Special Issue "Inborn Errors of Metabolism"

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A special issue of Metabolites (ISSN 2218-1989).

Deadline for manuscript submissions: closed (30 September 2014)

Special Issue Editor

Guest Editor
Dr. Maria Fuller (Website)

Head, Translational Research Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia

Special Issue Information

Dear Colleagues,

Archibald Garrod, at the start of the twentieth century, is credited with the notion of inborn errors of metabolism by recognizing that unique hereditary factors underpin the turnover of physiological metabolites. Half a century later, headways in technology, such as chromatography and electrophoresis, defined several of the disorders studied by Garrod to actually be the result of a block at some point in normal metabolism. More than a century later, over 1500 individual diseases have been reported and future investigations into metabolic networks are likely to see this number rise. The burgeoning field of mass spectrometry has enabled screening of infants for inborn errors of metabolism to become routine practice in mainstream neonatal care with the primary aim of early detection and treatment to minimize morbidity and mortality in early childhood. Although individually rare, inborn errors of metabolism are common, and we are only now beginning to appreciate the biochemical labyrinth and phenotypical diversity of what have traditionally been considered single gene disorders.

The natural histories of inborn errors of metabolism represent the best examples of the dynamic interplay between genetics and the milieu, and as such are a powerful tool to dissect both monogeneic and multifactorial diseases. This issue is devoted to piecing together the jigsaw of unique and common pathogenic cascades and perturbations in biochemical pathways that translate the primary metabolic defect into a clinical phenotype. Novel laboratory methodologies that will enable future implementation of more informative, accurate diagnostic and prognostic testing parameters for these important inherited diseases will also be considered. Defining disease threshold and pathophysiology makes therapeutic intervention particularly challenging for many of the complex inborn errors of metabolism, as therapies need to be directed towards correcting pathology in all affected tissues to restore health. Articles addressing therapies are highly desirable.

Dr. Maria Fuller
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • metabolic pathways
  • mass spectrometry
  • inherited metabolic disease
  • newborn screening
  • laboratory diagnostics
  • metabolites
  • enzymes
  • treatment

Published Papers (5 papers)

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Research

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Open AccessArticle Distribution of Heparan Sulfate Oligosaccharides in Murine Mucopolysaccharidosis Type IIIA
Metabolites 2014, 4(4), 1088-1100; doi:10.3390/metabo4041088
Received: 22 September 2014 / Revised: 27 November 2014 / Accepted: 3 December 2014 / Published: 11 December 2014
Cited by 2 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text
Abstract
Heparan sulfate (HS) catabolism begins with endo-degradation of the polysaccharide to smaller HS oligosaccharides, followed by the sequential action of exo-enzymes to reduce these oligosaccharides to monosaccharides and inorganic sulfate. In mucopolysaccharidosis type IIIA (MPS IIIA) the exo-enzyme, N-sulfoglucosamine sulfohydrolase, is deficient [...] Read more.
Heparan sulfate (HS) catabolism begins with endo-degradation of the polysaccharide to smaller HS oligosaccharides, followed by the sequential action of exo-enzymes to reduce these oligosaccharides to monosaccharides and inorganic sulfate. In mucopolysaccharidosis type IIIA (MPS IIIA) the exo-enzyme, N-sulfoglucosamine sulfohydrolase, is deficient resulting in an inability to hydrolyze non-reducing end glucosamine N-sulfate esters. Consequently, partially degraded HS oligosaccharides with non-reducing end glucosamine sulfate esters accumulate. We investigated the distribution of these HS oligosaccharides in tissues of a mouse model of MPS IIIA using high performance liquid chromatography electrospray ionization-tandem mass spectrometry. Oligosaccharide levels were compared to total uronic acid (UA), which was used as a measure of total glycosaminoglycan. Ten oligosaccharides, ranging in size from di- to hexasaccharides, were present in all the tissues examined including brain, spleen, lung, heart, liver, kidney and urine. However, the relative levels varied up to 10-fold, suggesting different levels of HS turnover and storage. The relationship between the di- and tetrasaccharides and total UA was tissue specific with spleen and kidney showing a different disaccharide:total UA ratio than the other tissues. The hexasaccharides showed a stronger correlation with total UA in all tissue types suggesting that hexasaccharides may more accurately reflect the storage burden in these tissues. Full article
(This article belongs to the Special Issue Inborn Errors of Metabolism)

Review

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Open AccessReview Neural Tube Defects: From a Proteomic Standpoint
Metabolites 2015, 5(1), 164-183; doi:10.3390/metabo5010164
Received: 10 October 2014 / Revised: 8 February 2015 / Accepted: 4 March 2015 / Published: 17 March 2015
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Abstract
Neural tube defects (NTDs) are congenital birth defects classified according to their resulting morphological characteristics in newborn patients. Current diagnosis of NTDs relies largely on the structural evaluation of fetuses using ultrasound imaging, with biochemical characterization used as secondary screening tools. The [...] Read more.
Neural tube defects (NTDs) are congenital birth defects classified according to their resulting morphological characteristics in newborn patients. Current diagnosis of NTDs relies largely on the structural evaluation of fetuses using ultrasound imaging, with biochemical characterization used as secondary screening tools. The multigene etiology of NTDs has been aided by genetic studies, which have discovered panels of genes mutated in these diseases that encode receptors and cytoplasmic signaling molecules with poorly defined functions. Animal models ranging from flies to mice have been used to determine the function of these genes and identify their associated molecular cascades. More emphasis is now being placed on the identification of biochemical markers from clinical samples and model systems based on mass spectrometry, which open novel avenues in the understanding of NTDs at protein, metabolic and molecular levels. This article reviews how the use of proteomics can push forward the identification of novel biomarkers and molecular networks implicated in NTDs, an indispensable step in the improvement of patient management. Full article
(This article belongs to the Special Issue Inborn Errors of Metabolism)
Open AccessReview New Strategies for the Treatment of Phenylketonuria (PKU)
Metabolites 2014, 4(4), 1007-1017; doi:10.3390/metabo4041007
Received: 21 May 2014 / Revised: 27 October 2014 / Accepted: 30 October 2014 / Published: 4 November 2014
Cited by 6 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
Phenylketonuria (PKU) was the first inherited metabolic disease in which dietary treatment was found to prevent the disease’s clinical features. Treatment of phenylketonuria remains difficult due to progressive decrease in adherence to diet and the presence of neurocognitive defects despite therapy. This [...] Read more.
Phenylketonuria (PKU) was the first inherited metabolic disease in which dietary treatment was found to prevent the disease’s clinical features. Treatment of phenylketonuria remains difficult due to progressive decrease in adherence to diet and the presence of neurocognitive defects despite therapy. This review aims to summarize the current literature on new treatment strategies. Additions to treatment include new, more palatable foods based on glycomacropeptide that contains very limited amount of aromatic amino acids, the administration of large neutral amino acids to prevent phenylalanine entry into the brain or tetrahydropterina cofactor capable of increasing residual activity of phenylalanine hydroxylase. Moreover, human trials have recently been performed with subcutaneous administration of phenylalanine ammonia-lyase, and further efforts are underway to develop an oral therapy containing phenylanine ammonia-lyase. Gene therapy also seems to be a promising approach in the near future. Full article
(This article belongs to the Special Issue Inborn Errors of Metabolism)
Open AccessReview Clinically Important Features of Porphyrin and Heme Metabolism and the Porphyrias
Metabolites 2014, 4(4), 977-1006; doi:10.3390/metabo4040977
Received: 31 May 2014 / Revised: 14 October 2014 / Accepted: 16 October 2014 / Published: 3 November 2014
Cited by 11 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based [...] Read more.
Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic porphyrias are further subdivided into acute porphyrias and chronic hepatic porphyrias. The acute porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic porphyrias include congenital erythropoietic porphyria (Gűnther’s disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria. Full article
(This article belongs to the Special Issue Inborn Errors of Metabolism)
Open AccessReview Establishment of Glycosaminoglycan Assays for Mucopolysaccharidoses
Metabolites 2014, 4(3), 655-679; doi:10.3390/metabo4030655
Received: 18 June 2014 / Revised: 26 July 2014 / Accepted: 28 July 2014 / Published: 11 August 2014
Cited by 6 | PDF Full-text (1010 KB) | HTML Full-text | XML Full-text
Abstract
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs results in dysfunction of multiple organs, resulting in distinct clinical manifestations. A range of methods have [...] Read more.
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs results in dysfunction of multiple organs, resulting in distinct clinical manifestations. A range of methods have been developed to measure specific GAGs in various human samples to investigate diagnosis, prognosis, pathogenesis, GAG interaction with other molecules, and monitoring therapeutic efficacy. We established ELISA, liquid chromatography tandem mass spectrometry (LC-MS/MS), and an automated high-throughput mass spectrometry (HT-MS/MS) system (RapidFire) to identify epitopes (ELISA) or disaccharides (MS/MS) derived from different GAGs (dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate). These methods have a high sensitivity and specificity in GAG analysis, applicable to the analysis of blood, urine, tissues, and cells. ELISA is feasible, sensitive, and reproducible with the standard equipment. HT-MS/MS yields higher throughput than conventional LC-MS/MS-based methods while the HT-MS/MS system does not have a chromatographic step and cannot distinguish GAGs with identical molecular weights, leading to a limitation of measurements for some specific GAGs. Here we review the advantages and disadvantages of these methods for measuring GAG levels in biological specimens. We also describe an unexpected secondary elevation of keratan sulfate in patients with MPS that is an indirect consequence of disruption of catabolism of other GAGs. Full article
(This article belongs to the Special Issue Inborn Errors of Metabolism)

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