects by these drugs. We have reported the basic separation and quantitation technology for pyrimidine metabolites using gas chromatography-mass spectrometry. A proposal to use the number (n) of standard deviations (SD) above the normal mean, as the index of the excessive urinary excretion of the metabolites appears not to be commonly used. When used, the values were too small, such as two or three, even in genetic disorders. Here, we applied the method to 11 urine specimens from proven cases including two DHP carriers and proved how specific the method is, because "n"-values were markedly large for thymine (T), uracil (U) and/or dihydrothymine (DHT) and dihydrouracil (DHU). In three cases with DHPD Deficiency, two were siblings, one with symptoms and the other without, n was 12 for T and 5.9 for U, and 5-hydroxymethyluracil was distinctly detected. These values indicate that the nature of genetic mutation relates closely to the degree of metabolite accumulation in pyrimidine disorders. In six patients with DHP Deficiency, n was 8.4-12 for DHT and 7.2-11 for DHU. Many mutations are known for both genes and the assay of residual enzyme activity may be time-consuming or invasive especially for those with DHP Deficiency. Thus, this noninvasive yet comprehensive urinalysis has great value for those without a family history, as the first trial, before DNA or the enzyme assay. Our findings again raise the question whether the metabolic block really causes the symptoms found in pyrimidine disorders. (C) 2003 Elsevier Science B.V. All rights reserved
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Dihydropyrimidine Dehydrogenase Deficiency and acute neurological presentation.
Journal of Inherited Metabolic Disease, 2003Co-Authors: Agata Fiumara, A.b.p. Van Kuilenburg, U. Caruso, C. Nucifora, Elisabetta Marzullo, Rita Barone, Concetta Meli, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency has been linked to 5-fluorouracil toxicity, but patients may present a wide clinical spectrum. We describe a 1-year-old Tunisian girl with a dramatic onset of neurological symptoms suggesting the possible triggering role of environmental factors.
A.b.p. Van Kuilenburg - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?
JIMD Reports, 2017Co-Authors: M. Fleger, Judith Meijer, Rutger Meinsma, J. Willomitzer, Marielle Alders, Raoul C.m. Hennekam, Martina Huemer, A.b.p. Van KuilenburgAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency is an autosomal recessive disorder of pyrimidine metabolism that impairs the first step of uracil und thymine degradation. The spectrum of clinical presentations in subjects with the full biochemical phenotype of DPD Deficiency ranges from asymptomatic individuals to severely affected patients suffering from seizures, microcephaly, muscular hypotonia, developmental delay and eye abnormalities.
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Screening for Dihydropyrimidine Dehydrogenase Deficiency to prevent severe 5-fluorouracil and capeciatbine-associated toxicity
2013Co-Authors: A.b.p. Van Kuilenburg, Sacha Ferdinandusse, R. J. A. WandersAbstract:5-Fluorouracil (5FU) and capecitabine are the cornerstones of all currently applied regimens for the treatment of patients with cancers of the gastrointestinal tract, breast, head and neck. Dihydropyrimidine Dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU and as such, a Deficiency of DPD has been recognised as an important risk factor, predisposing patients to develop severe 5FU-associated toxicity. In this manuscript, we discuss a wide range of methods that have been established to assess the genetic and functional status of DPD. Genotyping of DPYD is used to identify DPD deficient patients. However, its suitability for pre-treatment testing is under debate, not least due to conflicting genotype-phenotype rela tions in mutation carriers and relatively low positive predictive values. In addition to genetic screening, a number of phenotype-based methods have been introduced which appear to be well suited for clinical laboratories and which are an attractive option for monitoring of the DPD status. These phenotypebased screening approaches to detect DPD-deficient patients warrant further clinical validation.
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Dihydropyrimidine Dehydrogenase Deficiency caused by a novel genomic deletion c.505_513del of DPYD.
