Hereditary Orotic Aciduria with Epilepsy and without Megaloblastic Anemia

Grohmann, Karina; Lauffer, Heinz; Lauenstein, Peter; Hoffmann, Georg F.; Seidlitz, G

doi:10.1055/s-0035-1547341

Cited by 21 publications

(9 citation statements)

References 3 publications

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“…It might be due to a common analyte detected for example hereditary orotic aciduria as described below, or as part of the clinical differential diagnosis, for example, elevated citrulline in dihydrolipoamide dehydrogenase deficiency. 8 Hereditary orotic aciduria 11 is such a condition detected by our screening program. During the study period, seven cases of hereditary orotic aciduria were diagnosed and will be the subject of a separate publication.…”

Section: Discussionmentioning

confidence: 99%

“…9 Sensitivity of newborn screening for hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome is poor since ornithine level may be within the normal range in the first days of life, 10 and arginase deficiency (ARGD argininemia, MIM # 207800) is very rare. 11 Indeed, neither ARGD nor HHH has been identified in our 12 years of expanded NBS. Most NBS programs do not currently screen for the proximal UCDs N-acetylglutamate synthase deficiency (NAGSD, MIM #237310), Carbamoyl phosphate synthetase I deficiency (CPS1D, MIM # 237300) and OTCD due to the general instability of glutamine and the low specificity and sensitivity of low citrulline levels.…”

Section: Introductionmentioning

confidence: 89%

“…It may also be increased in the distal UCDs ASSD, ASLD, and ARGD, as well as in disorders due to defects of genes encoding cationic amino acid transporters such as the mitochondrial ornithine transporter 1 deficiency (ORNT 1; HHH syndrome, MIM # 238970), and the lysine transporter y + LAT-1 (SLC7A7; LPI, lysinuric protein intolerance, MIM # 222700). Increased orotic acid excretion also serves as a metabolic marker for orotic aciduria, a pyrimidine synthesis defect caused by uridine-5-monophosphate synthase deficiency (UMPS) 11 (MIM # 258900 and 258 920). D'Apolito in 2010 and in 2012 as well as Janzen and Held in 2014 described the method for orotic acid (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid; uracil-6-carboxylic acid) quantification from dried blood spots (DBS) by tandem mass spectrometry.…”

Section: Introductionmentioning

confidence: 99%

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The role of orotic acid measurement in routine newborn screening for urea cycle disorders

Staretz‐Chacham¹,

Daas

Ulanovsky

et al. 2020

J of Inher Metab Disea

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Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life‐threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow‐up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early‐onset and two males with late‐onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of orotic acid measurement in routine newborn screening for urea cycle disorders

Staretz‐Chacham¹,

Daas

Ulanovsky

et al. 2020

J of Inher Metab Disea

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“…To the best of our knowledge, the LC-MS/MS assay developed and presented here is the first one published to include the biomarkers SAICAr, AICAr, beta-ureidoisobutyric acid, 2,8-dihydroxyadenine and orotidine in a single method, in addition to the previously reported panel of purines and pyrimidines. This extension is expected to facilitate the detection of the disorders ADSL [1, 3], ATIC [1, 3], UPB1 [2, 3], APRT [1, 3] and UMPS [2, 18, 19], respectively, together with the deficiencies of HGPRT [1, 3], molybdenum cofactor (MoCoD) [1, 3], thymidine phosphorylase (TP) [2, 3], dihydropyrimidine dehydrogenase (DPD) [2, 3] and dihydropyrimidinase (DHP) [2, 3]. Based on the analyte panel, the presented assay should additionally be able to detect deficiencies of adenosine deaminase (ADA) [1, 3], purine nucleoside phosphorylase (PNP) [1, 3] and xanthine dehydrogenase (XDH) [1, 3], as well as phosphoribosylpyrophosphate synthetase (PRPPS) superactivity [1, 3].…”

Section: Discussionmentioning

confidence: 99%

Extended diagnosis of purine and pyrimidine disorders from urine: LC MS/MS assay development and clinical validation

et al. 2019

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Background and aims Inborn errors of purine and pyrimidine metabolism are a diverse group of disorders with possible serious or life-threatening symptoms. They may be associated with neurological symptoms, renal stone disease or immunodeficiency. However, the clinical presentation can be nonspecific and mild so that a number of cases may be missed. Previously published assays lacked detection of certain diagnostically important biomarkers, including SAICAr, AICAr, beta-ureidoisobutyric acid, 2,8-dihydroxyadenine and orotidine, necessitating the use of separate assays for their detection. Moreover, the limited sensitivity for some analytes in earlier assays may have hampered the reliable detection of mild cases. Therefore, we aimed to develop a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay that allows the simultaneous and sensitive detection of an extended range of purine and pyrimidine biomarkers in urine. Methods The assay was developed and validated using LC-MS/MS and clinically tested by analyzing ERNDIM Diagnostic Proficiency Testing (DPT) samples and further specimens from patients with various purine and pyrimidine disorders. Results Reliable determination of 27 analytes including SAICAr, AICAr, beta-ureidoisobutyric acid, 2,8-dihydroxyadenine and orotidine was achieved in urine following a simple sample preparation. The method clearly distinguished pathological and normal samples and differentiated between purine and pyrimidine defects in all clinical specimens. Conclusions A LC-MS/MS assay allowing the simultaneous, sensitive and reliable diagnosis of an extended range of purine and pyrimidine disorders has been developed. The validated method has successfully been tested using ERNDIM Diagnostic Proficiency Testing (DPT) samples and further clinical specimens from patients with various purine and pyrimidine disorders. Sample preparation is simple and assay duration is short, facilitating an easier inclusion of the assay into the diagnostic procedures.

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“…If untreated this disorder can lead to neutropenia, failure to thrive, growth retardation, sparse hair and nail growth, developmental delay, intellectual disability, and epilepsy. Gross excretion of orotic acid may also cause crystalluria in later life (Bailey 2009; Grohmann et al 2015). …”

Section: Introductionmentioning

confidence: 99%

Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences

Wortmann

Chen²,

Colombo

et al. 2017

J of Inher Metab Disea

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BackgroundElevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue.Methods and resultsWe identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members.ConclusionsWe therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias.

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Hereditary Orotic Aciduria with Epilepsy and without Megaloblastic Anemia

Cited by 21 publications

References 3 publications

The role of orotic acid measurement in routine newborn screening for urea cycle disorders

The role of orotic acid measurement in routine newborn screening for urea cycle disorders

Extended diagnosis of purine and pyrimidine disorders from urine: LC MS/MS assay development and clinical validation

Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences

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