Dataset Information

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

ABSTRACT: 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.We report on a boy with intellectual disability, significant impairment of speech development, highly active epileptiform discharges on EEG, microcephaly and impaired gross-motor development. This clinical presentation triggered metabolic workup that demonstrated the biochemical phenotype of DPD deficiency, which was confirmed by enzymatic and molecular genetic studies. The patient proved to be homozygous for a novel c.2059-22T>G mutation which resulted in an in-frame insertion of 21 base pairs (c.2059-21_c.2059-1) of intron 16 of DPYD. Family investigation showed that the asymptomatic father was also homozygous for the same mutation and enzymatic and biochemical findings were similar to his severely affected son. When the child deteriorated clinically, exome sequencing was initiated under the hypothesis that DPD deficiency did not explain the phenotype completely. A deletion of the maternal allele on chromosome 15q11.2-13-1 was identified allowing the diagnosis of Angelman syndrome (AS). This diagnosis explains the patient's clinical presentation sufficiently; the influence of DPD deficiency on the phenotype, however, remains uncertain.

SUBMITTER: Fleger M

PROVIDER: S-EPMC5740048 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

Fleger M M Willomitzer J J Meinsma R R Alders M M Meijer J J Hennekam R C M RCM Huemer M M van Kuilenburg A B P ABP

JIMD reports 20170309

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.We report on a boy with intellectual disability, signif ...[more]

PMID: 28275972

Similar Datasets

Project description:BackgroundThe main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations.MethodsThe survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted.ResultsWe received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics.ConclusionsThe EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

Project description:BackgroundPretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD-deficient patients remains elusive.MethodsAmong a nationwide cohort of 5886 phenotyped patients with cancer who were screened for DPD deficiency over a 3 years period, we assessed the characteristics of both DPD phenotypes and DPYD genotypes in a subgroup of 3680 patients who had completed the two tests. The extent to which defective allelic variants of DPYD predict DPD activity as estimated by the plasma concentrations of uracil [U] and its product dihydrouracil [UH2] was evaluated.ResultsWhen [U] was used to monitor DPD activity, 6.8% of the patients were classified as having DPD deficiency ([U] > 16 ng/ml), while the [UH2]:[U] ratio identified 11.5% of the patients as having DPD deficiency (UH2]:[U] < 10). [U] classified two patients (0.05%) with complete DPD deficiency (> 150 ng/ml), and [UH2]:[U] < 1 identified three patients (0.08%) with a complete DPD deficiency. A defective DPYD variant was present in 4.5% of the patients, and two patients (0.05%) carrying 2 defective variants of DPYD were predicted to have low metabolism. The mutation status of DPYD displayed a very low positive predictive value in identifying individuals with DPD deficiency, although a higher predictive value was observed when [UH2]:[U] was used to measure DPD activity. Whole exon sequencing of the DPYD gene in 111 patients with DPD deficiency and a "wild-type" genotype (based on the four most common variants) identified seven heterozygous carriers of a defective allelic variant.ConclusionsFrequent genetic DPYD variants have low performances in predicting partial DPD deficiency when evaluated by [U] alone, and [UH2]:[U] might better reflect the impact of genetic variants on DPD activity. A clinical trial comparing toxicity rates after dose adjustment according to the results of genotyping or phenotyping testing to detect DPD deficiency will provide critical information on the best strategy to identify DPD deficiency.

Project description:Dihydrolipoamide dehydrogenase (DLD; E3) oxidizes lipoic acid. Restoring the oxidized state allows lipoic acid to act as a necessary electron sink for the four mitochondrial keto-acid dehydrogenases: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain α-keto-acid dehydrogenase, and 2-oxoadipate dehydrogenase. DLD deficiency (DLDD) is caused by biallelic pathogenic variants in DLD. Three major forms have been described: encephalopathic, hepatic, and myopathic, although DLDD patients exhibit overlapping phenotypes. Hyperlactatemia, hyperexcretion of tricarboxylic acid cycle (TCA) metabolites and branched-chain keto acids, increased plasma branched-chain amino acids and allo-isoleucine are intermittent metabolic abnormalities reported in patients with DLDD. However, the diagnostic performance of these metabolites has never been studied. Therefore, we sought to systematically evaluate the diagnostic utility of these biomarkers for DLDD. We retrospectively analyzed the results of biochemical testing of six unrelated DLDD patients, including values obtained during both well visits and acute decompensation episodes. Elevation of branched-chain amino acid concentrations was not consistently observed. We found that five of six patients in our cohort had a maximum lifetime value of allo-isoleucine of 6 μmol/L, showing that alloisoleucine elevations even during illness may be subtle. Urine organic acid analysis (UOA) during acute decompensation episodes was abnormal in all cases; however, the pattern of abnormalities had high intersubject variability. No single biomarker was universally present, even in patients experiencing metabolic decompensation. We also observed novel biochemical associations: three patients had hyperexcretion of TCA cycle metabolites during crisis; in two patients, 2-ketoadipic and 2-hydroxyadipic acids, by products of lysine degradation, were detected. We propose that these result from 2-oxoadipate dehydrogenase deficiency, an underappreciated biochemical abnormality in DLD. Given the diversity of biochemical profiles among the patients with DLDD, we conclude that accurate biochemical diagnosis relies on a high index of suspicion and multipronged biochemical analysis, including both plasma amino acid and urine organic acid quantitation during decompensation. Biochemical diagnosis during the well state is challenging. We emphasize the critical importance of multiple simultaneous biochemical tests for diagnosis and monitoring of DLDD. We also highlight the under-recognized role of DLD in the lysine degradation pathway. Larger cohorts of patients are needed to establish a correlation between the biochemical pattern and clinical outcomes, as well as a genotype-phenotype correlation.

Dataset Information

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

Publications

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets