Inborn Errors of Metabolism

Ezgu, Fatih Süheyl

doi:10.1016/bs.acc.2015.12.001

Cited by 48 publications

(41 citation statements)

References 123 publications

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“…Generation of a comprehensive understanding of metabolic reactions in humans is important for several reasons: first, altered metabolite levels can cause clinical symptoms and diseases, as exemplified by elevated serum urate levels and gout and by many inborn errors of metabolism (IEMs) 5,6 . Such metabolites represent attractive therapeutic targets to prevent and treat these diseases.…”

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confidence: 99%

Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

et al. 2021

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Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.

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confidence: 99%

Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

et al. 2021

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“…A minority of IEMs are inherited in an autosomal dominant (AD) pattern. Another rare mode of inheritance is IEMs linked to mitochondrial DNA only of maternal origin, as in subsets of respiratory chain disorders [50,51]. The pathophysiology behind most IEM disorders is a specific enzyme defect that results in an inadequate conversion of substrates into their direct products.…”

Section: Inheritance and Causesmentioning

confidence: 99%

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics

2019

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Inborn errors of metabolism (IEMs) are a group of inherited diseases with variable incidences. IEMs are caused by disrupting enzyme activities in specific metabolic pathways by genetic mutations, either directly or indirectly by cofactor deficiencies, causing altered levels of compounds associated with these pathways. While IEMs may present with multiple overlapping symptoms and metabolites, early and accurate diagnosis of IEMs is critical for the long-term health of affected subjects. The prevalence of IEMs differs between countries, likely because different IEM classifications and IEM screening methods are used. Currently, newborn screening programs exclusively use targeted metabolic assays that focus on limited panels of compounds for selected IEM diseases. Such targeted approaches face the problem of false negative and false positive diagnoses that could be overcome if metabolic screening adopted analyses of a broader range of analytes. Hence, we here review the prospects of using untargeted metabolomics for IEM screening. Untargeted metabolomics and lipidomics do not rely on predefined target lists and can detect as many metabolites as possible in a sample, allowing to screen for many metabolic pathways simultaneously. Examples are given for nontargeted analyses of IEMs, and prospects and limitations of different metabolomics methods are discussed. We conclude that dedicated studies are needed to compare accuracy and robustness of targeted and untargeted methods with respect to widening the scope of IEM diagnostics.

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“…The treatment and management of IEMs are always individualized, based on each patient’s diagnosis and phenotype, and there is broad heterogeneity even within each category ( Argmann et al , 2016 ). Despite this heterogeneity in management approaches, the specific treatment usually falls into one of three classes: (I) enzyme replacement therapy, to replenish the deficient enzyme; (II) substrate reduction therapy; or (III) dietary treatment, although organ transplantation is also used in some cases ( Ezgu, 2016 ). Additional non-specific treatment may be necessary, depending on the presence of comorbidities, such as neuropsychiatric disorders in PKU patients ( Bilder et al , 2017 ), or renal and neurologic impairment in patients with tyrosinemia type I ( Santra et al , 2008 ; Chinsky et al , 2017 ).…”

Section: Inborn Errors Of Metabolism (Iem)mentioning

confidence: 99%

The microbiome and inborn errors of metabolism: Why we should look carefully at their interplay?

2018

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Research into the influence of the microbiome on the human body has been shedding new light on diseases long known to be multifactorial, such as obesity, mood disorders, autism, and inflammatory bowel disease. Although inborn errors of metabolism (IEMs) are monogenic diseases, genotype alone is not enough to explain the wide phenotypic variability observed in patients with these conditions. Genetics and diet exert a strong influence on the microbiome, and diet is used (alone or as an adjuvant) in the treatment of many IEMs. This review will describe how the effects of the microbiome on the host can interfere with IEM phenotypes through interactions with organs such as the liver and brain, two of the structures most commonly affected by IEMs. The relationships between treatment strategies for some IEMs and the microbiome will also be addressed. Studies on the microbiome and its influence in individuals with IEMs are still incipient, but are of the utmost importance to elucidating the phenotypic variety observed in these conditions.

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Inborn Errors of Metabolism

Cited by 48 publications

References 123 publications

Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics

The microbiome and inborn errors of metabolism: Why we should look carefully at their interplay?

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