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Metabolites
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Inborn Errors of Metabolism
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Inborn Errors of Metabolism

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (30 September 2014) | Viewed by 72333

Special Issue Editor

Dr. Maria Fuller

E-Mail Website
Guest Editor
1. Genetics and Molecular Pathology, SA Pathology (at Women's and Children's Hospital), North Adelaide 5006, Australia
2. Adelaide Medical School, University of Adelaide, Adelaide 5005, Australia
Interests: lysosomal storage disorders; diagnosis of inborn errors of metabolism; understanding and treating inherited neurodegenerative disease
Special Issues, Collections and Topics in MDPI journals

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

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

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

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Published Papers (5 papers)

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Research

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373 KiB  
Article
Distribution of Heparan Sulfate Oligosaccharides in Murine Mucopolysaccharidosis Type IIIA
by Kerryn Mason, Peter Meikle, John Hopwood and Maria Fuller
Metabolites 2014, 4(4), 1088-1100; https://doi.org/10.3390/metabo4041088 - 11 Dec 2014
Cited by 7 | Viewed by 6213
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 resulting [...] 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)
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Review

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1303 KiB  
Review
Neural Tube Defects: From a Proteomic Standpoint
by Tania M. Puvirajesinghe and Jean-Paul Borg
Metabolites 2015, 5(1), 164-183; https://doi.org/10.3390/metabo5010164 - 17 Mar 2015
Cited by 4 | Viewed by 7494
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 multigene [...] 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)
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240 KiB  
Review
New Strategies for the Treatment of Phenylketonuria (PKU)
by Pietro Strisciuglio and Daniela Concolino
Metabolites 2014, 4(4), 1007-1017; https://doi.org/10.3390/metabo4041007 - 4 Nov 2014
Cited by 51 | Viewed by 31760
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 review [...] 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)
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337 KiB  
Review
Clinically Important Features of Porphyrin and Heme Metabolism and the Porphyrias
by Siddesh Besur, Wehong Hou, Paul Schmeltzer and Herbert L. Bonkovsky
Metabolites 2014, 4(4), 977-1006; https://doi.org/10.3390/metabo4040977 - 3 Nov 2014
Cited by 99 | Viewed by 16101
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 on [...] 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)
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1010 KiB  
Review
Establishment of Glycosaminoglycan Assays for Mucopolysaccharidoses
by Shunji Tomatsu, Tsutomu Shimada, Robert W. Mason, Adriana M. Montaño, Joan Kelly, William A. LaMarr, Francyne Kubaski, Roberto Giugliani, Aratrik Guha, Eriko Yasuda, William Mackenzie, Seiji Yamaguchi, Yasuyuki Suzuki and Tadao Orii
Metabolites 2014, 4(3), 655-679; https://doi.org/10.3390/metabo4030655 - 11 Aug 2014
Cited by 46 | Viewed by 9473
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 been [...] 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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