[Gene therapy for the treatment of inborn errors of metabolism].

PubMed

Pérez-López, Jordi

2014-06-16

Due to the enzymatic defect in inborn errors of metabolism, there is a blockage in the metabolic pathways and an accumulation of toxic metabolites. Currently available therapies include dietary restriction, empowering of alternative metabolic pathways, and the replacement of the deficient enzyme by cell transplantation, liver transplantation or administration of the purified enzyme. Gene therapy, using the transfer in the body of the correct copy of the altered gene by a vector, is emerging as a promising treatment. However, the difficulty of vectors currently used to cross the blood brain barrier, the immune response, the cellular toxicity and potential oncogenesis are some limitations that could greatly limit its potential clinical application in human beings. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

PubMed Central

Byers, Stephanie L; Ficicioglu, Can

2014-01-01

Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of “red flags” which should prompt additional evaluation. PMID:25429327

Treatable newborn and infant seizures due to inborn errors of metabolism.

PubMed

Campistol, Jaume; Plecko, Barbara

2015-09-01

About 25% of seizures in the neonatal period have causes other than asphyxia, ischaemia or intracranial bleeding. Among these are primary genetic epileptic encephalopathies with sometimes poor prognosis and high mortality. In addition, some forms of neonatal infant seizures are due to inborn errors of metabolism that do not respond to common AEDs, but are amenable to specific treatment. In this situation, early recognition can allow seizure control and will prevent neurological deterioration and long-term sequelae. We review the group of inborn errors of metabolism that lead to newborn/infant seizures and epilepsy, of which the treatment with cofactors is very different to that used in typical epilepsy management.

Viral symbiosis and the holobiontic nature of the human genome.

PubMed

Ryan, Francis Patrick

2016-01-01

The human genome is a holobiontic union of the mammalian nuclear genome, the mitochondrial genome and large numbers of endogenized retroviral genomes. This article defines and explores this symbiogenetic pattern of evolution, looking at the implications for human genetics, epigenetics, embryogenesis, physiology and the pathogenesis of inborn errors of metabolism and many other diseases. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Expanded newborn metabolic screening programme in Hong Kong: a three-year journey.

PubMed

Chong, S C; Law, L K; Hui, J; Lai, C Y; Leung, T Y; Yuen, Y P

2017-10-01

No universal expanded newborn screening service for inborn errors of metabolism is available in Hong Kong despite its long history in developed western countries and rapid development in neighbouring Asian countries. To increase the local awareness and preparedness, the Centre of Inborn Errors of Metabolism of the Chinese University of Hong Kong started a private inborn errors of metabolism screening programme in July 2013. This study aimed to describe the results and implementation of this screening programme. We retrieved the demographics of the screened newborns and the screening results from July 2013 to July 2016. These data were used to calculate quality metrics such as call-back rate and false-positive rate. Clinical details of true-positive and false-negative cases and their outcomes were described. Finally, the call-back logistics for newborns with positive screening results were reviewed. During the study period, 30 448 newborns referred from 13 private and public units were screened. Of the samples, 98.3% were collected within 7 days of life. The overall call-back rate was 0.128% (39/30 448) and the false-positive rate was 0.105% (32/30 448). Six neonates were confirmed to have inborn errors of metabolism, including two cases of medium-chain acyl-coenzyme A dehydrogenase deficiency, one case of carnitine-acylcarnitine translocase deficiency, and three milder conditions. One case of maternal carnitine uptake defect was diagnosed. All patients remained asymptomatic at their last follow-up. The Centre of Inborn Errors of Metabolism has established a comprehensive expanded newborn screening programme for selected inborn errors of metabolism. It sets a standard against which the performance of other private newborn screening tests can be compared. Our experience can also serve as a reference for policymakers when they contemplate establishing a government-funded universal expanded newborn screening programme in the future.

Congenital Disorders of Glycosylation and Intellectual Disability

ERIC Educational Resources Information Center

Wolfe, Lynne A.; Krasnewich, Donna

2013-01-01

The congenital disorders of glycosylation (CDG) are a rapidly growing group of inborn errors of metabolism that result from defects in the synthesis of glycans. Glycosylation is a major post-translational protein modification and an estimated 2% of the human genome encodes proteins for glycosylation. The molecular bases for the current 60…

Modeling congenital disease and inborn errors of development in Drosophila melanogaster

PubMed Central

Moulton, Matthew J.; Letsou, Anthea

2016-01-01

ABSTRACT Fly models that faithfully recapitulate various aspects of human disease and human health-related biology are being used for research into disease diagnosis and prevention. Established and new genetic strategies in Drosophila have yielded numerous substantial successes in modeling congenital disorders or inborn errors of human development, as well as neurodegenerative disease and cancer. Moreover, although our ability to generate sequence datasets continues to outpace our ability to analyze these datasets, the development of high-throughput analysis platforms in Drosophila has provided access through the bottleneck in the identification of disease gene candidates. In this Review, we describe both the traditional and newer methods that are facilitating the incorporation of Drosophila into the human disease discovery process, with a focus on the models that have enhanced our understanding of human developmental disorders and congenital disease. Enviable features of the Drosophila experimental system, which make it particularly useful in facilitating the much anticipated move from genotype to phenotype (understanding and predicting phenotypes directly from the primary DNA sequence), include its genetic tractability, the low cost for high-throughput discovery, and a genome and underlying biology that are highly evolutionarily conserved. In embracing the fly in the human disease-gene discovery process, we can expect to speed up and reduce the cost of this process, allowing experimental scales that are not feasible and/or would be too costly in higher eukaryotes. PMID:26935104

21 CFR 882.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

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Code of Federal Regulations, 2012 CFR

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Code of Federal Regulations, 2013 CFR

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21 CFR 886.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Code of Federal Regulations, 2013 CFR

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21 CFR 892.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Code of Federal Regulations, 2011 CFR

2011-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES General... for lay use where the former intended use was by health care professionals only; (b) The modified... use in screening or diagnosis of familial or acquired genetic disorders, including inborn errors of...

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Analysis of leukotrienes in cerebrospinal fluid of a reference population and patients with inborn errors of metabolism: further evidence for a pathognomonic profile in LTC(4)-synthesis deficiency.

PubMed

Mayatepek, E; Zelezny, R; Hoffmann, G F

2000-02-25

Cysteinyl leukotrienes (LTC(4), LTD(4), LTE(4)) are potent lipid mediators derived from arachidonate in the 5-lipoxygenase pathway. Recently, the first inborn error of leukotriene synthesis, LTC(4)-synthesis deficiency, has been identified in association with a fatal developmental syndrome. The absence of leukotrienes in cerebrospinal fluid was one of the most striking biochemical findings in this disorder. We analysed leukotrienes in cerebrospinal fluid of patients with a broad spectrum of other well-defined inborn errors of metabolism, including glutathione synthetase deficiency (n=2), Zellweger syndrome (n=3), mitochondrial disorders (n=8), fatty acid oxidation defects (n=7), organic acidurias (n=7), neurotransmitter defects (n=5) and patients with non-specific neurological symptoms, as a reference population (n=120). The concentrations of leukotrienes were not related to age. Representative percentiles were calculated as reference intervals of each leukotriene. In all patients with an inborn error of metabolism concentration of cysteinyl leukotrienes and LTB(4) did not differ from the reference group. Our results indicate that absence of cysteinyl leukotrienes (<5 pg/ml) in association with normal or increased LTB(4) (50.0-67.3 pg/ml) is pathognomonic for LTC(4)-synthesis deficiency. The unique profile of leukotrienes in cerebrospinal fluid in this new disorder is primarily related to the defect and represents a new diagnostic approach.

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2014-04-01

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Code of Federal Regulations, 2011 CFR

2011-04-01

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Code of Federal Regulations, 2012 CFR

2012-04-01

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21 CFR 874.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Code of Federal Regulations, 2013 CFR

2013-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES... for lay use where the former intended use was by health care professionals only; (b) The modified... use in screening or diagnosis of familial or acquired genetic disorders, including inborn errors of...

Malformation syndromes caused by disorders of cholesterol synthesis

PubMed Central

Porter, Forbes D.; Herman, Gail E.

2011-01-01

Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome. PMID:20929975

Unraveling the unknown areas of the human metabolome: the role of infrared ion spectroscopy.

PubMed

Martens, Jonathan; Berden, Giel; Bentlage, Herman; Coene, Karlien L M; Engelke, Udo F; Wishart, David; van Scherpenzeel, Monique; Kluijtmans, Leo A J; Wevers, Ron A; Oomens, Jos

2018-05-01

The identification of molecular biomarkers is critical for diagnosing and treating patients and for establishing a fundamental understanding of the pathophysiology and underlying biochemistry of inborn errors of metabolism. Currently, liquid chromatography/high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy are the principle methods used for biomarker research and for structural elucidation of small molecules in patient body fluids. While both are powerful techniques, several limitations exist that often make the identification of unknown compounds challenging. Here, we describe how infrared ion spectroscopy has the potential to be a valuable orthogonal technique that provides highly-specific molecular structure information while maintaining ultra-high sensitivity. Here, we characterize and distinguish two well-known biomarkers of inborn errors of metabolism, glutaric acid for glutaric aciduria and ethylmalonic acid for short-chain acyl-CoA dehydrogenase deficiency, using infrared ion spectroscopy. In contrast to tandem mass spectra, in which ion fragments can hardly be predicted, we show that the prediction of an IR spectrum allows reference-free identification in the case that standard compounds are either commercially or synthetically unavailable. Finally, we illustrate how functional group information can be obtained from an IR spectrum for an unknown and how this is valuable information to, for example, narrow down a list of candidate structures resulting from a database query. Early diagnosis in inborn errors of metabolism is crucial for enabling treatment and depends on the identification of biomarkers specific for the disorder. Infrared ion spectroscopy has the potential to play a pivotal role in the identification of challenging biomarkers.

Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia.

PubMed

Alfadhel, Majid; Benmeakel, Mohammed; Hossain, Mohammad Arif; Al Mutairi, Fuad; Al Othaim, Ali; Alfares, Ahmed A; Al Balwi, Mohammed; Alzaben, Abdullah; Eyaid, Wafaa

2016-09-15

Inborn errors of metabolism (IEMs) are individually rare; however, they are collectively common. More than 600 human diseases caused by inborn errors of metabolism are now recognized, and this number is constantly increasing as new concepts and techniques become available for identifying biochemical phenotypes. The aim of this study was to determine the type and distribution of IEMs in patients presenting to a tertiary care center in Saudi Arabia. We conducted a retrospective review of children diagnosed with IEMs presenting to the Pediatric Department of King Abdulaziz Medical City in Riyadh, Saudi Arabia over a 13-year period. Over the 13- year period of this retrospective cohort, the total number of live births reached 110,601. A total of 187 patients were diagnosed with IEMs, representing a incidence of 169 in 100,000 births (1:591). Of these, 121 patients (64.7 %) were identified to have small molecule diseases and 66 (35.3 %) to have large molecule diseases. Organic acidemias were the most common small molecule IEMs, while lysosomal storage disorders (LSD) were the most common large molecule diseases. Sphingolipidosis were the most common LSD. Our study confirms the previous results of the high rate of IEMs in Saudi Arabia and urges the health care strategists in the country to devise a long-term strategic plan, including an IEM national registry and a high school carrier screening program, for the prevention of such disorders. In addition, we identified 43 novel mutations that were not described previously, which will help in the molecular diagnosis of these disorders.

Clinical Metabolomics: The New Metabolic Window for Inborn Errors of Metabolism Investigations in the Post-Genomic Era

PubMed Central

Tebani, Abdellah; Abily-Donval, Lenaig; Afonso, Carlos; Marret, Stéphane; Bekri, Soumeya

2016-01-01

Inborn errors of metabolism (IEM) represent a group of about 500 rare genetic diseases with an overall estimated incidence of 1/2500. The diversity of metabolic pathways involved explains the difficulties in establishing their diagnosis. However, early diagnosis is usually mandatory for successful treatment. Given the considerable clinical overlap between some inborn errors, biochemical and molecular tests are crucial in making a diagnosis. Conventional biological diagnosis procedures are based on a time-consuming series of sequential and segmented biochemical tests. The rise of “omic” technologies offers holistic views of the basic molecules that build a biological system at different levels. Metabolomics is the most recent “omic” technology based on biochemical characterization of metabolites and their changes related to genetic and environmental factors. This review addresses the principles underlying metabolomics technologies that allow them to comprehensively assess an individual biochemical profile and their reported applications for IEM investigations in the precision medicine era. PMID:27447622

Parenteral nutrition in patients with inborn errors of metabolism - a therapeutic problem.

PubMed

Kaluzny, L; Szczepanik, M; Siwinska-Mrozek, Z; Borkowska-Klos, M; Cichy, W; Walkowiak, J

2014-06-01

Parenteral nutrition is now a standard part of supportive treatment in pediatric departments. We describe four cases in which parenteral nutrition was extremely difficult due to coincidence with inborn errors of metabolism. The first two cases was fatty acid beta-oxidation disorders associated with necrotizing enterocolitis and congenital heart disease. Thus, limitations of intravenous lipid intake made it difficult to maintain a good nutritional status. The third case was phenylketonuria associated with a facial region tumour (rhabdomyosarcoma), in which parenteral nutrition was complicated because of a high phenylalanine content in the amino acid formulas for parenteral nutrition. The fourth patient was a child with late-diagnosed tyrosinemia type 1, complicated with encephalopathy - during intensive care treatment the patient needed nutritional support, including parenteral nutrition - we observed amino acid formula problems similar to those in the phenylketonuria patient. Parenteral nutrition in children with inborn errors of metabolism is a rare, but very important therapeutic problem. Total parenteral nutrition formulas are not prepared for this group of diseases.

Inborn errors of metabolism and the human interactome: a systems medicine approach.

PubMed

Woidy, Mathias; Muntau, Ania C; Gersting, Søren W

2018-02-05

The group of inborn errors of metabolism (IEM) displays a marked heterogeneity and IEM can affect virtually all functions and organs of the human organism; however, IEM share that their associated proteins function in metabolism. Most proteins carry out cellular functions by interacting with other proteins, and thus are organized in biological networks. Therefore, diseases are rarely the consequence of single gene mutations but of the perturbations caused in the related cellular network. Systematic approaches that integrate multi-omics and database information into biological networks have successfully expanded our knowledge of complex disorders but network-based strategies have been rarely applied to study IEM. We analyzed IEM on a proteome scale and found that IEM-associated proteins are organized as a network of linked modules within the human interactome of protein interactions, the IEM interactome. Certain IEM disease groups formed self-contained disease modules, which were highly interlinked. On the other hand, we observed disease modules consisting of proteins from many different disease groups in the IEM interactome. Moreover, we explored the overlap between IEM and non-IEM disease genes and applied network medicine approaches to investigate shared biological pathways, clinical signs and symptoms, and links to drug targets. The provided resources may help to elucidate the molecular mechanisms underlying new IEM, to uncover the significance of disease-associated mutations, to identify new biomarkers, and to develop novel therapeutic strategies.

Legacies of Garrod's brilliance. One hundred years--and counting.

PubMed

Rosenberg, L E

2008-10-01

One hundred years ago--in 1908--Archibald Garrod delivered his four Croonian Lectures. In these formerly forgotten, but now famous, dissertations, Garrod first used the expression, 'inborn errors of metabolism', to describe four rare disorders: albinism, alkaptonuria, cystinuria, and pentosuria. This prescient work proposed that such disorders resulted from enzymatic defects in the catabolic pathways for amino acids and sugars. Thus, Garrod can rightfully be called the first human geneticist. Much influenced by his colleague Bateson, who brought Mendel's work to his attention, Garrod then was the first to apply Gregor Mendel's law of gene segregation to humans, the first to propose recessive inheritance in humans, and the first to point out the importance of consanguinity. He even mentioned the role of ethnicity in inherited disorders. This would have been legacy enough, but Garrod did much more. He wrote about such other 'modern' topics as genetic predisposition to common disorders; the critical importance of physicians who were also scientists; and the proper role of the university in society. Although Garrod's work and ideas were not appreciated during his lifetime, they have echoed and reverberated ever since. He can rightly be deemed one of the most profound intellectuals of the 20th century, whose bequests to science and medicine continue to increase in value. All of us who study inborn errors of metabolism and who apply our knowledge in the hope of improving the diagnosis and treatment of affected patients are, in a genuine sense, Garrodians.

Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism.

PubMed

Camp, Kathryn M; Lloyd-Puryear, Michele A; Yao, Lynne; Groft, Stephen C; Parisi, Melissa A; Mulberg, Andrew; Gopal-Srivastava, Rashmi; Cederbaum, Stephen; Enns, Gregory M; Ershow, Abby G; Frazier, Dianne M; Gohagan, John; Harding, Cary; Howell, R Rodney; Regan, Karen; Stacpoole, Peter W; Venditti, Charles; Vockley, Jerry; Watson, Michael; Coates, Paul M

2013-08-01

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers. Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Does Your Patient's Urine Turns Dark? Alkaptonuria and Low Back Ache: A Literature Review.

PubMed

Kanniyan, Kalaivanan; Pathak, Aditya C; Dhammi, Ish Kumar; Jain, Anil Kumar

2014-01-01

Alkaptonuria is a very rare inborn error of amino acid metabolism due to deficient homogentisic acid (HGA) oxidase enzyme leading to accumulation of HGA in plasma, cartilage, other tissues of human body and its excretion in urine. It has both systemic and peripheral signs and symptoms. Though low back is a common symptom of alkaptonuria but, in the absence of ochronosis it is rare. Alkaptonuria itself is very rare occurrence with no specific treatment option available to reverse the effect as yet. A 38-year-old male, embroidery worker presented with chronic low back ache with history of staining of clothes in infancy. Later on laboratory and the radiological investigation patient was diagnosed to have alkaptonuria without ochronosis. No other systemic manifestation was present. Patient was treated conservatively and responded well. Though alkaptonuria is a very rare disease, and the occurrence of low back-ache in absence of ochronosis is much rarer. One must be aware of this inborn error of metabolism. Early diagnosis though being "diagnosis of exclusion" for low back-ache, high index of suspicion is advantageous as symptomatic treatment of the alkaptonuria can be initiated and evaluation of other systemic organs can be done in early stages itself.

Hereditary urea cycle abnormality

MedlinePlus

Nagamani SCS, Lichter-Konecki U. Inborn errors of urea synthesis. In: Swaiman KF, Ashwal S, Ferriero DM, et al, ... Elsevier; 2017:chap 38. Rezvani I, Yudkoff M. Urea cycle and ... errors of metabolism. In: Martin RJ, Fanaroff AA, Walsh MC, eds. ...

Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.

PubMed Central

Stöckler, S.; Isbrandt, D.; Hanefeld, F.; Schmidt, B.; von Figura, K.

1996-01-01

In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine. Images Figure 2 PMID:8651275

Analysis of organic acids and acylglycines for the diagnosis of related inborn errors of metabolism by GC- and HPLC-MS.

PubMed

la Marca, Giancarlo; Rizzo, Cristiano

2011-01-01

The analysis of organic acids in urine is commonly included in routine procedures for detecting many inborn errors of metabolism. Many analytical methods allow for both qualitative and quantitative determination of organic acids, mainly in urine but also in plasma, serum, whole blood, amniotic fluid, and cerebrospinal fluid. Liquid-liquid extraction and solid-phase extraction using anion exchange or silica columns are commonly employed approaches for sample treatment. Before analysis can be carried out using gas chromatography-mass spectrometry, organic acids must be converted into more thermally stable, volatile, and chemically inert forms, mainly trimethylsilyl ethers, esters, or methyl esters.

Inborn errors of metabolism in Latin America: challenges and opportunities.

PubMed

Giugliani, Roberto

2010-10-01

Latin America includes more than 40 countries and possessions, and its population of 570 million has an important representation of the three main human races. The area is experiencing an economic improvement, progressively bringing the inborn errors of metabolism (IEM) to a higher level among health priorities. Challenges to the progress of the IEM field include the huge disparities, the high prevalence of malnutrition and infections, the co-existence of very different models of public health services, the unstable socio-economic and political conditions, and the difficulties in integrating the countries. However, a rapidly changing social and economic environment is presenting many opportunities to the IEM field, like the improvements in infrastructure, the concentration of the population in urban areas, the continuous growth of neonatal screening, the use of filter paper samples, the availability of internet communication, and the interest in IEM by the new population medical genetics discipline. Analyzing this picture, several proposals are presented, such as the development of activities of provision of health services, education and research as an integrated package, the increase in training of human resources, the expansion of access to diagnostic tests, and the use the neonatal screening framework to expand the provision of services. In a continent with few IEM centers, there is a major need for such groups to work in collaboration, complementing each other's capabilities, providing training of human resources, and developing joint projects. The integration of these groups into a large transnational network of reference centers would be a major task for the coming years.

What Is a Pediatric Geneticist?

MedlinePlus

... or achondroplasia) Conditions that can cause disabilities (fetal alcohol syndrome, or fragile X syndrome) Inborn errors of metabolism (cystic fibrosis, phenylketonuria, or sickle cell disease) Familial ...

Text-based phenotypic profiles incorporating biochemical phenotypes of inborn errors of metabolism improve phenomics-based diagnosis.

PubMed

Lee, Jessica J Y; Gottlieb, Michael M; Lever, Jake; Jones, Steven J M; Blau, Nenad; van Karnebeek, Clara D M; Wasserman, Wyeth W

2018-05-01

Phenomics is the comprehensive study of phenotypes at every level of biology: from metabolites to organisms. With high throughput technologies increasing the scope of biological discoveries, the field of phenomics has been developing rapid and precise methods to collect, catalog, and analyze phenotypes. Such methods have allowed phenotypic data to be widely used in medical applications, from assisting clinical diagnoses to prioritizing genomic diagnoses. To channel the benefits of phenomics into the field of inborn errors of metabolism (IEM), we have recently launched IEMbase, an expert-curated knowledgebase of IEM and their disease-characterizing phenotypes. While our efforts with IEMbase have realized benefits, taking full advantage of phenomics requires a comprehensive curation of IEM phenotypes in core phenomics projects, which is dependent upon contributions from the IEM clinical and research community. Here, we assess the inclusion of IEM biochemical phenotypes in a core phenomics project, the Human Phenotype Ontology. We then demonstrate the utility of biochemical phenotypes using a text-based phenomics method to predict gene-disease relationships, showing that the prediction of IEM genes is significantly better using biochemical rather than clinical profiles. The findings herein provide a motivating goal for the IEM community to expand the computationally accessible descriptions of biochemical phenotypes associated with IEM in phenomics resources.

Does Your Patient’s Urine Turns Dark? Alkaptonuria and Low Back Ache: A Literature Review

PubMed Central

Kanniyan, Kalaivanan; Pathak, Aditya C; Dhammi, Ish Kumar; Jain, Anil Kumar

2014-01-01

Introduction: Alkaptonuria is a very rare inborn error of amino acid metabolism due to deficient homogentisic acid (HGA) oxidase enzyme leading to accumulation of HGA in plasma, cartilage, other tissues of human body and its excretion in urine. It has both systemic and peripheral signs and symptoms. Though low back is a common symptom of alkaptonuria but, in the absence of ochronosis it is rare. Alkaptonuria itself is very rare occurrence with no specific treatment option available to reverse the effect as yet. Case Report: A 38-year-old male, embroidery worker presented with chronic low back ache with history of staining of clothes in infancy. Later on laboratory and the radiological investigation patient was diagnosed to have alkaptonuria without ochronosis. No other systemic manifestation was present. Patient was treated conservatively and responded well. Conclusion: Though alkaptonuria is a very rare disease, and the occurrence of low back-ache in absence of ochronosis is much rarer. One must be aware of this inborn error of metabolism. Early diagnosis though being “diagnosis of exclusion” for low back-ache, high index of suspicion is advantageous as symptomatic treatment of the alkaptonuria can be initiated and evaluation of other systemic organs can be done in early stages itself. PMID:27298997

Stem Cell Transplant for Inborn Errors of Metabolism

ClinicalTrials.gov

2017-12-03

Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

Alkaptonuria--first inborn error of metabolism known for a century and new treatment option--preliminary report.

PubMed

Sykut-Cegielska, Jolanta

2015-01-01

Alkaptonuria is a rare inborn error of metabolism, identified over a century ago. But its basic pathomechanism (i.e. ochronosis) is still not completely explained. Though clinical onset of osteoarthropathy and complications from other organs (including: heart and blood vessels, skin, eyes, kidneys) occurs at adult age, the symptoms are progressive, cause severe pains and significantly limit everyday life of the patients. Until now no effective therapeutic methods have been known in alkaptonuria. Recently, thanks to an initiative of the international patient organization for alkaptonuria, a hope for a potential treatment availability, appears. So, alkaptonuria is an example of a role of multidysciplinary care, cooperation and ongoing progress in the area of rare diseases.

Cost-benefit analysis: newborn screening for inborn errors of metabolism in Lebanon.

PubMed

Khneisser, I; Adib, S; Assaad, S; Megarbane, A; Karam, P

2015-12-01

Few countries in the Middle East-North Africa region have adopted national newborn screening for inborn errors of metabolism by tandem mass spectrometry (MS/MS). We aimed to evaluate the cost-benefit of newborn screening for such disorders in Lebanon, as a model for other developing countries in the region. Average costs of expected care for inborn errors of metabolism cases as a group, between ages 0 and 18, early and late diagnosed, were calculated from 2007 to 2013. The monetary value of early detection using MS/MS was compared with that of clinical "late detection", including cost of diagnosis and hospitalizations. During this period, 126000 newborns were screened. Incidence of detected cases was 1/1482, which can be explained by high consanguinity rates in Lebanon. A reduction by half of direct cost of care, reaching on average 31,631 USD per detected case was shown. This difference more than covers the expense of starting a newborn screening programme. Although this model does not take into consideration the indirect benefits of the better quality of life of those screened early, it can be argued that direct and indirect costs saved through early detection of these disorders are important enough to justify universal publicly-funded screening, especially in developing countries with high consanguinity rates, as shown through this data from Lebanon. © The Author(s) 2015.

Histidinemia and Infantile Autism

ERIC Educational Resources Information Center

Kotsopoulos, S.; Kutty, K. M.

1979-01-01

The article presents a case history of a boy with both infantile autism and histidenia (an inborn error of amino acid metabolism), and discusses the possible relationship between the two conditions. (DLS)

Glutathione Synthetase Deficiency, an Inborn Error of Metabolism Involving the γ-Glutamyl Cycle in Patients with 5-Oxoprolinuria (Pyroglutamic Aciduria)

PubMed Central

Wellner, Vaira P.; Sekura, Ronald; Meister, Alton; Larsson, Agne

1974-01-01

Enzyme studies on placenta, cultured skin fibroblasts, and erythrocytes from two sisters with the inborn error 5-oxoprolinuria (pyroglutamic aciduria) indicate that the metabolic lesion in this disease is at the glutathione synthetase (EC 6.3.2.3) step of the γ-glutamyl cycle. Excessive urinary excretion of 5-oxoproline by these patients appears to be associated with increased synthesis of γ-glutamyl-cysteine and formation of 5-oxoproline from this dipeptide. Thus, 5-oxoproline is produced in amounts that exceed the normal capacity of 5-oxoprolinase to convert it to glutamate. The data indicate that it may be possible to identify individuals who are heterozygous for this trait by determinations of erythrocyte glutathione synthetase. PMID:4152248

Henry Friesen Award Lecture. Work, the clinician-scientist and human biochemical genetics.

PubMed

Scriver, C R

2001-08-01

The pursuit of human biochemical genetics has allowed us to understand better how the person with the (genetic) disease differs from the disease the person has and to develop the concept that genetics belongs in all aspects of health care. It is a perspective that comes quite readily to the clinician-scientist, and the restoration of that "species" in the era of functional genomics is strongly recommended. Garrod, the initial founder of human "biochemical genetics" belonged to the clinician-scientist community. Archibald Edward Garrod introduced a paradigm, new for its day, in medicine: biochemistry is dynamic and different from the static nature of organic chemistry. It led him to think about metabolic pathways and to recognize that variation in Mendelian heredity could explain an "inborn error of metabolism." At the time, Garrod had no idea about the nature of a gene. Genes are now well understood; genomes are being described for one organism after another (including Homo sapiens) and it is understood that genomes "speak biochemistry (not phenotype)." Accordingly, in the era of genomics, biochemistry and physiology become the bases of functional genomics, and it is possible to appreciate why "nothing in biology makes sense without evolution" (and nothing in medicine will make sense without biology). Mendelian, biochemical and molecular genetics together have revealed what lies behind the 4 canonical inborn errors described by Garrod (albinisn, alkaptonuria, cystinuria and pentosuria). Both older and newer ideas in genetics, new tools for applying them (and renewed respect for the clinician-scientist) will enhance our understanding of the human biological variation that accounts for variant states of health and overt disease. A so-called monogenic phenotype (phenylketonuria) is used to illustrate, in some detail, that all disease phenotypes are, in one way or another, likely to be complex in nature. What can be known and what ought to be done, with knowledge about human genetics, to benefit individuals, families and communities (society), is both opportunity and challenge.

Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review.

PubMed

van Karnebeek, Clara D M; Stockler, Sylvia

2012-03-01

Intellectual disability ('developmental delay' at age<5 years) affects 2.5% of population worldwide. Recommendations to investigate genetic causes of intellectual disability are based on frequencies of single conditions and on the yield of diagnostic methods, rather than availability of causal therapy. Inborn errors of metabolism constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. To identify all currently treatable inborn errors of metabolism presenting with predominantly intellectual disability, we performed a systematic literature review. We applied Cochrane Collaboration guidelines in formulation of PICO and definitions, and searched in Pubmed (1960-2011) and relevant (online) textbooks to identify 'all inborn errors of metabolism presenting with intellectual disability as major feature'. We assessed levels of evidence of treatments and characterised the effect of treatments on IQ/development and related outcomes. We identified a total of 81 'treatable inborn errors of metabolism' presenting with intellectual disability as a major feature, including disorders of amino acids (n=12), cholesterol and bile acid (n=2), creatine (n=3), fatty aldehydes (n=1); glucose homeostasis and transport (n=2); hyperhomocysteinemia (n=7); lysosomes (n=12), metals (n=3), mitochondria (n=2), neurotransmission (n=7); organic acids (n=19), peroxisomes (n=1), pyrimidines (n=2), urea cycle (n=7), and vitamins/co-factors (n=8). 62% (n=50) of all disorders are identified by metabolic screening tests in blood (plasma amino acids, homocysteine) and urine (creatine metabolites, glycosaminoglycans, oligosaccharides, organic acids, pyrimidines). For the remaining disorders (n=31) a 'single test per single disease' approach including primary molecular analysis is required. Therapeutic modalities include: sick-day management, diet, co-factor/vitamin supplements, substrate inhibition, stemcell transplant, gene therapy. Therapeutic effects include improvement and/or stabilisation of psychomotor/cognitive development, behaviour/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=45), Level 4-5 (n=27). In clinical practice more than 60% of treatments with evidence level 4-5 is internationally accepted as 'standard of care'. This literature review generated the evidence to prioritise treatability in the diagnostic evaluation of intellectual disability. Our results were translated into digital information tools for the clinician (www.treatable-id.org), which are part of a diagnostic protocol, currently implemented for evaluation of effectiveness in our institution. Treatments for these disorders are relatively accessible, affordable and with acceptable side-effects. Evidence for the majority of the therapies is limited however; international collaborations, patient registries, and novel trial methodologies are key in turning the tide for rare diseases such as these. Copyright © 2011 Elsevier Inc. All rights reserved.

Genetics Home Reference: sialuria

MedlinePlus

... inheritance of sialuria, an inborn error of feedback inhibition. Am J Hum Genet. 2001 Jun;68(6): ... Links Data Files & API Site Map Subscribe Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & Players ...

Galactose-1-phospate uridyltransferase

MedlinePlus

... normal diets, most galactose comes from the breakdown ( metabolism ) of lactose, which is found in milk and ... Elsevier; 2013:550. Zinn AB. Inborn errors of metabolism. In: Martin RJ, Fanaroff AA, Walsh MC, eds. ...

Genetics Home Reference: essential pentosuria

MedlinePlus

... MacCoss MJ, Levy-Lahad E, King MC, Motulsky AG. Garrod's fourth inborn error of metabolism solved by ... qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map Subscribe Customer Support USA. ...

α-Ketoglutaramate: An overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle

PubMed Central

Cooper, Arthur J. L.; Kuhara, Tomiko

2013-01-01

Glutamine metabolism is generally regarded as proceeding via glutaminase-catalyzed hydrolysis to glutamate and ammonia, followed by conversion of glutamate to α-ketoglutarate catalyzed by glutamate dehydrogenase or by a glutamate-linked aminotransferase (transaminase). However, another pathway exists for the conversion of glutamine to α-ketoglutarate that is often overlooked, but is widely distributed in nature. This pathway, referred to as the glutaminase II pathway, consists of a glutamine transaminase coupled to ω-amidase. Transamination of glutamine results in formation of the corresponding α-keto acid, namely, α-ketoglutaramate (KGM). KGM is hydrolyzed by ω-amidase to α-ketoglutarate and ammonia. The net glutaminase II reaction is: L-Glutamine + α-keto acid + H2O → α-ketoglutarate + L-amino acid + ammonia. In this mini-review the biochemical importance of the glutaminase II pathway is summarized, with emphasis on the key component KGM. Forty years ago it was noted that the concentration of KGM is increased in the cerebrospinal fluid (CSF) of patients with hepatic encephalopathy (HE) and that the level of KGM in the CSF correlates well with the degree of encephalopathy. In more recent work, we have shown that KGM is markedly elevated in the urine of patients with inborn errors of the urea cycle. It is suggested that KGM may be a useful biomarker for many hyperammonemic diseases including hepatic encephalopathy, inborn errors of the urea cycle, citrin deficiency and lysinuric protein intolerance. PMID:24234505

Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency

PubMed Central

Kohn, Donald B.; Weinberg, Kenneth I.; Nolta, Jan A.; Heiss, Linda N.; Lenarsky, Carl; Crooks, Gay M.; Hanley, Mary E.; Annett, Geralyn; Brooks, Judith S.; El-Khoureiy, Anthony; Lawrence, Kim; Wells, Susie; Moen, Robert C.; Bastian, John; Williams-Herman, Debora E.; Elder, Melissa; Wara, Diane; Bowen, Thomas; Hershfield, Michael S.; Mullen, Craig A.; Blaese, R. Michael; Parkman, Robertson

2010-01-01

Haematopoietic stem cells in umbilical cord blood are an attractive target for gene therapy of inborn errors of metabolism. Three neonates with severe combined immunodeficiency were treated by retroviral-mediated transduction of the CD34+ cells from their umbilical cord blood with a normal human adenosine deaminase complementary DNA followed by autologous transplantation. The continued presence and expression of the introduced gene in leukocytes from bone marrow and peripheral blood for 18 months demonstrates that umbilical cord blood cells may be genetically modified with retroviral vectors and engrafted in neonates for gene therapy. PMID:7489356

Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene.

PubMed

Goodman, Stephen I; Binard, Robert J; Woontner, Michael R; Frerman, Frank E

2002-01-01

Glutaric acidemia type II is a human inborn error of metabolism which can be due to defects in either subunit of electron transfer flavoprotein (ETF) or in ETF:ubiquinone oxidoreductase (ETF:QO), but few disease-causing mutations have been described. The ETF:QO gene is located on 4q33, and contains 13 exons. Primers to amplify these exons are presented, together with mutations identified by molecular analysis of 20 ETF:QO-deficient patients. Twenty-one different disease-causing mutations were identified on 36 of the 40 chromosomes.

Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts.

PubMed

Lionakis, Michail S; Levitz, Stuart M

2018-04-26

In the last few decades, the AIDS pandemic and the significant advances in the medical management of individuals with neoplastic and inflammatory conditions have resulted in a dramatic increase in the population of immunosuppressed patients with opportunistic, life-threatening fungal infections. The parallel development of clinically relevant mouse models of fungal disease and the discovery and characterization of several inborn errors of immune-related genes that underlie inherited human susceptibility to opportunistic mycoses have significantly expanded our understanding of the innate and adaptive immune mechanisms that protect against ubiquitous fungal exposures. This review synthesizes immunological knowledge derived from basic mouse studies and from human cohorts and provides an overview of mammalian antifungal host defenses that show promise for informing therapeutic and vaccination strategies for vulnerable patients.

North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2

ClinicalTrials.gov

2018-06-06

Epilepsy; Seizure; Neuromuscular Diseases; Brain Malformation; Intellectual Disability; Autism Spectrum Disorder; Hypotonia; Inborn Errors of Metabolism; Movement Disorders; Genetic Disease; Development Delay; Chromosome Abnormality; Hearing Loss; Dysmorphic Features; Skeletal Dysplasia; Congenital Abnormality; Microcephaly; Macrocephaly

Genetics Home Reference: glutathione synthetase deficiency

MedlinePlus

... Ristoff E, Larsson A. Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis. 2007 Mar 30;2:16. Review. Citation on PubMed or Free article on PubMed Central Wu G, Fang YZ, Yang S, ...

A next generation multiscale view of inborn errors of metabolism

PubMed Central

Argmann, Carmen A.; Houten, Sander M.; Zhu, Jun; Schadt, Eric E.

2015-01-01

Inborn errors of metabolism (IEM) are not unlike common diseases. They often present as a spectrum of disease phenotypes that correlates poorly with the severity of the disease-causing mutations. This greatly impacts patient care and reveals fundamental gaps in our knowledge of disease modifying biology. Systems biology approaches that integrate multi-omics data into molecular networks have significantly improved our understanding of complex diseases. Similar approaches to study IEM are rare despite their complex nature. We highlight that existing common disease-derived datasets and networks can be repurposed to generate novel mechanistic insight in IEM and potentially identify candidate modifiers. While understanding disease pathophysiology will advance the IEM field, the ultimate goal should be to understand per individual how their phenotype emerges given their primary mutation on the background of their whole genome, not unlike personalized medicine. We foresee that panomics and network strategies combined with recent experimental innovations will facilitate this. PMID:26712461

Detection of other inborn errors of metabolism in hyperphenylalaninemic babies picked up on narrow-spectrum screening programs.

PubMed

Unal, Ozlem; Oztürk-Hişmi, Burcu; Coşkun, Turgay; Tokatlı, Ayşegül; Dursun, Ali; Sivri, Hatice Serap

2012-01-01

In many countries, neonatal screening programs have been unable to expand and have been limited to a few diseases. We highlight herein the opportunity available for the early detection of some inborn errors of metabolism (IEMs) in those countries in which newborn screening programs are limited. All the newborns that are referred to us for hyperphenylalaninemia are examined physically and their blood samples are checked by both high-performance liquid chromatography (HPLC) for blood phenylalanine levels and by amino acid analyzer for the measurement of blood amino acid concentrations. Seven patients who had been referred to our unit for hyperphenylalaninemia were eventually diagnosed with another IEM. A careful physical examination of the babies sent for positive screening test result combined with the utilization of low expense screening techniques at the experienced referring centers might facilitate otherwise missed opportunities for the early detection of some IEMs.

Pilot study of newborn screening of inborn error of metabolism using tandem mass spectrometry in Malaysia: outcome and challenges.

PubMed

Yunus, Zabedah Md; Rahman, Salina Abdul; Choy, Yew Sing; Keng, Wee Teik; Ngu, Lock Hock

2016-09-01

The aim of this study was to determine the feasibility of performing newborn screening (NBS) of inborn errors of metabolism (IEMs) using tandem mass spectrometry (TMS) and the impact on its detection rate in Malaysia. During the study period between June 2006 and December 2008, 30,247 newborns from 11 major public hospitals in Malaysia were screened for 27 inborn errors of amino acid, organic acid and fatty acid metabolism by TMS. Dried blood spot (DBS) samples were collected between 24 h and 7 days with parental consent. Samples with abnormal results were repeated and the babies were recalled to confirm the diagnosis with follow-up testing. Cut-off values for amino acids and acylcarnitines were established. Eight newborns were confirmed to have IEM: two newborns with Maple syrup urine disease (MSUD), two with methylmalonic aciduria (MMA) one with ethylmalonic aciduria, two with argininosuccinic aciduria and one with isovaleric aciduria. Diagnosis was missed in two newborns. The detection rate of IEMs in this study was one in 2916 newborns. The sensitivity and specificity of TMS were 80% and 99%, respectively. IEMs are common in Malaysia. NBS of IEMs by TMS is a valuable preventive strategy by enabling the diagnosis and early treatment of IEM before the onset of symptoms aiming at prevention of mental retardation and physical handicap. A number of shortcomings warrant further solution so that in near future NBS for IEMs will become a standard of care for all babies in Malaysia in tandem with the developed world.

Genetics Home Reference: Imerslund-Gräsbeck syndrome

MedlinePlus

... 1172-7-56. Citation on PubMed or Free article on PubMed Central Watkins D, Rosenblatt DS. Lessons in biology from patients with inborn errors of vitamin B12 metabolism. Biochimie. 2013 May;95(5):1019-22. doi: ...

A Neurological Enigma: The Inborn Numerical Competence of Humans and Animals

NASA Astrophysics Data System (ADS)

Gross, Hans J.

2012-03-01

"Subitizing" means our ability to recognize and memorize object numbers precisely under conditions where counting is impossible. This is an inborn archaic process which was named after the Latin "subito" = suddenly, immediately, indicating that the objects in question are presented to test persons only for the fraction of a second in order to prevent counting. Sequential counting, however, is an outstanding cultural achievement of mankind and means to count "1, 2, 3, 4, 5, 6, 7, 8 ..." without a limit. In contrast to inborn "subitizing", counting has to be trained, beginning in our early childhood with the help of our fingers. For humans we know since 140 years that we can "subitize" only up to 4 objects correctly and that mistakes occur from 5 objects on. Similar results have been obtained for a number of non-human vertebrates from salamanders to pigeons and dolphins. To our surprise, we have detected this inborn numerical competence for the first time in case of an invertebrate, the honeybee which recognizes and memorizes 3 to 4 objects under rigorous test conditions. This common ability of humans and honeybees to "subitize" up to 4 objects correctly and the miraculous but rare ability of persons with Savant syndrome to "subitize" more than hundred objects precisely raises a number of intriguing questions concerning the evolution and the significance of this biological enigma.