Nucleosides Nucleotides and Nucleic Acids, 2010Co-Authors: A.b.p. Van Kuilenburg, J Meijer, G Gökcay, T Baykal, M E Rubio-gozalbo, A N P M Mul, C E M De Die-smulders, P Weber, A Capone Mori, J BierauAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels of uracil and thymine were detected in urine. No DPD activity could be detected in peripheral blood mononuclear cells. Analysis of the gene encoding DPD (DPYD) showed that the patient was homozygous for a novel c.505_513del (p.169_171del) mutation in exon 6 of DPYD.
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A pivotal role for beta-aminoisobutyric acid and oxidative stress in Dihydropyrimidine Dehydrogenase Deficiency?
Nucleosides Nucleotides and Nucleic Acids, 2006Co-Authors: A.b.p. Van Kuilenburg, N. G. G. M. Abeling, A. E. M. Stroomer, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) constitutes the first step of the pyrimidine degradation pathway in which the pyrimidine bases uracil and thymine are catabolised to β-alanine and β-aminoisobutyric acid (β-AIB), respectively. The mean concentration of β-AIB was approximately 5- to 8-fold lower in urine of patients with a DPD Deficiency, when compared to age-matched controls. Comparable levels of 8-hydroxydeoxyguanosine (8-OHdG) were present in urine from controls and DPD patients at the age 2 year, suggesting the presence of increased oxidative stress.
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Dihydropyrimidine Dehydrogenase Deficiency presenting at birth
Journal of Inherited Metabolic Disease, 2005Co-Authors: N. A. Al-sanna'a, A.b.p. Van Kuilenburg, T. M. Atrak, M. A. Abdul-jabbar, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency (McKusick 274270) is a clinically heterogeneous autosomal recessive disorder of pyrimidine metabolism. DPD is the enzyme that catalyses the first and the rate-limiting step in the catabolism of uracil, thymine and the analogue 5-fluorouracil. To date, more than 30 patients have been diagnosed with a complete enzyme Deficiency. Here, we describe the fifth case with a complete DPD Deficiency presenting at birth with severe neurological abnormalities. The patient was homozygous for the common splice-site mutation IVS14+1G > A.
Lori K. Mattison - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine Dehydrogenase Deficiency (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS
Pakistan journal of medical sciences, 2007Co-Authors: Muhammad Wasif Saif, Lori K. Mattison, Kostas N. Syrigos, Ranee Mehra, Robert B. DiasioAbstract:Objectives 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its Deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome.
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Increased Prevalence of Dihydropyrimidine Dehydrogenase Deficiency in African-Americans Compared with Caucasians
Clinical Cancer Research, 2006Co-Authors: Lori K. Mattison, Muhammad Wasif Saif, Jeanne Fourie, Renee A. Desmond, Anil S. Modak, Robert B. DiasioAbstract:Purpose: African-American patients with colorectal cancer were observed to have increased 5-fluorouracil (5-FU)–associated toxicity (leukopenia and anemia) and decreased overall survival compared with Caucasian patients. One potential source for this disparity may be differences in 5-FU metabolism. Dihydropyrimidine Dehydrogenase (DPD), the initial and rate-limiting enzyme of 5-FU catabolism, has previously been shown to have significant interpatient variability in activity. Several studies have linked reduced DPD activity to the development of 5-FU toxicity. Although the distribution of DPD enzyme activity and the frequency of DPD Deficiency have been well characterized in the Caucasian population, the distribution of DPD enzyme activity and the frequency of DPD Deficiency in the African-American population are unknown. Experimental Design: Healthy African-American ( n = 149) and Caucasian ( n = 109) volunteers were evaluated for DPD Deficiency using both the [2- 13 C]uracil breath test and peripheral blood mononuclear cell DPD radioassay. Results: African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26 ± 0.07 and 0.29 ± 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD Deficiency was 3-fold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P = 0.07). African-American women showed the highest prevalence of DPD Deficiency compared with African-American men, Caucasian women, and Caucasian men (12.3%, 4.0%, 3.5%, and 1.9%, respectively). Conclusion: These results indicate that African-Americans, particularly African-American women, have significantly reduced DPD enzyme activity compared with Caucasians, which may predispose this population to more 5-FU toxicity.
