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An incidental case of dihydropyrimidine dehydrogenase deficiency: One case, multiple challenges.

ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder that shows large phenotypical variability, ranging from no symptoms to intellectual disability, motor retardation, and convulsions. In addition, homozygous and heterozygous mutation carriers can develop severe 5-fluorouracil (5-FU) toxicity. The lack of genotype-phenotype correlation and the possibility of other factors playing a role in the manifestation of the neurological abnormalities, make the management and education of asymptomatic DPD individuals more challenging. We describe a 3-month-old baby who was incidentally found by urine organic acid testing (done as part of positive newborn screen) to have very high level of thymine and uracil, consistent with DPD deficiency. Since the prevalence of asymptomatic DPD deficiency in the general population is fairly significant (1 in 10,000), we emphasize in this case study the importance of developing a guideline in genetic counseling and patient education for this condition as well as other incidental laboratory findings.

SUBMITTER: Al Khallaf HH

PROVIDER: S-EPMC3897149 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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An incidental case of dihydropyrimidine dehydrogenase deficiency: One case, multiple challenges.

Al Khallaf Hamoud H HH He Miao M Wittenauer Angela A Woolley Elizabeth E EE Cunto Mariagrazia M Pervaiz Muhammad Ali MA

Indian journal of human genetics 20131001 4

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder that shows large phenotypical variability, ranging from no symptoms to intellectual disability, motor retardation, and convulsions. In addition, homozygous and heterozygous mutation carriers can develop severe 5-fluorouracil (5-FU) toxicity. The lack of genotype-phenotype correlation and the possibility of other factors playing a role in the manifestation of the neurological abnormalities, make the management and ...[more]

PMID: 24497719

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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:BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage in myofibers. Most MADD patients greatly benefit from riboflavin supplementation.Patients and methodsA retrospective study was conducted on patients with a diagnosis of vacuolar myopathy with lipid storage followed in our neuromuscular unit in the last 20 years. We selected 10 unrelated patients with the diagnosis of MADD according to clinical, morphological, and biochemical aspects. Clinical features, blood tests including serum acylcarnitines, EMG, and ENG were revised. Muscle biopsy was performed in all, and one individual underwent also a sural nerve biopsy. Gene sequencing of ETFA, ETFB, and ETFDH was performed as a first-tier genetic analysis followed by next-generation sequencing of an hyperCKemia gene panel in patients with undefined genotypes.ResultsClinical evaluation at onset in all our patients showed fatigue and muscle weakness; four patients showed difficulties in chewing, three patients complained of dysphagia, two patients had a dropped head, and a patient had an unexpected ataxia with numbness and dysesthesia. Laboratory blood tests revealed a variable increase in serum CK (266-6,500) and LDH levels (500-2,000). Plasma acylcarnitine profile evidenced increased levels of different chains intermediates. EMG was either normal or showed myogenic or neurogenic patterns. NCS demonstrated sensory neuropathy in two patients. Muscle biopsies showed a vacuolar myopathy with a variable increase in lipid content. Nerve biopsy evidenced an axonal degeneration with the loss of myelinated fibers. ETFDH genetic analysis identifies 14 pathogenic variants. Patients were treated with high doses of riboflavin (400 mg/die). All of them showed a rapid muscle strength improvement and normalization of abnormal values in laboratory tests. Neuropathic symptoms did not improve.ConclusionOur data confirmed that clinical features in MADD patients are extremely variable in terms of disease onset and symptoms making diagnosis difficult. Laboratory investigations, such as serum acylcarnitine profile and muscle biopsy evaluation, may strongly address to a correct diagnosis. The favorable response to riboflavin supplementation strengthens the importance of an early diagnosis of these disorders among the spectrum of metabolic myopathies.

Dataset Information

An incidental case of dihydropyrimidine dehydrogenase deficiency: One case, multiple challenges.

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An incidental case of dihydropyrimidine dehydrogenase deficiency: One case, multiple challenges.

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