Genetics Home Reference: neuroferritinopathy

MedlinePlus

... J. Neuroferritinopathy: a new inborn error of iron metabolism. Neurogenetics. 2012 Feb;13(1):93-6. doi: 10.1007/s10048-011-0310-9. Epub 2012 Jan 26. Citation on PubMed or Free article on PubMed Central Keogh MJ, Morris CM, Chinnery ...

Gastrointestinal Disorders in Children with Neurodevelopmental Disabilities

ERIC Educational Resources Information Center

Sullivan, Peter B.

2008-01-01

Children with neurodevelopmental disabilities such as cerebral palsy (CP), spina bifida, or inborn errors of metabolism frequently have associated gastrointestinal problems. These include oral motor dysfunction leading to feeding difficulties, risk of aspiration, prolonged feeding times, and malnutrition with its attendant physical compromise.…

Diagnosis and therapeutic monitoring of inborn errors of creatine metabolism and transport using liquid chromatography-tandem mass spectrometry in urine, plasma and CSF.

PubMed

Haas, Dorothea; Gan-Schreier, Hongying; Langhans, Claus-Dieter; Anninos, Alexandros; Haege, Gisela; Burgard, Peter; Schulze, Andreas; Hoffmann, Georg F; Okun, Jürgen G

2014-03-15

Biochemical detection of inborn errors of creatine metabolism or transport relies on the analysis of three main metabolites in biological fluids: guanidinoacetate (GAA), creatine (CT) and creatinine (CTN). Unspecific clinical presentation of the diseases might be the cause that only few patients have been diagnosed so far. We describe a LC-MS/MS method allowing fast and reliable diagnosis by simultaneous quantification of GAA, CT and CTN in urine, plasma and cerebrospinal fluid (CSF) and established reference values for each material. For quantification deuterated stable isotopes of each analyte were used as internal standards. GAA, CT and CTN were separated by reversed-phase HPLC. The characterization was carried out by scanning the ions of each compound by negative ion tandem mass spectrometry. Butylation is needed to achieve sufficient signal intensity for GAA and CT but it is not useful for analyzing CTN. The assay is linear in a broad range of analyte concentrations usually found in urine, plasma and CSF. Comparison of the "traditional" cation-exchange chromatography and LC-MS/MS showed proportional differences but linear relationships between the two methods. The described method is characterized by high speed and linearity over large concentration ranges comparable to other published LC-MS methods but with higher sensitivity for GAA and CT. In addition, we present the largest reference group ever published for guanidino compounds in all relevant body fluids. Therefore this method is applicable for high-throughput approaches for diagnosis and follow-up of inborn errors of creatine metabolism and transport. Copyright © 2014 Elsevier B.V. All rights reserved.

Pediatric neurological syndromes and inborn errors of purine metabolism.

PubMed

Camici, Marcella; Micheli, Vanna; Ipata, Piero Luigi; Tozzi, Maria Grazia

2010-02-01

This review is devised to gather the presently known inborn errors of purine metabolism that manifest neurological pediatric syndromes. The aim is to draw a comprehensive picture of these rare diseases, characterized by unexpected and often devastating neurological symptoms. Although investigated for many years, most purine metabolism disorders associated to psychomotor dysfunctions still hide the molecular link between the metabolic derangement and the neurological manifestations. This basically indicates that many of the actual functions of nucleosides and nucleotides in the development and function of several organs, in particular central nervous system, are still unknown. Both superactivity and deficiency of phosphoribosylpyrophosphate synthetase cause hereditary disorders characterized, in most cases, by neurological impairments. The deficiency of adenylosuccinate lyase and 5-amino-4-imidazolecarboxamide ribotide transformylase/IMP cyclohydrolase, both belonging to the de novo purine synthesis pathway, is also associated to severe neurological manifestations. Among catabolic enzymes, hyperactivity of ectosolic 5'-nucleotidase, as well as deficiency of purine nucleoside phosphorylase and adenosine deaminase also lead to syndromes affecting the central nervous system. The most severe pathologies are associated to the deficiency of the salvage pathway enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase: the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to a clear impairment of mitochondrial functions. The assessment of hypo- or hyperuricemic conditions is suggestive of purine enzyme dysfunctions, but most disorders of purine metabolism may escape the clinical investigation because they are not associated to these metabolic derangements. This review may represent a starting point stimulating both scientists and physicians involved in the study of neurological dysfunctions caused by inborn errors of purine metabolism with the aim to find novel therapeutical approaches. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

[Health and socio-educational needs of the families and children with rare metabolic diseases: Qualitative study in a tertiary hospital].

PubMed

Tejada-Ortigosa, Eva María; Flores-Rojas, Katherine; Moreno-Quintana, Laura; Muñoz-Villanueva, María Carmen; Pérez-Navero, Juan Luis; Gil-Campos, Mercedes

2018-05-28

Rare diseases are a challenge for public health due to the lack of information on their magnitude. These include inborn errors of metabolism. The objective of this study was to assess the quality of life and social, health, economic, and educational needs of a group of paediatric patients with inborn errors of metabolism attended to in a hospital. A questionnaire was developed based on the needs and expectations, based mainly on the Andalusian Plan for Rare Diseases. An analysis was performed on the variables of health, socioeconomic, and educational needs of 65 paediatric patients with inborn errors of metabolism. The respondents showed few possibilities to cope with medication (61%), special diet (86%), and other health benefits (79%). Just under half of them (43%) believed that the quality of family life had been greatly reduced since the onset of the disease. The main caregiver was the mother in 61.5% of cases, compared to 1.5% of cases in which it was the father. The primary caregivers had to reduce their working hours or give up their job in 77% of cases. The multidisciplinary treatment is affected by the inability of families to cope with a high cost, as well as with difficult access to these resources. In addition, there is great impact on the quality of life of patients, and their caregivers. Therefore, there is a need to evaluate the results of government health and socio-economic support plans for patients with rare diseases, and make a real response to their needs. Copyright © 2018. Publicado por Elsevier España, S.L.U.

OMEGA-3 LONG-CHAIN POLYUNSATURATED FATTY ACIDS IN OLDER CHILDREN

USDA-ARS?s Scientific Manuscript database

Phenylketonuria (PKU), the most prevalent inborn error of metabolism, is usually secondary to low hepatic activity of phenylalanine hydroxylase, the enzyme that catalyzes conversion of phenylalanine to tyrosine. Growth and development of infants and children with PKU who are managed by mandatory n...

Biomarker for Glycogen Storage Diseases

ClinicalTrials.gov

2017-07-03

Fructose Metabolism, Inborn Errors; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VI; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII

Management of Newborn Infants with Phenylketonuria.

ERIC Educational Resources Information Center

Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

The booklet covers the identification, diagnosis, and clinical treatment of newborns with Phenylketonuria (PKU), an inborn error of metabolism, which, if untreated, can lead to mental retardation. An initial section considers biochemical and genetic factors of PKU including a diagram of aromatic amino acid hydroxylation systems. Screening…

What's New with Newborn Screening

ERIC Educational Resources Information Center

Exceptional Parent, 2008

2008-01-01

Newborn screening is the process of testing and screening newborns shortly after birth for certain, potentially dangerous, conditions and/or impairments--conditions that include everything from inborn errors of metabolism and other genetic disorders to hearing impairment. Early detection through newborn screening is paramount, often allowing the…

[Expand newborn screening using tandem mass spectrometry: two years' experience in Nuevo León, Mexico].

PubMed

Torres-Sepúlveda, María del Rosario; Martínez-de Villarreal, Laura E; Esmer, Carmen; González-Alanís, Rogerio; Ruiz-Herrera, Consuelo; Sánchez-Peña, Alejandra; Mendoza-Cruz, José Alberto; Villarreal-Pérez, Jesús Z

2008-01-01

To initiate a statewide expanded metabolic screening program in neonates with the purpose of identifying the most common inborn errors of metabolism. From March 2002 through February 2004, a blood sample was obtained between 24 and 48 hours after delivery from every consecutive child born in public hospitals in Nuevo León. It was spotted on filter paper and analyzed by tandem mass spectrometry for expanded metabolic screening. A total of 42 264 samples were analyzed. Were obtained seven positive results, one for each disorder: homocystinuria, hyperphenylalaninemia, citrulinemia, transient tyrosinemia, 3-methylcrotonyl CoA carboxylase deficiency, 3-hydroxy-3-methylglutaryl CoA deficiency, and classic galactosemia. The estimated incidence of inborn errors of metabolism is 1:5 000, with a false positive rate of 0.22%. The program permitted the identification of metabolic disorders in the newborn, allowing an early intervention and prevention of life-threatening events and permanent neurological damage.

Metabolic emergencies and the emergency physician.

PubMed

Fletcher, Janice Mary

2016-02-01

Fifty percent of inborn errors of metabolism are present in later childhood and adulthood, with crises commonly precipitated by minor viral illnesses or increased protein ingestion. Many physicians only consider IEM after more common conditions (such as sepsis) have been considered. In view of the large number of inborn errors, it might appear that their diagnosis requires precise knowledge of a large number of biochemical pathways and their interrelationship. As a matter of fact, an adequate diagnostic approach can be based on the proper use of only a few screening tests. A detailed history of antecedent events, together with these simple screening tests, can be diagnostic, leading to life-saving, targeted treatments for many disorders. Unrecognised, IEM can lead to significant mortality and morbidity. Advice is available 24/7 through the metabolic service based at the major paediatric hospital in each state and Starship Children's Health in New Zealand. © 2016 The Author. Journal of Paediatrics and Child Health © 2016 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches

PubMed Central

Sharma, Suvasini; Prasad, Asuri N.

2017-01-01

Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term “metabolic epilepsy” can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Some of these disorders are amenable to specific treatment interventions; hence timely and appropriate diagnosis is critical to improve outcomes. In this review, we discuss those disorders in which epilepsy is a dominant feature and present an approach to the clinical recognition, diagnosis, and management of these disorders, with a greater focus on primarily treatable conditions. Finally, we propose a tiered approach that will permit a clinician to systematically investigate, identify, and treat these rare disorders. PMID:28671587

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococci

PubMed Central

Maródi, László; Cypowyj, Sophie; Tóth, Beáta; Chernyshova, Liudmyla; Puel, Anne; Casanova, Jean-Laurent

2013-01-01

Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 may disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococci, especially Staphylococcus aureus. Here, we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococci. PMID:23040277

How Darwinian reductionism refutes genetic determinism.

PubMed

Rosoff, Philip M; Rosenberg, Alex

2006-03-01

Genetic determinism labels the morally problematical claim that some socially significant traits, traits we care about, such as sexual orientation, gender roles, violence, alcoholism, mental illness, intelligence, are largely the results of the operation of genes and not much alterable by environment, learning or other human intervention. Genetic determinism does not require that genes literally fix these socially significant traits, but rather that they constrain them within narrow channels beyond human intervention. In this essay we analyze genetic determinism in light of what is now known about the inborn error of metabolism phenylketonuria (PKU), which has for so long been the poster child 'simple' argument in favor of some form of genetic determinism. We demonstrate that this case proves the exact opposite of what it has been proposed to support and provides a strong refutation of genetic determinism in all its guises.

PKU and the Schools: Information for Teachers, Administrators and Other School Personnel.

ERIC Educational Resources Information Center

Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

Designed to acquaint teachers, administrators and other school personnel with phenylketonuria (PKU - an inborn error of metabolism which requires dietary intervention), the booklet reviews school problems related to the condition. Introductory information concerns the nature, treatment, and screening and diagnosis of PKU. Diet management is…

78 FR 9060 - Request for Nominations for Voting Members on Public Advisory Panels or Committees

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-07

... diagnostic assays, e.g., hepatologists; molecular biologists. Molecular and Clinical 2 June 1, 2013. Genetics.... Individuals with training in inborn errors of metabolism, biochemical and/or molecular genetics, population genetics, epidemiology and related statistical training, and clinical molecular genetics testing (e.g...

Nutrition and Mental Retardation. An Annotated Bibliography, 1964-1970.

ERIC Educational Resources Information Center

Springer, Ninfa Saturnino

This annotated bibliography is primarily organized for nutritionists. It presents selected articles published from 1964 to the present. All aspects of nutrition in mental retardation are covered excepting inborn errors of metabolism. Sections are included on: (1) nutrition, birthweight, and mental retardation; (2) nutrition, growth, and mental…

To bee or not to bee, this is the question…: The inborn numerical competence of humans and honeybees.

PubMed

Gross, Hans J

2011-09-01

Human inborn numerical competence means our ability to recognize object numbers precisely under circumstances which do not allow sequential counting. This archaic process has been called "subitizing," from the Latin "subito" = suddenly, immediately, indicating that the objects in question are presented to test persons only for a fraction of a second in order to prevent counting. In contrast, however, sequential counting, an outstanding cultural achievement of mankind, means to count "1, 2, 3, 4, 5, 6, 7, 8…" without a limit. The following essay will explain how the limit of numerical competence, i.e., the recognition of object numbers without counting, has been determined for humans and how this has been achieved for the first time in case of an invertebrate, the honeybee. Finally, a hypothesis explaining the influence of our limited, inborn numerical competence on counting in our times, e.g., in the Russian language, will be presented. Subitizing versus counting by young Down syndrome infants and autistics and the Savant syndrome will be discussed.

Newborn Screening: National Library of Medicine Literature Search, January 1980 through March 1987. No. 87-2.

ERIC Educational Resources Information Center

Patrias, Karen

This bibliography, prepared by the National Library of Medicine through a literature search of its online databases, covers all aspects of newborn screening. It includes references to screening for: inborn errors of metabolism, such as phenylketonuria and galactosemia; hemoglobinopathies, particularly sickle cell disease; congenital hypothyroidism…

78 FR 21613 - Prescription Drug User Fee Act Patient-Focused Drug Development; Announcement of Disease Areas...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-11

... syndrome; narcolepsy; neurological manifestations of inborn errors of metabolism; Parkinson's disease and... available therapies. Patients who live with a disease have a direct stake in the outcome of FDA's decisions... of applications for new drugs in certain disease areas. For FDA's review divisions, this kind of...

Identification of Mutations Underlying 20 Inborn Errors of Metabolism in the United Arab Emirates Population

PubMed Central

Ben-Rebeh, Imen; Hertecant, Jozef L.; Al-Jasmi, Fatma A.; Aburawi, Hanan E.; Al-Yahyaee, Said A.; Al-Gazali, Lihadh

2012-01-01

Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders. PMID:22106832

A patient with an inborn error of vitamin B12 metabolism (cblF) detected by newborn screening.

PubMed

Armour, Christine M; Brebner, Alison; Watkins, David; Geraghty, Michael T; Chan, Alicia; Rosenblatt, David S

2013-07-01

A neonate, who was found to have an elevated C3/C2 ratio and minimally elevated propionylcarnitine on newborn screening, was subsequently identified as having the rare cblF inborn error of vitamin B12 (cobalamin) metabolism. This disorder is characterized by the retention of unmetabolized cobalamin in lysosomes such that it is not readily available for cellular metabolism. Although cultured fibroblasts from the patient did not show the expected functional abnormalities of the cobalamin-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase, they did show reduced synthesis of the active cobalamin cofactors adenosylcobalamin and methylcobalamin. Mutation analysis of LMBRD1 established that the patient had the cblF disorder. Treatment was initiated promptly, and the patient showed a robust response to regular injections of cyanocobalamin, and she was later switched to hydroxocobalamin. Currently, at 3 years of age, the child is clinically well, with appropriate development. Adjusted newborn screening cutoffs in Ontario allowed detection of a deficiency that might not have otherwise been identified, allowing early treatment and perhaps preventing the adverse sequelae seen in some untreated patients.

Uric acid, an important screening tool to detect inborn errors of metabolism: a case series.

PubMed

Jasinge, Eresha; Kularatnam, Grace Angeline Malarnangai; Dilanthi, Hewa Warawitage; Vidanapathirana, Dinesha Maduri; Jayasena, Kandana Liyanage Subhashinie Priyadarshika Kapilani Menike; Chandrasiri, Nambage Dona Priyani Dhammika; Indika, Neluwa Liyanage Ruwan; Ratnayake, Pyara Dilani; Gunasekara, Vindya Nandani; Fairbanks, Lynette Dianne; Stiburkova, Blanka

2017-09-06

Uric acid is the metabolic end product of purine metabolism in humans. Altered serum and urine uric acid level (both above and below the reference ranges) is an indispensable marker in detecting rare inborn errors of metabolism. We describe different case scenarios of 4 Sri Lankan patients related to abnormal uric acid levels in blood and urine. CASE 1: A one-and-half-year-old boy was investigated for haematuria and a calculus in the bladder. Xanthine crystals were seen in microscopic examination of urine sediment. Low uric acid concentrations in serum and low urinary fractional excretion of uric acid associated with high urinary excretion of xanthine and hypoxanthine were compatible with xanthine oxidase deficiency. CASE 2: An 8-month-old boy presented with intractable seizures, feeding difficulties, screaming episodes, microcephaly, facial dysmorphism and severe neuro developmental delay. Low uric acid level in serum, low fractional excretion of uric acid and radiological findings were consistent with possible molybdenum cofactor deficiency. Diagnosis was confirmed by elevated levels of xanthine, hypoxanthine and sulfocysteine levels in urine. CASE 3: A 3-year-10-month-old boy presented with global developmental delay, failure to thrive, dystonia and self-destructive behaviour. High uric acid levels in serum, increased fractional excretion of uric acid and absent hypoxanthine-guanine phosphoribosyltransferase enzyme level confirmed the diagnosis of Lesch-Nyhan syndrome. CASE 4: A 9-year-old boy was investigated for lower abdominal pain, gross haematuria and right renal calculus. Low uric acid level in serum and increased fractional excretion of uric acid pointed towards hereditary renal hypouricaemia which was confirmed by genetic studies. Abnormal uric acid level in blood and urine is a valuable tool in screening for clinical conditions related to derangement of the nucleic acid metabolic pathway.

Hypoxia as a therapy for mitochondrial disease.

PubMed

Jain, Isha H; Zazzeron, Luca; Goli, Rahul; Alexa, Kristen; Schatzman-Bone, Stephanie; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E; Zhang, Feng; Goessling, Wolfram; Zapol, Warren M; Mootha, Vamsi K

2016-04-01

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction. Copyright © 2016, American Association for the Advancement of Science.

Metabolic Diet App Suite for inborn errors of amino acid metabolism.

PubMed

Ho, Gloria; Ueda, Keiko; Houben, Roderick F A; Joa, Jeff; Giezen, Alette; Cheng, Barbara; van Karnebeek, Clara D M

2016-03-01

An increasing number of rare inborn errors of metabolism (IEMs) are amenable to targeted metabolic nutrition therapy. Daily adherence is important to attain metabolic control and prevent organ damage. This is challenging however, given the lack of information of disorder specific nutrient content of foods, the limited availability and cost of specialty products as well as difficulties in reliable calculation and tracking of dietary intake and targets. To develop apps for all inborn errors of amino acid metabolism for which the mainstay of treatment is a medical diet, and obtain patient and family feedback throughout the process to incorporate this into subsequent versions. The Metabolic Diet App Suite was created with input from health care professionals as a free, user-friendly, online tool for both mobile devices and desktop computers (http://www.metabolicdietapp.org) for 15 different IEMs. General information is provided for each IEM with links to useful online resources. Nutrient information is based on the MetabolicPro™, a North American food database compiled by the Genetic Metabolic Dietitians International (GMDI) Technology committee. After user registration, a personalized dashboard and management plan including specific nutrient goals are created. Each Diet App has a user-friendly interface and the functions include: nutrient intake counts, adding your own foods and homemade recipes and, managing a daily food diary. Patient and family feedback was overall positive and specific suggestions were used to further improve the App Suite. The Metabolic Diet App Suite aids individuals affected by IEMs to track and plan their meals. Future research should evaluate its impact on patient adherence, metabolic control, quality of life and health-related outcomes. The Suite will be updated and expanded to Apps for other categories of IEMs. Finally, this Suite is a support tool only, and does not replace medical/metabolic nutrition professional advice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery☆

PubMed Central

Kell, Douglas B.; Goodacre, Royston

2014-01-01

Metabolism represents the ‘sharp end’ of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus (community) models of the human metabolic network that include the important transporters. Small molecule ‘drug’ transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites, and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology. PMID:23892182

Black aorta in a patient with alkaptonuria (ochronosis).

PubMed

Concistrè, Giovanni; Fiorani, Brenno; Ranocchi, Federico; Casali, Giovanni; Loforte, Antonio; Musumeci, Francesco

2011-06-01

A rare cause of valvular heart disease is the deposition of foreign material in the valvular tissues, including material accumulating as a result of inborn errors of metabolism of the essential amino acids. Alkaptonuria can result in accumulation of homogentisic acid. We report the case of a patient with alkaptonuria undergoing surgery for aortic valve replacement.

Glutathione synthetase deficiency: a family report.

PubMed Central

Pejaver, R K; Watson, A H

1994-01-01

Glutathione synthetase deficiency is a rare inborn error of metabolism. Low levels of and at times unstable molecules of glutathione synthetase leads to glutathione deficiency affecting various systems of the body. The inheritance is thought to be of autosomal recessive variety. We diagnosed the condition in a neonate and proceeded to investigate the family. The results are discussed below. PMID:8158601

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species.

PubMed

Maródi, László; Cypowyj, Sophie; Tóth, Beáta; Chernyshova, Liudmyla; Puel, Anne; Casanova, Jean-Laurent

2012-11-01

Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococcus species, especially Staphylococcus aureus. Here we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococcus species. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Mutation-adapted U1 snRNA corrects a splicing error of the dopa decarboxylase gene.

PubMed

Lee, Ni-Chung; Lee, Yu-May; Chen, Pin-Wen; Byrne, Barry J; Hwu, Wuh-Liang

2016-12-01

Aromatic l-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis, which results in dopamine, serotonin, epinephrine and norepinephrine deficiencies. The DDC gene founder mutation IVS6 + 4A > T is highly prevalent in Chinese patients with AADC deficiency. In this study, we designed several U1 snRNA vectors to adapt U1 snRNA binding sequences of the mutated DDC gene. We found that only the modified U1 snRNA (IVS-AAA) that completely matched both the intronic and exonic U1 binding sequences of the mutated DDC gene could correct splicing errors of either the mutated human DDC minigene or the mouse artificial splicing construct in vitro. We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model. This treatment was well tolerated and improved both the survival and brain dopamine and serotonin levels of mice with AADC deficiency. Therefore, mutation-adapted U1 snRNA gene therapy can be a promising method to treat genetic diseases caused by splicing errors, but the efficiency of such a treatment still needs improvements. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Alkaptonuria: A case report.

PubMed

Damarla, Nirupama; Linga, Prathima; Goyal, Mallika; Tadisina, Sanjay Reddy; Reddy, G Satyanarayana; Bommisetti, Hymavathi

2017-06-01

Alkaptonuria is a rare inborn error of metabolism with autosomal recessive inheritance with a mutation in homogentisate 1,2-dioxygenase. It results in accumulation of homogentisic acid in connective tissues (ochronosis). Most common ocular manifestations are bluish-black discoloration of the conjunctiva, cornea, and sclera. In this case report, a 39-year-old Indian male patient with additional ocular features in the retina is described.

Alkaptonuria: A case report

PubMed Central

Damarla, Nirupama; Linga, Prathima; Goyal, Mallika; Tadisina, Sanjay Reddy; Reddy, G Satyanarayana; Bommisetti, Hymavathi

2017-01-01

Alkaptonuria is a rare inborn error of metabolism with autosomal recessive inheritance with a mutation in homogentisate 1,2-dioxygenase. It results in accumulation of homogentisic acid in connective tissues (ochronosis). Most common ocular manifestations are bluish-black discoloration of the conjunctiva, cornea, and sclera. In this case report, a 39-year-old Indian male patient with additional ocular features in the retina is described. PMID:28643719

Treatment strategies for acute metabolic disorders in neonates

PubMed Central

2011-01-01

Acute metabolic emergencies in neonates represent a challenge to the medical and nursing staff. If not treated optimally, these disorders are associated with poor outcome. Early diagnosis, supportive therapy and specific measures addressing the derranged metabolic process are the gold standards for favorable results. This review highlights treatment strategies for Inborn Errors of Metabolism (IEM) presenting in the neonatal period. PMID:27493313

Acute Pancreatitis in a Patient with Maple Syrup Urine Disease: A Management Paradox.

PubMed

Gold, Nina B; Blumenthal, Jennifer A; Wessel, Ann E; Stein, Deborah R; Scott, Adam; Fox, Victor L; Turner, Amy; Kritzer, Amy; Rajabi, Farrah; Peeler, Katherine; Tan, Wen-Hann

2018-04-19

Maple syrup urine disease (MSUD) is an inborn error of metabolism that causes elevated leucine in the setting of acute illnesses. We describe an 8-year-old boy with MSUD who developed acute pancreatitis and subsequent leucinosis. This case highlights the complexities of fluid management in patients with MSUD. Copyright © 2018 Elsevier Inc. All rights reserved.

Nutritional Treatment for Inborn Errors of Metabolism: Indications, Regulations, and Availability of Medical Foods and Dietary Supplements Using Phenylketonuria as an Example

PubMed Central

Camp, Kathryn M.; Lloyd-Puryear, Michele A.; Huntington, Kathleen L.

2012-01-01

Medical foods and dietary supplements are used to treat rare inborn errors of metabolism (IEM) identified through state-based universal newborn screening. These products are regulated under Food and Drug Administration (FDA) food and dietary supplement statutes. The lack of harmony in terminology used to refer to medical foods and dietary supplements and the misuse of words that imply that FDA regulates these products as drugs have led to confusion. These products are expensive and, although they are used for medical treatment of IEM, third-party payer coverage of these products is inconsistent across the United States. Clinicians and families report termination of coverage in late adolescence, failure to cover treatment during pregnancy, coverage for select conditions only, or no coverage. We describe the indications for specific nutritional treatment products for IEM and their regulation, availability, and categorization. We conclude with a discussion of the problems that have contributed to the paradox of identifying individuals with IEM through newborn screening but not guaranteeing that they receive optimal treatment. Throughout the paper, we use the nutritional treatment of phenylketonuria as an example of IEM treatment. PMID:22854513

Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning✰

PubMed Central

Therrell, Bradford L.; Lloyd-Puryear, Michele A.; Camp, Kathryn M.; Mann, Marie Y.

2014-01-01

Inborn errors of metabolism (IEM) are genetic disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. In the U.S., many IEM are detected through state newborn screening (NBS) programs. To inform research on IEM and provide necessary resources for researchers, we are providing: tabulation of ten-year state NBS data for selected IEM detected through NBS; costs of medical foods used in the management of IEM; and an assessment of corporate policies regarding provision of nutritional interventions at no or reduced cost to individuals with IEM. The calculated IEM incidences are based on analyses of ten-year data (2001–2011) from the National Newborn Screening Information System (NNSIS). Costs to feed an average person with an IEM were approximated by determining costs to feed an individual with an IEM, minus the annual expenditure for food for an individual without an IEM. Both the incidence and costs of nutritional intervention data will be useful in future research concerning the impact of IEM disorders on families, individuals and society. PMID:25085281

Newborn screening: need of the hour in India.

PubMed

Verma, Ishwar C; Bijarnia-Mahay, Sunita; Jhingan, Geetu; Verma, Jyotsna

2015-01-01

After a review of the current health scene in India, the authors suggest that the Government of India should consider seriously, the introduction of new born screening. As a first step, a central advisory committee should be constituted to recommend what is required to be done to strengthen the infrastructure and the manpower to carry out new born screening, and the disorders to be screened. In the urban hospitals newborn screening (NBS) for three disorders can be easily introduced (congenital hypothyroidism, congenital adrenal hyperplasia and G-6-PD deficiency), while in the rural areas this should begin with congenital hypothyroidism, especially in the sub Himalayan areas. Concurrently, logistic issues regarding diets and special therapies for inborn errors of metabolism should be sorted out, laboratories to confirm the diagnosis should be set up, and a cadre of metabolic physicians should be build up to treat those identified to have inborn errors of metabolism. Once these are established on a firm footing, tandem mass spectrometry should be introduced as it allows the identification of a number of disorders in an affordable manner. The recent improvements and current trends in health care in India have created the necessary infrastructure for adopting NBS for the benefit of infants in India.

Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders

PubMed Central

Burrage, Lindsay C.; Nagamani, Sandesh C.S.; Campeau, Philippe M.; Lee, Brendan H.

2014-01-01

Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism. PMID:24651065

New secondary metabolites of phenylbutyrate in humans and rats.

PubMed

Kasumov, Takhar; Brunengraber, Laura L; Comte, Blandine; Puchowicz, Michelle A; Jobbins, Kathryn; Thomas, Katherine; David, France; Kinman, Renee; Wehrli, Suzanne; Dahms, William; Kerr, Douglas; Nissim, Itzhak; Brunengraber, Henri

2004-01-01

Phenylbutyrate is used to treat inborn errors of ureagenesis, malignancies, cystic fibrosis, and thalassemia. High-dose phenylbutyrate therapy results in toxicity, the mechanism of which is unexplained. The known metabolites of phenylbutyrate are phenylacetate, phenylacetylglutamine, and phenylbutyrylglutamine. These are excreted in urine, accounting for a variable fraction of the dose. We identified new metabolites of phenylbutyrate in urine of normal humans and in perfused rat livers. These metabolites result from interference between the metabolism of phenylbutyrate and that of carbohydrates and lipids. The new metabolites fall into two categories, glucuronides and phenylbutyrate beta-oxidation side products. Two questions are raised by these data. First, is the nitrogen-excreting potential of phenylbutyrate diminished by ingestion of carbohydrates or lipids? Second, does competition between the metabolism of phenylbutyrate, carbohydrates, and lipids alter the profile of phenylbutyrate metabolites? Finally, we synthesized glycerol esters of phenylbutyrate. These are partially bioavailable in rats and could be used to administer large doses of phenylbutyrate in a sodium-free, noncaustic form.

Nitrous oxide in pediatric anesthesia: friend or foe?

PubMed

Schmitt, Erica L; Baum, Victor C

2008-06-01

Nitrous oxide has been used in clinical practice for over 150 years, often for pediatric procedures. Not only are there problems when used in patients with a variety of inborn errors of metabolism, but effects of nitrous oxide on the developing human brain are unknown. A recent adult human trial found that the use of nitrous oxide was associated with increased adverse outcome. Animal studies in several species have shown that nitrous oxide can be associated with apoptosis in the developing brain. Nitrous oxide can also inhibit major enzymatic pathways and repeated exposure may lead to neurologic damage. Single nucleotide polymorphisms in at least one of these enzymes are common in the population. There is a growing body of evidence that supports avoidance of nitrous oxide in both pediatric and adult patients, but the thousands of patients who have been exposed to nitrous oxide without apparent complications would suggest that further studies on long-term side effects and possible neurologic consequences need to be done.

Seizures and epilepsy in hypoglycaemia caused by inborn errors of metabolism.

PubMed

Gataullina, Svetlana; Delonlay, Pascale; Lemaire, Eric; Boddaert, Nathalie; Bulteau, Christine; Soufflet, Christine; Laín, Gemma Aznar; Nabbout, Rima; Chiron, Catherine; Dulac, Olivier

2015-02-01

The aim of the study was to characterize seizures and epilepsy related to hypoglycaemia. We analyzed the files of 170 consecutive patients referred for hypoglycaemia (onset 1h to 4y) caused by inborn errors of metabolism (glycogen storage disease type I, fatty acid β-oxidation disorders, and hyperinsulinism). Ninety patients (42 males and 48 females; 38 neonates and 52 infants/children) had brief hypoglycaemic seizures (68%) or status epilepticus (32%). Status epilepticus occurred earlier (mean 1.4d) than brief neonatal seizures (4.3d, p=0.02). Recurrent status epilepticus followed initial status epilepticus and was often triggered by fever. Epilepsy developed in 21 patients. In 18 patients, epilepsy followed hypoglycaemic status epilepticus and began with shorter delay when associated with grey matter lesions (1.9mo, standard error of the mean [SEM] 1mo) than with white matter damage (3.3y [SEM 1y], p=0.003). Three patients with hyperinsulinism developed idiopathic epilepsy following brief neonatal seizures. Brief neonatal hyperinsulinaemic hypoglycaemic seizures have characteristics of idiopathic neonatal seizures. Neonatal status epilepticus should be prevented by the systematic measurement of glucose blood level. Recurrent seizures never consist of status epilepticus when following brief initial seizures. Epilepsy is symptomatic of brain damage with shorter delay in the case of grey rather than white matter lesions, except in a few idiopathic cases in which epilepsy and hyperinsulinism may share a common genetic background. © 2014 Mac Keith Press.

Francis Galton: and eugenics today.

PubMed Central

Galton, D J; Galton, C J

1998-01-01

Eugenics can be defined as the use of science applied to the qualitative and quantitative improvement of the human genome. The subject was initiated by Francis Galton with considerable support from Charles Darwin in the latter half of the 19th century. Its scope has increased enormously since the recent revolution in molecular genetics. Genetic files can be easily obtained for individuals either antenatally or at birth; somatic gene therapy has been introduced for some rare inborn errors of metabolism; and gene manipulation of human germ-line cells will no doubt occur in the near future to generate organs for transplantation. The past history of eugenics has been appalling, with gross abuses in the USA between 1931 and 1945 when compulsory sterilization was practised; and in Germany between 1933 and 1945 when mass extermination and compulsory sterilization were performed. To prevent such abuses in the future statutory bodies, such as a genetics commission, should be established to provide guidance and rules of conduct for use of the new information and technologies as applied to the human genome. PMID:9602996

Restoring Ureagenesis in Hepatocytes by CRISPR/Cas9-mediated Genomic Addition to Arginase-deficient Induced Pluripotent Stem Cells.

PubMed

Lee, Patrick C; Truong, Brian; Vega-Crespo, Agustin; Gilmore, W Blake; Hermann, Kip; Angarita, Stephanie Ak; Tang, Jonathan K; Chang, Katherine M; Wininger, Austin E; Lam, Alex K; Schoenberg, Benjamen E; Cederbaum, Stephen D; Pyle, April D; Byrne, James A; Lipshutz, Gerald S

2016-11-29

Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism.

The G22A Polymorphism of the ADA Gene and Susceptibility to Autism Spectrum Disorders

ERIC Educational Resources Information Center

Hettinger, Joe A.; Liu, Xudong; Holden, Jeanette Jeltje Anne

2008-01-01

Inborn errors of purine metabolism have been implicated as a cause for some cases of autism. This hypothesis is supported by the finding of decreased adenosine deaminase (ADA) activity in the sera of some children with autism and reports of an association of the A allele of the ADA G22A (Asp8Asn) polymorphism in individuals with autism of…

Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. 3 cases of 'DIDMOAD' syndrome.

PubMed Central

Richardson, J E; Hamilton, W

1977-01-01

Three children with diabetes insipidus, diabetes mellitus, optic atrophy, and high-tone deafness were shown to lack vasopressin, indicative of degeneration of the cells of the hypothalamic supraoptic nuclei. The syndrome being due to a single gene defect, inherited as an autosomal recessive, is therefore likely to be the result of an inborn error of metabolism with variable periods of latency in those affected. PMID:931428

Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism.

PubMed

Muntau, Ania C; Gersting, Søren W

2010-12-01

The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.

Rare disease landscape in Brazil: report of a successful experience in inborn errors of metabolism.

PubMed

Giugliani, Roberto; Vairo, Filippo P; Riegel, Mariluce; de Souza, Carolina F M; Schwartz, Ida V D; Pena, Sérgio D J

2016-06-10

Brazil is a country of continental dimensions, with many social inequalities. The latter are reflected on its health system, which comprises a large public component called SUS, a small paid health insurance component and a third very small private component, in which patients pay personally for medical services. Seventy five percent of the population depends on SUS, which thus far does not provide adequate coverage for genetic medical procedures. In 2014, SUS introduced the "Policy for the Integral Attention to Subjects with Rare Diseases", establishing guidelines for offering diagnosis and treatment. The policy defines the two main axes, genetic and non-genetic rare diseases. In this fashion, public genetic services in SUS will be installed and funded not by themselves, but as part of the more general policy of rare diseases. Unfortunately, up to now this policy is still depending on financial allowances to be effectively launched. In this article, our intention was to describe activities developed in the area of inborn errors of metabolism by a Brazilian reference center. In spite of the lack of support of SUS, thousands of Brazilian families affected by rare genetic metabolic disorders, and many health professionals from all regions of Brazil, already have benefited from the services, training programs and research projects provided by this comprehensive center.

Omics-Based Strategies in Precision Medicine: Toward a Paradigm Shift in Inborn Errors of Metabolism Investigations

PubMed Central

Tebani, Abdellah; Afonso, Carlos; Marret, Stéphane; Bekri, Soumeya

2016-01-01

The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve systemic exploration of complex interactions in biological systems. Driven by high-throughput omics technologies and the computational surge, it enables multi-scale and insightful overviews of cells, organisms, and populations. Precision medicine capitalizes on these conceptual and technological advancements and stands on two main pillars: data generation and data modeling. High-throughput omics technologies allow the retrieval of comprehensive and holistic biological information, whereas computational capabilities enable high-dimensional data modeling and, therefore, accessible and user-friendly visualization. Furthermore, bioinformatics has enabled comprehensive multi-omics and clinical data integration for insightful interpretation. Despite their promise, the translation of these technologies into clinically actionable tools has been slow. In this review, we present state-of-the-art multi-omics data analysis strategies in a clinical context. The challenges of omics-based biomarker translation are discussed. Perspectives regarding the use of multi-omics approaches for inborn errors of metabolism (IEM) are presented by introducing a new paradigm shift in addressing IEM investigations in the post-genomic era. PMID:27649151

Simultaneous LC-MS/MS determination of phenylbutyrate, phenylacetate benzoate and their corresponding metabolites phenylacetylglutamine and hippurate in blood and urine.

PubMed

Laryea, Maurice D; Herebian, Diran; Meissner, Thomas; Mayatepek, Ertan

2010-12-01

Inborn errors of urea metabolism result in hyperammonemia. Treatment of urea cycle disorders can effectively lower plasma ammonium levels and results in survival in the majority of patients. Available medications for treating urea cycle disorders include sodium benzoate (BA), sodium phenylacetate (PAA), and sodium phenylbutyrate (PBA) and are given to provide alternate routes for disposition of waste nitrogen excretion. In this study, we develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of benzoic acid, phenylacetic acid, phenylbutyric acid, phenylacetylglutamine, and hippuric acid in plasma and urine from children with inborn errors of urea synthesis. Plasma extracts and diluted urine samples were injected on a reverse-phase column and identified and quantified by selected reaction monitoring (SRM) in negative ion mode. Deuterated analogues served as internal standards. Analysis time was 7 min. Assay precision, accuracy, and linearity and sample stability were determined using enriched samples. Quantification limits of the method were 100 ng/ml (0.3-0.8 μmol/L) for all analytes, and recoveries were >90%. Inter- and intraday relative standard deviations were <10%. Our newly developed LC-MS/MS represents a robust, sensitive, and rapid method that allows simultaneous determination of the five compounds in plasma and urine.

Toward a generalized computational workflow for exploiting transient pockets as new targets for small molecule stabilizers: Application to the homogentisate 1,2-dioxygenase mutants at the base of rare disease Alkaptonuria.

PubMed

Bernini, Andrea; Galderisi, Silvia; Spiga, Ottavia; Bernardini, Giulia; Niccolai, Neri; Manetti, Fabrizio; Santucci, Annalisa

2017-10-01

Alkaptonuria (AKU) is an inborn error of metabolism where mutation of homogentisate 1,2-dioxygenase (HGD) gene leads to a deleterious or misfolded product with subsequent loss of enzymatic degradation of homogentisic acid (HGA) whose accumulation in tissues causes ochronosis and degeneration. There is no licensed therapy for AKU. Many missense mutations have been individuated as responsible for quaternary structure disruption of the native hexameric HGD. A new approach to the treatment of AKU is here proposed aiming to totally or partially rescue enzyme activity by targeting of HGD with pharmacological chaperones, i.e. small molecules helping structural stability. Co-factor pockets from oligomeric proteins have already been successfully exploited as targets for such a strategy, but no similar sites are present at HGD surface; hence, transient pockets are here proposed as a target for pharmacological chaperones. Transient pockets are detected along the molecular dynamics trajectory of the protein and filtered down to a set of suitable sites for structural stabilization by mean of biochemical and pharmacological criteria. The result is a computational workflow relevant to other inborn errors of metabolism requiring rescue of oligomeric, misfolded enzymes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism

PubMed Central

Yubero, Dèlia; Brandi, Núria; Ormazabal, Aida; Garcia-Cazorla, Àngels; Pérez-Dueñas, Belén; Campistol, Jaime; Ribes, Antonia; Palau, Francesc

2016-01-01

Background Next-generation sequencing (NGS) technology has allowed the promotion of genetic diagnosis and are becoming increasingly inexpensive and faster. To evaluate the utility of NGS in the clinical field, a targeted genetic panel approach was designed for the diagnosis of a set of inborn errors of metabolism (IEM). The final aim of the study was to compare the findings for the diagnostic yield of NGS in patients who presented with consistent clinical and biochemical suspicion of IEM with those obtained for patients who did not have specific biomarkers. Methods The subjects studied (n = 146) were classified into two categories: Group 1 (n = 81), which consisted of patients with clinical and biochemical suspicion of IEM, and Group 2 (n = 65), which consisted of IEM cases with clinical suspicion and unspecific biomarkers. A total of 171 genes were analyzed using a custom targeted panel of genes followed by Sanger validation. Results Genetic diagnosis was achieved in 50% of patients (73/146). In addition, the diagnostic yield obtained for Group 1 was 78% (63/81), and this rate decreased to 15.4% (10/65) in Group 2 (X2 = 76.171; p < 0.0001). Conclusions A rapid and effective genetic diagnosis was achieved in our cohort, particularly the group that had both clinical and biochemical indications for the diagnosis. PMID:27243974

Omics-Based Strategies in Precision Medicine: Toward a Paradigm Shift in Inborn Errors of Metabolism Investigations.