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Dihydropyrimidine Dehydrogenase Deficiency (DPD) in GI malignancies: Experience of 4 years
Journal of Clinical Oncology, 2006Co-Authors: Ranee Mehra, Lori K. Mattison, Hany Ezzeldin, Robert B. Diasio, Leslie Ledbetter, Muhammad Wasif SaifAbstract:2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its Deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD Deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD Deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treate...
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Dihydropyrimidine Dehydrogenase Deficiency in an Indian population
Cancer Chemotherapy and Pharmacology, 2006Co-Authors: Muhammad Wasif Saif, Lori K. Mattison, Tom Carollo, Hany Ezzeldin, Robert B. DiasioAbstract:Background: Dihydropyrimidine Dehydrogenase (DPD) Deficiency is prevalent in 3–5% of the Caucasian population; however, the frequency of this pharmacogenetic syndrome in the Indian population and other racial and ethnic groups remains to be elucidated. Patients and methods: We describe an Indian patient who presented to clinic for the treatment of gastric adenocarcinoma with 5-flurouracil (5-FU) therapy who subsequently was diagnosed with DPD Deficiency by using the peripheral blood mononuclear cell (PBMC) DPD radioassay. This observation prompted us to examine the data generated from healthy (cancer-free) Indian subjects who were enrolled in a large population study to determine the sensitivity and specificity of the uracil breath test (UraBT) in the detection of DPD Deficiency. Thirteen Indian subjects performed the UraBT. UraBT results were confirmed by PBMC DPD radioassay. Results: The Indian cancer patient demonstrated reduced DPD activity (0.11 nmol/min/mg protein) and severe 5-FU toxicities commonly associated with DPD Deficiency. Of the 13 Indian subjects [ten men and three women; mean age, 26 years (range: 21–31 years)] enrolled in the UraBT, 12 Indian subjects demonstrated UraBT breath profiles and PBMC DPD activity within the normal range; one Indian subject demonstrated a reduced breath profile and partial DPD Deficiency. Conclusions: DPD Deficiency is a pharmacogenetic syndrome which is also present in the Indian population. If undiagnosed, the DPD Deficiency can lead to death. Future epidemiological studies would be helpful to determine the prevalence of DPD Deficiency among racial and ethnic groups, allowing for the optimization of 5-FU chemotherapy.
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Methylation of the DPYD promoter: an alternative mechanism for Dihydropyrimidine Dehydrogenase Deficiency in cancer patients.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2005Co-Authors: Hany Ezzeldin, Lori K. Mattison, Adam M. Lee, Robert B. DiasioAbstract:Dihydropyrimidine Dehydrogenase (DPD) Deficiency, a known pharmacogenetic syndrome associated with 5-fluorouracil (5-FU) toxicity, has been detected in 3% to 5% of the population. Genotypic studies have identified >32 sequence variants in the DPYD gene; however, in a number of cases, sequence variants could not explain the molecular basis of DPD Deficiency. Recent studies in cell lines indicate that hypermethylation of the DPYD promoter might down-regulate DPD expression. The current study investigates the role of methylation in cancer patients with an unexplained molecular basis of DPD Deficiency. DPD Deficiency was identified phenotypically by both enzyme assay and uracil breath test, and genotypically by denaturing high-performance liquid chromatography. The methylation status was evaluated in PCR products (209 bp) of bisulfite-modified DPYD promoter, using a novel denaturing high-performance liquid chromatography method that distinguishes between methylated and unmethylated alleles. Clinical samples included five volunteers with normal DPD enzyme activity, five DPD-deficient volunteers, and five DPD-deficient cancer patients with a history of 5-FU toxicity. No evidence of methylation was detected in samples from volunteers with normal DPD. Methylation was detected in five of five DPD-deficient volunteers and in three of five of the DPD-deficient cancer patient samples. Of note, one of the two samples from patients with DPD-deficient cancer with no evidence of methylation had the mutation DPYD*2A, whereas the other had DPYD*13. Methylation of the DPYD promoter region is associated with down-regulation of DPD activity in clinical samples and should be considered as a potentially important regulatory mechanism of DPD activity and basis for 5-FU toxicity in cancer patients.