PubMed

Tebani, Abdellah; Afonso, Carlos; Marret, Stéphane; Bekri, Soumeya

2016-09-14

The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve systemic exploration of complex interactions in biological systems. Driven by high-throughput omics technologies and the computational surge, it enables multi-scale and insightful overviews of cells, organisms, and populations. Precision medicine capitalizes on these conceptual and technological advancements and stands on two main pillars: data generation and data modeling. High-throughput omics technologies allow the retrieval of comprehensive and holistic biological information, whereas computational capabilities enable high-dimensional data modeling and, therefore, accessible and user-friendly visualization. Furthermore, bioinformatics has enabled comprehensive multi-omics and clinical data integration for insightful interpretation. Despite their promise, the translation of these technologies into clinically actionable tools has been slow. In this review, we present state-of-the-art multi-omics data analysis strategies in a clinical context. The challenges of omics-based biomarker translation are discussed. Perspectives regarding the use of multi-omics approaches for inborn errors of metabolism (IEM) are presented by introducing a new paradigm shift in addressing IEM investigations in the post-genomic era.

The history and development of the Human Genetics Society of Australasia.

PubMed

Sutherland, Grant R

2008-08-01

The Human Genetics Society of Australasia is a vibrant professional society with more than 900 members that promotes and regulates the practice of human and medical genetics in Australia and New Zealand. The growth of human genetics was stimulated by the development of diagnostic clinical cytogenetics laboratories in the early to mid 1960s. This coincided with the recognition by medical specialists, mainly pediatricians, that genetic disorders, especially inborn errors of metabolism and birth defects, were of clinical interest and potentially challenging areas for their skills. The organization of professionals in human genetics was slow to evolve. There was an early Western Australian Human Genetics Society, and the cytogenetics community had begun to meet annually from about 1966 but was coordinated by a mailing list rather than as a formal organization. In 1976, as part of the celebrations of the Centenary Year of the Adelaide Children's Hospital, a clinical genetics meeting involving several high profile international speakers and most of the senior medical geneticists in Australia and New Zealand along with the annual meeting of the loose-knit cytogeneticists group agreed that a small working group be charged with setting up a Human Genetics Society. The society was formally incorporated in South Australia in 1977.

Of Hissing Snakes and Angry Voices: Human Infants Are Differentially Responsive to Evolutionary Fear-Relevant Sounds

ERIC Educational Resources Information Center

Erlich, Nicole; Lipp, Ottmar V.; Slaughter, Virginia

2013-01-01

Adult humans demonstrate differential processing of stimuli that were recurrent threats to safety and survival throughout evolutionary history. Recent studies suggest that differential processing of evolutionarily ancient threats occurs in human infants, leading to the proposal of an inborn mechanism for rapid identification of, and response to,…

Metabolomics in Newborns.

PubMed

Noto, Antonio; Fanos, Vassilios; Dessì, Angelica

2016-01-01

Metabolomics is the quantitative analysis of a large number of low molecular weight metabolites that are intermediate or final products of all the metabolic pathways in a living organism. Any metabolic profiles detectable in a human biological fluid are caused by the interaction between gene expression and the environment. The metabolomics approach offers the possibility to identify variations in metabolite profile that can be used to discriminate disease. This is particularly important for neonatal and pediatric studies especially for severe ill patient diagnosis and early identification. This property is of a great clinical importance in view of the newer definitions of health and disease. This review emphasizes the workflow of a typical metabolomics study and summarizes the latest results obtained in neonatal studies with particular interest in prematurity, intrauterine growth retardation, inborn errors of metabolism, perinatal asphyxia, sepsis, necrotizing enterocolitis, kidney disease, bronchopulmonary dysplasia, and cardiac malformation and dysfunction. © 2016 Elsevier Inc. All rights reserved.

Malonyl-CoA Decarboxylase (MCD) as a Potential Therapeutic Target for Breast Cancer

DTIC Science & Technology

2010-05-01

Kreb cycle and electron transport activity. Clinical and biochemical studies of MCD deficiency, a rare inborn error of metabolism, provide another... mitochondria and is the rate limiting enzymatic step of mitochondrial fatty acid oxidation (Figure 1) (McGarry and Brown, 1997). Indeed, the 10-fold...1 activity and fatty acid oxidation, thereby preventing a futile cycle of fatty acid synthesis and oxidation. As FAS could consume malonyl-CoA, it was

Neuroradiological findings in maple syrup urine disease

PubMed Central

Indiran, Venkatraman; Gunaseelan, R. Emmanuel

2013-01-01

Maple syrup urine disease is a rare inborn error of amino acid metabolism involving catabolic pathway of the branched-chain amino acids. This disease, if left untreated, may cause damage to the brain and may even cause death. These patients typically present with distinctive maple syrup odour of sweat and urine. Patients typically present with skin and urine smelling like maple syrup. Here we describe a case with relevant magnetic resonance imaging findings and confirmatory biochemical findings. PMID:23772241

Neuroradiological findings in maple syrup urine disease.

PubMed

Indiran, Venkatraman; Gunaseelan, R Emmanuel

2013-01-01

Maple syrup urine disease is a rare inborn error of amino acid metabolism involving catabolic pathway of the branched-chain amino acids. This disease, if left untreated, may cause damage to the brain and may even cause death. These patients typically present with distinctive maple syrup odour of sweat and urine. Patients typically present with skin and urine smelling like maple syrup. Here we describe a case with relevant magnetic resonance imaging findings and confirmatory biochemical findings.

Herpetiform keratitis and palmoplantar hyperkeratosis: warning signs for Richner-Hanhart syndrome.

PubMed

Soares, Diogo C; Stroparo, Mariana N; Lian, Yu C; Takakura, Cristina Y; Wolf, Sabrina; Betz, Regina; Kim, Chong A

2017-05-01

Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database

PubMed Central

Pena, Loren D.M.; van Calcar, Sandra C.; Hansen, Joyanna; Edick, Mathew J.; Vockley, Cate Walsh; Leslie, Nancy; Cameron, Cynthia; Mohsen, Al-Walid; Berry, Susan A; Arnold, Georgianne L; Vockley, Jerry

2016-01-01

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1–18 years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1–3 years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified. PMID:27209629

Drug treatment of inborn errors of metabolism: a systematic review

PubMed Central

Alfadhel, Majid; Al-Thihli, Khalid; Moubayed, Hiba; Eyaid, Wafaa; Al-Jeraisy, Majed

2013-01-01

Background The treatment of inborn errors of metabolism (IEM) has seen significant advances over the last decade. Many medicines have been developed and the survival rates of some patients with IEM have improved. Dosages of drugs used for the treatment of various IEM can be obtained from a range of sources but tend to vary among these sources. Moreover, the published dosages are not usually supported by the level of existing evidence, and they are commonly based on personal experience. Methods A literature search was conducted to identify key material published in English in relation to the dosages of medicines used for specific IEM. Textbooks, peer reviewed articles, papers and other journal items were identified. The PubMed and Embase databases were searched for material published since 1947 and 1974, respectively. The medications found and their respective dosages were graded according to their level of evidence, using the grading system of the Oxford Centre for Evidence-Based Medicine. Results 83 medicines used in various IEM were identified. The dosages of 17 medications (21%) had grade 1 level of evidence, 61 (74%) had grade 4, two medications were in level 2 and 3 respectively, and three had grade 5. Conclusions To the best of our knowledge, this is the first review to address this matter and the authors hope that it will serve as a quickly accessible reference for medications used in this important clinical field. PMID:23532493

Consanguinity, endogamy and inborn errors of metabolism in Oman: a cross-sectional study.

PubMed

Al-Thihli, Khalid; Al-Murshedi, Fathiya; Al-Hashmi, Nadia; Al-Mamari, Watfa; Islam, M Mazharul; Al-Yahyaee, Said A

2014-01-01

The Sultanate of Oman, like many other Arab countries, has relatively high rates of consanguinity. Reports suggest that the incidence of inborn errors of metabolism (IEM) is also high in Oman. This retrospective cross-sectional study was designed to evaluate the number of patients with IEM being followed at the only two tertiary centers in Oman treating such patients, and to calculate the consanguinity rates among these families. The electronic medical records of all patients were reviewed for demographic and clinical characteristics. A total of 285 patients with IEM were being followed at the 2 centers involved; 162 (56.8%) were male and 123 (43.2%) were female. The history of consanguinity was documented or available for 241 patients: 229 patients (95%) were born to consanguineous parents related as second cousins or closer. First-cousin marriages were reported in 191 families (79.3%), while 31 patients (12.9%) were born to second cousins. The parents of 5 patients (2%) were related as double first cousins, and 2 patients (1%) were born to first cousins once removed. The average coefficient of inbreeding (F) in our study was 0.081. Seventeen patients (6%) had associated comorbid conditions other than IEM. Our study highlights the clinical burden of IEM in Oman and emphasizes the high consanguinity rates among the parents of affected patients. © 2014 S. Karger AG, Basel

Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.

PubMed

Watkins, David; Schwartzentruber, Jeremy A; Ganesh, Jaya; Orange, Jordan S; Kaplan, Bernard S; Nunez, Laura Dempsey; Majewski, Jacek; Rosenblatt, David S

2011-09-01

An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts. Exome sequencing was performed on patient genomic DNA. Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism. This protein is essential for the generation of formyltetrahydrofolate and methylenetetrahydrofolate and important for nucleotide and homocysteine metabolism. One mutation (c.727+1G>A) affects the splice acceptor site of intron 8. The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity. Both parents carry a single mutation and an unaffected sibling carries neither mutation. The combination of two mutations in the MTHFRD1 gene, predicted to have severe consequences, in the patient and their absence in the unaffected sibling, supports causality. This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study.

Tyrosinase, could it be a missing link in ochronosis in alkaptonuria?

PubMed

Taylor, Adam M; Kammath, Vishnu; Bleakley, Aaron

2016-06-01

The hypothesis that is proposed is that tyrosinase, an enzyme widely found within the human body is implicated in the ochronosis that occurs in alkaptonuria; an autosomal recessive condition first used by Archibald Garrod to describe the theory of "Inborn Errors of Metabolism." The disease results from the absence of a single enzyme in the liver that breaks down homogentisic acid; this molecule becomes systemically elevated in sufferers. The condition is characterised by a clinical triad of symptoms; homogentisic aciduria from birth, ochronosis (darkening) of collagenous tissues (from ∼30years of age) and ochronotic osteoarthropathy in weight bearing joints due to long term ochronosis in them (from ∼40years of age). Tyrosinase, a polyphenol oxidase has been shown in many species to contribute to the darkening of tissues in many organisms; including humans in the production of melanin. Tyrosinase under the right conditions shows alterations in its substrate specificity and may contribute to the darkening seen in AKU where it moves away from polymerising tyrosine but also homogentisic acid, the causative molecule in alkaptonuria, that is present in excess. Copyright © 2016. Published by Elsevier Ltd.

Magnetic resonance imaging findings of central nervous system in lysosomal storage diseases: A pictorial review.

PubMed

Fagan, Nathan; Alexander, Allen; Irani, Neville; Saade, Charbel; Naffaa, Lena

2017-06-01

Lysosomal storage diseases (LSD) are a complex group of genetic disorders that are a result of inborn errors of metabolism. These errors result in a variety of metabolic dysfunction and build-up certain molecules within the tissues of the central nervous system (CNS). Although, they have discrete enzymatic deficiencies, symptomology and CNS imaging findings can overlap with each other, which can become challenging to radiologists. The purpose of this paper is to review the most common CNS imaging findings in LSD in order to familiarize the radiologist with their imaging findings and help narrow down the differential diagnosis. © 2016 The Royal Australian and New Zealand College of Radiologists.

[Evaluation of the usefulness for neonatal mass screening in light of 35 years personal experience].

PubMed

Bozkowa, K; Cabalska, B; Radomyska, B; Ołtarzewski, M; Lenartowska, I

1999-01-01

The results and the significance of neonatal mass-screening programmes for inborn errors of metabolism, conducted by the National Research Institute of Mother and Child (NRIMC), are discussed. As the first in Poland, in 1964, mass-screening for phenylketonuria (PKU) was introduced. The BIA-Guthrie test was used. Other Guthrie tests (GBIA) were applied in homocystinuria, tyrosinemia, histidinemia and leucinosis (Maple Syrup Urine Disease-MSUD). In the middle of the 60. the Beutler and Baluda test was introduced for galactosaemia, as well as the Efron urine test in infant screening for different inborn errors of metabolism. In the middle of the 70., neonatal mass-screening for cystic fibrosis (CF, mucoviscidosis) was started. Meconium tests and the sweat test with ion selective chloride electrode were used. Apart from inborn errors of metabolism, we also introduced a screening programme for neuroblastoma in which vaniline mandelic acid (VMA) in urine was estimated and for congenital hypothyroidism were TSH level was assessed. The results of screening are shown in the tables and in the figures. In our opinion the best clinical results are obtained with screening for congenital hypothyroidism and for PKU, since very early detection and treatment in these diseases prevents severe mental retardation. We therefore consider that both these screening programmes should be treated as obligatory examinations in all neonates. Taking into consideration the fact that there are different types of hyperhenylalaninemias, the principles of differential diagnosis are discussed. Molecular genetic investigations, carried out in the NRIMC Department of Genetics proved to be a very important procedure in the verification of diagnosis of different mutations. The authors also discuss the problem of dietary treatment duration in PKU. In our opinion the hypophenyloalanine diet regimen in girls, should not be discontinued during adolescence, since there is the problem of maternal PKU and the possibility of foetal damage. The results of our own investigations of maternal PKU are discussed. The significance of mass-screening for galactosemia is still under discussion. In our opinion, mass-screening for galactosemia is not useful and we have discontinued it. Selective screening has been started combined with molecular genetic studies in high risk families. In the future, we plan to prepare guidelines on the principles of diagnosis and treatment of galactosemia in children and women in the reproductive age. Mass-screening for cystic fibrosis is also still under discussion. The results of the early screening programmes were not satisfactory and the tests were discontinued. In 1998, after reorganisation of the whole system, CF screening, using tripsin-radioimmune assays, was started again. The new screening programme is combined with molecular genetic investigation of different mutations. It is still too early to assess the importance and success of this CF mass-screening programme. We decided to discontinue the screening for homocystinuria, histidinemia, tyrosinemia, leucinosis and for neuroblastoma, since these programmes did not comply with criteria of mass-screening. In 1997, major reorganisation of screening programmes for inborn errors of metabolism, at NRIMC, was undertaken. The Guthrie test for PKU was changed to a quantitative colorimetric method. The immuno-luminometric method is used for TSH estimation. The whole system is based on complete computer control of all the steps of screening, from blood sampling on filter paper until the final diagnosis. The advantages of this modern system of organisation of the screening programme are discussed.

A novel ETFB mutation in a patient with glutaric aciduria type II.

PubMed

Sudo, Yosuke; Sasaki, Ayako; Wakabayashi, Takashi; Numakura, Chikahiko; Hayasaka, Kiyoshi

2015-01-01

Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth.

A novel ETFB mutation in a patient with glutaric aciduria type II

PubMed Central

Sudo, Yosuke; Sasaki, Ayako; Wakabayashi, Takashi; Numakura, Chikahiko; Hayasaka, Kiyoshi

2015-01-01

Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth. PMID:27081516

Selective screening for inborn errors of metabolism and secondary methylmalonic aciduria in pregnancy at high risk district of neural tube defects: a human metabolome study by GC-MS in China.

PubMed

Song, Yuan-Zong; Li, Bing-Xiao; Hao, Hu; Xin, Ruo-Lei; Zhang, Ting; Zhang, Chun-Hua; Kobayashi, Keiko; Wang, Zi-Neng; Zheng, Xiao-Ying

2008-05-01

Urease pretreatment-gas chromatography-mass spectrometry (UP-GC-MS) has become a valuable tool in the field of metabolome research, including analysis of inborn errors of metabolism (IEMs) and acquired metabolic disturbances secondary to nutrition or drugs. This research aims to screen IEMs in Chinese patients and to explore the cause of neural tube defects (NTDs), a congenital malformation very common in North China. Urine samples from 618 patients at high risk of IEMs in China were collected, and UP-GC-MS was performed in the selective screening. Urinary methylmalonate (MMA) levels in pregnancy with and without NTDs fetus, respectively, at Luliang district, a countryside region with NTDs incidence 227/10,000, Shanxi Province, North China, were analyzed by GC-MS-selective ion monitoring, and compared with that from control region. Among the 618 patients, 22 kinds and 59 cases of IEM were found. Methylmalonic aciduria (MMAuria) is on top of the list, followed by neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), phenylketonuria (PKU), multiple carboxylase deficiency (MCD), etc. Satisfactory therapeutic effects have been achieved in patients such as NICCD, MCD, and galactosemia. At Luliang district, urinary MMA levels in pregnancy, no matter NTDs-affected or unaffected, are both significantly (P<0.01) higher than that in normal control, while serum B(12) levels in NTDs-affected pregnancy are significantly lower than that both in NTDs-unaffected group (P<0.01) and in normal control (P<0.01). Furthermore, B(12) <52.5 pmol/L is associated with a 7.78-fold increased NTDs risk (P<0.01) at Luliang district. Selective screening for IEMs by UP-GC-MS provides valuable evidences for the diagnosis of IEMs. MMAuria secondary to B(12) deficiency is quite common at Luliang district, suggesting B(12) deficiency is involved in the development of NTDs in the specific population. This metabolome research by UP-GC-MS provides valuable epidemiological information that helps to understand the prevalence and the possible intervention strategy of NTDs and IEMs, especially in Chinese population.

Assessment of quality of life of the children and parents affected by inborn errors of metabolism with restricted diet: preliminary results of a cross-sectional study.

PubMed

Fabre, Alexandre; Baumstarck, Karine; Cano, Aline; Loundou, Anderson; Berbis, Julie; Chabrol, Brigitte; Auquier, Pascal

2013-09-19

The development in therapeutic strategies has increased survival of children affected by inborn errors of metabolism with restricted diet (IEMRD). These diseases have mild- and long-term consequences on the health. Little is known about the impact on the quality of life (QoL) of children and their families. The aims of this study were: to compare the QoL of the children and parents affected by IEMRD with the QoL of the general population and one pathology associated with long-term consequences. This cross-sectional study was performed at the French Reference Center for inborn metabolic disorders (Marseille, France). Inclusion criteria were: a child with a diagnosis of organic aciduria, urea cycle defect, or maple syrups urine disease (MSUD). Socio-demographics, clinical data, and QoL were recorded. Twenty-one of 32 eligible families were included during a planned routine visit. Ten (47%, 95% CI 27-69%) children were affected by organic aciduria, six (29%, 95% CI 10-48%) by urea cycle defects, and five (24%, 95% CI 6-42%) by MSUD. Among the younger children, the general well-being was significantly lower in the children with IEMRD than in the leukemia children (58 ± 16 versus 76 ± 15, p = 0.012), and among the older children, the leisure activities were significantly lower in the children with IEMRD than in the leukemia children (29 ± 18 versus 62 ± 22, p < 10-3), while the relationships with teachers were better (76 ± 23 versus 60 ± 23, p = 0.01). The physical QoL score was lower in the parents than in the French norms (66 ± 21 versus 75 ± 1, p = 0.05). Factors modulating QoL were: eating and neurologic disorders, enteral nutrition, and feeding modalities. The children and the parents of children affected presented altered 'physical' and 'social' QoL scores compared with the norms and patients with leukemia and their families. Future studies based on larger cohort studies should determine the different weights of potential predictive factors of QoL.

Developing treatments for inborn errors: incentives available to the clinician.

PubMed

Haffner, Marlene E

2004-04-01

Disorders resulting from inborn errors of metabolism (IEM) affect very small numbers of individuals. The entire population, however, of patients suffering the results of inherited metabolic disorders is large, and has been of increasing concern to patient groups and health care professionals in the United States as well as other countries throughout the world. The 1983 US Orphan Drug Act (ODA) serves to facilitate the development of drugs to treat rare diseases by providing several economic incentives. The sponsor of a product designated as an orphan by the Food & Drugs Administration (FDA) Office of Orphan Products Development (OPD) qualifies for tax credits on clinical trial expenses, the award of grant funding by FDA, through the OPD, and 7 years of marketing exclusivity for a designated drug, or biological product that receives FDA market approval. Orphan drug legislation in the US has benefited victims of IEM by encouraging development of drugs for metabolic deficiencies affecting populations that otherwise would be ignored. America's solution to the orphan drug problem has had worldwide impact. The success of this legislation was a factor leading to the 1993 orphan drug law in Japan; the 1997 implementation of a process whereby most FDA-approved orphan drugs and biological products will be similarly approved in Australia; and, in 1999, regulation on orphan medicinal products in the European Union (EU). Today, international support for rare disease research is providing stimulus and motivation to overcome the financial barriers and encourage development of treatment for very rare diseases throughout the world.

Quantitative charge-tags for sterol and oxysterol analysis.

PubMed

Crick, Peter J; William Bentley, T; Abdel-Khalik, Jonas; Matthews, Ian; Clayton, Peter T; Morris, Andrew A; Bigger, Brian W; Zerbinati, Chiara; Tritapepe, Luigi; Iuliano, Luigi; Wang, Yuqin; Griffiths, William J

2015-02-01

Global sterol analysis is challenging owing to the extreme diversity of sterol natural products, the tendency of cholesterol to dominate in abundance over all other sterols, and the structural lack of a strong chromophore or readily ionized functional group. We developed a method to overcome these challenges by using different isotope-labeled versions of the Girard P reagent (GP) as quantitative charge-tags for the LC-MS analysis of sterols including oxysterols. Sterols/oxysterols in plasma were extracted in ethanol containing deuterated internal standards, separated by C18 solid-phase extraction, and derivatized with GP, with or without prior oxidation of 3β-hydroxy to 3-oxo groups. By use of different isotope-labeled GPs, it was possible to analyze in a single LC-MS analysis both sterols/oxysterols that naturally possess a 3-oxo group and those with a 3β-hydroxy group. Intra- and interassay CVs were <15%, and recoveries for representative oxysterols and cholestenoic acids were 85%-108%. By adopting a multiplex approach to isotope labeling, we analyzed up to 4 different samples in a single run. Using plasma samples, we could demonstrate the diagnosis of inborn errors of metabolism and also the export of oxysterols from brain via the jugular vein. This method allows the profiling of the widest range of sterols/oxysterols in a single analytical run and can be used to identify inborn errors of cholesterol synthesis and metabolism. © 2014 American Association for Clinical Chemistry.

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests.

PubMed

Wang, Li-Yun; Chen, Nien-I; Chen, Pin-Wen; Chiang, Shu-Chuan; Hwu, Wuh-Liang; Lee, Ni-Chung; Chien, Yin-Hsiu

2013-02-10

Tandem mass spectrometry (MS/MS) analysis is a powerful tool for newborn screening, and many rare inborn errors of metabolism are currently screened using MS/MS. However, the sensitivity of MS/MS screening for several inborn errors, including citrin deficiency (screened by citrulline level) and carnitine uptake defect (CUD, screened by free carnitine level), is not satisfactory. This study was conducted to determine whether a second-tier molecular test could improve the sensitivity of citrin deficiency and CUD detection without increasing the false-positive rate. Three mutations in the SLC25A13 gene (for citrin deficiency) and one mutation in the SLC22A5 gene (for CUD) were analyzed in newborns who demonstrated an inconclusive primary screening result (with levels between the screening and diagnostic cutoffs). The results revealed that 314 of 46 699 newborns received a second-tier test for citrin deficiency, and two patients were identified; 206 of 30 237 newborns received a second-tier testing for CUD, and one patient was identified. No patients were identified using the diagnostic cutoffs. Although the incidences for citrin deficiency (1:23 350) and CUD (1:30 000) detected by screening are still lower than the incidences calculated from the mutation carrier rates, the second-tier molecular test increases the sensitivity of newborn screening for citrin deficiency and CUD without increasing the false-positive rate. Utilizing a molecular second-tier test for citrin deficiency and carnitine transporter deficiency is feasible.

Recent insights into the Smith-Lemli-Opitz syndrome.

PubMed

Yu, H; Patel, S B

2005-11-01

Recent insights into the Smith-Lemli-Opitz syndrome. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation disorder caused by an inborn error of post-squalene cholesterol biosynthesis. Deficient cholesterol synthesis in SLOS is caused by inherited mutations of 3beta-hydroxysterol-Delta7 reductase gene (DHCR7). DHCR7 deficiency impairs both cholesterol and desmosterol production, resulting in elevated 7DHC/8DHC levels, typically decreased cholesterol levels and, importantly, developmental dysmorphology. The discovery of SLOS has led to new questions regarding the role of the cholesterol biosynthesis pathway in human development. To date, a total of 121 different mutations have been identified in over 250 patients with SLOS who represent a continuum of clinical severity. Two genetic mouse models have been generated which recapitulate some of the developmental abnormalities of SLOS and have been useful in elucidating the pathogenesis. This mini review summarizes the recent insights into SLOS genetics, pathophysiology and potential therapeutic approaches for the treatment of SLOS.

Protein Homeostasis Defects of Alanine-Glyoxylate Aminotransferase: New Therapeutic Strategies in Primary Hyperoxaluria Type I

PubMed Central

Pey, Angel L.; Albert, Armando; Salido, Eduardo

2013-01-01

Alanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5′-phosphate (PLP) as cofactor. Human alanine-glyoxylate aminotransferase is a peroxisomal enzyme expressed in the hepatocytes, the main site of glyoxylate detoxification. Its deficit causes primary hyperoxaluria type I, a rare but severe inborn error of metabolism. Single amino acid changes are the main type of mutation causing this disease, and considerable effort has been dedicated to the understanding of the molecular consequences of such missense mutations. In this review, we summarize the role of protein homeostasis in the basic mechanisms of primary hyperoxaluria. Intrinsic physicochemical properties of polypeptide chains such as thermodynamic stability, folding, unfolding, and misfolding rates as well as the interaction of different folding states with protein homeostasis networks are essential to understand this disease. The view presented has important implications for the development of new therapeutic strategies based on targeting specific elements of alanine-glyoxylate aminotransferase homeostasis. PMID:23956997

Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.

PubMed

Dusi, Sabrina; Valletta, Lorella; Haack, Tobias B; Tsuchiya, Yugo; Venco, Paola; Pasqualato, Sebastiano; Goffrini, Paola; Tigano, Marco; Demchenko, Nikita; Wieland, Thomas; Schwarzmayr, Thomas; Strom, Tim M; Invernizzi, Federica; Garavaglia, Barbara; Gregory, Allison; Sanford, Lynn; Hamada, Jeffrey; Bettencourt, Conceição; Houlden, Henry; Chiapparini, Luisa; Zorzi, Giovanna; Kurian, Manju A; Nardocci, Nardo; Prokisch, Holger; Hayflick, Susan; Gout, Ivan; Tiranti, Valeria

2014-01-02

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome.

PubMed

Parkes, J D

1999-06-01

Sleep-wake problems are common in specific inborn errors of metabolism and structure of the central nervous system. Psychological factors, behavioural difficulties, metabolic disturbances, and widespread rather than focal damage to the nervous system are present in many of these diseases and all influence the sleep-wake cycle. However, a number of conditions cause relatively focal damage to the neuroanatomical substrate of sleeping and waking. These include fatal familial insomnia, with involvement of the prion protein gene on chromosome 20, Norrie disease, the Prader-Willi syndrome and the Moebius syndrome. The last three important conditions, although rare, are considered in detail in this review. They result in sensory deprivation, hypothalamic and mid-brain damage, and involve the X-chromosome, chromosome 15, and chromosome 13, respectively. These conditions cause a wide variety of sleep disturbance, including parasomnias, daytime sleepiness, and a condition like cataplexy. The place of the relevant gene products in normal sleep regulation needs further exploration.

Aspartylglucosaminuria: psychomotor retardation masquerading as a mucopolysaccharidosis.

PubMed

Isenberg, J N; Sharp, H L

1975-05-01

A 5-year-old girl with coarse facies, visceromegaly, and vacuolated lymphocytes is presented as the first case of aspartylglucosaminuria diagnosed in this country. This metabolic defect in glycoprotein catabolism can be clinically confused with other storage diseases such as the mucopolysaccharidoses and mucolipidoses. It is not diagnosed by routine laboratory screening methods. Special studies are required to confirm the diagnosis, but a thin-layer chromatography method for screening urine is presented for use when the diagnosis is suspected. The developmental potential in this inborn error of metabolism is documented.

Cerebrotendinous xanthomatosis.

PubMed

van Hellenberg Hubar, J L; Joosten, E M; Wevers, R A

1992-01-01

Cerebrotendinous xanthomatosis (CTX) is a familial sterol storage disease based on an inborn error of metabolism involving bile acid synthesis. Predominant clinical features are a chronic progressive neurological syndrome, mental deterioration, bilateral cataract and xanthomas. The presence of xanthomas usually leads to the diagnosis, and the reverse is probably also true: without xanthomas the diagnosis will often not be made. CTX may therefore be less rare than commonly thought, and the incidence of xanthomas in CTX may be overestimated. Four cases without xanthomas among the presenting symptoms are described, and the relevance of xanthomas in CTX is discussed.

Toxigenic and metabolic causes of ketosis and ketoacidotic syndromes.

PubMed

Cartwright, Martina M; Hajja, Waddah; Al-Khatib, Sofian; Hazeghazam, Maryam; Sreedhar, Dharmashree; Li, Rebecca Na; Wong-McKinstry, Edna; Carlson, Richard W

2012-10-01

Ketoacidotic syndromes are frequently encountered in acute care medicine. This article focuses on ketosis and ketoacidotic syndromes associated with intoxications, alcohol abuse, starvation, and certain dietary supplements as well as inborn errors of metabolism. Although all of these various processes are characterized by the accumulation of ketone bodies and metabolic acidosis, there are differences in the mechanisms, clinical presentations, and principles of therapy for these heterogeneous disorders. Pathophysiologic mechanisms that account for these disorders are presented, as well as guidance regarding identification and management. Copyright © 2012 Elsevier Inc. All rights reserved.

Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

PubMed Central

Lamborn, Ian T.; Jing, Huie; Zhang, Yu; Munir, Shirin; Bade, Sangeeta; Murdock, Heardley M.; Santos, Celia P.; Brock, Linda G.; Masutani, Evan; Matthews, Helen F.; Collins, Peter L.; Subbarao, Kanta; Gelfand, Erwin W.

2017-01-01

MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV infection while increasing IFN-stimulated gene expression and IFN-β/λ. However, wild-type MDA5 did not restrict influenza virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus. PMID:28606988

21 CFR 107.50 - Terms and conditions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HUMAN CONSUMPTION INFANT FORMULA Exempt Infant Formulas § 107.50 Terms and conditions. (a) Terms and...) of the act infant formulas that are represented and labeled for use by an infant who has an inborn... establish the terms and conditions that a manufacturer must meet with respect to such infant formulas. (b...

21 CFR 107.50 - Terms and conditions.

Code of Federal Regulations, 2013 CFR

2013-04-01

... apply to an infant formula specially and individually prepared for one or more specific infants on a... HUMAN CONSUMPTION INFANT FORMULA Exempt Infant Formulas § 107.50 Terms and conditions. (a) Terms and...) of the act infant formulas that are represented and labeled for use by an infant who has an inborn...

IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

PubMed Central

Bustamante, Jacinta; Feinberg, Jacqueline; Samarina, Arina; Grant, Audrey V.; Janniere, Lucile; El Hafidi, Naima; Hassani, Amal; Nolan, Daniel; Najib, Jilali; Camcioglu, Yildiz; Hatipoglu, Nevin; Aydogmus, Cigdem; Tanir, Gonul; Aytekin, Caner; Keser, Melike; Somer, Ayper; Aksu, Guside; Kutukculer, Necil; Mansouri, Davood; Mahdaviani, Alireza; Mamishi, Setareh; Alcais, Alexandre; Abel, Laurent; Casanova, Jean-Laurent

2011-01-01

Background and Objectives In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. Methods and Principal Findings We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. Significance This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity. PMID:21533230

A targeted metabolomics approach for clinical diagnosis of inborn errors of metabolism.

PubMed

Jacob, Minnie; Malkawi, Abeer; Albast, Nour; Al Bougha, Salam; Lopata, Andreas; Dasouki, Majed; Abdel Rahman, Anas M

2018-09-26

Metabolome, the ultimate functional product of the genome, can be studied through identification and quantification of small molecules. The global metabolome influences the individual phenotype through clinical and environmental interventions. Metabolomics has become an integral part of clinical research and allowed for another dimension of better understanding of disease pathophysiology and mechanism. More than 95% of the clinical biochemistry laboratory routine workload is based on small molecular identification, which can potentially be analyzed through metabolomics. However, multiple challenges in clinical metabolomics impact the entire workflow and data quality, thus the biological interpretation needs to be standardized for a reproducible outcome. Herein, we introduce the establishment of a comprehensive targeted metabolomics method for a panel of 220 clinically relevant metabolites using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) standardized for clinical research. The sensitivity, reproducibility and molecular stability of each targeted metabolite (amino acids, organic acids, acylcarnitines, sugars, bile acids, neurotransmitters, polyamines, and hormones) were assessed under multiple experimental conditions. The metabolic tissue distribution was determined in various rat organs. Furthermore, the method was validated in dry blood spot (DBS) samples collected from patients known to have various inborn errors of metabolism (IEMs). Using this approach, our panel appears to be sensitive and robust as it demonstrated differential and unique metabolic profiles in various rat tissues. Also, as a prospective screening method, this panel of diverse metabolites has the ability to identify patients with a wide range of IEMs who otherwise may need multiple, time-consuming and expensive biochemical assays causing a delay in clinical management. Copyright © 2018 Elsevier B.V. All rights reserved.

Congenital central hypoventilation syndrome associated with Hirschsprung's Disease: case report and literature review.

PubMed

Sandoval, Renata Lazari; Zaconeta, Carlos Moreno; Margotto, Paulo Roberto; Cardoso, Maria Teresinha de Oliveira; França, Evely Mirella Santos; Medina, Cristina Touguinha Neves; Canó, Talyta Matos; Faria, Aline Saliba de

2016-09-01

To report the case of a newborn with recurrent episodes of apnea, diagnosed with Congenital Central hypoventilation syndrome (CCHS) associated with Hirschsprung's disease (HD), configuring Haddad syndrome. Third child born at full-term to a non-consanguineous couple through normal delivery without complications, with appropriate weight and length for gestational age. Soon after birth he started to show bradypnea, bradycardia and cyanosis, being submitted to tracheal intubation and started empiric antibiotic therapy for suspected early neonatal sepsis. During hospitalization in the NICU, he showed difficulty to undergo extubation due to episodes of desaturation during sleep and wakefulness. He had recurrent episodes of hypoglycemia, hyperglycemia, metabolic acidosis, abdominal distension, leukocytosis, increase in C-reactive protein levels, with negative blood cultures and suspected inborn error of metabolism. At 2 months of age he was diagnosed with long-segment Hirschsprung's disease and was submitted to segment resection and colostomy through Hartmann's procedure. A genetic research was performed by polymerase chain reaction for CCHS screening, which showed the mutated allele of PHOX2B gene, confirming the diagnosis. This is a rare genetic, autosomal dominant disease, caused by mutation in PHOX2B gene, located in chromosome band 4p12, which results in autonomic nervous system dysfunction. CCHS can also occur with Hirschsprung's disease and tumors derived from the neural crest. There is a correlation between phenotype and genotype, as well as high intrafamilial phenotypic variability. In the neonatal period it can simulate cases of sepsis and inborn errors of metabolism. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

Living with an inborn error of metabolism detected by newborn screening-parents' perspectives on child development and impact on family life.

PubMed

Gramer, Gwendolyn; Haege, Gisela; Glahn, Esther M; Hoffmann, Georg F; Lindner, Martin; Burgard, Peter

2014-03-01

Newborn screening for inborn errors of metabolism is regarded as highly successful by health professionals. Little is known about parents' perspectives on child development and social impact on families. Parents of 187 patients with metabolic disorders detected by newborn screening rated child development, perceived burdens on child and family, and future expectations on a questionnaire with standardized answers. Parental ratings were compared with standardized psychometric test results. Regression analysis was performed to identify factors associated with extent of perceived burden. In 26.2% of patients, parents perceived delays in global development and/or specific developmental domains (physical, social, intellectual, language). Parents expected normal future development in 95.7%, and an independent adult life for their child in 94.6%. Comparison with psychometric test results showed that parents of children with cognitive impairments tended to overrate their child's abilities. Mild/medium burden posed on the family (child) by the metabolic disorder was stated by 56.1% (48.9%) of parents, severe/very severe burden by 19.3% (8.6%). One third of families reported financial burden due to the metabolic disorder. Dietary treatment and diagnoses with risk for metabolic decompensation despite treatment were associated with higher perceived burden for the family. Disorders rated as potentially very burdensome by experts were not rated accordingly by parents, demonstrating different perspectives of professionals and parents. Although newborn screening leads to favourable physical and cognitive outcome, living with a metabolic disorder may cause considerable stress on patients and families, emphasizing the need for comprehensive multidisciplinary care including psychological and social support.

Challenges in the management of patients with maple syrup urine disease diagnosed by newborn screening in a developing country.

PubMed

De Castro-Hamoy, Leniza G; Chiong, Mary Anne D; Estrada, Sylvia C; Cordero, Cynthia P

2017-01-01

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism resulting from a deficiency in the branched-chain alpha-ketoacid dehydrogenase complex. MSUD has been reported to be the most common inborn error of metabolism in the Philippines. We described all patients with maple syrup urine disease patients diagnosed through newborn screening during its first 2 years of implementation and the challenges encountered during their medical management. There were 24 patients diagnosed with maple syrup urine disease for the 2-year period. All patients needed hospital admission. The most common complication during hospital admission was infection, needing intravenous antibiotics which were given to 21 of the patients. Out of the 24 diagnosed, 16 patients are alive, while eight have died. Several neurologic and non-neurologic complications have been observed during the follow-up of the patients. The common challenges of MSUD management in a low-resource setting identified in this study were late diagnosis, lack of access to metabolic specialists and medical supplies, nosocomial septicemia, and protein deficiency. Aside from early properly timed collection, improvement in other logistical concerns will also help in earlier diagnosis. Mechanisms of transfer of critically ill patients must be improved. Hospitals in difficult-to-reach areas must be equipped to handle critical metabolic cases when transfers are not possible. Newborn screening has been proven to improve outcome in patients with MSUD but the success of the program in preventing disability is also dependent on improvements in other aspects of healthcare.

Therapies for inborn errors of metabolism: what has the orphan drug act delivered?

PubMed

Talele, Sonali S; Xu, Kui; Pariser, Anne R; Braun, M Miles; Farag-El-Massah, Sheiren; Phillips, M Ian; Thompson, Barry H; Coté, Timothy R

2010-07-01

The 1983 US Orphan Drug Act established a process through which promising therapies are designated as orphan products and, later, with satisfactory safety and efficacy data, receive marketing approval and fiscal incentives. We examined accomplishments in drug development for inborn errors of metabolism (IEMs). Food and Drug Administration data were used to identify orphan product designations and approvals for IEMs, and the trends for the past 26 years were summarized. Individual clinical development times (CDTs) from filing investigational new drug application to marketing approval were determined. We examined 1956 orphan product designations from 1983 through 2008 and found 93 (4.8%) for IEMs. Of those, 24 (25.8%) received marketing approval. This proportion of approval was significantly (P = .036) higher than that for non-IEM orphan products (17%). Among the IEM products, disorders of complex molecules received the most designations and approvals (61 and 11, respectively). Among the subgroups, lysosomal storage diseases received the most designations and approvals (43 and 9, respectively), whereas mitochondrial diseases (other than fatty acid oxidation disorders) received 7 designations with no approvals. We then examined the CDTs for the approved IEM products and found a median of 6.4 years (range: 2.6-25.1 years). Biological products had significantly shorter CDTs than drugs (mean: 4.6 vs 11.0 years; P = .003). For 26 years, the Orphan Drug Act has generated new therapies for IEMs. Why some IEMs have motivated successful drug development and others have not remains enigmatic; yet the needs of IEM patients without treatment are a certainty.

[Quantitative Color Vision Defect Evaluation - Lanthony Test and its Modified Interpretation].

PubMed

Veselý, P; Urbánek, D; Synek, S; Hanák, L

2016-01-01

Our aim was to develop quick and exact instrument for examination of color vision defects (CVD). We used Lanthony saturated and desaturated test. Data were evaluated according the Vingrys and King-Smith study. We had together 123 eyes of 86 patients. From all subjects we received these average values: AA 44.32 (min -87.13, max 80.64), TES 13.36 (min 8.84, max 30.30), SI 1.97 (min 1.22, max 5.69) and CI 1.66 (min 1.0, max 3.94). At the base of counting algorithm and average values form saturated and desaturated test we revealed 25 (29 %) patients with CVD. Twelve patients (14 %) classified as CVD+ had dichromacy and all had inborn CVD. Eight patients (9 %) from this group had deutranopia and four patient (5 %) protanopia. Anomaly trichromacy we revealed in thirteen patients (15 %). Eight (9 %) of these patients had inborn CVD. Six (7 %) of these patients had protanomalia, one (1 %) had deuteranomalia and one tritanomalia. We established and specified TES, CI and SI critical values, which was used to dividing patients into specific groups. Lanthony test, color vision defect, index of selectivity, index of confusion, total error score.

The patterns and causes of neonatal mortality at a tertiary hospital in oman.

PubMed

Abdellatif, Mohamed; Ahmed, Masood; Bataclan, Maria Flordeliz; Khan, Ashfaq Ahmed; Al Battashi, Abeer; Al Maniri, Abdullah

2013-11-01

To report the patterns and causes of neonatal death from a tertiary care neonatal intensive care unit over a period of four years. This is a retrospective cohort study where four years data (January 2006 - December 2009) of all inborn neonatal admissions and deaths were collected from the neonatal intensive care unit at Sultan Qaboos University hospital on predesigned forms. All out born admissions and deaths were excluded. The causes of neonatal death were classified using Wigglesworth's classification. The number of inborn live births during the study period was 10064 and the total number of inborn neonatal admissions was 1475. The total deaths (neonatal and post neonatal) at the neonatal intensive care unit was 73 (63 inborn and 10 out born). Among the inborn, five deaths were post neonatal deaths and hence, excluded from analysis. Among the remaining inborn neonatal deaths (n=58), 34 (59%) were males and 24 (41%) were females. The number of neonatal admissions increased over the years during the study period from 248 to 356, while the number of deaths also increased from 10 deaths in 2006, to 20 deaths in 2009. The primary causes of neonatal deaths were prematurity and its complications 52% (n=30). Lethal congenital malformations lead to 17 (29%) newborn deaths, specific diagnosis in 7 newborns (12%), and birth asphyxia in four (7%) of cases. There was an increasing trend of neonatal admissions and deaths among inborn babies. Prematurity, with sepsis as its major complication and congenital malformations were the leading cause of neonatal mortality.

The Patterns and Causes of Neonatal Mortality at a Tertiary Hospital in Oman

PubMed Central

Abdellatif, Mohamed; Ahmed, Masood; Bataclan, Maria Flordeliz; Khan, Ashfaq Ahmed; Al Battashi, Abeer; Al Maniri, Abdullah

2013-01-01

Objective To report the patterns and causes of neonatal death from a tertiary care neonatal intensive care unit over a period of four years. Methods This is a retrospective cohort study where four years data (January 2006 - December 2009) of all inborn neonatal admissions and deaths were collected from the neonatal intensive care unit at Sultan Qaboos University hospital on predesigned forms. All out born admissions and deaths were excluded. The causes of neonatal death were classified using Wigglesworth's classification. Results The number of inborn live births during the study period was 10064 and the total number of inborn neonatal admissions was 1475. The total deaths (neonatal and post neonatal) at the neonatal intensive care unit was 73 (63 inborn and 10 out born). Among the inborn, five deaths were post neonatal deaths and hence, excluded from analysis. Among the remaining inborn neonatal deaths (n=58), 34 (59%) were males and 24 (41%) were females. The number of neonatal admissions increased over the years during the study period from 248 to 356, while the number of deaths also increased from 10 deaths in 2006, to 20 deaths in 2009. The primary causes of neonatal deaths were prematurity and its complications 52% (n=30). Lethal congenital malformations lead to 17 (29%) newborn deaths, specific diagnosis in 7 newborns (12%), and birth asphyxia in four (7%) of cases. Conclusion There was an increasing trend of neonatal admissions and deaths among inborn babies. Prematurity, with sepsis as its major complication and congenital malformations were the leading cause of neonatal mortality. PMID:24223246

To bee or not to bee, this is the question…

PubMed Central

2011-01-01

Human inborn numerical competence means our ability to recognize object numbers precisely under circumstances which do not allow sequential counting. This archaic process has been called “subitizing,” from the Latin “subito” = suddenly, immediately, indicating that the objects in question are presented to test persons only for a fraction of a second in order to prevent counting. In contrast, however, sequential counting, an outstanding cultural achievement of mankind, means to count “1, 2, 3, 4, 5, 6, 7, 8…” without a limit. The following essay will explain how the limit of numerical competence, i.e., the recognition of object numbers without counting, has been determined for humans and how this has been achieved for the first time in case of an invertebrate, the honeybee. Finally, a hypothesis explaining the influence of our limited, inborn numerical competence on counting in our times, e.g., in the Russian language, will be presented. Subitizing versus counting by young Down syndrome infants and autistics and the Savant syndrome will be discussed. PMID:22046473

Sequential, solid-phase assay for biotin in physiologic fluids that correlates with expected biotin status

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mock, D.M.; DuBois, D.B.

1986-03-01

Interest in accurate measurement of biotin concentrations in plasma and urine has been stimulated by recent advances in the understanding of biotin-responsive inborn errors of metabolism and by several reports describing acquired biotin deficiency during parenteral alimentation. This paper presents a biotin assay utilizing radiolabeled avidin in a sequential, solid-phase method; the assay has increased sensitivity compared to previous methods (greater than or equal to 10 fmol/tube), correlates with expected trends in biotin concentrations in blood and urine in a rat model of biotin deficiency, and can utilize commercially available radiolabeled avidin.

Creatine Transporter Deficiency in Two Brothers with Autism Spectrum Disorder.

PubMed

Aydin, Halil Ibrahim

2018-01-15

Creatine transporter deficiency (CTD) is a treatable, X-linked, inborn error of metabolism. Two brothers with autism spectrum disorder were diagnosed with CTD at the ages of 17 and 12 years. Both were found to have a previously reported hemizygous p.408delF (c.1216_1218delTTC) deletion mutation. Both patients were given creatine monohydrate, L-arginine, L-glycine and S-adenosylmethionine, which partially improved the behavioral problems. Serum creatinine levels, creatine peak at brain MR spectroscopy or creatine/creatinine ratio in urine should be evaluated to identify CTD in children with autistic behavior and language disorders.

Glutaric Aciduria Type I: A Rare Metabolic Disorder Mimicking as Choreoathetoid Cerebral Palsy

PubMed Central

Sarangi, Pradosh Kumar; Sahoo, Lulup Kumar; Mallick, Ashok Kumar; Dash, Prafulla Kumar

2017-01-01

Glutaric aciduria type I (GA I) is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. This disorder is characterized by progressive dystonia, choreoathetosis, and dyskinesia. It is often misdiagnosed as athetoid cerebral palsy. Laboratory evaluation usually demonstrates increased urinary excretion of gluataric acid and 3-hydroxyglutaric acid. We report a case of a 7-year-old boy presenting with choreoathetosis and dystonia, mimicking as choreoathetoid cerebral palsy. The presence of characteristic neuroimaging and biochemical studies led to the diagnosis of GA I. PMID:28553392

Glutaric Aciduria Type I: A Rare Metabolic Disorder Mimicking as Choreoathetoid Cerebral Palsy.

PubMed

Sarangi, Pradosh Kumar; Sahoo, Lulup Kumar; Mallick, Ashok Kumar; Dash, Prafulla Kumar

2017-01-01

Glutaric aciduria type I (GA I) is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. This disorder is characterized by progressive dystonia, choreoathetosis, and dyskinesia. It is often misdiagnosed as athetoid cerebral palsy. Laboratory evaluation usually demonstrates increased urinary excretion of gluataric acid and 3-hydroxyglutaric acid. We report a case of a 7-year-old boy presenting with choreoathetosis and dystonia, mimicking as choreoathetoid cerebral palsy. The presence of characteristic neuroimaging and biochemical studies led to the diagnosis of GA I.

Nutrition and hair: deficiencies and supplements.

PubMed

Finner, Andreas M

2013-01-01

Hair follicle cells have a high turnover. A caloric deprivation or deficiency of several components, such as proteins, minerals, essential fatty acids, and vitamins, caused by inborn errors or reduced uptake, can lead to structural abnormalities, pigmentation changes, or hair loss, although exact data are often lacking. The diagnosis is established through a careful history, clinical examination of hair loss activity, and hair quality and confirmed through targeted laboratory tests. Examples of genetic hair disorders caused by reduced nutritional components are zinc deficiency in acrodermatitis enteropathica and copper deficiency in Menkes kinky hair syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.

Role of Mass Spectrometry in Clinical Endocrinology.

PubMed

Ketha, Siva S; Singh, Ravinder J; Ketha, Hemamalini

2017-09-01

The advent of mass spectrometry into the clinical laboratory has led to an improvement in clinical management of several endocrine diseases. Liquid chromatography tandem mass spectrometry found some of its first clinical applications in the diagnosis of inborn errors of metabolism, in quantitative steroid analysis, and in drug analysis laboratories. Mass spectrometry assays offer analytical sensitivity and specificity that is superior to immunoassays for many analytes. This article highlights several areas of clinical endocrinology that have witnessed the use of liquid chromatography tandem mass spectrometry to improve clinical outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

Urea cycle disorder--argininosuccinic lyase deficiency.

PubMed

Mehta, Neeta; Kirk, Pia Chatterjee; Holder, Ray; Precheur, Harry V

2012-01-01

An increased level of ammonia in the bloodstream, or hyperammonemia, is a symptom associated with metabolic disorders referred to as inborn errors of metabolism. Urea cycle disorder is a congenital abnormality or absence of one of the six enzymes involved in the elimination of ammonia. Administration of certain medications, high protein diet, excessive exercise, surgical procedures, or trauma can precipitate symptoms of mental confusion, seizure-like activity, and ataxia. This paper reviews the literature with insight into current treatment and management options of the disorder and modification of treatment for the dental patient. © 2012 Special Care Dentistry Association and Wiley Periodicals, Inc.

The Measurement of Ammonia in Human Breath and its Potential in Clinical Diagnostics.

PubMed

Brannelly, N T; Hamilton-Shield, J P; Killard, A J

2016-11-01

Ammonia is an important component of metabolism and is involved in many physiological processes. During normal physiology, levels of blood ammonia are between 11 and 50 µM. Elevated blood ammonia levels are associated with a variety of pathological conditions such as liver and kidney dysfunction, Reye's syndrome and a variety of inborn errors of metabolism including urea cycle disorders (UCD), organic acidaemias and hyperinsulinism/hyperammonaemia syndrome in which ammonia may reach levels in excess of 1 mM. It is highly neurotoxic and so effective measurement is critical for assessing and monitoring disease severity and treatment. Ammonia is also a potential biomarker in exercise physiology and studies of drug metabolism. Current ammonia testing is based on blood sampling, which is inconvenient and can be subject to significant analytical errors due to the quality of the sample draw, its handling and preparation for analysis. Blood ammonia is in gaseous equilibrium with the lungs. Recent research has demonstrated the potential use of breath ammonia as a non-invasive means of measuring systemic ammonia. This requires measurement of ammonia in real breath samples with associated temperature, humidity and gas characteristics at concentrations between 50 and several thousand parts per billion. This review explores the diagnostic applications of ammonia measurement and the impact that the move from blood to breath analysis could have on how these processes and diseases are studied and managed.

First report of HGD mutations in a Chinese with alkaptonuria.

PubMed

Yang, Yong-jia; Guo, Ji-hong; Chen, Wei-jian; Zhao, Rui; Tang, Jin-song; Meng, Xiao-hua; Zhao, Liu; Tu, Ming; He, Xin-yu; Wu, Ling-qian; Zhu, Yi-min

2013-04-15

Alkaptonuria (AKU) is one of the first prototypic inborn errors in metabolism and the first human disease found to be transmitted via Mendelian autosomal recessive inheritance. It is caused by HGD mutations, which leads to a deficiency in homogentisate 1,2-dioxygenase (HGD) activity. To date, several HGD mutations have been identified as the cause of the prototypic disease across different ethnic populations worldwide. However, in Asia, the HGD mutation is very rarely reported. For the Chinese population, no literature on HGD mutation screening is available to date. In this paper, we describe two novel HGD mutations in a Chinese AKU family, the splicing mutation of IVS7+1G>C, a donor splice site of exon 7, and a missense mutation of F329C in exon 12. The predicted new splicing site of the mutated exon 7 sequence demonstrated a 303bp extension after the mutation site. The F329C mutation most probably disturbed the stability of the conformation of the two loops critical to the Fe(2+) active site of the HGD enzyme. Copyright © 2013 Elsevier B.V. All rights reserved.

Novel alpha-galactosidase A mutation in a female with recurrent strokes.

PubMed

Tuttolomondo, Antonino; Duro, Giovanni; Miceli, Salvatore; Di Raimondo, Domenico; Pecoraro, Rosaria; Serio, Antonia; Albeggiani, Giuseppe; Nuzzo, Domenico; Iemolo, Francesco; Pizzo, Federica; Sciarrino, Serafina; Licata, Giuseppe; Pinto, Antonio

2012-11-01

Anderson-Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The complete genomic and cDNA sequences of the human alpha-galactosidase A gene have been determined and to date, several disease-causing alpha-galactosidase A mutations have been identified, including missense mutations, small deletions/insertions, splice mutations, and large gene rearrangements We report a case of a 56-year-old woman with recurrent cryptogenic strokes. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. She did not show other typical signs of Fabry disease such as acroparesthesias and angiokeratoma. The patient's alpha-galactosidase A activity was 4.13 nmol/mL/h in whole blood. Alpha-galactosidase A gene sequence analysis revealed a heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4 in this woman, leading to the p.Tyr184Asn amino acid substitution. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Metabolic Encephalopathy and Lipid Storage Myopathy Associated with a Presumptive Mitochondrial Fatty Acid Oxidation Defect in a Dog

PubMed Central

Biegen, Vanessa R.; McCue, John P.; Donovan, Taryn A.; Shelton, G. Diane

2015-01-01

A 1-year-old spayed female Shih Tzu presented for episodic abnormalities of posture and mentation. Neurological examination was consistent with a bilaterally symmetric multifocal encephalopathy. The dog had a waxing-and-waning hyperlactemia and hypoglycemia. Magnetic resonance imaging revealed bilaterally symmetric cavitated lesions of the caudate nuclei with less severe abnormalities in the cerebellar nuclei. Empirical therapy was unsuccessful, and the patient was euthanized. Post-mortem histopathology revealed bilaterally symmetric necrotic lesions of the caudate and cerebellar nuclei and multi-organ lipid accumulation, including a lipid storage myopathy. Malonic aciduria and ketonuria were found on urinary organic acid screen. Plasma acylcarnitine analysis suggested a fatty acid oxidation defect. Fatty acid oxidation disorders are inborn errors of metabolism documented in humans, but poorly described in dogs. Although neurological signs have been described in humans with this group of diseases, descriptions of advanced imaging, and histopathology are severely lacking. This report suggests that abnormalities of fatty acid metabolism may cause severe, bilateral gray matter necrosis, and lipid accumulation in multiple organs including the skeletal muscles, liver, and kidneys. Veterinarians should be aware that fatty acid oxidation disorders, although potentially fatal, may be treatable. A timely definitive diagnosis is essential in guiding therapy. PMID:26664991

Genetic screening: programs, principles, and research--thirty years later. Reviewing the recommendations of the Committee for the Study of Inborn Errors of Metabolism (SIEM).

PubMed

Simopoulos, A P

2009-01-01

Screening programs for genetic diseases and characteristics have multiplied in the last 50 years. 'Genetic Screening: Programs, Principles, and Research' is the report of the Committee for the Study of Inborn Errors of Metabolism (SIEM Committee) commissioned by the Division of Medical Sciences of the National Research Council at the National Academy of Sciences in Washington, DC, published in 1975. The report is considered a classic in the field worldwide, therefore it was thought appropriate 30 years later to present the Committee's modus operandi and bring the Committee's recommendations to the attention of those involved in genetics, including organizational, educational, legal, and research aspects of genetic screening. The Committee's report anticipated many of the legal, ethical, economic, social, medical, and policy aspects of genetic screening. The recommendations are current, and future committees should be familiar with them. In 1975 the Committee stated: 'As new screening tests are devised, they should be carefully reviewed. If the experimental rate of discovery of new genetic characteristics means an accelerating rate of appearance of new screening tests, now is the time to develop the medical and social apparatus to accommodate what later on may otherwise turn out to be unmanageable growth.' What a prophetic statement that was. If the Committee's recommendations had been implemented on time, there would be today a federal agency in existence, responsive and responsible to carry out the programs and support research on various aspects of genetic screening, including implementation of a federal law that protects consumers from discrimination by their employers and the insurance industry on the basis of genetic information. Copyright 2008 S. Karger AG, Basel.

Identification and Quantitation of Malonic Acid Biomarkers of In-Born Error Metabolism by Targeted Metabolomics

NASA Astrophysics Data System (ADS)

Ambati, Chandra Shekar R.; Yuan, Furong; Abu-Elheiga, Lutfi A.; Zhang, Yiqing; Shetty, Vivekananda

2017-05-01

Malonic acid (MA), methylmalonic acid (MMA), and ethylmalonic acid (EMA) metabolites are implicated in various non-cancer disorders that are associated with inborn-error metabolism. In this study, we have slightly modified the published 3-nitrophenylhydrazine (3NPH) derivatization method and applied it to derivatize MA, MMA, and EMA to their hydrazone derivatives, which were amenable for liquid chromatography- mass spectrometry (LC-MS) quantitation. 3NPH was used to derivatize MA, MMA, and EMA, and multiple reaction monitoring (MRM) transitions of the corresponding derivatives were determined by product-ion experiments. Data normalization and absolute quantitation were achieved by using 3NPH derivatized isotopic labeled compounds 13C2-MA, MMA-D3, and EMA-D3. The detection limits were found to be at nanomolar concentrations and a good linearity was achieved from nanomolar to millimolar concentrations. As a proof of concept study, we have investigated the levels of malonic acids in mouse plasma with malonyl-CoA decarboxylase deficiency (MCD-D), and we have successfully applied 3NPH method to identify and quantitate all three malonic acids in wild type (WT) and MCD-D plasma with high accuracy. The results of this method were compared with that of underivatized malonic acid standards experiments that were performed using hydrophilic interaction liquid chromatography (HILIC)-MRM. Compared with HILIC method, 3NPH derivatization strategy was found to be very efficient to identify these molecules as it greatly improved the sensitivity, quantitation accuracy, as well as peak shape and resolution. Furthermore, there was no matrix effect in LC-MS analysis and the derivatized metabolites were found to be very stable for longer time.

Exome Sequencing and the Management of Neurometabolic Disorders.

PubMed

Tarailo-Graovac, Maja; Shyr, Casper; Ross, Colin J; Horvath, Gabriella A; Salvarinova, Ramona; Ye, Xin C; Zhang, Lin-Hua; Bhavsar, Amit P; Lee, Jessica J Y; Drögemöller, Britt I; Abdelsayed, Mena; Alfadhel, Majid; Armstrong, Linlea; Baumgartner, Matthias R; Burda, Patricie; Connolly, Mary B; Cameron, Jessie; Demos, Michelle; Dewan, Tammie; Dionne, Janis; Evans, A Mark; Friedman, Jan M; Garber, Ian; Lewis, Suzanne; Ling, Jiqiang; Mandal, Rupasri; Mattman, Andre; McKinnon, Margaret; Michoulas, Aspasia; Metzger, Daniel; Ogunbayo, Oluseye A; Rakic, Bojana; Rozmus, Jacob; Ruben, Peter; Sayson, Bryan; Santra, Saikat; Schultz, Kirk R; Selby, Kathryn; Shekel, Paul; Sirrs, Sandra; Skrypnyk, Cristina; Superti-Furga, Andrea; Turvey, Stuart E; Van Allen, Margot I; Wishart, David; Wu, Jiang; Wu, John; Zafeiriou, Dimitrios; Kluijtmans, Leo; Wevers, Ron A; Eydoux, Patrice; Lehman, Anna M; Vallance, Hilary; Stockler-Ipsiroglu, Sylvia; Sinclair, Graham; Wasserman, Wyeth W; van Karnebeek, Clara D

2016-06-09

Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).

Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis

PubMed Central

Al-Shamsi, Aisha; Hertecant, Jozef L.; Al-Hamad, Sania; Souid, Abdul-Kader; Al-Jasmi, Fatma

2014-01-01

Objectives: This study aimed to determine the mutation spectrum and prevalence of inborn errors of metabolism (IEM) among Emiratis. Methods: The reported mutation spectrum included all patients who were diagnosed with IEM (excluding those with lysosomal storage diseases [LSD]) at Tawam Hospital Metabolic Center in Abu Dhabi, United Arab Emirates, between January 1995 and May 2013. Disease prevalence (per 100,000 live births) was estimated from data available for 1995–2011. Results: In 189 patients, 57 distinct IEM were diagnosed, of which 20 (35%) entities were previously reported LSD (65 patients with 39 mutations), with a birth prevalence of 26.87/100,000. This study investigated the remaining 37 (65%) patients with other IEM (124 patients with 62 mutations). Mutation analysis was performed on 108 (87%) of the 124 patients. Five patients with biotinidase deficiency had compound heterozygous mutations, and two siblings with lysinuric protein intolerance had two homozygous mutations. The remaining 103 (95%) patients had homozygous mutations. As of this study, 29 (47%) of the mutations have been reported only in Emiratis. Two mutations were found in three tribes (biotinidase deficiency [BTD, c.1330G>C] and phenylketonuria [PAH, c.168+5G>C]). Two mutations were found in two tribes (isovaleric aciduria [IVD, c.1184G>A] and propionic aciduria [PCCB, c.990dupT]). The remaining 58 (94%) mutations were each found in individual tribes. The prevalence was 48.37/100,000. The most prevalent diseases (2.2–4.9/100,000) were biotinidase deficiency; tyrosinemia type 1; phenylketonuria; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type Ia, and mitochondrial deoxyribonucleic acid depletion. Conclusion: The IEM birth prevalence (LSD and non-LSD) was 75.24/100,000. These results justify implementing prevention programmes that incorporate genetic counselling and screening. PMID:24516753

Exome Sequencing and the Management of Neurometabolic Disorders

PubMed Central

Tarailo-Graovac, M.; Shyr, C.; Ross, C.J.; Horvath, G.A.; Salvarinova, R.; Ye, X.C.; Zhang, L.-H.; Bhavsar, A.P.; Lee, J.J.Y.; Drögemöller, B.I.; Abdelsayed, M.; Alfadhel, M.; Armstrong, L.; Baumgartner, M.R.; Burda, P.; Connolly, M.B.; Cameron, J.; Demos, M.; Dewan, T.; Dionne, J.; Evans, A.M.; Friedman, J.M.; Garber, I.; Lewis, S.; Ling, J.; Mandal, R.; Mattman, A.; McKinnon, M.; Michoulas, A.; Metzger, D.; Ogunbayo, O.A.; Rakic, B.; Rozmus, J.; Ruben, P.; Sayson, B.; Santra, S.; Schultz, K.R.; Selby, K.; Shekel, P.; Sirrs, S.; Skrypnyk, C.; Superti-Furga, A.; Turvey, S.E.; Van Allen, M.I.; Wishart, D.; Wu, J.; Wu, J.; Zafeiriou, D.; Kluijtmans, L.; Wevers, R.A.; Eydoux, P.; Lehman, A.M.; Vallance, H.; Stockler-Ipsiroglu, S.; Sinclair, G.; Wasserman, W.W.; van Karnebeek, C.D.

2016-01-01

BACKGROUND Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.) PMID:27276562

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.

PubMed

Olsen, Rikke K J; Koňaříková, Eliška; Giancaspero, Teresa A; Mosegaard, Signe; Boczonadi, Veronika; Mataković, Lavinija; Veauville-Merllié, Alice; Terrile, Caterina; Schwarzmayr, Thomas; Haack, Tobias B; Auranen, Mari; Leone, Piero; Galluccio, Michele; Imbard, Apolline; Gutierrez-Rios, Purificacion; Palmfeldt, Johan; Graf, Elisabeth; Vianey-Saban, Christine; Oppenheim, Marcus; Schiff, Manuel; Pichard, Samia; Rigal, Odile; Pyle, Angela; Chinnery, Patrick F; Konstantopoulou, Vassiliki; Möslinger, Dorothea; Feichtinger, René G; Talim, Beril; Topaloglu, Haluk; Coskun, Turgay; Gucer, Safak; Botta, Annalisa; Pegoraro, Elena; Malena, Adriana; Vergani, Lodovica; Mazzà, Daniela; Zollino, Marcella; Ghezzi, Daniele; Acquaviva, Cecile; Tyni, Tiina; Boneh, Avihu; Meitinger, Thomas; Strom, Tim M; Gregersen, Niels; Mayr, Johannes A; Horvath, Rita; Barile, Maria; Prokisch, Holger

2016-06-02

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Alimentary Epigenetics: A Developmental Psychobiological Systems View of the Perception of Hunger, Thirst and Satiety

ERIC Educational Resources Information Center

Harshaw, Christopher

2008-01-01

Hunger, thirst and satiety have an enormous influence on cognition, behavior and development, yet we often take for granted that they are simply inborn or innate. Converging data and theory from both comparative and human domains, however, supports the conclusion that the phenomena hunger, thirst and satiety are not innate but rather emerge…

Atypical MR lenticular signal change in infantile isovaleric acidemia.

PubMed

Wani, Nisar A; Qureshi, Umer Amin; Jehangir, Majid; Ahmad, Kaiser; Hussain, Zahid

2016-01-01

Isovaleric acidemia (IVA) is an inborn error of branched chain amino acid metabolism that may manifest as acute neonatal metabolic acidosis or as chronic intermittent form with developmental delay or recurrent episodes of acute metabolic acidosis. Early diagnosis is the key to prevent morbidity and mortality. Brain imaging abnormalities are rarely described in IVA. We report a case of chronic intermittent IVA with acute presentation in a 4-month-old infant who presented with acute metabolic acidosis. Brain magnetic resonance imaging (MRI) revealed symmetric signal intensity changes in bilateral lentiform nuclei with an unreported T1-weighted (T1W) symmetric hyperintense ring-like appearance in bilateral putamen.

Oral findings in patients with mucolipidosis type III.

PubMed

Cavalcante, Weber Céo; Santos, Luciano Cincurá Silva; Dos Santos, Josiane Nascimento; de Vasconcellos, Sara Juliana de Abreu; de Azevedo, Roberto Almeida; Dos Santos, Jean Nunes

2012-01-01

Mucolipidosis type III is a rare, autosomal recessive disorder, which is part of a group of storage diseases as a result of inborn error of lysosomal enzyme metabolism. It is characterized by the gradual onset of signs and symptoms affecting the physical and mental development as well as visual changes, heart, skeletal and joint. Although oral findings associated with mucolipidosis type II have been extensively reported, there is a shortage of information on mucolipidosis type III. This paper presents radiological and histological findings of multiple radiolucent lesions associated with impacted teeth in the jaw of a 16 year-old youngster with mucolipidosis type III.

Metabolic screening and metabolomics analysis in the Intellectual Developmental Disorders Mexico Study.

PubMed

Ibarra-González, Isabel; Rodríguez-Valentín, Rocío; Lazcano-Ponce, Eduardo; Vela-Amieva, Marcela

2017-01-01

Inborn errors of metabolism (IEM) are genetic conditions that are sometimes associated with intellectual developmental disorders (IDD). The aim of this study is to contribute to the metabolic characterization of IDD of unknown etiology in Mexico. Metabolic screening using tandem mass spectrometry and fluorometry will be performed to rule out IEM. In addition, target metabolomic analysis will be done to characterize the metabolomic profile of patients with IDD. Identification of new metabolomic profiles associated with IDD of unknown etiology and comorbidities will contribute to the development of novel diagnostic and therapeutic schemes for the prevention and treatment of IDD in Mexico.

Inborn Errors of Metabolism with Hyperammonemia: Urea Cycle Defects and Related Disorders.

PubMed

Summar, Marshall L; Mew, Nicholas Ah

2018-04-01

The urea cycle disorders are a group of inherited biochemical diseases caused by a complete or partial deficiency of any one of the enzymes or transport proteins required to convert toxic ammonia into urea and to produce arginine and citrulline. The clinical manifestations of these disorders are mostly the result of acute or chronic hyperammonemia, which affects the central nervous system. Affected individuals can also develop hepatic dysfunction. These disorders can present at any age from the immediate newborn to later in life. Early diagnosis and treatment are key to improving outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

Diversity Within the U.S. Air Force Senior Leadership

DTIC Science & Technology

2010-02-17

15 1 Introduction The United States Air Force is committed to equal opportunity and diversity within its ranks. According to...Office. Diversity and Equal Opportunity in Our Air Force. AFTV Video. 9 min., March 2009. 2 What is diversity and is it important? When...attributes reflect unchangeable human differences that are either inborn or developed in our early socialization . Secondary dimensions of diversity

[PULMONARY COMPLICATIONS IN CHILDREN, OPERATED ON FOR INBORN HEART FAILURES IN THE ARTIFICIAL BLOOD CIRCULATION ENVIRONMENT].

PubMed

Moshkivska, L V; Nastenko, E A; Golovenko, O S; Lazoryshynets, V V

2015-11-01

The risk factors of pulmonary complications occurrence were analyzed in children, operated on for inborn heart failures in atrificial blood circulation environment. Pulmonary complications rate and the risk factors of their occurrence were analyzed.

Cerebral ketone body metabolism.

PubMed

Morris, A A M

2005-01-01

Ketone bodies (KBs) are an important source of energy for the brain. During the neonatal period, they are also precursors for the synthesis of lipids (especially cholesterol) and amino acids. The rate of cerebral KB metabolism depends primarily on the concentration in blood; high concentrations occur during fasting and on a high-fat diet. Cerebral KB metabolism is also regulated by the permeability of the blood-brain barrier (BBB), which depends on the abundance of monocarboxylic acid transporters (MCT1). The BBB's permeability to KBs increases with fasting in humans. In rats, permeability increases during the suckling period, but human neonates have not been studied. Monocarboxylic acid transporters are also present in the plasma membranes of neurons and glia but their role in regulating KB metabolism is uncertain. Finally, the rate of cerebral KB metabolism depends on the activities of the relevant enzymes in brain. The activities vary with age in rats, but reliable results are not available for humans. Cerebral KB metabolism in humans differs from that in the rat in several respects. During fasting, for example, KBs supply more of the brain's energy in humans than in the rat. Conversely, KBs are probably used more extensively in the brain of suckling rats than in human neonates. These differences complicate the interpretation of rodent studies. Most patients with inborn errors of ketogenesis develop normally, suggesting that the only essential role for KBs is as an alternative fuel during illness or prolonged fasting. On the other hand, in HMG-CoA lyase deficiency, imaging generally shows asymptomatic white-matter abnormalities. The ability of KBs to act as an alternative fuel explains the effectiveness of the ketogenic diet in GLUT1 deficiency, but its effectiveness in epilepsy remains unexplained.

The role of surface electrostatics on the stability, function and regulation of human cystathionine β-synthase, a complex multidomain and oligomeric protein.

PubMed

Pey, Angel L; Majtan, Tomas; Kraus, Jan P

2014-09-01

Human cystathionine β-synthase (hCBS) is a key enzyme of sulfur amino acid metabolism, controlling the commitment of homocysteine to the transsulfuration pathway and antioxidant defense. Mutations in hCBS cause inherited homocystinuria (HCU), a rare inborn error of metabolism characterized by accumulation of toxic homocysteine in blood and urine. hCBS is a complex multidomain and oligomeric protein whose activity and stability are independently regulated by the binding of S-adenosyl-methionine (SAM) to two different types of sites at its C-terminal regulatory domain. Here we study the role of surface electrostatics on the complex regulation and stability of hCBS using biophysical and biochemical procedures. We show that the kinetic stability of the catalytic and regulatory domains is significantly affected by the modulation of surface electrostatics through noticeable structural and energetic changes along their denaturation pathways. We also show that surface electrostatics strongly affect SAM binding properties to those sites responsible for either enzyme activation or kinetic stabilization. Our results provide new insight into the regulation of hCBS activity and stability in vivo with implications for understanding HCU as a conformational disease. We also lend experimental support to the role of electrostatic interactions in the recently proposed binding modes of SAM leading to hCBS activation and kinetic stabilization. Copyright © 2014 Elsevier B.V. All rights reserved.

D-lactic acidosis in humans: systematic literature review.

PubMed

Bianchetti, Davide G A M; Amelio, Giacomo S; Lava, Sebastiano A G; Bianchetti, Mario G; Simonetti, Giacomo D; Agostoni, Carlo; Fossali, Emilio F; Milani, Gregorio P

2018-04-01

D-lactic acidosis is an uncommon and challenging form of metabolic acidosis that may develop in short bowel syndrome. It has been documented exclusively in case reports and small case series. We performed a review of the literature in the National Library of Medicine and Excerpta Medica databases. We identified 84 original reports published between 1977 and 2017. D-lactic acidosis was observed in 98 individuals ranging in age from 7 months to 86 years with short bowel syndrome. The clinical presentation included Kussmaul breathing, confusion, slurred speech, and gait disturbances. Furthermore, among 99 consecutive patients with short bowel syndrome, 21 reported having episodes with symptoms consistent with D-lactic acidosis. In addition, D-lactic acid might also contribute to acidosis in diabetes mellitus. Finally, abnormally high D-lactic acid was documented after administration or ingestion of large amounts of propylene glycol, as paraneoplastic phenomenon and perhaps also in a so far poorly characterized inherited inborn error of metabolism. In humans with short bowel syndrome (or carbohydrate malabsorption), D-lactic acidosis is likely rather common and under-recognized. This condition should be included in the differential diagnosis of unexplained high-gap metabolic acidosis where the anion causing the acidosis is not known. Furthermore, diabetic acidosis might be caused by accumulation of both ketone bodies and D-lactic acid. Finally, there are endogenous sources of D-lactic acid in subjects with propylene glycol intoxication.

The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England.

PubMed

Hardelid, P; Cortina-Borja, M; Munro, A; Jones, H; Cleary, M; Champion, M P; Foo, Y; Scriver, C R; Dezateux, C

2008-01-01

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (OMIM 261600). Treatment with a low-phenylalanine diet following early ascertainment by newborn screening prevents impaired cognitive development, the major disease phenotype in PKU. The overall birth prevalence of PKU in European, Chinese and Korean populations is approximately 1/10,000. Since the human PAH locus contains PKU-causing alleles and polymorphic core haplotypes that describe and corroborate an out-of-Africa range expansion in modern human populations, it is of interest to know the prevalence of PKU in different ethnic groups with diverse geographical origin. We estimated PKU prevalence in South East England, where a sizeable proportion of the population are of Sub-Saharan African or South Asian ancestry. Over the period 1994 to 2004 167 children were diagnosed with PKU. Using birth registration and census data to derive denominators, PKU birth prevalence per 10,000 live births (95% Bayesian credible intervals) was estimated to be 1.14 (0.96-1.33) among white, 0.11 (0.02-0.37) among black, and 0.29 (0.10-0.63) among Asian ethnic groups. This suggests that PKU is up to an order of magnitude less prevalent in populations with Sub-Saharan African and South Asian ancestry that have migrated to the UK.

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

PubMed Central

Dang, Lenny; White, David W.; Gross, Stefan; Bennett, Bryson D.; Bittinger, Mark A.; Driggers, Edward M.; Fantin, Valeria R.; Jang, Hyun Gyung; Jin, Shengfang; Keenan, Marie C.; Marks, Kevin M.; Prins, Robert M.; Ward, Patrick S.; Yen, Katharine E.; Liau, Linda M.; Rabinowitz, Joshua D.; Cantley, Lewis C.; Thompson, Craig B.; Vander Heiden, Matthew G.; Su, Shinsan M.

2009-01-01

Summary Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site resulting in loss of the enzyme’s ability to catalyze conversion of isocitrate to α-ketoglutarate. However, only a single copy of the gene is mutated in tumors, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when R132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert α-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumors in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harboring IDH1 mutations, we find dramatically elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and suggest that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas. PMID:19935646

Amyloidosis in alkaptonuria.

PubMed

Millucci, Lia; Braconi, Daniela; Bernardini, Giulia; Lupetti, Pietro; Rovensky, Josef; Ranganath, Lakshminaryan; Santucci, Annalisa

2015-09-01

Alkaptonuria (AKU) is an ultra-rare inborn error of metabolism developed from the lack of homogentisic acid oxidase activity, causing homogentisic acid (HGA) accumulation that produces an HGA-melanin ochronotic pigment, of hitherto unknown composition. Besides the accumulation of HGA, the potential role and presence of unidentified proteins has been hypothesized as additional causal factors involved in ochronotic pigment deposition. Evidence has been provided on the presence of serum amyloid A (SAA) in several AKU tissues, which allowed classifying AKU as a novel secondary amyloidosis. In this paper, we will briefly review all direct and indirect lines of evidence related to the presence of amyloidosis in AKU. We also report the first data on abnormal SAA serum levels in a cohort of AKU patients.

Mutational analysis of the HGO gene in Finnish alkaptonuria patients

PubMed Central

de Bernabe, D. B.-V.; Peterson, P.; Luopajarvi, K.; Matintalo, P.; Alho, A.; Konttinen, Y.; Krohn, K.; de Cordoba, S. R.; Ranki, A.

1999-01-01

Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1,2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.


Keywords: alkaptonuria; homogentisate-1,2-dioxygenase; Finland PMID:10594001

Update on gene therapy of inherited immune deficiencies.

PubMed

Engel, Barbara C; Kohn, Donald B; Podsakoff, Greg M

2003-10-01

Gene therapy has been under development as a way to correct inborn errors for many years. Recently, patients with two forms of inherited severe combined immunodeficiency (SCID), adenosine deaminase and X-linked, treated by three different clinical investigative teams, have shown significant immune reconstitution leading to protective immunity. These advances irrefutably prove the concept that hematopoietic progenitor cell gene therapy can ameliorate these diseases. However, due to proviral insertional oncogenesis, two individuals in one of the X-SCID studies developed T-cell leukemia more than two years after the gene transfer. Depending upon the results of long-term follow-up, the successes together with the side effects highlight the relative merits of this therapeutic approach.

Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis.

PubMed

Green, Thomas J; Bijlsma, Jan Jaap; Sweet, David D

2010-09-01

The workup of the emergency patient with a raised anion gap metabolic acidosis includes assessment of the components of “MUDPILES” (methanol; uremia; diabetic ketoacidosis; paraldehyde; isoniazid, iron or inborn errors of metabolism; lactic acid; ethylene glycol; salicylates). This approach is usually sufficient for the majority of cases in the emergency department; however, there are many other etiologies not addressed in this mnemonic. Organic acids including 5-oxoproline (pyroglutamic acid) are rare but important causes of anion gap metabolic acidosis. We present the case of a patient with profound metabolic acidosis with raised anion gap, due to pyroglutamic acid in the setting of malnutrition and chronic ingestion of acetaminophen.

Recurrent truncating mutations in alanine-glyoxylate aminotransferase gene in two South Indian families with primary hyperoxaluria type 1 causing later onset end-stage kidney disease

PubMed Central

Dutta, A. K.; Paulose, B. K.; Danda, S.; Alexander, S.; Tamilarasi, V.; Omprakash, S.

2016-01-01

Primary hyperoxaluria type 1 is an autosomal recessive inborn error of metabolism due to liver-specific peroxisomal enzyme alanine-glyoxylate transaminase deficiency. Here, we describe two unrelated patients who were diagnosed to have primary hyperoxaluria. Homozygous c.445_452delGTGCTGCT (p.L151Nfs*14) (Transcript ID: ENST00000307503; human genome assembly GRCh38.p2) (HGMD ID CD073567) mutation was detected in both the patients and the parents were found to be heterozygous carriers. Our patients developed end-stage renal disease at 23 years and 35 years of age. However, in the largest series published from OxalEurope cohort, the median age of end-stage renal disease for null mutations carriers was 9.9 years, which is much earlier than our cases. Our patients had slower progressions as compared to three unrelated patients from North India and Pakistan, who had homozygous c.302T>C (p.L101P) (HGMD ID CM093792) mutation in exon 2. Further, patients need to be studied to find out if c.445_452delGTGCTGCT mutation represents a founder mutation in Southern India. PMID:27512303

Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages.

PubMed

Neehus, Anna-Lena; Lam, Jenny; Haake, Kathrin; Merkert, Sylvia; Schmidt, Nico; Mucci, Adele; Ackermann, Mania; Schubert, Madline; Happle, Christine; Kühnel, Mark Philipp; Blank, Patrick; Philipp, Friederike; Goethe, Ralph; Jonigk, Danny; Martin, Ulrich; Kalinke, Ulrich; Baumann, Ulrich; Schambach, Axel; Roesler, Joachim; Lachmann, Nico

2018-01-09

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNγ) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNγ is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNγR1 deficiency and received bone-marrow transplantation. Loss of IFNγR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNγR1 in iMSMD-cohet macrophages abolished IFNγ-dependent phosphorylation of STAT1 and induction of IFNγ-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guérin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNγ signaling in macrophages. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Genetic epidemiology of single gene defects in Chile.

PubMed Central

Cruz-Coke, R; Moreno, R S

1994-01-01

We have studied the correlation between the ethnic structure and the prevalence of single gene defects in Chile. At present the Chilean population is approximately 64% white and 35% Amerindian with traces of other admixture. Fewer than 4% of the Chilean population are foreign born. Investigations indicate that all severe diseases and many others without impaired reproduction have mutation rates within the range of the white population. Classical ethnic diseases are very rare. Autosomal recessive disorders have a wide range of variability: cystic fibrosis has a low incidence and PKU has a similar incidence to English rates. Only 30% of the inborn errors of metabolism have been described in Chilean medical publications. In addition, no Chilean haemoglobin or haptoglobin variants have been described. Some rare inherited diseases in Chilean human isolates have been described, including achromatopsia, chondrocalcinosis, and Creutzfeldt-Jakob disease. The prevalence of intrahepatic cholestasis of pregnancy and supernumerary nipples is the highest in the world and they are associated with aboriginal origin. Single gene defects in Chile are probably shaped by factors related to its ethnic population structure. These local rare single gene defects may be good markers of population admixture for genetic epidemiological studies. PMID:7815439

Faces Are Special for Newly Hatched Chicks: Evidence for Inborn Domain-Specific Mechanisms Underlying Spontaneous Preferences for Face-Like Stimuli

ERIC Educational Resources Information Center

Rosa-Salva, Orsola; Regolin, Lucia; Vallortigara, Giorgio

2010-01-01

It is currently being debated whether human newborns' preference for faces is due to an unlearned, domain-specific and configural representation of the appearance of a face, or to general mechanisms, such as an up-down bias (favouring top-heavy stimuli, which have more elements in their upper part). Here we show that 2-day-old domestic chicks,…

Computational Modeling of Human Metabolism and Its Application to Systems Biomedicine.

PubMed

Aurich, Maike K; Thiele, Ines

2016-01-01

Modern high-throughput techniques offer immense opportunities to investigate whole-systems behavior, such as those underlying human diseases. However, the complexity of the data presents challenges in interpretation, and new avenues are needed to address the complexity of both diseases and data. Constraint-based modeling is one formalism applied in systems biology. It relies on a genome-scale reconstruction that captures extensive biochemical knowledge regarding an organism. The human genome-scale metabolic reconstruction is increasingly used to understand normal cellular and disease states because metabolism is an important factor in many human diseases. The application of human genome-scale reconstruction ranges from mere querying of the model as a knowledge base to studies that take advantage of the model's topology and, most notably, to functional predictions based on cell- and condition-specific metabolic models built based on omics data.An increasing number and diversity of biomedical questions are being addressed using constraint-based modeling and metabolic models. One of the most successful biomedical applications to date is cancer metabolism, but constraint-based modeling also holds great potential for inborn errors of metabolism or obesity. In addition, it offers great prospects for individualized approaches to diagnostics and the design of disease prevention and intervention strategies. Metabolic models support this endeavor by providing easy access to complex high-throughput datasets. Personalized metabolic models have been introduced. Finally, constraint-based modeling can be used to model whole-body metabolism, which will enable the elucidation of metabolic interactions between organs and disturbances of these interactions as either causes or consequence of metabolic diseases. This chapter introduces constraint-based modeling and describes some of its contributions to systems biomedicine.

The Affective Core of the Self: A Neuro-Archetypical Perspective on the Foundations of Human (and Animal) Subjectivity.

PubMed

Alcaro, Antonio; Carta, Stefano; Panksepp, Jaak

2017-01-01

Psychologists usually considered the "Self" as an object of experience appearing when the individual perceives its existence within the conscious field. In accordance with such a view, the self-representing capacity of the human mind has been related to corticolimbic learning processes taking place within individual development. On the other hand, Carl Gustav Jung considered the Self as the core of our personality, in its conscious and unconscious aspects, as well as in its actual and potential forms. According to Jung, the Self originates from an inborn dynamic structure integrating the essential drives of our "brain-mind," and leading both to instinctual behavioral actions and to archetypal psychological experiences. Interestingly, recent neuroethological studies indicate that our subjective identity rests on ancient neuropsychic processes that humans share with other animals as part of their inborn constitutional repertoire. Indeed, brain activity within subcortical midline structures (SCMSs) is intrinsically related to the emergence of prototypical affective states, that not only influence our behavior in a flexible way, but alter our conscious field, giving rise to specific feelings or moods, which constitute the first form of self-orientation in the world. Moreover, such affective dynamics play a central role in the organization of individual personality and in the evolution of all other (more sophisticated) psychological functions. Therefore, on the base of the convergence between contemporary cutting-edge scientific research and some psychological intuitions of Jung, we intend here to explore the first neuroevolutional layer of human mind, that we call the affective core of the Self.

The Affective Core of the Self: A Neuro-Archetypical Perspective on the Foundations of Human (and Animal) Subjectivity

PubMed Central

Alcaro, Antonio; Carta, Stefano; Panksepp, Jaak

2017-01-01

Psychologists usually considered the “Self” as an object of experience appearing when the individual perceives its existence within the conscious field. In accordance with such a view, the self-representing capacity of the human mind has been related to corticolimbic learning processes taking place within individual development. On the other hand, Carl Gustav Jung considered the Self as the core of our personality, in its conscious and unconscious aspects, as well as in its actual and potential forms. According to Jung, the Self originates from an inborn dynamic structure integrating the essential drives of our “brain–mind,” and leading both to instinctual behavioral actions and to archetypal psychological experiences. Interestingly, recent neuroethological studies indicate that our subjective identity rests on ancient neuropsychic processes that humans share with other animals as part of their inborn constitutional repertoire. Indeed, brain activity within subcortical midline structures (SCMSs) is intrinsically related to the emergence of prototypical affective states, that not only influence our behavior in a flexible way, but alter our conscious field, giving rise to specific feelings or moods, which constitute the first form of self-orientation in the world. Moreover, such affective dynamics play a central role in the organization of individual personality and in the evolution of all other (more sophisticated) psychological functions. Therefore, on the base of the convergence between contemporary cutting-edge scientific research and some psychological intuitions of Jung, we intend here to explore the first neuroevolutional layer of human mind, that we call the affective core of the Self. PMID:28919868

Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency.

PubMed

Balasubramaniam, S; Riley, L G; Bratkovic, D; Ketteridge, D; Manton, N; Cowley, M J; Gayevskiy, V; Roscioli, T; Mohamed, M; Gardeitchik, T; Morava, E; Christodoulou, J

2017-09-01

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.

The role of dietary creatine.

PubMed

Brosnan, Margaret E; Brosnan, John T

2016-08-01

The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body Creatine is a carninutrient, which means that it is only available to adults via animal foodstuffs, principally skeletal muscle, or via supplements. Infants receive creatine in mother's milk or in milk-based formulas. Vegans and infants fed on soy-based formulas receive no dietary creatine. Plasma and muscle creatine levels are usually somewhat lower in vegetarians than in omnivores. Human intake of creatine was probably much higher in Paleolithic times than today; some groups with extreme diets, such as Greenland and Alaskan Inuit, ingest much more than is currently typical. Creatine is synthesized from three amino acids: arginine, glycine and methionine (as S-adenosylmethionine). Humans can synthesize sufficient creatine for normal function unless they have an inborn error in a creatine-synthetic enzyme or a problem with the supply of substrate amino acids. Carnivorous animals, such as lions and wolves, ingest much larger amounts of creatine than humans would. The gastrointestinal tract and the liver are exposed to dietary creatine in higher concentrations before it is assimilated by other tissues. In this regard, our observations that creatine supplementation can prevent hepatic steatosis (Deminice et al. J Nutr 141:1799-1804, 2011) in a rodent model may be a function of the route of dietary assimilation. Creatine supplementation has also been reported to improve the intestinal barrier function of the rodent suffering from inflammatory bowel disease.

Determination of Phenylalanine and Tyrosine by High Performance Liquid Chromatography-Tandem Mass Spectrometry.

PubMed

Peat, Judy; Garg, Uttam

2016-01-01

Hyperphenylalaninemia/phenylketonuria (PKU) is one of the most common inborn errors of amino acid metabolism affecting about 1:15,000 infants in the United States. PKU is an autosomal recessive disorder that if untreated results in mental retardation. The most common cause of PKU is deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. Tyrosine deficiency results in impaired synthesis of catecholamines and thyroxine. Less commonly, it can result from defects in the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase. Increased phenylalanine and decreased tyrosine in blood are used in the diagnosis and follow-up of patients with PKU. LC/MS/MS method is described for the quantification of phenylalanine and tyrosine.

Setting up an emergency stock for metabolic diseases.

PubMed

Fernandez-Llamazares, C M; Serrano, M L; Manrique-Rodríguez, S; Sanjurjo-Sáez, M

2010-01-01

Therapeutic management of inborn errors of metabolism (IEMs) is complicated. The drugs involved are classified as orphan, and their supply depends on whether they are orphan medicines, investigational drugs, or need to be prepared as a compounded formula. We analyzed emergency criteria, availability, and permanent location of metabolic drugs within the hospital. Information on therapeutic usage, administration, and dosage was also recorded. A stock for treating IEMs should include chelating agents, drugs to treat deficiencies, enzyme supplements, and other specific treatments. Hyperammonemia was considered to be life-threatening; therefore, an emergency supply of drugs to treat this condition should be kept permanently in the hospitalization unit. Emergency drug stocks are highly recommended in tertiary hospitals in order to improve care for patients susceptible to IEM.

Glutaric aciduria type 1 as a cause of dystonic cerebral palsy

PubMed Central

Mohamed, Sarar; Hamad, Muddathir H.; Hassan, Hamdy H.; Salih, Mustafa A.

2015-01-01

Glutaric aciduria type 1 (GA1) is an inherited inborn error of metabolism caused by a deficiency of the enzyme glutaryl Co-A dehydrogenase (GCDH). Here, we report a 14-month-old Saudi boy with GA1 who presented with severe dystonia and was mis-diagnosed as cerebral palsy (CP). He presented to our institute with encephalopathy following an episode of gastroenteritis. His physical examination showed dystonia and spastic quadriplegia. His investigations revealed elevated both urinary 3-hydroxy glutaric acid, and serum glutarylcarnitine. The DNA analysis confirmed homozygosity for a mutation in the GCDH-coding gene (c.482G>A;p.R161Q). This case alerts pediatricians to consider GA1 as a differential diagnosis of children presenting with dystonic CP. PMID:26593172

Glutaric aciduria type 1 as a cause of dystonic cerebral palsy.

PubMed

Mohamed, Sarar; Hamad, Muddathir H; Hassan, Hamdy H; Salih, Mustafa A

2015-11-01

Glutaric aciduria type 1 (GA1) is an inherited inborn error of metabolism caused by a deficiency of the enzyme glutaryl Co-A dehydrogenase (GCDH). Here, we report a 14-month-old Saudi boy with GA1 who presented with severe dystonia and was mis-diagnosed as cerebral palsy (CP). He presented to our institute with encephalopathy following an episode of gastroenteritis. His physical examination showed dystonia and spastic quadriplegia. His investigations revealed elevated both urinary 3-hydroxy glutaric acid, and serum glutarylcarnitine. The DNA analysis confirmed homozygosity for a mutation in the GCDH-coding gene (c.482G greater than A; p.R161Q). This case alerts pediatricians to consider GA1 as a differential diagnosis of children presenting with dystonic CP.

Glutaric Aciduria type I and acute renal failure - Coincidence or causality?

PubMed

Pode-Shakked, Ben; Marek-Yagel, Dina; Rubinshtein, Marina; Pessach, Itai M; Paret, Gideon; Volkov, Alexander; Anikster, Yair; Lotan, Danny

2014-01-01

Glutaric Aciduria type I (GA-I) is a rare organic acidemia, caused by mutations in the GCDH gene, and characterized by encephalopathic crises with neurological sequelae. We report herein a patient with GA-I who presented with severe acute renal failure requiring dialysis, following an acute diarrheal illness. Histopathological evaluation demonstrated acute tubular necrosis, and molecular diagnosis revealed the patient to be homozygous for a previously unreported mutation, p.E64D. As renal impairment is not part of the clinical spectrum typical to GA-I, possible associations of renal failure and the underlying inborn error of metabolism are discussed, including recent advancements made in the understanding of the renal transport of glutaric acid and its derivatives during metabolic disturbance in GA-I.

Therapeutic uses of microencapsulated genetically engineered cells.

PubMed

Chang, T M; Prakash, S

1998-05-01

Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.

Therapies in inborn errors of oxidative metabolism

PubMed Central

Schiff, Manuel; Bénit, Paule; Jacobs, Howard T.; Vockley, Jerry; Rustin, Pierre

2014-01-01

Mitochondrial diseases encompass a wide range of presentations and mechanisms, dictating a need to consider both broad-based and disease-specific therapies. The manifestations of mitochondrial dysfunction and the response to therapy vary between individuals. This probably reflects the genetic complexity of mitochondrial biology, which requires an excess of 2000 genes for proper function, with numerous interfering epigenetic and environmental factors. Accordingly, we are increasingly aware of the complexity of these diseases which involve far more than merely decreased ATP supply. Indeed, recent therapeutic progress has addressed only specific disease entities. In this review present and prospective therapeutic approaches will be discussed on the basis of targets and mechanism of action, but with a broad outlook on their potential applications. PMID:22633959

Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency.

PubMed

Cameron, Jessie M; Maj, Mary C; Levandovskiy, Valeriy; MacKay, Neviana; Shelton, G Diane; Robinson, Brian H

2007-01-01

Exercise intolerance syndromes are well known to be associated with inborn errors of metabolism affecting glycolysis (phosphorylase and phosphofructokinase deficiency) and fatty acid oxidation (palmitoyl carnitine transferase deficiency). We have identified a canine model for profound exercise intolerance caused by a deficit in PDP1 (EC 3.1.3.43), the phosphatase enzyme that activates the pyruvate dehydrogenase complex (PDHc). The Clumber spaniel breed was originated in 1760 by the Duc de Noailles, as a hunting dog with a gentle temperament suitable for the 'elderly gentleman'. Here we report that 20% of the current Clumber and Sussex spaniel population are carriers for a null mutation in PDP1, and that homozygosity produces severe exercise intolerance. Human pyruvate dehydrogenase phosphatase deficiency was recently characterized at the molecular level. However, the nature of the human mutation (loss of a single amino acid altering PDP1 activity) made it impossible to discern the role of the second phosphatase isoform, PDP2, in the deficient phenotype. Here we show that the null mutation in dogs provides a valuable animal model with which to study the effects of dysregulation of the PDHc. Knowledge of the molecular defect has allowed for the institution of a rapid restriction enzyme test for the canine mutation that will allow for selective breeding and has led to a suggested dietary therapy for affected dogs that has proven to be beneficial. Pharmacological and genetic therapies for PDP1 deficiency can now be investigated and the role of PDP2 can be fully characterized.

Inborn and experience-dependent models of categorical brain organization. A position paper

PubMed Central

Gainotti, Guido

2015-01-01

The present review aims to summarize the debate in contemporary neuroscience between inborn and experience-dependent models of conceptual representations that goes back to the description of category-specific semantic disorders for biological and artifact categories. Experience-dependent models suggest that categorical disorders are the by-product of the differential weighting of different sources of knowledge in the representation of biological and artifact categories. These models maintain that semantic disorders are not really category-specific, because they do not respect the boundaries between different categories. They also argue that the brain structures which are disrupted in a given type of category-specific semantic disorder should correspond to the areas of convergence of the sensory-motor information which play a major role in the construction of that category. Furthermore, they provide a simple interpretation of gender-related categorical effects and are supported by studies assessing the importance of prior experience in the cortical representation of objects On the other hand, inborn models maintain that category-specific semantic disorders reflect the disruption of innate brain networks, which are shaped by natural selection to allow rapid identification of objects that are very relevant for survival. From the empirical point of view, these models are mainly supported by observations of blind subjects, which suggest that visual experience is not necessary for the emergence of category-specificity in the ventral stream of visual processing. The weight of the data supporting experience-dependent and inborn models is thoroughly discussed, stressing the fact observations made in blind subjects are still the subject of intense debate. It is concluded that at the present state of knowledge it is not possible to choose between experience-dependent and inborn models of conceptual representations. PMID:25667570

Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes.

PubMed

Ellinwood, N Matthew; Ausseil, Jérôme; Desmaris, Nathalie; Bigou, Stéphanie; Liu, Song; Jens, Jackie K; Snella, Elizabeth M; Mohammed, Eman E A; Thomson, Christopher B; Raoul, Sylvie; Joussemet, Béatrice; Roux, Françoise; Chérel, Yan; Lajat, Yaouen; Piraud, Monique; Benchaouir, Rachid; Hermening, Stephan; Petry, Harald; Froissart, Roseline; Tardieu, Marc; Ciron, Carine; Moullier, Philippe; Parkes, Jennifer; Kline, Karen L; Maire, Irène; Vanier, Marie-Thérèse; Heard, Jean-Michel; Colle, Marie-Anne

2011-02-01

Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.

Phenylketonuria and Gut Microbiota: A Controlled Study Based on Next-Generation Sequencing.

PubMed

Pinheiro de Oliveira, Felipe; Mendes, Roberta Hack; Dobbler, Priscila Thiago; Mai, Volker; Pylro, Victor Salter; Waugh, Sheldon G; Vairo, Filippo; Refosco, Lilia Farret; Roesch, Luiz Fernando Würdig; Schwartz, Ida Vanessa Doederlein

2016-01-01

Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear.

Hepatocyte Transplantation Improves Phenotype and Extends Survival in a Murine Model of Intermediate Maple Syrup Urine Disease

PubMed Central

Skvorak, Kristen J; Paul, Harbhajan S; Dorko, Kenneth; Marongiu, Fabio; Ellis, Ewa; Chace, Donald; Ferguson, Carolyn; Gibson, K Michael; Homanics, Gregg E; Strom, Stephen C

2009-01-01

Maple syrup urine disease (MSUD; OMIM 248600) is an inborn error of metabolism of the branched chain α-ketoacid dehydrogenase (BCKDH) complex that is treated primarily by dietary manipulation of branched-chain amino acids (BCAA). Dietary restriction is lifelong and compliance is difficult. Liver transplantation significantly improves outcomes; however, alternative therapies are needed. To test novel therapies such as hepatocyte transplantation (HTx), we previously created a murine model of intermediate MSUD (iMSUD), which closely mimics human iMSUD. LacZ-positive murine donor hepatocytes were harvested and directly injected (105 cells/50 µl) into liver of iMSUD mice (two injections at 1–10 days of age). Donor hepatocytes engrafted into iMSUD recipient liver, increased liver BCKDH activity, improved blood total BCAA/alanine ratio, increased body weight at weaning, and extended the lifespan of HTx-treated iMSUD mice compared to phosphate-buffered saline (PBS)–treated and untreated iMSUD mice. Based on these data demonstrating partial metabolic correction of iMSUD in a murine model, coupled to the fact that multiple transplants are possible to enhance these results, we suggest that HTx represents a promising therapeutic intervention for MSUD that warrants further investigation. PMID:19436271

Phenylketonuria and Gut Microbiota: A Controlled Study Based on Next-Generation Sequencing

PubMed Central

Pinheiro de Oliveira, Felipe; Mendes, Roberta Hack; Dobbler, Priscila Thiago; Mai, Volker; Pylro, Victor Salter; Waugh, Sheldon G; Vairo, Filippo; Refosco, Lilia Farret; Schwartz, Ida Vanessa Doederlein

2016-01-01

Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear. PMID:27336782

Mapping an atlas of tissue-specific Drosophila melanogaster metabolomes by high resolution mass spectrometry.

PubMed

Chintapalli, Venkateswara R; Al Bratty, Mohammed; Korzekwa, Dominika; Watson, David G; Dow, Julian A T

2013-01-01

Metabolomics can provide exciting insights into organismal function, but most work on simple models has focussed on the whole organism metabolome, so missing the contributions of individual tissues. Comprehensive metabolite profiles for ten tissues from adult Drosophila melanogaster were obtained here by two chromatographic methods, a hydrophilic interaction (HILIC) method for polar metabolites and a lipid profiling method also based on HILIC, in combination with an Orbitrap Exactive instrument. Two hundred and forty two polar metabolites were putatively identified in the various tissues, and 251 lipids were observed in positive ion mode and 61 in negative ion mode. Although many metabolites were detected in all tissues, every tissue showed characteristically abundant metabolites which could be rationalised against specific tissue functions. For example, the cuticle contained high levels of glutathione, reflecting a role in oxidative defence; the alimentary canal (like vertebrate gut) had high levels of acylcarnitines for fatty acid metabolism, and the head contained high levels of ether lipids. The male accessory gland uniquely contained decarboxylated S-adenosylmethionine. These data thus both provide valuable insights into tissue function, and a reference baseline, compatible with the FlyAtlas.org transcriptomic resource, for further metabolomic analysis of this important model organism, for example in the modelling of human inborn errors of metabolism, aging or metabolic imbalances such as diabetes.

The discovery of medicines for rare diseases

PubMed Central

Swinney, David C; Xia, Shuangluo

2015-01-01

There is a pressing need for new medicines (new molecular entities; NMEs) for rare diseases as few of the 6800 rare diseases (according to the NIH) have approved treatments. Drug discovery strategies for the 102 orphan NMEs approved by the US FDA between 1999 and 2012 were analyzed to learn from past success: 46 NMEs were first in class; 51 were followers; and five were imaging agents. First-in-class medicines were discovered with phenotypic assays (15), target-based approaches (12) and biologic strategies (18). Identification of genetic causes in areas with more basic and translational research such as cancer and in-born errors in metabolism contributed to success regardless of discovery strategy. In conclusion, greater knowledge increases the chance of success and empirical solutions can be effective when knowledge is incomplete. PMID:25068983

Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis.

PubMed

Bradshaw, K D; Carr, B R

1986-07-01

PSD-X-linked ichthyosis are manifestations of a similar disorder of an inborn error of metabolism characterized by a deficiency of steroid sulfatase. The decreased enzyme activity is due to the absence of the expression of enzyme (steroid sulfatase) protein. Affected individuals with this disorder are males (X-linked inheritance) with a frequency of 1/2000 to 1/6000 births. Homozygous females from cosanguineous marriages have been reported with this disorder. The diagnosis is suspected and confirmed by: Low estriol excretion; Negative DHEAS loading test Increased DHEAS in amnionic fluid; Normal DHEAS in cord plasma; Possible delayed or abnormal labor patterns; Decreased sulfatase activity in the placenta, fibroblast, erythrocytes, lymphocytes or leukocytes of affected individuals; Development of ichthyosis in male infants at 2 to 3 months of age.

McArdle Disease and Exercise Physiology.

PubMed

Kitaoka, Yu

2014-02-25

McArdle disease (glycogen storage disease Type V; MD) is a metabolic myopathy caused by a deficiency in muscle glycogen phosphorylase. Since muscle glycogen is an important fuel for muscle during exercise, this inborn error of metabolism provides a model for understanding the role of glycogen in muscle function and the compensatory adaptations that occur in response to impaired glycogenolysis. Patients with MD have exercise intolerance with symptoms including premature fatigue, myalgia, and/or muscle cramps. Despite this, MD patients are able to perform prolonged exercise as a result of the "second wind" phenomenon, owing to the improved delivery of extra-muscular fuels during exercise. The present review will cover what this disease can teach us about exercise physiology, and particularly focuses on the compensatory pathways for energy delivery to muscle in the absence of glycogenolysis.

The Smith-Lemli-Opitz syndrome

PubMed Central

Kelley, R.; Hennekam, R.

2000-01-01

The Smith-Lemli-Opitz syndrome (SLOS) is one of the archetypical multiple congenital malformation syndromes. The recent discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism have led to important new treatment possibilities for affected patients. Moreover, the recent recognition of the important role of cholesterol in vertebrate embryogenesis, especially with regard to the hedgehog embryonic signalling pathway and its effects on the expression of homeobox genes, has provided an explanation for the abnormal morphogenesis in the syndrome. The well known role of cholesterol in the formation of steroid hormones has also provided a possible explanation for the abnormal behavioural characteristics of SLOS.


Keywords: Smith-Lemli-Opitz syndrome; cholesterol metabolism; 7-dehydrocholesterol reductase; clinical history; management PMID:10807690

Imaging findings of anaplastic astrocytoma in a child with maple syrup urine disease: a case report.

PubMed

Aw-Zoretic, Jessie; Wadhwani, Nitin R; Lulla, Rishi R; Rishi, Lulla R; Ryan, Maura E

2015-09-01

Maple syrup urine disease (MSUD) is an inborn error of branched-chain amino acid metabolism, which usually presents in childhood with encephalopathy due to cerebral edema and dysmyelination. Even with treatment, metabolic stressors may precipitate later episodes of acute decompensation. Changes related to cerebral and white matter edema have been described by magnetic resonance imaging (MRI), and imaging can aid in both initial diagnosis and evaluation of decompensation. To date, there are no published known reports of cancer in patients with MSUD. Here, we present the first case report of an anaplastic astrocytoma in a teenager with MSUD, with a discussion of imaging findings and the use of magnetic resonance spectroscopy (MRS) to help distinguish between tumor and metabolic changes.

Newborn screening: a review of history, recent advancements, and future perspectives in the era of next generation sequencing.

PubMed

Almannai, Mohammed; Marom, Ronit; Sutton, V Reid

2016-12-01

The purpose of this review is to summarize the development and recent advancements of newborn screening. Early initiation of medical care has modified the outcome for many disorders that were previously associated with high morbidity (such as cystic fibrosis, primary immune deficiencies, and inborn errors of metabolism) or with significant neurodevelopmental disabilities (such as phenylketonuria and congenital hypothyroidism). The new era of mass spectrometry and next generation sequencing enables the expansion of the newborn screen panel, and will help to address technical issues such as turnaround time, and decreasing false-positive and false-negative rates for the testing. The newborn screening program is a successful public health initiative that facilitates early diagnosis of treatable disorders to reduce long-term morbidity and mortality.

Metabolic evaluation of children with global developmental delay.

PubMed

Eun, So-Hee; Hahn, Si Houn

2015-04-01

Global developmental delay (GDD) is a relatively common early-onset chronic neurological condition, which may have prenatal, perinatal, postnatal, or undetermined causes. Family history, physical and neurological examinations, and detailed history of environmental risk factors might suggest a specific disease. However, diagnostic laboratory tests, brain imaging, and other evidence-based evaluations are necessary in most cases to elucidate the causes. Diagnosis of GDD has recently improved because of remarkable advances in genetic technology, but this is an exhaustive and expensive evaluation that may not lead to therapeutic benefits in the majority of GDD patients. Inborn metabolic errors are one of the main targets for the treatment of GDD, although only a small proportion of GDD patients have this type of error. Nevertheless, diagnosis is often challenging because the phenotypes of many genetic or metabolic diseases often overlap, and their clinical spectra are much broader than currently known. Appropriate and cost-effective strategies including up-to-date information for the early identification of the "treatable" causes of GDD are needed for the development of well-timed therapeutic applications with the potential to improve neurodevelopmental outcomes.

Enzyme replacement therapy for murine hypophosphatasia.

PubMed

Millán, José Luis; Narisawa, Sonoko; Lemire, Isabelle; Loisel, Thomas P; Boileau, Guy; Leonard, Pierre; Gramatikova, Svetlana; Terkeltaub, Robert; Camacho, Nancy Pleshko; McKee, Marc D; Crine, Philippe; Whyte, Michael P

2008-06-01

Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment. Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2-/-), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, microCT, and histomorphometry. Akp2-/- mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2-/- mice.

Enzyme Replacement Therapy for Murine Hypophosphatasia*

PubMed Central

Millán, José Luis; Narisawa, Sonoko; Lemire, Isabelle; Loisel, Thomas P; Boileau, Guy; Leonard, Pierre; Gramatikova, Svetlana; Terkeltaub, Robert; Camacho, Nancy Pleshko; McKee, Marc D; Crine, Philippe; Whyte, Michael P

2008-01-01

Introduction Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5`-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment. Materials and Methods Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2−/−), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, μCT, and histomorphometry. Results Akp2−/− mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Conclusions Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2−/− mice. PMID:18086009

Neurodevelopmental Outcomes of Infants Born at <29 Weeks of Gestation Admitted to Canadian Neonatal Intensive Care Units Based on Location of Birth.

PubMed

Amer, Reem; Moddemann, Diane; Seshia, Mary; Alvaro, Ruben; Synnes, Anne; Lee, Kyong-Soon; Lee, Shoo K; Shah, Prakesh S

2018-05-01

To compare mortality and neurodevelopmental outcomes of outborn and inborn preterm infants born at <29 weeks of gestation admitted to Canadian neonatal intensive care units (NICUs). Data were obtained from the Canadian Neonatal Network and Canadian Neonatal Follow-up Network databases for infants born at <29 weeks of gestation admitted to NICUs from April 2009 to September 2011. Rates of death, severe neurodevelopmental impairment (NDI), and overall NDI were compared between outborn and inborn infants at 18-21 months of age, corrected for prematurity. Of 2951 eligible infants, 473 (16%) were outborn. Mean birth weight (940 ± 278 g vs 897 + 237 g), rates of treatment with antenatal steroids (53.9% vs 92.9%), birth weight small for gestational age (5.3% vs 9.4%), and maternal college education (43.7% vs 53.9%) differed between outborn and inborn infants, respectively (all P values <.01). The median Score for Neonatal Acute Physiology-II (P = .01) and Apgar score at 5 minutes (P < .01) were higher in inborn infants. Severe brain injury was more common among outborn infants (25.3% vs 14.7%, P < .01). Outborn infants had higher odds of death or severe NDI (aOR 1.7, 95% CI 1.3-2.2), death or overall NDI (aOR 1.6, 95% CI 1.2-2.2), death (aOR 2.1, 95% CI 1.5-3.0), and cerebral palsy (aOR 1.9, 95% CI 1.1-3.3). The composite outcomes of death or neurodevelopmental impairment were significantly higher in outborn compared with inborn infants admitted to Canadian NICUs. Adverse outcomes were mainly attributed to increased mortality and cerebral palsy in outborn neonates. Copyright © 2017 Elsevier Inc. All rights reserved.

Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz Syndrome (SLOS)

PubMed Central

Korade, Zeljka; Xu, Libin; Harrison, Fiona E.; Ahsen, Refayat; Hart, Sarah E; Folkes, Oakleigh M; Mirnics, Karoly; Porter, Ned A

2013-01-01

Background Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-DHC is highly reactive, giving rise to biologically active oxysterols. Methods 7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using HPLC-MS-MS. Expression of lipid biosynthesis genes was ascertained by qPCR and Western blot. The effects of an antioxidant mixture, vitamin A, coenzyme Q10, vitamin C and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice. Results In cultured human SLOS fibroblasts the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, DHCEO. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased DHCEO levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant females led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups. Conclusions Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures, and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of Dhcr7 mutations. PMID:23896203

Pectus carinatum.

PubMed

Robicsek, Francis; Watts, Larry T

2010-11-01

Pectus carinatum or keel chest is a spectrum of progressive inborn anomalies of the anterior chest wall, named after the keel (carina) of ancient Roman ships. It defines a wide spectrum of inborn protrusion anomalies of the sternum and/or the adjacent costal cartilages. Pectus carinatum is often associated with various conditions, notably Marfan disease, homocystinuria, prune belly, Morquio syndrome, osteogenesis imperfecta, Noonan syndrome, and mitral valve prolapse. Treatment of pectus carinatum by nonsurgical methods such as exercise and casting has not been worthwhile, whereas surgical management is simple and successful.

Neonatal liver cell donation: a case report.

PubMed

Godfrey, Kathleen; Kish, Mary Z

2014-01-01

Traditional organ transplant options for newborns have been rare. There continues to be an increasing need for organs for transplant and a limited number of available organs, especially for small children. Liver cell transplantation is a promising alternative to orthotopic liver transplantation to treat liver-based inborn errors of metabolism.1 The procedure is minimally invasive and can be performed repeatedly. The safety of the procedure has been well established, and the clinical results are encouraging.1 The liver cell donation process is an option for families who experience the loss of a newborn and offers them a legacy for their child by providing life for others. The purpose of this article is to discuss the neonatal liver cell donation process and present a case report of an anencephalic infant whose parents chose to participate in this unique program.

Hereditary Causes of Kidney Stones and Chronic Kidney Disease

PubMed Central

Edvardsson, Vidar O.; Goldfarb, David S.; Lieske, John C.; Beara-Lasic, Lada; Anglani, Franca; Milliner, Dawn S.; Palsson, Runolfur

2013-01-01

Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC and PH with emphasis on childhood manifestations. PMID:23334384

[First report of alkaptonuria in Peru].

PubMed

Guillén-Mendoza, Daniel; Quiroga de Michelena, María

2014-01-01

Alkaptonuria is an inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD) which produces an excess of homogentisic acid (HGA). A case is presented of a 57 year old woman whose urine has turned black since birth. For 9 years she presented a greenish pigmentation in her nail beds that did not improve with antifungal treatments, and in the last 9 months she showed worsening large joint osteoarthritis. This situation forced her to use a wheelchair due to the intense pain caused by osteoarthritis in her hips and lumbar spine. From the description of symptoms, her urinary HGA was measured which confirmed the diagnosis of alkaptonuria. Analgesics and a diet without tyrosine-containing products were suggested. The patient was also referred for hip replacement surgery. This is the first reported case of alkaptonuria in Peru.

X-linked adult-onset adrenoleukodystrophy: Psychiatric and neurological manifestations

PubMed Central

Shamim, Daniah; Alleyne, Karen

2017-01-01

Adult-onset adrenoleukodystrophy is a rare x-linked inborn error of metabolism occurring predominantly in males with onset in early 30s. Here, we report a 34-year-old male with first signs of disease in early 20s manifesting as a pure psychiatric disorder. Prior to onset of neurological symptoms, this patient demonstrated a schizophrenia and bipolar-like presentation. The disease progressed over the next 10–13 years and his memory and motor problems became evident around the age of 33 years. Subsequently, diagnostic testing showed the typical magnetic resonance imaging and lab findings for adult-onset adrenoleukodystrophy. This case highlights adult-onset adrenoleukodystrophy which may present as a pure psychiatric disturbance in early adulthood and briefly discusses the prolonged time between the onset of psychiatric symptoms and the onset of neurological disease. PMID:29201369

X-linked adult-onset adrenoleukodystrophy: Psychiatric and neurological manifestations.

PubMed

Shamim, Daniah; Alleyne, Karen

2017-01-01

Adult-onset adrenoleukodystrophy is a rare x-linked inborn error of metabolism occurring predominantly in males with onset in early 30s. Here, we report a 34-year-old male with first signs of disease in early 20s manifesting as a pure psychiatric disorder. Prior to onset of neurological symptoms, this patient demonstrated a schizophrenia and bipolar-like presentation. The disease progressed over the next 10-13 years and his memory and motor problems became evident around the age of 33 years. Subsequently, diagnostic testing showed the typical magnetic resonance imaging and lab findings for adult-onset adrenoleukodystrophy. This case highlights adult-onset adrenoleukodystrophy which may present as a pure psychiatric disturbance in early adulthood and briefly discusses the prolonged time between the onset of psychiatric symptoms and the onset of neurological disease.

Adherence to tetrahydrobiopterin therapy in patients with phenylketonuria.

PubMed

Rohr, Frances; Wessel, Ann; Brown, Matthew; Charette, Kalin; Levy, Harvey L

2015-01-01

Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism due to deficiency of the enzyme, phenylalanine hydroxylase (PAH). Treatment includes restriction of dietary phenylalanine, and in some individuals, supplementation with the PAH cofactor, tetrahydrobiopterin (sapropterin dihydrochloride). A survey was conducted among patients with PKU who had been prescribed sapropterin to assess reasons for continuing or discontinuing the drug. The primary reason that sapropterin responders discontinued the drug was because of side effects, followed by insufficient reduction of blood phenylalanine and insurance issues. Conversely, those who remained on therapy cited increased tolerance for dietary protein as the main reason for continuation, along with lower blood phenylalanine concentrations and feeling better. This study suggests that adherence to sapropterin therapy is mainly dependent upon the increase in dietary protein allowed when on the drug. Copyright © 2014 Elsevier Inc. All rights reserved.

White matter changes in an untreated, newly diagnosed case of classical homocystinuria.

PubMed

Brenton, J Nicholas; Matsumoto, Julie A; Rust, Robert S; Wilson, William G

2014-01-01

The authors report the case of a 4-year-old boy who developed progressive unilateral weakness and developmental delays prior to his diagnosis of classical homocystinuria. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse white matter changes, raising the concern for a secondary diagnosis causing leukoencephalopathy, since classical homocystinuria is not typically associated with these changes. Other inborn errors of the transsulfuration pathway have been reported as causing these changes. Once begun on therapy for his homocystinuria, his neurologic deficits resolved and his delays rapidly improved. Repeat MRI performed one year after instating therapy showed resolution of his white matter abnormalities. This case illustrates the need to consider homocystinuria and other amino acidopathies in the differential diagnosis of childhood white matter diseases and lends weight to the hypothesis that hypermethioninemia may induce white matter changes.

Gastrointestinal disorders in children with neurodevelopmental disabilities.

PubMed

Sullivan, Peter B

2008-01-01

Children with neurodevelopmental disabilities such as cerebral palsy (CP), spina bifida, or inborn errors of metabolism frequently have associated gastrointestinal problems. These include oral motor dysfunction leading to feeding difficulties, risk of aspiration, prolonged feeding times, and malnutrition with its attendant physical compromise. Gastrostomy tube feeding is increasingly being used in these children to circumvent oral motor dysfunction and prevent malnutrition. Foregut dysmotility causes several problems such as dysphagia from oesophageal dysmotility, gastro-oesophageal reflux disease, and delayed gastric emptying. Gastro-oesophageal reflux disease is common in these children but often fails to respond to medical management and may require surgical treatment. Finally, constipation is often a problem that may be overlooked in this population. This article focuses on these associated gastrointestinal manifestations and discusses the current diagnostic and therapeutic options available. (c) 2008 Wiley-Liss, Inc.

Necropsy findings in lysinuric protein intolerance.

PubMed Central

McManus, D T; Moore, R; Hill, C M; Rodgers, C; Carson, D J; Love, A H

1996-01-01

Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism, characterised by defective transport of the cationic amino acids lysine, arginine and ornithine. To date there are few reported necropsy cases. This report describes the necropsy findings in a 21 year old female patient originally diagnosed as having LPI in 1973. Liver function tests deteriorated and immediately before death jaundice, hyperammonaemia, coma, metabolic acidosis, and a severe bleeding diathesis developed. At necropsy, there was micronodular cirrhosis of the liver with extensive fatty change in hepatocytes. The lungs showed pulmonary alveolar proteinosis. Immunofluorescence and electron microscopy revealed the presence of a glomerulonephritis with predominant IgA deposition. These necropsy findings reflect the spectrum of lesions reported in LPI, providing further evidence of an association between this condition and pulmonary alveolar proteinosis, cirrhosis and glomerulonephritis. Images PMID:8655715

Creatine and guanidinoacetate content of human milk and infant formulas: implications for creatine deficiency syndromes and amino acid metabolism.

PubMed

Edison, Erica E; Brosnan, Margaret E; Aziz, Khalid; Brosnan, John T

2013-09-28

Creatine is essential for normal neural development; children with inborn errors of creatine synthesis or transport exhibit neurological symptoms such as mental retardation, speech delay and epilepsy. Creatine accretion may occur through dietary intake or de novo creatine synthesis. The objective of the present study was to determine how much creatine an infant must synthesise de novo. We have calculated how much creatine an infant needs to account for urinary creatinine excretion (creatine's breakdown product) and new muscle lay-down. To measure an infant's dietary creatine intake, we measured creatine in mother's milk and in various commercially available infant formulas. Knowing the amount of milk/formula ingested, we calculated the amount of creatine ingested. We have found that a breast-fed infant receives about 9 % of the creatine needed in the diet and that infants fed cows' milk-based formula receive up to 36 % of the creatine needed. However, infants fed a soya-based infant formula receive negligible dietary creatine and must rely solely on de novo creatine synthesis. This is the first time that it has been shown that neonatal creatine accretion is largely due to de novo synthesis and not through dietary intake of creatine. This has important implications both for infants suffering from creatine deficiency syndromes and for neonatal amino acid metabolism.

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood

PubMed Central

Boisson-Dupuis, Stéphanie; Bustamante, Jacinta; El-Baghdadi, Jamila; Camcioglu, Yildiz; Parvaneh, Nima; Azbaoui, Safaa El; Agader, Aomar; Hassani, Amal; Hafidi, Naima El; Mrani, Nidal Alaoui; Jouhadi, Zineb; Ailal, Fatima; Najib, Jilali; Reisli, Ismail; Zamani, Adil; Yosunkaya, Sebnem; Gulle-Girit, Saniye; Yildiran, Alisan; Cipe, Funda Erol; Torun, Selda Hancerli; Metin, Ayse; Atikan, Basak Yildiz; Hatipoglu, Nevin; Aydogmus, Cigdem; Kilic, Sara Sebnem; Dogu, Figen; Karaca, Neslihan; Aksu, Guzide; Kutukculer, Necil; Keser-Emiroglu, Melike; Somer, Ayper; Tanir, Gonul; Aytekin, Caner; Adimi, Parisa; Mahdaviani, Seyed Alireza; Mamishi, Setareh; Bousfiha, Aziz; Sanal, Ozden; Mansouri, Davood; Casanova, Jean-Laurent; Abel, Laurent

2015-01-01

Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey. PMID:25703555

Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain's "operating system": how NAA metabolism supports meaningful intercellular frequency-encoded communications.

PubMed

Baslow, Morris H

2010-11-01

N-acetylaspartate (NAA), an acetylated derivative of L-aspartate (Asp), and N-acetylaspartylglutamate (NAAG), a derivative of NAA and L-glutamate (Glu), are synthesized by neurons in brain. However, neurons cannot catabolize either of these substances, and so their metabolism requires the participation of two other cell types. Neurons release both NAA and NAAG to extra-cellular fluid (ECF) upon stimulation, where astrocytes, the target cells for NAAG, hydrolyze it releasing NAA back into ECF, and oligodendrocytes, the target cells for NAA, hydrolyze it releasing Asp to ECF for recycling to neurons. This sequence is unique as it is the only known amino acid metabolic cycle in brain that requires three cell types for its completion. The results of this cycling are two-fold. First, neuronal metabolic water is transported to ECF for its removal from brain. Second, the rate of neuronal activity is coupled with focal hyperemia, providing stimulated neurons with the energy required for transmission of meaningful frequency-encoded messages. In this paper, it is proposed that the tri-cellular metabolism of NAA functions as the "operating system" of the brain, and is essential for normal cognitive and motor activities. Evidence in support of this hypothesis is provided by the outcomes of two human inborn errors in NAA metabolism.

Secondary NAD+ deficiency in the inherited defect of glutamine synthetase.

PubMed

Hu, Liyan; Ibrahim, Khalid; Stucki, Martin; Frapolli, Michele; Shahbeck, Noora; Chaudhry, Farrukh A; Görg, Boris; Häussinger, Dieter; Penberthy, W Todd; Ben-Omran, Tawfeg; Häberle, Johannes

2015-11-01

Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD(+) depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD(+) depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD(+) depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder.

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency.

PubMed

Hannibal, Luciana; Lysne, Vegard; Bjørke-Monsen, Anne-Lise; Behringer, Sidney; Grünert, Sarah C; Spiekerkoetter, Ute; Jacobsen, Donald W; Blom, Henk J

2016-01-01

Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.

Enzyme replacement prevents enamel defects in hypophosphatasia mice

PubMed Central

Yadav, Manisha C.; de Oliveira, Rodrigo Cardoso; Foster, Brian L.; Fong, Hanson; Cory, Esther; Narisawa, Sonoko; Sah, Robert L.; Somerman, Martha; Whyte, Michael P.; Millán, José Luis

2012-01-01

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity leading to rickets or osteomalacia and to dental defects. HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl−/−, a.k.a. Akp2−/−) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl−/− mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the Alpl−/− mice, histological, μCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP (sALP-FcD10, a.k.a. ENB-0040) at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization, and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP. PMID:22461224

Experimental analysis of nature-nurture interactions.

PubMed

Wyman, Robert J

2005-06-01

The presumed opposition of nature and nurture has been a major concern of western civilization since its beginnings. Christian theologians interpreted Adam and Eve's eating of the forbidden fruit as the origin of an inherited 'original sin'. Saint Augustine explicitly applied the concept to human mental development, arguing that, because of original sin, children are inclined toward evil and education requires physical punishment. For centuries, it was considered parents' moral and religious obligation, not to nurture their children, in our current sense of that word, but to beat the willfulness out of them. 16thC humanists fought back, arguing that "schools have become torture chambers" while it is adults "who corrupt young minds with evil". Locke's (1690) statement that children are born as a 'white paper' was crucial in rejecting the dogma of an inborn (and sinful) nature. The original sin vs. white paper argument merged with another ancient dichotomy: inborn instinct (which controls animal behavior) vs. the reason and free will which humans have. Darwin made the concept of inherited instinct, common to both man and animals, one cornerstone of his theory of evolution. The 20(th)C saw scientists recast the debate as instinct vs. learning, bitterly argued between behaviorists and ethologists. Laboratory experimentation and field observation showed that behavior could develop without learning but also that conditioning paradigms could powerfully mold behavior. The progress of genetics and neurobiology has led to the modern synthesis that neural development, and hence behavior, results from the interdependent action of both heredity and environment. Copyright 2005 Wiley-Liss, Inc.

CAP/ACMG proficiency testing for biochemical genetics laboratories: a summary of performance.

PubMed

Oglesbee, Devin; Cowan, Tina M; Pasquali, Marzia; Wood, Timothy C; Weck, Karen E; Long, Thomas; Palomaki, Glenn E

2018-01-01

PurposeTesting for inborn errors of metabolism is performed by clinical laboratories worldwide, each utilizing laboratory-developed procedures. We sought to summarize performance in the College of American Pathologists' (CAP) proficiency testing (PT) program and identify opportunities for improving laboratory quality. When evaluating PT data, we focused on a subset of laboratories that have participated in at least one survey since 2010.MethodsAn analysis of laboratory performance (2004 to 2014) on the Biochemical Genetics PT Surveys, a program administered by CAP and the American College of Medical Genetics and Genomics. Analytical and interpretive performance was evaluated for four tests: amino acids, organic acids, acylcarnitines, and mucopolysaccharides.ResultsSince 2010, 150 laboratories have participated in at least one of four PT surveys. Analytic sensitivities ranged from 88.2 to 93.4%, while clinical sensitivities ranged from 82.4 to 91.0%. Performance was higher for US participants and for more recent challenges. Performance was lower for challenges with subtle findings or complex analytical patterns.ConclusionUS clinical biochemical genetics laboratory proficiency is satisfactory, with a minority of laboratories accounting for the majority of errors. Our findings underscore the complex nature of clinical biochemical genetics testing and highlight the necessity of continuous quality management.

Peak hyperammonemia and atypical acute liver failure: The eruption of an urea cycle disorder during hyperemesis gravidarum.

PubMed

Weiss, Nicolas; Mochel, Fanny; Rudler, Marika; Demeret, Sophie; Lebray, Pascal; Conti, Filomena; Galanaud, Damien; Ottolenghi, Chris; Bonnefont, Jean-Paul; Dommergues, Marc; Bernuau, Jacques; Thabut, Dominique

2017-09-20

Inborn urea cycle disorders are under-recognised metabolic causes of hyperammonemia in adults. A 28-year-old primigravida, seven weeks pregnant, affected by hyperemesis gravidarum developed acute liver injury (ALI) and then acute liver failure (ALF) in less than 48 h. Because the patient developed atypical features, especially mildly elevated aminotransferases contrasting with very high blood ammonia levels (281 μmol/L), concomitant with normal serum creatinine, an inborn error of metabolism was suspected. We performed emergency metabolic analyses, stopped all protein intake and started with intravenous (i.v.) high caloric intake, nitrogen scavenger drugs and haemodialysis. The neurological and hepatic status of the patient quickly improved together with normalisation of her ammonemia levels. High plasma glutamine and urinary orotic acid, alongside low plasma arginine, citrulline and ornithine were suggestive of an ornithine transcarbamylase deficiency, later confirmed by molecular analyses. Foetal sex was female, as determined by foetal DNA analysis in maternal blood, and foetal development was unremarkable throughout the pregnancy. Delivery was induced at 39 weeks with a close monitoring of ammonemia levels and i.v. perfusion of carbohydrates and lipids during labour and immediately post-partum to avoid hypercatabolism. Delivery was uneventful and the patient delivered a healthy female baby. Urea cycle disorders should be contemplated in non-jaundiced patients with ALI or ALF, severe hyperammonemia and normal serum creatinine regardless of serum aminotransferase levels. The prompt recognition of this rare condition and the rapid initiation of adequate metabolic therapy are mandatory to prevent irreversible neurological sequelae and to avoid liver transplantation. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Ochronotic Arthropathy: Two Case Reports from a Developing Country

PubMed Central

Rathore, Farooq A.; Ayaz, Saeed B.; Mansoor, Sahibzada N.

2016-01-01

Alkaptonuria is a rare inborn error of metabolism, which is classified as an orphan disease. It is due to the lack of an enzyme homogentisate 1,2-dioxygenase, which results in an accumulation of homogentisic acid in different areas of the body, including sclera, skin, cardiac valves, articular cartilage of the large joints and intervertebral disks. We present two cases of alkaptonuria resulting in ochronotic arthropathy with advanced secondary generalized osteoarthritis, intervertebral disk calcifications, skin and scleral pigmentation. In these case reports, both patients had symptoms for >10 years before being diagnosed. Conservative management in the form of high-dose ascorbic acid, exercises, and gait aids was offered to both of them, which resulted in some symptomatic improvement in the first case, while the second case was lost to follow-up. Alkaptonuria is a rare disease, and although it does not clearly impact mortality, early diagnosis may improve the quality of life. PMID:26884684

Ochronotic Arthropathy: Two Case Reports from a Developing Country.

PubMed

Rathore, Farooq A; Ayaz, Saeed B; Mansoor, Sahibzada N

2016-01-01

Alkaptonuria is a rare inborn error of metabolism, which is classified as an orphan disease. It is due to the lack of an enzyme homogentisate 1,2-dioxygenase, which results in an accumulation of homogentisic acid in different areas of the body, including sclera, skin, cardiac valves, articular cartilage of the large joints and intervertebral disks. We present two cases of alkaptonuria resulting in ochronotic arthropathy with advanced secondary generalized osteoarthritis, intervertebral disk calcifications, skin and scleral pigmentation. In these case reports, both patients had symptoms for >10 years before being diagnosed. Conservative management in the form of high-dose ascorbic acid, exercises, and gait aids was offered to both of them, which resulted in some symptomatic improvement in the first case, while the second case was lost to follow-up. Alkaptonuria is a rare disease, and although it does not clearly impact mortality, early diagnosis may improve the quality of life.

An unfortunate challenge: Ketogenic diet for the treatment of Lennox-Gastaut syndrome in tyrosinemia type 1.

PubMed

De Lucia, Silvana; Pichard, Samia; Ilea, Adina; Greneche, Marie-Odile; François, Laurent; Delanoë, Catherine; Schiff, Manuel; Auvin, Stéphane

2016-07-01

The ketogenic diet is an evidence-based treatment for resistant epilepsy including Lennox-Gastaut syndrome. This diet is based on low carbohydrate-high fat intakes. Dietary treatment is also therapeutic for inborn errors of metabolism such as aminoacdiopathies. We report a child with both Lennox-Gastaut syndrome and tyrosinemia type 1. This epilepsy syndrome resulted form a porencephalic cyst secondary to brain abscesses that occurred during the management of malnutrition due to untreated tyrosinemia type 1. We used a ketogenic diet as treatment for Lennox-Gastaut syndrome taking into account dietary requirements for tyrosinemia type 1. The patient was transiently responder during a 6-month period. This report illustrates that ketogenic diet remains a therapeutic option even when additional dietary requirements are needed. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

New mechanisms of disease and parasite-host interactions.

PubMed

de Souza, Tiago Alves Jorge; de Carli, Gabriel Jose; Pereira, Tiago Campos

2016-09-01

An unconventional interaction between a patient and parasites was recently reported, in which parasitic cells invaded host's tissues, establishing several tumors. This finding raises various intriguing hypotheses on unpredicted forms of interplay between a patient and infecting parasites. Here we present four unusual hypothetical host-parasite scenarios with intriguing medical consequences. Relatively simple experimental designs are described in order to evaluate such hypotheses. The first one refers to the possibility of metabolic disorders in parasites intoxicating the host. The second one is on possibility of patients with inborn errors of metabolism (IEM) being more resistant to parasites (due to accumulation of toxic compounds in the bloodstream). The third one refers to a mirrored scenario: development of tumors in parasites due to ingestion of host's circulating cancer cells. The last one describes a complex relationship between parasites accumulating a metabolite and supplying it to a patient with an IEM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of mutations in Colombian patients affected with Fabry disease.

PubMed

Uribe, Alfredo; Mateus, Heidi Eliana; Prieto, Juan Carlos; Palacios, Maria Fernanda; Ospina, Sandra Yaneth; Pasqualim, Gabriela; da Silveira Matte, Ursula; Giugliani, Roberto

2015-12-15

Fabry Disease (FD) is an X-linked inborn error of glycosphingolipid catabolism, caused by a deficiency of the lisosomal α-galactosidase A (AGAL). The disorder leads to a vascular disease secondary to the involvement of kidney, heart and the central nervous system. The mutation analysis is a valuable tool for diagnosis and genetic counseling. Although more than 600 mutations have been identified, most mutations are private. Our objective was to describe the analysis of nine Colombian patients with Fabry disease by automated sequencing of the seven exons of the GLA gene. Two novel mutations were identified in two patients affected with the classical subtype of FD, in addition to other 6 mutations previously reported. The present study confirms the heterogeneity of mutations in Fabry disease and the importance of molecular analysis for genetic counseling, female heterozygotes detection as well as therapeutic decisions. Copyright © 2015 Elsevier B.V. All rights reserved.

Physicochemical hair conformation of patients with Sanfilippo disease type IIIA.

PubMed

Charan, R K; Nauer, G; Wagner, U; Klabuschnig, A; Lubec, G

1986-01-01

Sanfilippo disease type IIIA is an inborn error of metabolism with a deficiency in the heparan sulfamidase. Besides severe psychomotor retardation hair changes are obligatory. Hair is found to be coarse like a brush. We applied X-ray diffraction and infrared spectroscopy to characterize the conformation of hair samples of Sanfilippo patients. In healthy subjects as well as in the affected hair samples we found the wave numbers of structural relevance 1450, 1500, 1630, 1730, the pair 2337 and 2362, the quadruplet 2850, 2870, 2917, 2930 and 3080 cm-1. Also on X-ray diffraction analysis no differences could be detected. Though morphological-macroscopically and microscopically-changes were described for Sanfilippo hair samples, we could not find any change in supramolecular structure. The physical properties of coarseness of those hair specimen seems to be due to differences in the structural assembly of hair fibres and storage of heparan sulfate.

3-Methylglutaconic aciduria, a frequent but underrecognized finding in carbamoyl phosphate synthetase I deficiency.

PubMed

Rokicki, Dariusz; Pajdowska, Magdalena; Trubicka, Joanna; Thong, Meow-Keong; Ciara, Elżbieta; Piekutowska-Abramczuk, Dorota; Pronicki, Maciej; Sikora, Roman; Haidar, Rijad; Ołtarzewski, Mariusz; Jabłońska, Ewa; Muthukumarasamy, Premala; Sthaneswar, Pavai; Gan, Chin-Seng; Krajewska-Walasek, Małgorzata; Carrozzo, Rosalba; Verrigni, Daniela; Semeraro, Michela; Rizzo, Cristiano; Taurisano, Roberta; Alhaddad, Bader; Kovacs-Nagy, Reka; Haack, Tobias B; Dionisi-Vici, Carlo; Pronicka, Ewa; Wortmann, Saskia B

2017-08-01

The urea cycle disorder carbamoyl phosphate synthetase I deficiency is an important differential diagnosis in the encephalopathic neonate. This intoxication type inborn error of metabolism often leads to neonatal death or severe and irreversible damage of the central nervous system, even despite appropriate treatment. Timely diagnosis is crucial, but can be difficult on routine metabolite level. Here, we report ten neonates from eight families (finally) diagnosed with CPS1 deficiency at three tertiary metabolic centres. In seven of them the laboratory findings were dominated by significantly elevated urinary 3-methylglutaconic acid levels which complicated the diagnostic process. Our findings are both important for the differential diagnosis of patients with urea cycle disorders and also broaden the differential diagnosis of hyperammonemia associated with 3-methylglutaconic aciduria, which was earlier only reported in TMEM70 and SERAC1 defect. Copyright © 2017 Elsevier B.V. All rights reserved.

[Influence of hCG glycosylation on its functions in female reproduction].

PubMed

Oborná, I; Fingerová, H

To review contemporary knowledge of the hCG molecule, its isoforms and the importance of glycosylation. Biologic variants and glycoforms of hCG have different biological activities and functions related to the control of menstrual cycle, conception, gestation as well as gynaecologic and non-gynaecologic malignancies. A review. Department of Obstetrics and Gynaecology, University Hospital Olomouc. To present own experience and an overview of recent literature in molecular biology, clinical biochemistry and clinical practice. Recent knowledge of the role of hCG glycosylation in physiologic and pathologic events in female organism will provide a better understanding of regulation of processes like ovulation (co-operation of pituitary hCG with LH), implantation and hemochorial placentation (invasivity of hyperglycosylated hCG). Some biologic variants and isoforms of hCG are important for the prediction of certain pathologies of pregnancy, prenatal screening of inborn errors (free beta hCG) as well as in the treatment of infertility.

Food Products Made With Glycomacropeptide, a Low Phenylalanine Whey Protein, Provide a New Alternative to Amino Acid-Based Medical Foods for Nutrition Management of Phenylketonuria

PubMed Central

Van Calcar, Sandra C.; Ney, Denise M.

2012-01-01

Phenylketonuria (PKU), an inborn error in phenylalanine (phe) metabolism, requires lifelong nutrition management with a low-phe diet, which includes a phe-free amino acid-based medical formula to provide the majority of an individual’s protein needs. Compliance with this diet is often difficult for older children, adolescents and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet since it is naturally low in phe. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein utilization and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phe dietary protein for those with PKU. PMID:22818728

ENT manifestations of alkaptonuria: report on a case series.

PubMed

Steven, R A; Kinshuck, A J; McCormick, M S; Ranganath, L R

2015-10-01

Alkaptonuria is an inborn error of metabolism. It is a multisystem disease with characteristic ENT manifestations. This paper reports, for the first time, the ENT findings in a cohort of alkaptonuria patients. Patients attending the National Centre for Alkaptonuria (Royal Liverpool and Broadgreen University Hospitals NHS Trust) underwent a full ENT assessment. Eighteen of the 20 patients (90 per cent) had an ENT sign or symptom. These included discolouration of the pinna, cerumen, nasal septum and pharynx. Discolouration of cerumen may occur before 30 years of age and may therefore be an important early clinical sign. Further audiological assessment of patients is needed to clarify if an association exists between alkaptonuria and hearing loss. Alkaptonuria is a condition that could present to the otolaryngologist. Successful early diagnosis and referral to a specialist centre is essential so that patients can be offered disease-modifying therapy.

Primary Hyperoxaluria

PubMed Central

Harambat, Jérôme; Fargue, Sonia; Bacchetta, Justine; Acquaviva, Cécile; Cochat, Pierre

2011-01-01

Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxylate and oxalate. PH type 1, the most common form, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine, glyoxylate aminotransferase (AGT) resulting in overproduction and excessive urinary excretion of oxalate. Recurrent urolithiasis and nephrocalcinosis are the hallmarks of the disease. As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates leading to systemic oxalosis. Diagnosis is often delayed and is based on clinical and sonographic findings, urinary oxalate assessment, DNA analysis, and, if necessary, direct AGT activity measurement in liver biopsy tissue. Early initiation of conservative treatment, including high fluid intake, inhibitors of calcium oxalate crystallization, and pyridoxine in responsive cases, can help to maintain renal function in compliant subjects. In end-stage renal disease patients, the best outcomes have been achieved with combined liver-kidney transplantation which corrects the enzyme defect. PMID:21748001

Neuropsychiatric manifestations in late-onset urea cycle disorder patients.

PubMed

Serrano, Mercedes; Martins, Cecilia; Pérez-Dueñas, Belén; Gómez-López, Lilian; Murgui, Empar; Fons, Carmen; García-Cazorla, Angels; Artuch, Rafael; Jara, Fernando; Arranz, José A; Häberle, Johannes; Briones, Paz; Campistol, Jaume; Pineda, Mercedes; Vilaseca, Maria A

2010-03-01

Inherited urea cycle disorders represent one of the most common groups of inborn errors of metabolism. Late-onset urea cycle disorders caused by partial enzyme deficiencies may present with unexpected clinical phenotypes. We report 9 patients followed up in our hospital presenting late-onset urea cycle disorders who initially manifested neuropsychiatric/neurodevelopmental symptoms (the most prevalent neuropsychiatric/neurodevelopmental diagnoses were mental retardation, attention-deficit hyperactivity disorder [ADHD], language disorder, and delirium). Generally, these clinical pictures did not benefit from pharmacological treatment. Conversely, dietary treatment improved the symptoms. Regarding biochemical data, 2 patients showed normal ammonium but high glutamine levels. This study highlights the fact that neuropsychiatric/neurodevelopmental findings are common among the initial symptomatology of late-onset urea cycle disorders. The authors recommend that unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a study of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder.

Acute Illness Protocol for Maple Syrup Urine Disease.

PubMed

Rodan, Lance H; Aldubayan, Saud H; Berry, Gerard T; Levy, Harvey L

2018-01-01

Inborn errors of metabolism (IEMs) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare but collectively have an incidence of 1:1000. Most patients with IEMs are followed up by a physician with expertise in biochemical genetics (metabolism), but may present outside this setting. Because IEMs can present acutely with life-threatening crises that require specific interventions, it is critical for the emergency medicine physician, pediatrician, internist, and critical care physician as well as the biochemical geneticist to have information on the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist, but rather to improve early care and increase the level of comfort of the acute care physician with initial management of maple syrup urine disease until specialty consultation is obtained.

Clinical and neuropathological picture of ethylmalonic aciduria - diagnostic dilemma.

PubMed

Jamroz, Ewa; Paprocka, Justyna; Adamek, Dariusz; Pytel, Justyna; Szczechowska, Katarzyna; Grabska, Natalia; Malec, Michalina; Głuszkiewicz, Ewa; Daab, Michał; Wodołażski, Anatolij

2011-01-01

Increased ethylmalonic acid (EMA) in urine is a non-specific finding, and is observed in a number of inborn errors of metabolism, as well as in individuals who carry one of two common polymorphisms identified in the SCAD coding region. The authors present an 8-month-old girl with a suspicion of neuroinfection, although the clinical presentation led to diagnosis of ethylmalonic aciduria. From the neuropathological point of view the most remarkable changes were observed in the brain cortex, which was diffusely damaged practically in all regions of the brain. Of note, the most severe destruction was observed in the deepest regions of the sulci. The cortex of the affected regions showed no normal stratification and its structure was almost totally replaced by a form of "granulation tissue" with a markedly increased number of capillaries. To the authors' knowledge this is the first clinical report of ethylmalonic aciduria with brain autopsy findings.

Primary Immunodeficiencies: “New” Disease in an Old Country

PubMed Central

Lee, Pamela P W; Lau, Yu-Lung

2009-01-01

Primary immunodeficiency disorders (PIDs) are rare inborn errors of the immune system. Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections, autoimmunity, lymphoproliferation, allergy and cancer. Over 150 PID syndromes were characterized in the past 60 years, with an ever growing list of new entities being discovered. Because of their rarity, multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs. In this article, we summarize our research findings on PIDs in Chinese population in the past 20 years. Close collaboration among various immunology centers, cross-referrals and systematic data analysis constitute the foundation for research on PIDs. Future directions include establishment of a national PID registry, raising awareness of PIDs and securing sufficient resources for patient care and scientific research. PMID:20003815

[Severe familial hypercholesterolemia treatment].

PubMed

Vrablík, Michal; Freiberger, Tomáš; Bláha, Vladimír; Češka, Richard

Familial hypercholesterolemia (FH) represents the most frequent of inborn errors of metabolism. It is a group of disorders with a codominant mode of inheritance characterized by marked elevations of LDL-cholesterol as well as atherosclerotic cardiovascular disease risk. Clinical (phenotypic) picture of FH varies widely depending on genotype and concomitant risk factors. Identification of most seriously affected FH individuals is necessary for proper clinical management. The therapeutic approach must be complex and comprehensive. The corner stone of pharmacotherapy is high-intensity statin therapy usually combined with ezetimibe (possibly complemented with bile acid sequestrant). Even this multi-drug combination do not lead majority of patients to their treatment goals. Thus, combinations with other pharmacological (PCSK9 inhibitors, apoB-100 anti-sense therapy, MTP inhibition) and non-pharmacological (LDL-apheresis, liver transplantation) approaches is being used.Key words: ezetimibe - LDL-apheresis - lomitapide - mipomersen - PCSK9 inhibitors - severe familial hypercholesterolemia - statins.

Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation

PubMed Central

Dusi, Sabrina; Valletta, Lorella; Haack, Tobias B.; Tsuchiya, Yugo; Venco, Paola; Pasqualato, Sebastiano; Goffrini, Paola; Tigano, Marco; Demchenko, Nikita; Wieland, Thomas; Schwarzmayr, Thomas; Strom, Tim M.; Invernizzi, Federica; Garavaglia, Barbara; Gregory, Allison; Sanford, Lynn; Hamada, Jeffrey; Bettencourt, Conceição; Houlden, Henry; Chiapparini, Luisa; Zorzi, Giovanna; Kurian, Manju A.; Nardocci, Nardo; Prokisch, Holger; Hayflick, Susan; Gout, Ivan; Tiranti, Valeria

2014-01-01

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA. PMID:24360804

Identification of HIBCH gene mutations causing autosomal recessive Leigh syndrome: a gene involved in valine metabolism.

PubMed

Soler-Alfonso, Claudia; Enns, Gregory M; Koenig, Mary Kay; Saavedra, Heather; Bonfante-Mejia, Eliana; Northrup, Hope

2015-03-01

Leigh syndrome is a progressive neurodegenerative disorder with usual onset of symptoms during the first year of life. The disorder has been associated with mutations in over 30 genes. This difficulty with genetic heterogeneity makes whole exome sequencing a more cost-effective approach for investigation of etiology. We describe an individual with typical Leigh syndrome who was found to have compound heterozygous mutations in the gene HIBCH (3-hydroxyisobutyryl coenzyme A hydrolase), an enzyme involved in the catabolism of valine. She exhibited significant clinical improvement after a valine-restricted diet. A subset of patients with uncharacterized Leigh syndrome present with specific biochemical abnormalities. This report highpoints the challenges and restrictions of routine metabolic testing and features the recognition of inborn errors of metabolism as potential treatable causes of Leigh syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

Enzyme replacement therapy on hypophosphatasia mouse model

PubMed Central

Montaño, Adriana M.; Shimada, Tsutomu; Sly, William S.

2013-01-01

Hypophosphatasia (HPP) is an inborn error of metabolism caused by deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP), resulting in a defect of bone mineralization. Natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5-phosphate (PLP), a co-factor form of vitamin B6. Enzyme replacement therapy (ERT) for HPP by functional TNSALP is one of the therapeutic options. The C-terminal-anchorless human recombinant TNSALP derived from Chinese hamster ovary cell lines was purified. TNSALP-null mice (Akp2−/−), an infantile model of HPP, were treated from birth using TNSALP and vitamin B6 diet. Long-term efficacy studies of ERT consisted of every 3 days subcutaneous or intravenous injections till 28 days old (dose 20 U/g) and subsequently every 3 days intravenous injections for 6 months (dose 10 U/g). We assessed therapeutic effect by growth and survival rates, fertility, skeletal manifestations, and radiographic and pathological finding. Treated Akp2−/− mice grew normally till 4 weeks and appeared well with a minimum skeletal abnormality as well as absence of epilepsy, compared with untreated mice which died by 3 weeks old. The prognosis of TNSALP-treated Akp2−/− mice was improved substantially: 1) prolonged life span over 6 months, 2) improvement of the growth, and 3) normal fertility. After 6 months of treatment, we found moderate hypomineralization with abnormal proliferative chondrocytes in growth plate and articular cartilage. In conclusion, ERT with human native TNSALP improves substantial clinical manifestations in Akp2−/− mice, suggesting that ERT with anchorless TNSALP is also a potential therapy for HPP. PMID:23978959

Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

PubMed Central

Vockley, Jerry; Ensenauer, Regina

2008-01-01

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years. PMID:16602101

The position of DNA cleavage by TALENs and cell synchronization influences the frequency of gene editing directed by single-stranded oligonucleotides.

PubMed

Rivera-Torres, Natalia; Strouse, Bryan; Bialk, Pawel; Niamat, Rohina A; Kmiec, Eric B

2014-01-01

With recent technological advances that enable DNA cleavage at specific sites in the human genome, it may now be possible to reverse inborn errors, thereby correcting a mutation, at levels that could have an impact in a clinical setting. We have been developing gene editing, using single-stranded DNA oligonucleotides (ssODNs), as a tool to direct site specific single base changes. Successful application of this technique has been demonstrated in many systems ranging from bacteria to human (ES and somatic) cells. While the frequency of gene editing can vary widely, it is often at a level that does not enable clinical application. As such, a number of stimulatory factors such as double-stranded breaks are known to elevate the frequency significantly. The majority of these results have been discovered using a validated HCT116 mammalian cell model system where credible genetic and biochemical readouts are available. Here, we couple TAL-Effector Nucleases (TALENs) that execute specific ds DNA breaks with ssODNs, designed specifically to repair a missense mutation, in an integrated single copy eGFP gene. We find that proximal cleavage, relative to the mutant base, is key for enabling high frequencies of editing. A directionality of correction is also observed with TALEN activity upstream from the target base being more effective in promoting gene editing than activity downstream. We also find that cells progressing through S phase are more amenable to combinatorial gene editing activity. Thus, we identify novel aspects of gene editing that will help in the design of more effective protocols for genome modification and gene therapy in natural genes.

Breath acetone as a potential marker in clinical practice.

PubMed

Ruzsányi, Veronika; Péter Kalapos, Miklós

2017-06-01

In recent decades, two facts have changed the opinion of researchers about the function of acetone in humans. Firstly, it has turned out that acetone cannot be regarded as simply a waste product of metabolism, because there are several pathways in which acetone is produced or broken down. Secondly, methods have emerged making possible its detection in exhaled breath, thereby offering an attractive alternative to investigation of blood and urine samples. From a clinical point of view the measurement of breath acetone levels is important, but there are limitations to its wide application. These limitations can be divided into two classes, technical and biological limits. The technical limits include the storage of samples, detection threshold, standardization of clinical settings, and the price of instruments. When considering the biological ranges of acetone, personal factors such as race, age, gender, weight, food consumption, medication, illicit drugs, and even profession/class have to be taken into account to use concentration information for disorders. In some diseases such as diabetes mellitus and lung cancer, as well as in nutrition-related behavior such as starvation and ketogenic diet, breath acetone has been extensively examined. At the same time, there is a lack of investigations in other cases in which ketosis is also evident, such as in alcoholism or an inborn error of metabolism. In summary, the detection of acetone in exhaled breath is a useful and promising tool for diagnosis and it can be used as a marker to follow the effectiveness of treatments in some disorders. However, further endeavors are needed for clarification of the exact distribution of acetone in different body compartments and evaluation of its complex role in humans, especially in those cases in which a ketotic state also occurs.

Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

PubMed Central

Beltrán-Valero de Bernabé, D; Granadino, B; Chiarelli, I; Porfirio, B; Mayatepek, E; Aquaron, R; Moore, M M; Festen, J J; Sanmartí, R; Peñalva, M A; de Córdoba, S R

1998-01-01

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles. PMID:9529363

T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis.

PubMed

Ott, Mariliis; Jing, Lichen; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying; Koelle, David M

2017-08-01

Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell-acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1-specific immunity in HSE survivors. We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators. All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups. The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.

An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand.

PubMed

Thiboonboon, Kittiphong; Leelahavarong, Pattara; Wattanasirichaigoon, Duangrurdee; Vatanavicharn, Nithiwat; Wasant, Pornswan; Shotelersuk, Vorasuk; Pangkanon, Suthipong; Kuptanon, Chulaluck; Chaisomchit, Sumonta; Teerawattananon, Yot

2015-01-01

Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem.

Thiamine Deprivation Produces a Liver ATP Deficit and Metabolic and Genomic Effects in Mice: Findings Are Parallel to Those of Biotin Deficiency and Have Implications for Energy Disorders.

PubMed

Hernandez-Vazquez, Alain de J; Garcia-Sanchez, Josue Andres; Moreno-Arriola, Elizabeth; Salvador-Adriano, Ana; Ortega-Cuellar, Daniel; Velazquez-Arellano, Antonio

2016-01-01

Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine. They are similar to the ones we have previously found in biotin deficiency, another ATP generation cofactor. Here we show that thiamine deficiency substantially reduced the energy state in the liver and activated the energy sensor AMP-activated kinase. With this vitamin deficiency, several metabolic parameters changed: blood glucose was diminished and serum lactate was increased, but insulin, triglycerides, and cholesterol, as well as liver glycogen, were reduced. These results indicate a severe change in the energy status of the whole organism. Our findings were associated with modified hepatic levels of the mRNAs of several carbon metabolism genes: a reduction of transcripts for liver glucokinase and fatty acid synthase and augmentation of those for carnitine palmitoyl transferase 1 and phosphoenolpyruvate carboxykinase as markers for glycolysis, fatty acid synthesis, beta-oxidation, and gluconeogenesis, respectively. Glucose tolerance was initially increased, suggesting augmented insulin sensitivity, as we had found in biotin deficiency; however, in the case of thiamine, it was diminished from the 3rd week on, when the deficient animals became undernourished, and paralleled the changes in AKT and mTOR, 2 main proteins in the insulin signaling pathway. Since many of the metabolic and gene expression effects on mice deprived of thiamine are similar to those in biotin deficiency, it may be that they result from a more general impairment of oxidative phosphorylation due to a shortage of ATP generation cofactors. These findings may be relevant to energy-related disorders, among them several inborn errors of metabolism, as well as common energy disorders like obesity, diabetes, and neurodegenerative illnesses. © 2017 S. Karger AG, Basel.

Variable clinical spectrum of the most common inborn error of bile acid metabolism--3beta-hydroxy-Delta 5-C27-steroid dehydrogenase deficiency.

PubMed

Subramaniam, Pushpa; Clayton, Peter T; Portmann, Bernard C; Mieli-Vergani, Giorgina; Hadzić, Nedim

2010-01-01

We studied the clinical features of children with 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase (3beta-HSDH) deficiency presenting to King's College and Great Ormond Street hospitals between 1989 and 2005. The diagnosis was made biochemically by detection of sulphated dihydroxycholenoic acids and trihydroxycholenoic acids in urine by fast atom bombardment mass spectrometry or electrospray ionisation tandem mass spectrophotometry and a plasma bile acid profile showing absent or low cholic and chenodeoxycholic acid levels and high concentrations of 3beta-7 alpha-dihydroxy-5-cholenoic acid and 3beta-7 alpha-12 alpha-trihydroxy-5-cholenoic acid. Eighteen children (12 male) with 3beta-HSDH deficiency were identified and diagnosed at a median age of 1.35 years (range 8 weeks-11 years). The presenting features included neonatal cholestasis (n = 11), rickets (n = 8, 1 of whom also had hypocalcaemic tetany, seizures, and normal liver biochemical markers), hepatomegaly (n = 7), pruritus (n = 3), and steatorrhoea and failure to thrive (n = 3). Ten children had low serum 25-OH vitamin D levels, of whom 8 also had low vitamin E and 6 had low vitamin A serum levels. Liver histology showed giant cell change and hepatocyte disarray in all with added features of cholestasis in 11, bridging fibrosis in 6, micronodular cirrhosis in 1, fatty change in 1, and active lobular and portal inflammation in 1. Five patients were treated with cholic acid and chenodeoxycholic acid (7 mg x kg(-1) x day(-1) of each), 7 with chenodeoxycholic acid only (7-18 mg x kg(-1) x day(-1)), and 1 with cholic acid (8 mg x kg(-1) x day(-1)) only. Repeated liver biopsies performed in 4 patients 6 months after starting replacement therapy showed improved histological changes. Three children died untreated before 5 years of age. After a median follow-up of 5.5 years (range 1-17 years) 12 out of 13 treated children have no clinical signs of liver disease or of fat-soluble vitamin deficiency. 3beta-HSDH deficiency is a rare inborn error of metabolism with diverse clinical features. Early replacement treatment leads to clinical and biochemical control and prevents chronic liver and bone disease, at least in the medium term.

An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand

PubMed Central

Thiboonboon, Kittiphong; Leelahavarong, Pattara; Wattanasirichaigoon, Duangrurdee; Vatanavicharn, Nithiwat; Wasant, Pornswan; Shotelersuk, Vorasuk; Pangkanon, Suthipong; Kuptanon, Chulaluck; Chaisomchit, Sumonta; Teerawattananon, Yot

2015-01-01

Background Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. Method A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. Results The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. Conclusion At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem. PMID:26258410

Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

PubMed

Pollitt, R J; Green, A; McCabe, C J; Booth, A; Cooper, N J; Leonard, J V; Nicholl, J; Nicholson, P; Tunaley, J R; Virdi, N K

1997-01-01

OBJECTIVES. To systematically review the literature on inborn errors of metabolism, neonatal screening technology and screening programmes in order to analyse the costs and benefits of introducing screening based on tandem mass-spectrometry (tandem MS) for a wide range of disorders of amino acid and organic acid metabolism in the UK. To evaluate screening for cystic fibrosis, Duchenne muscular dystrophy and other disorders which are tested on an individual basis. HOW THE RESEARCH WAS CONDUCTED. Systematic searches were carried out of the literature on inborn errors of metabolism, neonatal screening programmes, tandem MS-based neonatal screening technology, economic evaluations of neonatal screening programmes and psychological aspects of neonatal screening. Background material on the biology of inherited metabolic disease, the basic philosophy, and the history and current status of the UK screening programme was also collected. Relevant papers in the grey literature and recent publications were identified by hand-searching. Each paper was graded. For each disease an aggregate grade for the state of knowledge in six key areas was awarded. Additional data were prospectively collected on activity and costs in UK neonatal screening laboratories, and expert clinical opinion on current treatment modalities and outcomes. These data were used to construct a decision-analysis model of neonatal screening technologies, comparing tandem MS with the existing phenylketonuria screening methods. This model determined the cost per additional case identified and, for each disease, the additional treatment costs per case, and the cost per life-year saved. All costs and benefits were discounted at 6% per annum. One-way sensitivity analysis was performed showing the effect of varying the discount rate, the incidence rate of each disorder, the number of neonates screened and the cost of tandem MS, on the cost per life-year gained. RESEARCH FINDINGS. The UK screening programmes for phenylketonuria and congenital hypothyroidism have largely achieved the expected objectives and are cost-effective. Current concerns are the difficulty of maintaining adequate coverage, perceived organisational weaknesses, and a lack of overview. For many of the organic acid disorders it was necessary to rely on data obtained from clinically-diagnosed cases. Many of these diseases can be treated very effectively and a sensitive screening test was available for most of the diseases. Except for cystic fibrosis, there have been no randomised controlled trials of the overall effectiveness of neonatal screening. Despite the anxiety generated by the screening process, there is strong parental support for screening. The effects of diagnosis through screening on subsequent reproductive behaviour is less clear. Conflicts exist between current concepts and the traditional principles of screening. The availability of effective treatment is not an absolute prerequisite: early diagnosis is of value to the family concerned and, to the extent that is leads to increased use of prenatal diagnosis, may help to reduce the overall burden of disease. Neonatal screening is also of value in diseases which present early but with non-specific symptoms. Indeed, almost all of the diseases considered could merit neonatal screening. The majority of economic evaluations failed to incorporate the health benefits from screening, and therefore failed to address the value of the information which the screening programmes provided to parents. The marginal cost of changing from present technology to tandem MS would be approximately 0.60 pounds per baby at a workload of 100,000 samples a year, and 0.87 pounds at 50,000 samples per year. The ability to screen for a wider range of diseases would lead to the identification of some 20 additional cases per 100,000 infants screened, giving a laboratory cost per additional diagnosis of 3000 pounds at an annual workload of 100,000 babies per year.(ABSTRACT TRUNCATED)

Quantitative RT-PCR Comparison of the Urea and Nitric Oxide Cycle Gene Transcripts in Adult Human Tissues

PubMed Central

Neill, Meaghan Anne; Aschner, Judy; Barr, Frederick; Summar, Marshall L.

2009-01-01

The urea cycle and nitric oxide cycle play significant roles in complex biochemical and physiologic reactions. These cycles have distinct biochemical goals including the clearance of waste nitrogen; the production of the intermediates ornithine, citrulline, and arginine for the urea cycle; and the production of nitric oxide for the nitric oxide pathway. Despite their disparate functions, the two pathways share two enzymes, argininosuccinic acid synthase and argininosuccinic acid lyase, and a transporter, citrin. Studying the gene expression of these enzymes is paramount in understanding these complex biochemical pathways. Here, we examine the expression of genes involved in the urea cycle and the nitric oxide cycle in a panel of eleven different tissue samples obtained from individual adults without known inborn errors of metabolism. In this study, the pattern of co-expressed enzymes provides a global view of the metabolic activity of the urea and nitric oxide cycles in human tissues. Our results show that these transcripts are differentially expressed in different tissues. The pattern of co-expressed enzymes provides a global view of the metabolic activity of the urea and nitric oxide cycles in human tissues. Using the co-expression profiles, we discovered that the combination of expression of enzyme transcripts as detected in our study, might serve to fulfill specific physiologic function(s) in tissue including urea production/nitrogen removal, arginine/citrulline production, nitric oxide production, and ornithine production. Our study reveals the importance of studying not only the expression profile of an enzyme of interest, but also studying the expression profiles of the other enzymes involved in a particular pathway so as to better understand the context of expression. The tissue patterns we observed highlight the variety of important functions they conduct and provide insight into many of the clinical observations from their disruption. PMID:19345634

Production and characterization of murine models of classic and intermediate maple syrup urine disease

PubMed Central

Homanics, Gregg E; Skvorak, Kristen; Ferguson, Carolyn; Watkins, Simon; Paul, Harbhajan S

2006-01-01

Background Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched-chain keto acid dehydrogenase. MSUD has several clinical phenotypes depending on the degree of enzyme deficiency. Current treatments are not satisfactory and require new approaches to combat this disease. A major hurdle in developing new treatments has been the lack of a suitable animal model. Methods To create a murine model of classic MSUD, we used gene targeting and embryonic stem cell technologies to create a mouse line that lacked a functional E2 subunit gene of branched-chain keto acid dehydrogenase. To create a murine model of intermediate MSUD, we used transgenic technology to express a human E2 cDNA on the knockout background. Mice of both models were characterized at the molecular, biochemical, and whole animal levels. Results By disrupting the E2 subunit gene of branched-chain keto acid dehydrogenase, we created a gene knockout mouse model of classic MSUD. The homozygous knockout mice lacked branched-chain keto acid dehydrogenase activity, E2 immunoreactivity, and had a 3-fold increase in circulating branched-chain amino acids. These metabolic derangements resulted in neonatal lethality. Transgenic expression of a human E2 cDNA in the liver of the E2 knockout animals produced a model of intermediate MSUD. Branched-chain keto acid dehydrogenase activity was 5–6% of normal and was sufficient to allow survival, but was insufficient to normalize circulating branched-chain amino acids levels, which were intermediate between wildtype and the classic MSUD mouse model. Conclusion These mice represent important animal models that closely approximate the phenotype of humans with the classic and intermediate forms of MSUD. These animals provide useful models to further characterize the pathogenesis of MSUD, as well as models to test novel therapeutic strategies, such as gene and cellular therapies, to treat this devastating metabolic disease. PMID:16579849

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency

PubMed Central

Hannibal, Luciana; Lysne, Vegard; Bjørke-Monsen, Anne-Lise; Behringer, Sidney; Grünert, Sarah C.; Spiekerkoetter, Ute; Jacobsen, Donald W.; Blom, Henk J.

2016-01-01

Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders. PMID:27446930

Heparin-binding growth factor 1 induces the formation of organoid neovascular structures in vivo.

PubMed Central

Thompson, J A; Haudenschild, C C; Anderson, K D; DiPietro, J M; Anderson, W F; Maciag, T

1989-01-01

One of the promises of modern molecular biology has been the opportunity to use genetically modified human cells in a patient to permanently restore inborn errors of metabolism. Although it has been possible to introduce genes into mammalian cells and to control their expression, it has proven difficult to introduce mammalian cells as carriers of the modified genetic information into hosts. The successful implantation of selective cells cannot be achieved without adequate vascular support, an essential step toward integration and reconstitution of a new biological function. Although a partial solution to this problem has been found by inducing specific site-directed neovessel formation using heparin-binding growth factor 1 (HBGF-1) adsorbed to a collagen matrix, these implants function for only a short period (weeks). We now report the formation of organoid neovascular structures using polytetrafluoroethylene fibers coated with collagen and HBGF-1 implanted in the peritoneal cavity of the rat. The organoid structures contained readily visible vascular lumina and nonvascular structures that resemble nerve tissue. It was also possible to demonstrate that the vascular system on the implant is continuous with the vascular tree of the host. This feature was used to demonstrate that the organoid structures are capable of sustaining the biological function of implanted normal rat hepatocytes over long periods of time (months) in the homozygous Gunn rat, thereby facilitating future applications involving the delivery of new genetic information. Images PMID:2479012

Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria

PubMed Central

Fiori, Elena; Oddi, Diego; Ventura, Rossella; Colamartino, Marco; Valzania, Alessandro; D’Amato, Francesca Romana; Bruinenberg, Vibeke; van der Zee, Eddy; Puglisi-Allegra, Stefano

2017-01-01

Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment. The development and the study of new treatments continue to be sought, taking advantage of preclinical models, the most used of which is the PAHenu2 (BTBR ENU2), the genetic murine model of PKU. To date, adult behavioral and neurochemical alterations have been mainly investigated in ENU2 mice, whereas there are no clear indications about the onset of these deficiencies. Here we investigated and report, for the first time, a comprehensive behavioral and neurochemical assay of the developing ENU2 mice. Overall, our findings demonstrate that ENU2 mice are significantly smaller than WT until pnd 24, present a significant delay in the acquisition of tested developmental reflexes, impaired communicative, motor and social skills, and have early reduced biogenic amine levels in several brain areas. Our results extend the understanding of behavioral and cerebral abnormalities in PKU mice, providing instruments to an early preclinical evaluation of the effects of new treatments. PMID:28850618

The genetic theory of infectious diseases: a brief history and selected illustrations.

PubMed

Casanova, Jean-Laurent; Abel, Laurent

2013-01-01

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.

Phenylbutyrate Therapy for Pyruvate Dehydrogenase Complex Deficiency and Lactic Acidosis

PubMed Central

Ferriero, Rosa; Manco, Giuseppe; Lamantea, Eleonora; Nusco, Edoardo; Ferrante, Mariella I.; Sordino, Paolo; Stacpoole, Peter W.; Lee, Brendan; Zeviani, Massimo; Brunetti-Pierri, Nicola

2014-01-01

Lactic acidosis is a build-up of lactic acid in the blood and tissues, which can be due to several inborn errors of metabolism as well as nongenetic conditions. Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder leading to lactic acidosis. Phosphorylation of specific serine residues of the E1α subunit of PDHC by pyruvate dehydrogenase kinase (PDK) inactivates the enzyme, whereas dephosphorylation restores PDHC activity. We found that phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of PDK. Phenylbutyrate given to C57B6/L wild-type mice results in a significant increase in PDHC enzyme activity and a reduction of phosphorylated E1α in brain, muscle, and liver compared to saline-treated mice. By means of recombinant enzymes, we showed that phenylbutyrate prevents phosphorylation of E1α through binding and inhibition of PDK, providing a molecular explanation for the effect of phenylbutyrate on PDHC activity. Phenylbutyrate increases PDHC activity in fibroblasts from PDHC-deficient patients harboring various molecular defects and corrects the morphological, locomotor, and biochemical abnormalities in the noam631 zebrafish model of PDHC deficiency. In mice, phenylbutyrate prevents systemic lactic acidosis induced by partial hepatectomy. Because phenylbutyrate is already approved for human use in other diseases, the findings of this study have the potential to be rapidly translated for treatment of patients with PDHC deficiency and other forms of primary and secondary lactic acidosis. PMID:23467562

The Genetic Theory of Infectious Diseases: A Brief History and Selected Illustrations

PubMed Central

Casanova, Jean-Laurent; Abel, Laurent

2016-01-01

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases. PMID:23724903

Left brain, right brain: facts and fantasies.

PubMed

Corballis, Michael C

2014-01-01

Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the "norm" of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal.

Effect of Benralizumab in Atopic Dermatitis

ClinicalTrials.gov

2018-06-22

Dermatitis, Atopic; Dermatitis; Eczema; Skin Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases, Eczematous; Hypersensitivity; Hypersensitivity, Immediate; Immune System Diseases

Multiomics tools for the diagnosis and treatment of rare neurological disease.

PubMed

Crowther, L M; Poms, M; Plecko, Barbara

2018-05-01

Conventional workup of rare neurological disease is frequently hampered by diagnostic delay or lack of diagnosis. While biomarkers have been established for many neurometabolic disorders, improved methods are required for diagnosis of previously unidentified or underreported causes of rare neurological disease. This would result in a higher diagnostic yield and increased patient numbers required for interventional studies. Recent studies using next-generation sequencing and metabolomics have led to identification of novel disease-causing genes and biomarkers. This combined approach can assist in overcoming challenges associated with analyzing and interpreting the large amount of data obtained from each technique. In particular, metabolomics can support the pathogenicity of sequence variants in genes encoding enzymes or transporters involved in metabolic pathways. Moreover, metabolomics can show the broader perturbation caused by inborn errors of metabolism and identify a metabolic fingerprint of metabolic disorders. As such, using "omics" has great potential to meet the current needs for improved diagnosis and elucidation of rare neurological disease.

Monogenic Auto-inflammatory Syndromes: A Review of the Literature.

PubMed

Azizi, Gholamreza; Khadem Azarian, Shahin; Nazeri, Sepideh; Mosayebian, Ali; Ghiasy, Saleh; Sadri, Ghazal; Mohebi, Ali; Khan Nazer, Nikoo Hossein; Afraei, Sanaz; Mirshafiey, Abbas

2016-12-01

Auto-inflammatory syndromes are a new group of distinct hereditable disorders characterized by episodes of seemingly unprovoked inflammation (most commonly in skin, joints, gut, and eye), the absence of a high titer of auto-antibodies or auto-reactive T cells, and an inborn error of innate immunity. A narrative literature review was carried out of studies related to auto-inflammatory syndromes to discuss the pathogenesis and clinical manifestation of these syndromes. This review showed that the main monogenic auto-inflammatory syndromes are familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). The data suggest that correct diagnosis and treatment of monogenic auto-inflammatory diseases relies on the physicians' awareness. Therefore, understanding of the underlying pathogenic mechanisms of auto-inflammatory syndromes, and especially the fact that these disorders are mediated by IL-1 secretion stimulated by monocytes and macrophages, facilitated significant progress in patient management.

Hereditary xanthinuria and urolithiasis in a domestic shorthair cat

PubMed Central

Furman, E.; Hooijberg, E.H.; Leidinger, E.; Zedinger, C.; Giger, U.; Leidinger, J.

2015-01-01

A 2-year-old domestic shorthair cat was presented with a history of hematuria, stranguria and intermittent urethral obstruction. Urine sediment showed hematuria, pyuria, and yellow-brown, amorphous and spherical crystals. Upon surgical correction of the obstructed urethra by perineal urethrostomy, many dark yellow to grey, irregular, gravel-like to millet grain-sized uroliths, consisting of 100% xanthine by crystallography were found. The urinary xanthine concentration was high. The cat subsequently developed bilateral nephroliths, recurrent urinary tract infection, and chronic kidney failure. Dietary management with a low-purine diet failed in part due to poor compliance, and the cat was euthanized at 6 years of age. Xanthinuria is rare inborn error of metabolism in cats and other species but should be considered as a differential diagnosis in cases of feline urolithiasis. No associated molecular genetic defect has been elucidated, and management of these cases is difficult. In the absence of calculi for analysis, measuring urinary xanthine concentration can help in diagnosing this metabolic defect. PMID:26478726

Quantitation of 5-Methyltetrahydrofolate in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray Tandem Mass Spectrometry.

PubMed

Arning, Erland; Bottiglieri, Teodoro

2016-01-01

We describe a simple stable isotope dilution method for accurate and precise measurement of cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF) as a clinical diagnostic test. 5-MTHF is the main biologically active form of folic acid and is involved in regulation of homocysteine and DNA synthesis. Measurement of 5-MTHF in CSF provides diagnostic information regarding diseases affecting folate metabolism within the central nervous system, in particular inborn errors of folate metabolism. Determination of 5-MTHF in CSF (50 μL) was performed utilizing high performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). 5-MTHF in CSF is determined by a 1:2 dilution with internal standard (5-MTHF-(13)C5) and injected directly onto the HPLC-ESI-MS/MS system. Each assay is quantified using a five-point standard curve (25-400 nM) and has an analytical measurement range of 3-1000 nM.

An infant with glutaric aciduria type IIc diagnosed with a novel mutation.

PubMed

Işıkay, Sedat; Yaman, Ayhan; Ceylaner, Serdar

2017-01-01

Işıkay S, Yaman A, Ceylaner S. An infant with glutaric aciduria type IIc diagnosed with a novel mutation. Turk J Pediatr 2017; 59: 315-317. Glutaric aciduria type II is a rare inborn error of metabolism. The clinical picture is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases. Herein we described a 7-month-old female patient presented with respiratory failure and diagnosed with glutaric aciduria type II via whole exome sequencing that exhibited one known and a novel mutation. Her blood and urine analyses were all normal. After the diagnosis, dramatic and sustained improvement on a low-fat, low-protein, and high-carbohydrate diet supplemented with oral riboflavin and carnitine was determined. In especially hypotonic patients with unknown etiologies, though the blood and urine analyses are normal, glutaric aciduria type II should also be kept in mind and genetic tests may be required for the diagnosis.

Mutation analysis of GLDC, AMT and GCSH in cataract captive-bred vervet monkeys (Chlorocebus aethiops).

PubMed

Chauke, Chesa G; Magwebu, Zandisiwe E; Sharma, Jyoti R; Arieff, Zainunisha; Seier, Jürgen V

2016-08-01

Non-ketotic hyperglycinaemia (NKH) is an autosomal recessive inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. This study describes the first screening of NKH in cataract captive-bred vervet monkeys (Chlorocebus aethiops). Glycine dehydrogenase (GLDC), aminomethyltransferase (AMT) and glycine cleavage system H protein (GCSH) were prioritized. Mutation analysis of the complete coding sequence of GLDC and AMT revealed six novel single-base substitutions, of which three were non-synonymous missense and three were silent nucleotide changes. Although deleterious effects of the three amino acid substitutions were not evaluated, one substitution of GLDC gene (S44R) could be disease-causing because of its drastic amino acid change, affecting amino acids conserved in different primate species. This study confirms the diagnosis of NKH for the first time in vervet monkeys with cataracts. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical social work roles in an integrative, interdisciplinary team: enhancing parental compliance.

PubMed

Terry, P O

1981-01-01

This paper is directed toward those attempting to develop effective social work functions within an interdisciplinary treatment team and utilizes a specialized group as a demonstration model. The Inborn Errors of Metabolism Team at the University of Tennessee Child Development Center deals with children whose genetic disorders require precise dietary management for the prevention of various handicapping conditions including mental retardation. Representatives of the six disciplines forming the core team recognize that professional interdependence must combine with parental cooperation if the program is to succeed. The clinical social worker is a permanent member of the team and focuses on the family during the years each child is followed. Social work roles are multiple and include those of crisis interventionist, family therapist, marriage counselor, patient advocate, and team interpreter. Such social work involvement is essential in the holistic approach to long-term patient care which recognizes that no disorder exists apart from the patient, nor the patient from his family.

Hyperargininemia: 7-month follow-up under sodium benzoate therapy in an Italian child presenting progressive spastic paraparesis, cognitive decline, and novel mutation in ARG1 gene.

PubMed

Baranello, Giovanni; Alfei, Enrico; Martinelli, Diego; Rizzetto, Manuela; Cazzaniga, Fabiana; Dionisi-Vici, Carlo; Gellera, Cinzia; Castellotti, Barbara

2014-09-01

Hyperargininemia due to mutations in ARG1 gene is an autosomal recessive inborn error of metabolism caused by a defect in the final step of the urea cycle. Common clinical presentation is a variable association of progressive spastic paraparesis, epilepsy, and cognitive deficits. We describe the clinical history of an Italian child presenting progressive spastic paraparesis, carrying a new homozygous missense mutation in the ARG1 gene. A detailed clinical, biochemical, and neurophysiological follow-up after 7 months of sodium benzoate therapy is reported. Laboratory findings, gait abnormalities, spastic paraparesis, and electroencephalographic and neurophysiological abnormalities remained quite stable over the follow-up. Conversely, a mild cognitive deterioration has been detected by means of the neuropsychologic assessment. Further longitudinal studies by means of longer follow-up and using clinical, biochemical, radiological, and neurophysiological assessments are needed in such patients to describe natural history and monitor the effects of treatments. Copyright © 2014 Elsevier Inc. All rights reserved.

Multidisciplinary management of ornithine transcarbamylase (OTC) deficiency in pregnancy: essential to prevent hyperammonemic complications

PubMed Central

Lamb, Stephanie; Aye, Christina Yi Ling; Murphy, Elaine; Mackillop, Lucy

2013-01-01

Ornithine transcarbamylase (OTC) deficiency is the most common inborn error in the metabolism of the urea cycle with an incidence of 1 in 14 000 live births. Pregnancy can trigger potentially fatal hyperammonemic crises. We report a successful pregnancy in a 29-year-old primiparous patient with a known diagnosis of OTC deficiency since infancy. Hyperammonemic complications were avoided due to careful multidisciplinary management which included a detailed antenatal, intrapartum and postnatal plan. Management principles include avoidance of triggers, a low-protein diet and medications which promote the removal of nitrogen by alternative pathways. Triggers include metabolic stress such as febrile illness, particularly gastroenteritis, fasting and any protein loading. In our case the patient, in addition to a restricted protein intake, was prescribed sodium benzoate 4 g four times a day, sodium phenylbutyrate 2 g four times a day and arginine 500 mg four times a day to aid excretion of ammonia and reduce flux through the urea cycle. PMID:23283608

Recognition, assessment and management of hypoglycaemia in childhood.

PubMed

Ghosh, Arunabha; Banerjee, Indraneel; Morris, Andrew A M

2016-06-01

Hypoglycaemia is frequent in children and prompt management is required to prevent brain injury. In this article we will consider hypoglycaemia in children after the neonatal period. The most common causes are diabetes mellitus and idiopathic ketotic hypoglycaemia (IKH) but a number of endocrine disorders and inborn errors of metabolism (IEMs) need to be excluded. Elucidation of the diagnosis relies primarily on investigations during a hypoglycaemic episode but may also involve biochemical tests between episodes, dynamic endocrine tests and molecular genetics. Specific treatment such as cortisol replacement and pancreatic surgery may be required for endocrine causes of hypoglycaemia, such as adrenal insufficiency and congenital hyperinsulinism. In contrast, in IKH and most IEMs, hypoglycaemia is prevented by limiting the duration of fasting and maintaining a high glucose intake during illnesses. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Comparative proteomics in alkaptonuria provides insights into inflammation and oxidative stress.

PubMed

Braconi, Daniela; Bernardini, Giulia; Paffetti, Alessandro; Millucci, Lia; Geminiani, Michela; Laschi, Marcella; Frediani, Bruno; Marzocchi, Barbara; Santucci, Annalisa

2016-12-01

Alkaptonuria (AKU) is an ultra-rare inborn error of metabolism associated with a defective catabolism of phenylalanine and tyrosine leading to increased systemic levels of homogentisic acid (HGA). Excess HGA is partly excreted in the urine, partly accumulated within the body and deposited onto connective tissues under the form of an ochronotic pigment, leading to a range of clinical manifestations. No clear genotype/phenotype correlation was found in AKU, and today there is the urgent need to identify biomarkers able to monitor AKU progression and evaluate response to treatment. With this aim, we provided the first proteomic study on serum and plasma samples from alkaptonuric individuals showing pathological SAA, CRP and Advanced Oxidation Protein Products (AOPP) levels. Interesting similarities with proteomic studies on other rheumatic diseases were highlighted together with proteome alterations supporting the existence of oxidative stress and inflammation in AKU. Potential candidate biomarkers to assess disease severity, monitor disease progression and evaluate response to treatment were identified as well. Copyright © 2016 Elsevier Ltd. All rights reserved.

First description of phosphofructokinase deficiency in spain: identification of a novel homozygous missense mutation in the PFKM gene

PubMed Central

Vives-Corrons, Joan-Lluis; Koralkova, Pavla; Grau, Josep M.; Mañú Pereira, Maria del Mar; Van Wijk, Richard

2013-01-01

Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-years-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anemia. After ruling out the most common causes of chronic haemolytic anemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells (RBCs) from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain. PMID:24427140

Isolated sulfite oxidase deficiency.

PubMed

Rupar, C A; Gillett, J; Gordon, B A; Ramsay, D A; Johnson, J L; Garrett, R M; Rajagopalan, K V; Jung, J H; Bacheyie, G S; Sellers, A R

1996-12-01

Isolated sulfite oxidase (SO) deficiency is an autosomal recessively inherited inborn error of sulfur metabolism. In this report of a ninth patient the clinical history, laboratory results, neuropathological findings and a mutation in the sulfite oxidase gene are described. The data from this patient and previously published patients with isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are summarized to characterize this rare disorder. The patient presented neonatally with intractable seizures and did not progress developmentally beyond the neonatal stage. Dislocated lenses were apparent at 2 months. There was increased urine excretion of sulfite and S-sulfocysteine and a decreased concentration of plasma cystine. A lactic acidemia was present for 6 months. Liver sulfite oxidase activity was not detectable but xanthine dehydrogenase activity was normal. The boy died of respiratory failure at 32 months. Neuropathological findings of cortical necrosis and extensive cavitating leukoencephalopathy were reminiscent of those seen in severe perinatal asphyxia suggesting an etiology of energy deficiency. A point mutation that resulted in a truncated protein missing the molybdenum-binding site has been identified.

Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1

PubMed Central

Castello, Raffaele; Borzone, Roberta; D’Aria, Stefania; Annunziata, Patrizia; Piccolo, Pasquale; Brunetti-Pierri, Nicola

2015-01-01

Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) which catalyzes conversion of glyoxylate into glycine. AGT deficiency results in overproduction of oxalate which ultimately leads to end-stage renal disease and death. Organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation is the only available therapy to prevent disease progression. Gene therapy is an attractive option to provide an alternative treatment for PH1. Towards this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. Compared to saline controls, AGT-deficient mice injected with an HDAd encoding the AGT under the control of a liver-specific promoter showed a significant reduction of hyperoxaluria and less increase of urinary oxalate following challenge with Ethylene Glycol (EG), a precursor of glyoxylate. These studies may thus pave the way to clinical application of HDAd for PH1 gene therapy. PMID:26609667

Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review.

PubMed

Tan, Hu; Chen, Xin; Lv, Weigang; Linpeng, Siyuan; Liang, Desheng; Wu, Lingqian

2018-04-27

3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency.

Urea cycle disorders: a life-threatening yet treatable cause of metabolic encephalopathy in adults.

PubMed

Blair, Nicholas F; Cremer, Philip D; Tchan, Michel C

2015-02-01

Urea cycle disorders are inborn errors of metabolism that, in rare cases, can present for the first time in adulthood. We report a perplexing presentation in a woman 4 days postpartum of bizarre and out-of-character behaviour interspersed with periods of complete normality. Without any focal neurological signs or abnormality on initial investigations, the diagnosis became clear with the finding of a significantly elevated plasma ammonia level, just as she began to deteriorate rapidly. She improved following intravenous dextrose and lipid emulsion, together with sodium benzoate, arginine and a protein-restricted diet. She remains well 12 months later with no permanent sequelae. Whilst this is a rare presentation of an uncommon disease, it is a treatable disorder and its early diagnosis can prevent a fatal outcome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Pilot study of sodium phenylbutyrate as adjuvant in cyclophosphamide-resistant endemic Burkitt's lymphoma.

PubMed

Phillips, John A; Griffin, Beverly E

2007-12-01

Burkitt's lymphoma (BL) accounts for the majority of childhood malignancies seen in sub-Saharan Africa. In Malawi, cyclophosphamide (CPM), the mainstay of treatment for endemic BL, is effective in around 50% of cases. Evidence exists in support of an association between activation of replication of Epstein-Barr virus (EBV) in the tumour and response to this chemotheraupeutic agent. Phenylbutyrate (PB), approved for treatment of inborn errors of the urea cycle with minimal toxicity in children, induces EBV replication and cell lysis in BL-derived cell cultures. It has also shown some success as adjuvant in treatment of chronic leukaemia and lymphoma. We tested in African BL patients with CPM-resistant tumours, and thus unlikely to survive, the hypothesis that PB can reverse this resistance. A study of five patients showed PB before CPM to induce shrinkage of CPM-resistant tumours in two of them. Findings suggested that for this effect PB pre-treatment should be given for a week before CPM treatment. A larger study is indicated.

Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation.

PubMed

Chen, P W; Hwu, W L; Ho, M C; Lee, N C; Chien, Y H; Ni, Y H; Lee, P H

2010-05-01

Methylmalonic acidemia with complete mutase deficiency (mut(0) type) is an inborn error of metabolism with high mortality and morbidity. LT has been suggested to be a solution to this disease, but elevation of urinary and blood MMA was still observed after LT. In this study, we measured dry blood spot MMA and its precursor propionyl-carnitine (C3-carnitine) for mut(0) patients. The results revealed that when C3-carnitine rose during metabolic stress, MMA rose exponentially (up to 1000 micromol/L) in patients who did not undergo LT. In patients who underwent LT, MMA rose to 100-200 micromol/L when C3-carnitine reached 10-20 micromol/L. However, when C3-carnitine rose further to 40-50 micromol/L, MMA levels just stayed put. Therefore, LT stabilized blood MMA level, though there might be a threshold for blood MMA clearance by the donor liver. This finding should be critical to understand the long-term outcome for LT in methylmalonic acidemia.

[Hepatic cell transplantation: a new therapy in liver diseases].

PubMed

Pareja, Eugenia; Cortés, Miriam; Martínez, Amparo; Vila, Juan José; López, Rafael; Montalvá, Eva; Calzado, Angeles; Mir, José

2010-07-01

Liver transplantation has been remarkably effective in the treatment in patients with end-stage liver disease. However, disparity between solid-organ supply and increased demand is the greatest limitation, resulting in longer waiting times and increase in mortality of transplant recipients. This situation creates the need to seek alternatives to orthotopic liver transplantation.Hepatocyte transplantation or liver cell transplantation has been proposed as the best method to support patients. The procedure consists of transplanting individual cells to a recipient organ in sufficient quantity to survive and restore the function. The capacity of hepatic regeneration is the biological basis of hepatocyte transplantation. This therapeutic option is an experimental procedure in some patients with inborn errors of metabolism, fulminant hepatic failure and acute and chronic liver failure, as a bridge to orthotopic liver transplantation. In the Hospital La Fe of Valencia, we performed the first hepatocyte transplantation in Spain creating a new research work on transplant program. Copyright 2009 AEC. Published by Elsevier Espana. All rights reserved.

A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome

PubMed

Thompson Legault, Julie; Strittmatter, Laura; Tardif, Jessica; Sharma, Rohit; Tremblay-Vaillancourt, Vanessa; Aubut, Chantale; Boucher, Gabrielle; Clish, Clary B; Cyr, Denis; Daneault, Caroline; Waters, Paula J; Vachon, Luc; Morin, Charles; Laprise, Catherine; Rioux, John D; Mootha, Vamsi K; Des Rosiers, Christine

2015-11-03

A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism. It is also associated with common age-associated diseases and the aging process. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD(+) biosynthesis (kynurenine and 3-hydroxyanthranilic acid). Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Identification of a Novel GLA Mutation (L206 P) in a Patient with Fabry Disease.

PubMed

Kim, Ji-Hoon; Kim, Gee-Hee; Park, Hoon-Suk; Choi, Jin-A; Bae, Jung-Min; Cho, Uiju

2017-03-01

We report a new α-Galactosidase A (αGal-A) mutation in a 39-year-old Korean born, male Fabry disease patient. Fabry disease is a devastating, progressive inborn error of metabolism caused by X-linked genetic mutations. In this case, the first clinical symptom to occur was in childhood consisting of a burning pain originating in the extremities then radiating inwards to the limbs. This patient also stated to have ringing in his ears, angiokeratomas on his trunk, and cornea verticillata. He visited an outpatient cardiologist due to intermittent and atypical chest discomfort at the age of 39. Electrocardiographic and echocardiographic examination showed left ventricular hypertrophy. A physical examination revealed proteinuria without hematuria. The patient's plasma αGal-A activity was markedly lower than the mean value of the controls. After genetic counseling and obtaining written informed consent, we identified one hemizygous mutation in exon 4 of galactosidase alpha, c.617T>C (p.Leu206 Pro). He was eventually diagnosed as having Fabry disease.

Temperature-mediated phase transformation, pore geometry and pore hysteresis transformation of borohydride derived in-born porous zirconium hydroxide nanopowders

PubMed Central

Nayak, Nadiya B.; Nayak, Bibhuti B.

2016-01-01

Development of in-born porous nature of zirconium hydroxide nanopowders through a facile hydrogen (H2) gas-bubbles assisted borohydride synthesis route using sodium borohydride (NaBH4) and novel information on the temperature-mediated phase transformation, pore geometry as well as pore hysteresis transformation of in-born porous zirconium hydroxide nanopowders with the help of X-ray diffraction (XRD), Brunauer–Emmett–Teller (BET) isotherm and Transmission Electron Microscopy (TEM) images are the main theme of this research work. Without any surfactants or pore forming agents, the borohydride derived amorphous nature of porous powders was stable up to 500 °C and then the seed crystals start to develop within the loose amorphous matrix and trapping the inter-particulate voids, which led to develop the porous nature of tetragonal zirconium oxide at 600 °C and further sustain this porous nature as well as tetragonal phase of zirconium oxide up to 800 °C. The novel hydrogen (H2) gas-bubbles assisted borohydride synthesis route led to develop thermally stable porous zirconium hydroxide/oxide nanopowders with an adequate pore size, pore volume, and surface area and thus these porous materials are further suggested for promising use in different areas of applications. PMID:27198738

Target Discovery for Precision Medicine Using High-Throughput Genome Engineering.

PubMed

Guo, Xinyi; Chitale, Poonam; Sanjana, Neville E

2017-01-01

Over the past few years, programmable RNA-guided nucleases such as the CRISPR/Cas9 system have ushered in a new era of precision genome editing in diverse model systems and in human cells. Functional screens using large libraries of RNA guides can interrogate a large hypothesis space to pinpoint particular genes and genetic elements involved in fundamental biological processes and disease-relevant phenotypes. Here, we review recent high-throughput CRISPR screens (e.g. loss-of-function, gain-of-function, and targeting noncoding elements) and highlight their potential for uncovering novel therapeutic targets, such as those involved in cancer resistance to small molecular drugs and immunotherapies, tumor evolution, infectious disease, inborn genetic disorders, and other therapeutic challenges.

Preventing Mitochondrial Diseases: Embryo-Sparing Donor-Independent Options.

PubMed

Adashi, Eli Y; Cohen, I Glenn

2018-05-01

Mutant mitochondrial DNA gives rise to a broad range of incurable inborn maladies. Prevention may now be possible by replacing the mutation-carrying mitochondria of zygotes or oocytes at risk with donated unaffected counterparts. However, mitochondrial replacement therapy is being held back by theological, ethical, and safety concerns over the loss of human zygotes and the involvement of a donor. These concerns make it plain that the identification, validation, and regulatory adjudication of novel embryo-sparing donor-independent technologies remains a pressing imperative. This Opinion highlights three emerging embryo-sparing donor-independent options that stand to markedly allay theological, ethical, and safety concerns raised by mitochondrial replacement therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability.

PubMed

Anikster, Yair; Haack, Tobias B; Vilboux, Thierry; Pode-Shakked, Ben; Thöny, Beat; Shen, Nan; Guarani, Virginia; Meissner, Thomas; Mayatepek, Ertan; Trefz, Friedrich K; Marek-Yagel, Dina; Martinez, Aurora; Huttlin, Edward L; Paulo, Joao A; Berutti, Riccardo; Benoist, Jean-François; Imbard, Apolline; Dorboz, Imen; Heimer, Gali; Landau, Yuval; Ziv-Strasser, Limor; Malicdan, May Christine V; Gemperle-Britschgi, Corinne; Cremer, Kirsten; Engels, Hartmut; Meili, David; Keller, Irene; Bruggmann, Rémy; Strom, Tim M; Meitinger, Thomas; Mullikin, James C; Schwartz, Gerard; Ben-Zeev, Bruria; Gahl, William A; Harper, J Wade; Blau, Nenad; Hoffmann, Georg F; Prokisch, Holger; Opladen, Thomas; Schiff, Manuel

2017-02-02

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH 4 ) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH 4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH 4 -activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH 4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA. Copyright © 2017 American Society of Human Genetics. All rights reserved.

From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug.

PubMed

Lock, E A; Ellis, M K; Gaskin, P; Robinson, M; Auton, T R; Provan, W M; Smith, L L; Prisbylla, M P; Mutter, L C; Lee, D L

1998-08-01

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.

Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders

PubMed Central

MacLeod, Erin L.; Hall, Kevin D.; McGuire, Peter J.

2015-01-01

SUMMARY Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection. PMID:26260782

Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders.

PubMed

MacLeod, Erin L; Hall, Kevin D; McGuire, Peter J

2016-01-01

Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection.

Nutrigenomics in the modern era.

PubMed

Mathers, John C

2017-08-01

The concept that interactions between nutrition and genetics determine phenotype was established by Garrod at the beginning of the 20th century through his ground-breaking work on inborn errors of metabolism. A century later, the science and technologies involved in sequencing of the human genome stimulated development of the scientific discipline which we now recognise as nutritional genomics (nutrigenomics). Much of the early hype around possible applications of this new science was unhelpful and raised expectations, which have not been realised as quickly as some would have hoped. However, major advances have been made in quantifying the contribution of genetic variation to a wide range of phenotypes and it is now clear that for nutrition-related phenotypes, such as obesity and common complex diseases, the genetic contribution made by SNP alone is often modest. There is much scope for innovative research to understand the roles of less well explored types of genomic structural variation, e.g. copy number variants, and of interactions between genotype and dietary factors, in phenotype determination. New tools and models, including stem cell-based approaches and genome editing, have huge potential to transform mechanistic nutrition research. Finally, the application of nutrigenomics research offers substantial potential to improve public health e.g. through the use of metabolomics approaches to identify novel biomarkers of food intake, which will lead to more objective and robust measures of dietary exposure. In addition, nutrigenomics may have applications in the development of personalised nutrition interventions, which may facilitate larger, more appropriate and sustained changes in eating (and other lifestyle) behaviours and help to reduce health inequalities.

Biochemical, metabolic, and behavioral characteristics of immature chronic hyperphenylalanemic rats

PubMed Central

Dienel, Gerald A.; Cruz, Nancy F.

2015-01-01

Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25–27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least three weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired. PMID:26224289

Autoinhibition and signaling by the switch II motif in the G-protein chaperone of a radical B12 enzyme.

PubMed

Lofgren, Michael; Koutmos, Markos; Banerjee, Ruma

2013-10-25

MeaB is an accessory GTPase protein involved in the assembly, protection, and reactivation of 5'-deoxyadenosyl cobalamin-dependent methylmalonyl-CoA mutase (MCM). Mutations in the human ortholog of MeaB result in methylmalonic aciduria, an inborn error of metabolism. G-proteins typically utilize conserved switch I and II motifs for signaling to effector proteins via conformational changes elicited by nucleotide binding and hydrolysis. Our recent discovery that MeaB utilizes an unusual switch III region for bidirectional signaling with MCM raised questions about the roles of the switch I and II motifs in MeaB. In this study, we addressed the functions of conserved switch II residues by performing alanine-scanning mutagenesis. Our results demonstrate that the GTPase activity of MeaB is autoinhibited by switch II and that this loop is important for coupling nucleotide-sensitive conformational changes in switch III to elicit the multiple chaperone functions of MeaB. Furthermore, we report the structure of MeaB·GDP crystallized in the presence of AlFx(-) to form the putative transition state analog, GDP·AlF4(-). The resulting crystal structure and its comparison with related G-proteins support the conclusion that the catalytic site of MeaB is incomplete in the absence of the GTPase-activating protein MCM and therefore unable to stabilize the transition state analog. Favoring an inactive conformation in the absence of the client MCM protein might represent a strategy for suppressing the intrinsic GTPase activity of MeaB in which the switch II loop plays an important role.

Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis.

PubMed Central

Demers, S. I.; Phaneuf, D.; Tanguay, R. M.

1994-01-01

Hereditary tyrosinemia type 1 (HT1), a severe inborn error of tyrosine catabolism, is caused by deficiency of the terminal enzyme, fumarylacetoacetate hydrolase (FAH). The highest reported frequency of HT1 is in the French Canadian population, especially in the Saguenay-Lac-St-Jean region. Using human FAH cDNA probes, we have identified 10 haplotypes with TaqI, KpnI, RsaI, BglII, and MspI RFLPs in 118 normal chromosomes from the French Canadian population. Interestingly, in 29 HT1 children, a prevalent haplotype, haplotype 6, was found to be strongly associated with the disease, at a frequency of 90% of alleles, as compared with approximately 18% in 35 control individuals. This increased to 96% in the 24 patients originating from Saguenay-Lac-St-Jean. These results suggest that one or only a few prevailing mutations are responsible for most of the HT1 cases in Saguenay-Lac-St-Jean. Since most patients were found to be homozygous for a specific haplotype in this population, FAH RFLPs have permitted simple carrier detection in nine different informative HT1 families, with a confidence level of 99.9%. Heterozygosity rate values obtained from 52 carriers indicated that approximately 88% of families at risk from Saguenay-Lac-St-Jean are fully or partially informative. Prenatal diagnosis was also achieved in an American family. Analysis of 24 HT1 patients from nine countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association, worldwide, of HT1 with this haplotype. Images Figure 1 PMID:7913582

Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

ClinicalTrials.gov

2018-05-16

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Disease; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Risk of neurodevelopmental impairment for outborn extremely preterm infants in an Australian regional network.

PubMed

Mahoney, Kate; Bajuk, Barbara; Oei, Julee; Lui, Kei; Abdel-Latif, Mohamed E

2017-01-01

To compare neurodevelopmental outcomes at 2-3 years in extremely premature outborn and inborn infants. Population-based retrospective cohort study. Geographically defined area of New South Wales (NSW) and the Australian Capital Territory (ACT) served by a network of 10 neonatal intensive care units (NICUs). All premature infants <29 weeks gestation born between 1998 and 2004 in the setting. At 2-3 years, corrected age, 1473 children were assessed with either the Griffiths Mental Developmental Scales (GMDS) or the Bayley Scales of Infant Development (BSID-II). Moderate/severe functional disability (FD) defined as: developmental delay (GMDS general quotient (GQ) or BSID-II mental developmental index (MDI)) > 2 standard deviations (SD) below the mean; cerebral palsy (CP) requiring aids; sensorineural or conductive deafness (requiring amplification); or bilateral blindness (visual acuity <6/60 in better eye). At 2-3 years, moderate/severe functional disability does not appear to be significantly different between outborn and inborn infants (adjusted OR 0.782; 95% CI 0.424-1.443). However, there were a significant number of outborn infants lost to follow up (23.3% versus 42.9%). In this cohort, at 2-3 years follow up neurodevelopmental outcome does not appear to be significantly different between outborn and inborn infants. These results should be interpreted with caution given the limitation of this study.

HMG-CoA lyase (HL) gene: Cloning and characterization of the 5{prime} end of the mouse gene, gene targeting in ES cells, and demonstration of large deletions in three HL-deficient patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, S.; Robert, M.F.; Mitchell, G.A.

1994-09-01

3-hydroxy-3-methylglutaryl CoA lyase (HL) is a mitochondrial matrix enzyme which catalyzes the last step of leucine catabolism and of ketogenesis. Autosomal recessive HL deficiency in humans results in episodes of hypoglycemia and coma. We are interested in the pathophysiology of HL deficiency as a model for both amino acid and fatty acid inborn errors. We have cloned the human and mouse HL genes. In order to analyze the 5{prime} nontranslated region of mouse HL gene, we cloned and sequenced a 1.8 kb fragment containing the 5{prime} extremity including exon 1 and about 1.6 kb of 5{prime} nontranslated sequence. The regionmore » surrounding exon 1 is CpG-rich (66.4%). Using the criteria of West, the Observed/Expected ratio for CpG dinucleotides is 0.7 ({ge}0.6 is consistent with a CpG island). We are carrying out primer extension and RNase protection experiments to determine the transcription initiation site. We constructed a gene targeting vector by introducing the neomycin resistance gene into exon 2 of a 7.5 kb genomic subclone of the mouse HL gene. Targeting was performed by electroporating 10 mg linearized vector into 10{sup 7} ES cells and selecting for 12 days with G418. 5/228 colonies (2.2%) had homologous recombination as shown by PCR screening and Southern analysis. We are microinjecting the 5 targeted clones into blastocysts to create an HL-deficient mouse. To date we have obtained two chimeras with contributions of 95% and 55% from 129, by coat color estimates. Three of 27 (11%) of the HL-deficient patients studied were suggested by genomic Southern analysis to be homozygous for large intragenic deletions. We confirmed this and defined the boundaries using exonic PCR.« less

Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat

PubMed Central

Raj, Karthik; Osborne, Carl; Giger, Urs

2016-01-01

Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus) with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats. PMID:27404572

Mutations in ACY1, the Gene Encoding Aminoacylase 1, Cause a Novel Inborn Error of Metabolism

PubMed Central

Sass, Jörn Oliver; Mohr, Verena; Olbrich, Heike; Engelke, Udo; Horvath, Judit; Fliegauf, Manfred; Loges, Niki Tomas; Schweitzer-Krantz, Susanne; Moebus, Ralf; Weiler, Polly; Kispert, Andreas; Superti-Furga, Andrea; Wevers, Ron A.; Omran, Heymut

2006-01-01

N-terminal acetylation of proteins is a widespread and highly conserved process. Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography–mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients’ lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses. PMID:16465618

The Effect of Multiple Sulfatase Deficiency (MSD) on Dental Development: Can We Use the Teeth as an Early Diagnostic Tool?

PubMed

Zilberman, Uri; Bibi, Haim

2016-01-01

Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of metabolism due to reduced catalytic activity of the different sulfatase. Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and skin changes as in X-linked ichthyosis. The only organ that was not examined in MSD patients is the dentition. To evaluate the effect of the metabolic error on dental development in a patient with the intermediate severe late-infantile form of MSD (S155P). Histological and chemical study were performed on three deciduous and five permanent teeth from MSD patient and pair-matched normal patients. Tooth germ size and enamel thickness were reduced in both deciduous and permanent MSD teeth, and the scalloping feature of the DEJ was missing in MSD teeth causing enamel to break off from the dentin. The mineral components in the enamel and dentin were different. The metabolic error insults the teeth in the stage of organogenesis in both the deciduous and permanent dentition. The end result is teeth with very sharp cusp tips, thin hypomineralized enamel, and exposed dentin due to the break off of enamel. These findings are different from all other types of MPS syndromes.Clinically the phenotype of intermediate severe late-infantile form of MSD appeared during the third year of life. In children of parents that are carriers, we can diagnose the disease as early as birth using X-ray radiograph of the anterior upper region or as early as 6-8 months when the first deciduous tooth erupt and consider very early treatment to ameliorate the symptoms.

A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy

ClinicalTrials.gov

2018-06-16

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

ClinicalTrials.gov

2017-12-11

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18

PubMed Central

Gondré-Lewis, Marjorie C; Gboluaje, Temitayo; Reid, Shaina N; Lin, Stephen; Wang, Paul; Green, William; Diogo, Rui; Fidélia-Lambert, Marie N; Herman, Mary M

2015-01-01

The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon – closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain, face and their skeletal support. PMID:26278930

The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18.

PubMed

Gondré-Lewis, Marjorie C; Gboluaje, Temitayo; Reid, Shaina N; Lin, Stephen; Wang, Paul; Green, William; Diogo, Rui; Fidélia-Lambert, Marie N; Herman, Mary M

2015-09-01

The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon - closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain, face and their skeletal support. © 2015 Anatomical Society.

Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Dystrophinopathy

ClinicalTrials.gov

2018-01-16

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients

ClinicalTrials.gov

2017-06-09

Charcot Marie Tooth Disease (CMT); Hereditary Sensory and Motor Neuropathy; Nerve Compression Syndromes; Tooth Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System

Human Error: A Concept Analysis

NASA Technical Reports Server (NTRS)

Hansen, Frederick D.

2007-01-01

Human error is the subject of research in almost every industry and profession of our times. This term is part of our daily language and intuitively understood by most people however, it would be premature to assume that everyone's understanding of human error s the same. For example, human error is used to describe the outcome or consequence of human action, the causal factor of an accident, deliberate violations,a nd the actual action taken by a human being. As a result, researchers rarely agree on the either a specific definition or how to prevent human error. The purpose of this article is to explore the specific concept of human error using Concept Analysis as described by Walker and Avant (1995). The concept of human error is examined as currently used in the literature of a variety of industries and professions. Defining attributes and examples of model, borderline, and contrary cases are described. The antecedents and consequences of human error are also discussed and a definition of human error is offered.

Pathogenic cascades in lysosomal disease-Why so complex?

PubMed

Walkley, S U

2009-04-01

Lysosomal disease represents a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome. The lysosome is an integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin-proteosomal and autophagosomal systems, which together comprise essential cell machinery for substrate degradation and recycling, homeostatic control, and signalling. More than two-thirds of lysosomal diseases affect the brain, with neurons appearing particularly vulnerable to lysosomal compromise and showing diverse consequences ranging from specific axonal and dendritic abnormalities to neuron death. While failure of lysosomal function characteristically leads to lysosomal storage, new studies argue that lysosomal diseases may also be appropriately viewed as 'states of deficiency' rather than simply overabundance (storage). Interference with signalling events and salvage processing normally controlled by the endosomal/lysosomal system may represent key mechanisms accounting for the inherent complexity of lysosomal disorders. Analysis of lysosomal disease pathogenesis provides a unique window through which to observe the importance of the greater lysosomal system for normal cell health.

Adoptive T Cell Immunotherapy for Patients with Primary Immunodeficiency Disorders.

PubMed

McLaughlin, Lauren P; Bollard, Catherine M; Keller, Michael

2017-01-01

Primary immunodeficiency disorders (PID) are a group of inborn errors of immunity with a broad range of clinical severity but often associated with recurrent and serious infections. While hematopoietic stem cell transplantation (HSCT) can be curative for some forms of PID, chronic and/or refractory viral infections remain a cause of morbidity and mortality both before and after HSCT. Although antiviral pharmacologic agents exist for many viral pathogens, these are associated with significant costs and toxicities and may not be effective for increasingly drug-resistant pathogens. Thus, the emergence of adoptive immunotherapy with virus-specific T lymphocytes (VSTs) is an attractive option for addressing the underlying impaired T cell immunity in many PID patients. VSTs have been utilized for PID patients following HSCT in many prior phase I trials, and may potentially be beneficial before HSCT in patients with chronic viral infections. We review the various methods of generating VSTs, clinical experience using VSTs for PID patients, and current limitations as well as potential ways to broaden the clinical applicability of adoptive immunotherapy for PID patients.

Comprehensive evaluation of the child with intellectual disability or global developmental delays.

PubMed

Moeschler, John B; Shevell, Michael

2014-09-01

Global developmental delay and intellectual disability are relatively common pediatric conditions. This report describes the recommended clinical genetics diagnostic approach. The report is based on a review of published reports, most consisting of medium to large case series of diagnostic tests used, and the proportion of those that led to a diagnosis in such patients. Chromosome microarray is designated as a first-line test and replaces the standard karyotype and fluorescent in situ hybridization subtelomere tests for the child with intellectual disability of unknown etiology. Fragile X testing remains an important first-line test. The importance of considering testing for inborn errors of metabolism in this population is supported by a recent systematic review of the literature and several case series recently published. The role of brain MRI remains important in certain patients. There is also a discussion of the emerging literature on the use of whole-exome sequencing as a diagnostic test in this population. Finally, the importance of intentional comanagement among families, the medical home, and the clinical genetics specialty clinic is discussed. Copyright © 2014 by the American Academy of Pediatrics.

High phenobarbital clearance during continuous renal replacement therapy: a case report and pharmacokinetic analysis.

PubMed

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-08-01

Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring.A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure.Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus.The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed.Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring.

High Phenobarbital Clearance During Continuous Renal Replacement Therapy

PubMed Central

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-01-01

Abstract Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring. A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure. Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus. The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed. Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring. PMID:25101986

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel

PubMed Central

Angelucci, Emanuele; Matthes-Martin, Susanne; Baronciani, Donatella; Bernaudin, Françoise; Bonanomi, Sonia; Cappellini, Maria Domenica; Dalle, Jean-Hugues; Di Bartolomeo, Paolo; de Heredia, Cristina Díaz; Dickerhoff, Roswitha; Giardini, Claudio; Gluckman, Eliane; Hussein, Ayad Achmed; Kamani, Naynesh; Minkov, Milen; Locatelli, Franco; Rocha, Vanderson; Sedlacek, Petr; Smiers, Frans; Thuret, Isabelle; Yaniv, Isaac; Cavazzana, Marina; Peters, Christina

2014-01-01

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management. PMID:24790059

Lysosomal Storage Disorders in the Newborn

PubMed Central

Staretz-Chacham, Orna; Lang, Tess C.; LaMarca, Mary E.; Krasnewich, Donna; Sidransky, Ellen

2009-01-01

Lysosomal storage disorders are rare inborn errors of metabolism, with a combined incidence of 1 in 1500 to 7000 live births. These relatively rare disorders are seldom considered when evaluating a sick newborn. A significant number of the >50 different lysosomal storage disorders, however, do manifest in the neonatal period and should be part of the differential diagnosis of several perinatal phenotypes. We review the earliest clinical features, diagnostic tests, and treatment options for lysosomal storage disorders that can present in the newborn. Although many of the lysosomal storage disorders are characterized by a range in phenotypes, the focus of this review is on the specific symptoms and clinical findings that present in the perinatal period, including neurologic, respiratory, endocrine, and cardiovascular manifestations, dysmorphic features, hepatosplenomegaly, skin or ocular involvement, and hydrops fetalis/congenital ascites. A greater awareness of these features may help to reduce misdiagnosis and promote the early detection of lysosomal storage disorders. Implementing therapy at the earliest stage possible is crucial for several of the lysosomal storage disorders; hence, an early appreciation of these disorders by physicians who treat newborns is essential. PMID:19336380

Diagnosis and treatment of urea cycle disorder in Japan.

PubMed

Nakamura, Kimitoshi; Kido, Jun; Mitsubuchi, Hiroshi; Endo, Fumio

2014-08-01

Urea cycle disorder (UCD) is an inborn error of the metabolic pathway producing urea from ammonia, which occurs primarily in the liver. Decreased excretion of nitrogen in the urea cycle due to deficiency of carbamoyl phosphate synthase I (CPSI), ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and N-acetyl glutamate synthase (NAGS) causes hyperammonemia. We examined the clinical manifestations, treatment, and prognosis of 177 patients with UCD from January 1999 to March 2009 in Japan. Compared with a previous study conducted in Japan, a larger number of patients survived without mental retardation, even when the peak blood ammonia was >360 μmol/L. In those with peak blood ammonia >360 μmol/L, an indicator of poor prognosis, the frequency of convulsions, mental retardation, brain abnormality on magnetic resonance imaging, hemodialysis, liver transplantation, and intake of non-protein formulas was significantly higher than in those with peak blood ammonia <360 μmol/L. In this article, we have reported the current state of UCD to evaluate prognosis and its relationship with peak blood ammonia and hemodialysis. © 2014 Japan Pediatric Society.

Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease.

PubMed

Imtiaz, Faiqa; Al-Mostafa, Abeer; Allam, Rabab; Ramzan, Khushnooda; Al-Tassan, Nada; Tahir, Asma I; Al-Numair, Nouf S; Al-Hamed, Mohamed H; Al-Hassnan, Zuhair; Al-Owain, Mohammad; Al-Zaidan, Hamad; Al-Amoudi, Mohammad; Qari, Alya; Balobaid, Ameera; Al-Sayed, Moeenaldeen

2017-06-01

Maple syrup urine disease (MSUD), an autosomal recessive inborn error of metabolism due to defects in the branched-chain α-ketoacid dehydrogenase (BCKD) complex, is commonly observed among other inherited metabolic disorders in the kingdom of Saudi Arabia. This report presents the results of mutation analysis of three of the four genes encoding the BCKD complex in 52 biochemically diagnosed MSUD patients originating from Saudi Arabia. The 25 mutations (20 novel) detected spanned across the entire coding regions of the BCKHDA , BCKDHB and DBT genes. There were no mutations found in the DLD gene in this cohort of patients. Prediction effects, conservation and modelling of novel mutations demonstrated that all were predicted to be disease-causing. All mutations presented in a homozygous form and we did not detect the presence of a "founder" mutation in any of three genes. In addition, prenatal molecular genetic testing was successfully carried out on chorionic villus samples or amniocenteses in 10 expectant mothers with affected children with MSUD, molecularly characterized by this study.

Maple syrup urine disease: mechanisms and management.

PubMed

Blackburn, Patrick R; Gass, Jennifer M; Vairo, Filippo Pinto E; Farnham, Kristen M; Atwal, Herjot K; Macklin, Sarah; Klee, Eric W; Atwal, Paldeep S

2017-01-01

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients.

Maple syrup urine disease: mechanisms and management

PubMed Central

Farnham, Kristen M; Atwal, Herjot K; Macklin, Sarah; Klee, Eric W; Atwal, Paldeep S

2017-01-01

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients. PMID:28919799

The Bloodgen Project of the European Union, 2003–2009

PubMed Central

Avent, Neil D.; Martinez, Antonio; Flegel, Willy A.; Olsson, Martin L.; Scott, Marion L.; Nogués, Núria; Písăcka, Martin; Daniels, Geoff L.; Muñiz-Diaz, Eduardo; Madgett, Tracey E.; Storry, Jill R.; Beiboer, Sigrid; Maaskant-van Wijk, Petra M.; von Zabern, Inge; Jiménez, Elisa; Tejedor, Diego; López, Monica; Camacho, Emma; Cheroutre, Goedele; Hacker, Anita; Jinoch, Pavel; Svobodova, Irena; van der Schoot, Ellen; de Haas, Masja

2009-01-01

Summary The Bloodgen project was funded by the European Commission between 2003 and 2006, and involved academic blood centres, universities, and Progenika Biopharma S.A., a commercial supplier of genotyping platforms that incorporate glass arrays. The project has led to the development of a commercially available product, BLOODchip, that can be used to comprehensively genotype an individual for all clinically significant blood groups. The intention of making this system available is that blood services and perhaps even hospital blood banks would be able to obtain extended information concerning the blood group of routine blood donors and vulnerable patient groups. This may be of significant use in the current management of multi-transfused patients who become alloimmunised due to incomplete matching of blood groups. In the future it can be envisaged that better matching of donor-patient blood could be achieved by comprehensive genotyping of every blood donor, especially regular ones. This situation could even be extended to genotyping every individual at birth, which may prove to have significant long-term health economic benefits as it may be coupled with detection of inborn errors of metabolism. PMID:21113258

Alteration of the coenzyme A biosynthetic pathway in neurodegeneration with brain iron accumulation syndromes.

PubMed

Venco, Paola; Dusi, Sabrina; Valletta, Lorella; Tiranti, Valeria

2014-08-01

NBIA (neurodegeneration with brain iron accumulation) comprises a heterogeneous group of neurodegenerative diseases having as a common denominator, iron overload in specific brain areas, mainly basal ganglia and globus pallidus. In the past decade a bunch of disease genes have been identified, but NBIA pathomechanisms are still not completely clear. PKAN (pantothenate kinase-associated neurodegeneration), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA. It is caused by mutations in the PANK2 (pantothenate kinase 2) gene, coding for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the CoA (coenzyme A) biosynthetic pathway. A distinct form of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration), is caused by mutations in the CoASY (CoA synthase) gene coding for a bifunctional mitochondrial enzyme, which catalyses the final steps of CoA biosynthesis. These two inborn errors of CoA metabolism further support the concept that dysfunctions in CoA synthesis may play a crucial role in the pathogenesis of NBIA.

A biphasic dialytic strategy for the treatment of neonatal hyperammonemia

PubMed Central

Avasare, Sonal; Tsai, Eileen; Yadin, Ora; Zaritsky, Joshua

2018-01-01

Background Neonates with inborn errors of metabolism (IEM) often develop hyperammonemia which, if not corrected quickly, may result in poor neurologic outcomes. As pharmacologic therapy cannot rapidly lower ammonia levels, dialysis is frequently required. Both hemodialysis (HD) and standard-dose continuous renal replacement therapy (CRRT) are effective; however, HD may be followed by post-dialytic ammonia rebound, and standard-dose CRRT may not effect a rapid enough decrease in ammonia levels. Case-Diagnosis/Treatment We present two cases of IEM-associated neonatal hyperammonemia in which we employed a biphasic, high-dose CRRT treatment strategy, initially using dialysate flow rates of 5,000 mL/h (approximately 40,000 mL/h/1.73 m2) in order to rapidly decrease ammonia levels, then decreasing the dialysate flow rates to 500 mL/h (approximately 4,000 mL/h/1.73 m2) in order to prevent ammonia rebound. Conclusions This biphasic dialytic treatment strategy for neonatal hyperammonemia effected rapid ammonia reduction without rebound and accomplished during a single dialysis run without equipment changes. PMID:24122260

A Study Comparing the Quality of Life of Patients in the Treatment of Eczema by Pediatric Generalists and Specialists

ClinicalTrials.gov

2018-01-09

Eczema; Dermatitis; Dermatitis, Atopic; Genetic Disease, Inborn; Hypersensitivity; Hypersensitivity, Immediate; Immune System Diseases; Skin Diseases; Skin Diseases, Eczematous; Skin Diseases, Genetic

Law-medicine interfacing: patenting of human genes and mutations.

PubMed

Fialho, Arsenio M; Chakrabarty, Ananda M

2011-08-01

Mutations, Single Nucleotide Polymorphisms (SNPs), deletions and genetic rearrangements in specific genes in the human genome account for not only our physical characteristics and behavior, but can lead to many in-born and acquired diseases. Such changes in the genome can also predispose people to cancers, as well as significantly affect the metabolism and efficacy of many drugs, resulting in some cases in acute toxicity to the drug. The testing of the presence of such genetic mutations and rearrangements is of great practical and commercial value, leading many of these genes and their mutations/deletions and genetic rearrangements to be patented. A recent decision by a judge in the Federal District Court in the Southern District of New York, has created major uncertainties, based on the revocation of BRCA1 and BRCA2 gene patents, in the eligibility of all human and presumably other gene patents. This article argues that while patents on BRCA1 and BRCA2 genes could be challenged based on a lack of utility, the patenting of the mutations and genetic rearrangements is of great importance to further development and commercialization of genetic tests that can save human lives and prevent suffering, and should be allowed.

Human genetic basis of interindividual variability in the course of infection

PubMed Central

Casanova, Jean-Laurent

2015-01-01

The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue. PMID:26621739

Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

PubMed Central

Lafaille, Fabien G; Pessach, Itai M.; Zhang, Shen-Ying; Ciancanelli, Michael J.; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A.; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten M.; Daley, George Q.; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, Luigi D.

2012-01-01

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies. PMID:23103873

Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function.

PubMed

Bjursell, Magnus K; Blom, Henk J; Cayuela, Jordi Asin; Engvall, Martin L; Lesko, Nicole; Balasubramaniam, Shanti; Brandberg, Göran; Halldin, Maria; Falkenberg, Maria; Jakobs, Cornelis; Smith, Desiree; Struys, Eduard; von Döbeln, Ulrika; Gustafsson, Claes M; Lundeberg, Joakim; Wedell, Anna

2011-10-07

Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Crystal Structure And Mutagenisis of the Metallochaperone MeaB: Insight Into the Causes of the Methylmalonic Aciduria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hubbard, P.A.; Padovani, D.; Labunska, T.

MeaB is an auxiliary protein that plays a crucial role in the protection and assembly of the B{sub 12}-dependent enzyme methylmalonyl-CoA mutase. Impairments in the human homologue of MeaB, MMAA, lead to methylmalonic aciduria, an inborn error of metabolism. To explore the role of this metallochaperone, its structure was solved in the nucleotide-free form, as well as in the presence of product, GDP. MeaB is a homodimer, with each subunit containing a central {alpha}/{beta}-core G domain that is typical of the GTPase family, as well as a-helical extensions at the N and C termini that are not found in othermore » metalloenzyme chaperone GTPases. The C-terminal extension appears to be essential for nucleotide-independent dimerization, and the N-terminal region is implicated in protein-protein interaction with its partner protein, methylmalonyl-CoA mutase. The structure of MeaB confirms that it is a member of the G3E family of P-loop GTPases, which contains other putative metallochaperones HypB, CooC, and UreG. Interestingly, the so-called switch regions, responsible for signal transduction following GTP hydrolysis, are found at the dimer interface of MeaB instead of being positioned at the surface of the protein where its partner protein methylmalonyl-CoA mutase should bind. This observation suggests a large conformation change of MeaB must occur between the GDP- and GTP-bound forms of this protein. Because of their high sequence homology, the missense mutations in MMAA that result in methylmalonic aciduria have been mapped onto MeaB and, in conjunction with mutagenesis data, provide possible explanations for the pathology of this disease.« less

Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum

PubMed Central

Wanders, Ronald J. A.; Waterham, Hans R.; Ferdinandusse, Sacha

2016-01-01

Peroxisomes are unique subcellular organelles which play an indispensable role in several key metabolic pathways which include: (1.) etherphospholipid biosynthesis; (2.) fatty acid beta-oxidation; (3.) bile acid synthesis; (4.) docosahexaenoic acid (DHA) synthesis; (5.) fatty acid alpha-oxidation; (6.) glyoxylate metabolism; (7.) amino acid degradation, and (8.) ROS/RNS metabolism. The importance of peroxisomes for human health and development is exemplified by the existence of a large number of inborn errors of peroxisome metabolism in which there is an impairment in one or more of the metabolic functions of peroxisomes. Although the clinical signs and symptoms of affected patients differ depending upon the enzyme which is deficient and the extent of the deficiency, the disorders involved are usually (very) severe diseases with neurological dysfunction and early death in many of them. With respect to the role of peroxisomes in metabolism it is clear that peroxisomes are dependent on the functional interplay with other subcellular organelles to sustain their role in metabolism. Indeed, whereas mitochondria can oxidize fatty acids all the way to CO2 and H2O, peroxisomes are only able to chain-shorten fatty acids and the end products of peroxisomal beta-oxidation need to be shuttled to mitochondria for full oxidation to CO2 and H2O. Furthermore, NADH is generated during beta-oxidation in peroxisomes and beta-oxidation can only continue if peroxisomes are equipped with a mechanism to reoxidize NADH back to NAD+, which is now known to be mediated by specific NAD(H)-redox shuttles. In this paper we describe the current state of knowledge about the functional interplay between peroxisomes and other subcellular compartments notably the mitochondria and endoplasmic reticulum for each of the metabolic pathways in which peroxisomes are involved. PMID:26858947

The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans.

PubMed

Soltész, Beáta; Tóth, Beáta; Sarkadi, Adrien Katalin; Erdős, Melinda; Maródi, László

2015-01-01

The discovery of interleukin (IL)-17-mediated immunity has provided a robust framework upon which our current understanding of the mechanism involved in host defense against mucocutaneous candidiasis (CMC) has been built. Studies have shed light on how pattern recognition receptors expressed by innate immune cells recognize various components of Candida cell wall. Inborn errors of immunity affecting IL-17+ T cell differentiation have recently been defined, such as deficiencies of signal transducer and activator of transcription (STAT)3, STAT1, IL-12Rβ1 and IL-12p40, and caspase recruitment domain 9. Impaired receptor-ligand coupling was identified in patients with IL-17F and IL-17 receptor A (IL17RA) deficiency and autoimmune polyendocrine syndrome (APS) type 1. Mutation in the nuclear factor kappa B activator (ACT) 1 was described as a cause of impaired IL-17R-mediated signaling. CMC may be part of a complex clinical phenotype like in patients with deficiencies of STAT3, IL-12Rβ1/IL-12p40 and APS-1 or may be the only or dominant phenotypic manifestation of disease which is referred to as CMC disease. CMCD may result from deficiencies of STAT1, IL-17F, IL-17RA and ACT1. In this review we discuss how recent research on IL-17-mediated immunity shed light on host defense against mucocutaneous infection by Candida and how the discovery of various germ-line mutations and the characterization of associated clinical phenotypes have provided insights into the role of CD4+IL-17+ lymphocytes in the regulation of anticandidal defense of body surfaces.

Hepatology in the 21st century. Gene transfer, hepatocyte transplantation, DNA chips, cyberspace and ... a friendly hospital.

PubMed

Jansen, P L

1999-12-01

What to expect for hepatology in the 21st century? If science is allowed to proceed at its current rate, expectations can hardly be underestimated. Bound by the present day's limitations we are only able to see a glimpse of what could be available 100 years from now. For the next few decades, the global eradication of viral hepatitis will be on the agenda. For the treatment of inherited and acquired metabolic, toxic and immune liver disease, targeted drugs, genes and antisense oligonucleotides will be added to our therapeutic repertoire. The completion of the human genome project in 2003 will have far-reaching consequences: the widespread use of prenatal diagnosis, using DNA chip technology, may be expected to cause a dramatic decrease in the incidence of inherited diseases. Liver cirrhosis, hepatocellular carcinoma and inborn errors of metabolism may be treated by gene transfer or gene repair therapy. Although eventually these developments may decrease the need for organ transplantation, this by no means is the case yet and no solution is available for an increased demand and a decreased supply of organs. In the long run, diseases caused by multi-drug-resistant infectious agents and diseases associated with the abuse of alcohol and drugs are expected to become major problems. The future of university-based research is uncertain. The staggering costs of research and limited career possibilities may force universities to the limited task of higher education, with as a result biotech companies, shareholders and corporate finance ruling the scientific waves in the next century. The 21st century patient will know the way in cyberspace and will go shopping for the best doctor, for the best treatment and for the best, or friendliest, hospital.

Study of a fetal brain affected by a severe form of tyrosine hydroxylase deficiency, a rare cause of early parkinsonism.

PubMed

Tristán-Noguero, Alba; Díez, Héctor; Jou, Cristina; Pineda, Mercè; Ormazábal, Aida; Sánchez, Aurora; Artuch, Rafael; Garcia-Cazorla, Àngels

2016-06-01

Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine synthesis. Two clinical phenotypes have been described. The THD "B" phenotype produces a severe encephalopathy of early-onset with sub-optimal L-Dopa response, whereas the "A" phenotype has a better L-Dopa response and outcome. The objective of the study is to describe the expression of key synaptic proteins and neurodevelopmental markers in a fetal brain of THD "B" phenotype. The brain of a 16-week-old miscarried human fetus was dissected in different brain areas and frozen until the analysis. TH gene study revealed the p.R328W/p.T399M mutations, the same mutations that produced a B phenotype in her sister. After protein extraction, western blot analyses were performed to assess protein expression. The results were compared to an age-matched control. We observed a decreased expression in TH and in other dopaminergic proteins, such as VMAT 1 and 2 and dopamine receptors, especially D2DR. GABAergic and glutamatergic proteins such as GABA VT, NMDAR1 and calbindin were also altered. Developmental markers for synapses, axons and dendrites were decreased whereas markers of neuronal volume were preserved. Although this is an isolated case, this brain sample is unique and corresponds to the first reported study of a THD brain. It provides interesting information about the influence of dopamine as a regulator of other neurotransmitter systems, brain development and movement disorders with origin at the embryological state. This study could also contribute to a better understanding of the pathophysiology of THD at early fetal stages.

VT-1161 protects mice against oropharyngeal candidiasis caused by fluconazole-susceptible and -resistant Candida albicans

PubMed Central

Break, Timothy J; Desai, Jigar V; Ferre, Elise M N; Henderson, Christina; Zelazny, Adrian M; Siebenlist, Ulrich; Hoekstra, William J; Schotzinger, Robert J; Garvey, Edward P; Lionakis, Michail S

2018-01-01

Abstract Background Candida albicans, the most common human fungal pathogen, causes chronic mucosal infections in patients with inborn errors of IL-17 immunity that rely heavily on chronic, often lifelong, azole antifungal agents for treatment. However, a rise in azole resistance has predicated a need for developing new antifungal drugs. Objectives To test the in vitro and in vivo efficacy of VT-1161 and VT-1129 in the treatment of oropharyngeal candidiasis with azole-susceptible or -resistant C. albicans strains. Methods MICs of VT-1161, VT-1129 and nine licensed antifungal drugs were determined for 31 Candida clinical isolates. The drug concentrations in mouse serum and tongues were measured following oral administration. IL-17-signalling-deficient Act1−/− mice were infected with fluconazole-susceptible or fluconazole-resistant C. albicans strains, and the amount of mucosal fungal burden was determined after fluconazole or VT-1161 treatment. Results Fourteen isolates (45%) were not fluconazole susceptible (MIC ≥4 mg/L). VT-1161 and VT-1129 showed significant in vitro activity against the majority of the 31 mucosal clinical isolates (MIC50 0.03 and 0.06 mg/L, respectively), including Candida glabrata (MIC50, 0.125 and 0.25 mg/L, respectively). After oral doses, VT-1161 and VT-1129 concentrations in mouse serum and tongues were well above their MIC50 values. VT-1161 was highly effective as treatment of both fluconazole-susceptible and -resistant oropharyngeal candidiasis in Act1−/− mice. Conclusions VT-1129 and VT-1161 exhibit significant in vitro activity against Candida strains, including fluconazole-resistant C. albicans and C. glabrata. VT-1161 administration in mice results in significant mucosal drug accumulation and eradicates infection caused by fluconazole-susceptible and -resistant Candida strains. PMID:29040636

Infants' preferences for toys, colors, and shapes: sex differences and similarities.

PubMed

Jadva, Vasanti; Hines, Melissa; Golombok, Susan

2010-12-01

Girls and boys differ in their preferences for toys such as dolls and trucks. These sex differences are present in infants, are seen in non-human primates, and relate, in part, to prenatal androgen exposure. This evidence of inborn influences on sex-typed toy preferences has led to suggestions that object features, such as the color or the shape of toys, may be of intrinsically different interest to males and females. We used a preferential looking task to examine preferences for different toys, colors, and shapes in 120 infants, ages 12, 18, or 24 months. Girls looked at dolls significantly more than boys did and boys looked at cars significantly more than girls did, irrespective of color, particularly when brightness was controlled. These outcomes did not vary with age. There were no significant sex differences in infants' preferences for different colors or shapes. Instead, both girls and boys preferred reddish colors over blue and rounded over angular shapes. These findings augment prior evidence of sex-typed toy preferences in infants, but suggest that color and shape do not determine these sex differences. In fact, the direction of influence could be the opposite. Girls may learn to prefer pink, for instance, because the toys that they enjoy playing with are often colored pink. Regarding within sex differences, as opposed to differences between boys and girls, both boys and girls preferred dolls to cars at age 12-months. The preference of young boys for dolls over cars suggests that older boys' avoidance of dolls may be acquired. Similarly, the sex similarities in infants' preferences for colors and shapes suggest that any subsequent sex differences in these preferences may arise from socialization or cognitive gender development rather than inborn factors.

UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

ClinicalTrials.gov

2018-03-15

Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

Intergenerational neural mediators of early-life anxious temperament.

PubMed

Fox, Andrew S; Oler, Jonathan A; Shackman, Alexander J; Shelton, Steven E; Raveendran, Muthuswamy; McKay, D Reese; Converse, Alexander K; Alexander, Andrew; Davidson, Richard J; Blangero, John; Rogers, Jeffrey; Kalin, Ned H

2015-07-21

Understanding the heritability of neural systems linked to psychopathology is not sufficient to implicate them as intergenerational neural mediators. By closely examining how individual differences in neural phenotypes and psychopathology cosegregate as they fall through the family tree, we can identify the brain systems that underlie the parent-to-child transmission of psychopathology. Although research has identified genes and neural circuits that contribute to the risk of developing anxiety and depression, the specific neural systems that mediate the inborn risk for these debilitating disorders remain unknown. In a sample of 592 young rhesus monkeys that are part of an extended multigenerational pedigree, we demonstrate that metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression. Importantly, although brain volume is highly heritable early in life, it is brain metabolism-not brain structure-that is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.

Human Error In Complex Systems

NASA Technical Reports Server (NTRS)

Morris, Nancy M.; Rouse, William B.

1991-01-01

Report presents results of research aimed at understanding causes of human error in such complex systems as aircraft, nuclear powerplants, and chemical processing plants. Research considered both slips (errors of action) and mistakes (errors of intention), and influence of workload on them. Results indicated that: humans respond to conditions in which errors expected by attempting to reduce incidence of errors; and adaptation to conditions potent influence on human behavior in discretionary situations.

Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS)

NASA Technical Reports Server (NTRS)

Alexander, Tiffaney Miller

2017-01-01

Research results have shown that more than half of aviation, aerospace and aeronautics mishaps incidents are attributed to human error. As a part of Safety within space exploration ground processing operations, the identification and/or classification of underlying contributors and causes of human error must be identified, in order to manage human error. This research provides a framework and methodology using the Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS), as an analysis tool to identify contributing factors, their impact on human error events, and predict the Human Error probabilities (HEPs) of future occurrences. This research methodology was applied (retrospectively) to six (6) NASA ground processing operations scenarios and thirty (30) years of Launch Vehicle related mishap data. This modifiable framework can be used and followed by other space and similar complex operations.

Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS)

NASA Technical Reports Server (NTRS)

Alexander, Tiffaney Miller

2017-01-01

Research results have shown that more than half of aviation, aerospace and aeronautics mishaps/incidents are attributed to human error. As a part of Safety within space exploration ground processing operations, the identification and/or classification of underlying contributors and causes of human error must be identified, in order to manage human error. This research provides a framework and methodology using the Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS), as an analysis tool to identify contributing factors, their impact on human error events, and predict the Human Error probabilities (HEPs) of future occurrences. This research methodology was applied (retrospectively) to six (6) NASA ground processing operations scenarios and thirty (30) years of Launch Vehicle related mishap data. This modifiable framework can be used and followed by other space and similar complex operations.

Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS)

NASA Technical Reports Server (NTRS)

Alexander, Tiffaney Miller

2017-01-01

Research results have shown that more than half of aviation, aerospace and aeronautics mishaps incidents are attributed to human error. As a part of Quality within space exploration ground processing operations, the identification and or classification of underlying contributors and causes of human error must be identified, in order to manage human error.This presentation will provide a framework and methodology using the Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS), as an analysis tool to identify contributing factors, their impact on human error events, and predict the Human Error probabilities (HEPs) of future occurrences. This research methodology was applied (retrospectively) to six (6) NASA ground processing operations scenarios and thirty (30) years of Launch Vehicle related mishap data. This modifiable framework can be used and followed by other space and similar complex operations.

What are we telling the parents of extremely preterm babies?

PubMed

Boland, Rosemarie Anne; Davis, Peter Graham; Dawson, Jennifer Anne; Doyle, Lex William

2016-06-01

Parent counselling and decision-making regarding the management of preterm labour and birth are influenced by information provided by healthcare professionals regarding potential infant outcomes. The aim of this study was to determine whether perinatal healthcare providers had accurate perceptions of survival and major neurosensory disability rates of very preterm infants born in non-tertiary hospitals ('outborn') and tertiary perinatal centres ('inborn'). A web-based survey was distributed to midwives, nurses, obstetricians and neonatologists working in non-tertiary and tertiary maternity hospitals, and the perinatal/neonatal emergency transport services in Victoria, Australia. Estimates of survival rates at 24 and 28-weeks' gestation were compared with actual survival rates of a population-based cohort of 24 and 28-weeks' gestation infants, born free of lethal anomalies in Victoria in 2001-2009. Estimates of major neurosensory disability rates in 24 and 28-week survivors were compared with actual disability rates in 24 and 28-week children born in Victoria averaged over three eras: 1991-1992, 1997 and 2005. Response rates varied as follows: 83% of non-tertiary midwives, 4% of obstetricians, 55% of tertiary centre staff and 68% of transport team staff responded (total of 30%). Overall, respondents underestimated survival and overestimated major neurosensory disability rates in both outborn and inborn 24 and 28-week infants. Outborn infants were perceived to have much worse prospects for survival and for survival with major disability compared with inborn peers. Many clinicians overestimated rates of adverse outcomes. These clinicians may be misinforming parents about their child's potential for a favourable outcome. © 2016 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Understanding human management of automation errors

PubMed Central

McBride, Sara E.; Rogers, Wendy A.; Fisk, Arthur D.

2013-01-01

Automation has the potential to aid humans with a diverse set of tasks and support overall system performance. Automated systems are not always reliable, and when automation errs, humans must engage in error management, which is the process of detecting, understanding, and correcting errors. However, this process of error management in the context of human-automation interaction is not well understood. Therefore, we conducted a systematic review of the variables that contribute to error management. We examined relevant research in human-automation interaction and human error to identify critical automation, person, task, and emergent variables. We propose a framework for management of automation errors to incorporate and build upon previous models. Further, our analysis highlights variables that may be addressed through design and training to positively influence error management. Additional efforts to understand the error management process will contribute to automation designed and implemented to support safe and effective system performance. PMID:25383042

Understanding human management of automation errors.

PubMed

McBride, Sara E; Rogers, Wendy A; Fisk, Arthur D

2014-01-01

Automation has the potential to aid humans with a diverse set of tasks and support overall system performance. Automated systems are not always reliable, and when automation errs, humans must engage in error management, which is the process of detecting, understanding, and correcting errors. However, this process of error management in the context of human-automation interaction is not well understood. Therefore, we conducted a systematic review of the variables that contribute to error management. We examined relevant research in human-automation interaction and human error to identify critical automation, person, task, and emergent variables. We propose a framework for management of automation errors to incorporate and build upon previous models. Further, our analysis highlights variables that may be addressed through design and training to positively influence error management. Additional efforts to understand the error management process will contribute to automation designed and implemented to support safe and effective system performance.

Human operator response to error-likely situations in complex engineering systems

NASA Technical Reports Server (NTRS)

Morris, Nancy M.; Rouse, William B.

1988-01-01

The causes of human error in complex systems are examined. First, a conceptual framework is provided in which two broad categories of error are discussed: errors of action, or slips, and errors of intention, or mistakes. Conditions in which slips and mistakes might be expected to occur are identified, based on existing theories of human error. Regarding the role of workload, it is hypothesized that workload may act as a catalyst for error. Two experiments are presented in which humans' response to error-likely situations were examined. Subjects controlled PLANT under a variety of conditions and periodically provided subjective ratings of mental effort. A complex pattern of results was obtained, which was not consistent with predictions. Generally, the results of this research indicate that: (1) humans respond to conditions in which errors might be expected by attempting to reduce the possibility of error, and (2) adaptation to conditions is a potent influence on human behavior in discretionary situations. Subjects' explanations for changes in effort ratings are also explored.

Human error and human factors engineering in health care.

PubMed

Welch, D L

1997-01-01

Human error is inevitable. It happens in health care systems as it does in all other complex systems, and no measure of attention, training, dedication, or punishment is going to stop it. The discipline of human factors engineering (HFE) has been dealing with the causes and effects of human error since the 1940's. Originally applied to the design of increasingly complex military aircraft cockpits, HFE has since been effectively applied to the problem of human error in such diverse systems as nuclear power plants, NASA spacecraft, the process control industry, and computer software. Today the health care industry is becoming aware of the costs of human error and is turning to HFE for answers. Just as early experimental psychologists went beyond the label of "pilot error" to explain how the design of cockpits led to air crashes, today's HFE specialists are assisting the health care industry in identifying the causes of significant human errors in medicine and developing ways to eliminate or ameliorate them. This series of articles will explore the nature of human error and how HFE can be applied to reduce the likelihood of errors and mitigate their effects.

Applications of integrated human error identification techniques on the chemical cylinder change task.

PubMed

Cheng, Ching-Min; Hwang, Sheue-Ling

2015-03-01

This paper outlines the human error identification (HEI) techniques that currently exist to assess latent human errors. Many formal error identification techniques have existed for years, but few have been validated to cover latent human error analysis in different domains. This study considers many possible error modes and influential factors, including external error modes, internal error modes, psychological error mechanisms, and performance shaping factors, and integrates several execution procedures and frameworks of HEI techniques. The case study in this research was the operational process of changing chemical cylinders in a factory. In addition, the integrated HEI method was used to assess the operational processes and the system's reliability. It was concluded that the integrated method is a valuable aid to develop much safer operational processes and can be used to predict human error rates on critical tasks in the plant. Copyright © 2014 Elsevier Ltd and The Ergonomics Society. All rights reserved.

The influence of early postnatal nutrition on retinopathy of prematurity in extremely low birth weight infants.

PubMed

Porcelli, Peter J; Weaver, R Grey

2010-06-01

Retinopathy of prematurity(ROP) is the most common serious ophthalmic disease in preterm infants. Human milk may provide a protective effect for ROP; however, beneficial effects of human milk preclude randomized trials. Therefore, we conducted a retrospective analysis comparing early postnatal nutrition with ROP development. Evaluate relationship between early postnatal nutriture and ROP surgery. Nutrition data was collected for inborn AGA infants, BW 700-1000 g. ROP surgery was the primary outcome variable. A single pediatric ophthalmologist supervised examinations. All infants received triweekly IM vitamin A as chronic lung disease prophylaxis (Tyson: NEJM, 1999). BW and gestational age were 867+/-85 g and 26.3+/-1.2 weeks (n=77, mean+/-1SD). ROP surgery infants(n=11) received more parenteral nutrition, 1648 mL, and less human milk, 13.8 mL/kg-day, and vitamin E, 1.4 mg/kg-day, during the second postnatal week. Human milk was a negative predictor for ROP surgery, odds ratio=0.94. Both groups met vitamin A recommendations; however, 74% was administered via IM injections. Neither group met vitamin E recommendations. Human milk feeding, parenteral nutrition volume and vitamin E intake were predictors for ROP surgery. IM vitamin A injections provided the majority of vitamin A; vitamin E administration was insufficient. Improving human milk feeding rates and vitamin dosing options may affect ROP surgery rates. Copyright 2010 Elsevier Ltd. All rights reserved.

Efficacy and Safety of Dupilumab in Patients ≥12 to <18 Years of Age, With Moderate-to-Severe Atopic Dermatitis

ClinicalTrials.gov

2017-12-18

Moderate-to-Severe Atopic Dermatitis; Dermatitis, Dermatitis Atopic; Eczema, Skin Diseases, Skin; Diseases Genetic, Genetic; Diseases Inborn, Skin; Disease, Eczematous Skin; Hypersensitivity, Immediate; Hypersensitivity, Immune System Diseases; Dermatitis, Atopic

Human error in airway facilities.

DOT National Transportation Integrated Search

2001-01-01

This report examines human errors in Airway Facilities (AF) with the intent of preventing these errors from being : passed on to the new Operations Control Centers. To effectively manage errors, they first have to be identified. : Human factors engin...

Latent human error analysis and efficient improvement strategies by fuzzy TOPSIS in aviation maintenance tasks.

PubMed

Chiu, Ming-Chuan; Hsieh, Min-Chih

2016-05-01

The purposes of this study were to develop a latent human error analysis process, to explore the factors of latent human error in aviation maintenance tasks, and to provide an efficient improvement strategy for addressing those errors. First, we used HFACS and RCA to define the error factors related to aviation maintenance tasks. Fuzzy TOPSIS with four criteria was applied to evaluate the error factors. Results show that 1) adverse physiological states, 2) physical/mental limitations, and 3) coordination, communication, and planning are the factors related to airline maintenance tasks that could be addressed easily and efficiently. This research establishes a new analytic process for investigating latent human error and provides a strategy for analyzing human error using fuzzy TOPSIS. Our analysis process complements shortages in existing methodologies by incorporating improvement efficiency, and it enhances the depth and broadness of human error analysis methodology. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Information systems and human error in the lab.

PubMed

Bissell, Michael G

2004-01-01

Health system costs in clinical laboratories are incurred daily due to human error. Indeed, a major impetus for automating clinical laboratories has always been the opportunity it presents to simultaneously reduce cost and improve quality of operations by decreasing human error. But merely automating these processes is not enough. To the extent that introduction of these systems results in operators having less practice in dealing with unexpected events or becoming deskilled in problemsolving, however new kinds of error will likely appear. Clinical laboratories could potentially benefit by integrating findings on human error from modern behavioral science into their operations. Fully understanding human error requires a deep understanding of human information processing and cognition. Predicting and preventing negative consequences requires application of this understanding to laboratory operations. Although the occurrence of a particular error at a particular instant cannot be absolutely prevented, human error rates can be reduced. The following principles are key: an understanding of the process of learning in relation to error; understanding the origin of errors since this knowledge can be used to reduce their occurrence; optimal systems should be forgiving to the operator by absorbing errors, at least for a time; although much is known by industrial psychologists about how to write operating procedures and instructions in ways that reduce the probability of error, this expertise is hardly ever put to use in the laboratory; and a feedback mechanism must be designed into the system that enables the operator to recognize in real time that an error has occurred.

Evaluating Innovations in Transition From Pediatric to Adult Care - The Transition Navigator Trial

ClinicalTrials.gov

2018-06-06

Diabetes; Endocrine System Diseases; Gastro-Intestinal Disorder; Neuro-Degenerative Disease; Epilepsy; Autoimmune Diseases; Renal Disease; Cardiac Disease; Metabolic Disease; Genetic Diseases, Inborn; Respiratory Disease; Hematologic Diseases; Autism Spectrum Disorder; Fetal Alcohol Spectrum Disorders; Traumatic Brain Injury; Stroke

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency

PubMed Central

Bozalija, Adnan; Jashari, Fisnik; Krasniqi, Shaip

2018-01-01

Monogenic and polygenic mutations are important contributors in patients suffering from epilepsy, including metabolic epilepsies which are inborn errors of metabolism with a good respond to specific dietetic treatments. Heterozygous variation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) and mutations of the GLUT1/SLC2A2 gene results in the failure of glucose transport, which is related with a glucose type-1 transporter (GLUT1) deficiency syndrome (GLUT1DS). GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene which are the cause of different neurological disorders also with different types of epilepsy and related clinical phenotypes. Since patients continue to experience seizures due to a pharmacoresistance, an early clinical diagnosis associated with specific genetic testing in SLC2A1 pathogenic variants in clinical phenotypes could predict pure drug response and might improve safety and efficacy of treatment with the initiation of an alternative energy source including ketogenic or analog diets in such patients providing individualized strategy approaches. PMID:29303961

[3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome].

PubMed

Eirís, J; Ribes, A; Fernández-Prieto, R; Rodríguez-García, J; Rodríguez-Segade, S; Castro-Gago, M

1998-06-01

3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMG-CoA lyase) is an inborn error of ketogenesis and Leucine catabolism. HMG-CoA lyase catalyses the final step in leucine degradation, converting HMG-CoA to acetyl-CoA and acetoacetic acid. Clinical manifestations include hepatomegaly, lethargy or coma and apnoea. Biochemically there is a characteristic absence of ketosis with hypoglycemia, acidosis, hipertransaminasemia and variable hyperammoniemia. The urinary organic acid profile includes elevated concentrations of 3-hydroxy-3-isovaleric, 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-methylglutaric acids. Here, we report the case of a 17-year-old girl who presented in both ten months and five years of age a clinical picture characterized by lethargy leading to apnea and coma, hepatomegaly, hypoglycemia, metabolic acidosis, hyperammoniemia, elevated serum transaminases and absence of ketonuria. Diagnostic of Reye syndrome was suggested by hystopathologic finding of hepatic steatosis and clinical and biochemical data. As of 11 years old, laboratory investigations revealed carnitine deficiency and characteristic aciduria. Confirmatory enzyme diagnosis revealing deficiency of HMG-CoA lyase was made in cultured fibroblasts. Our report constitutes an example of the presentation of HMG-CoA lyase deficiency as recurrent Reye-like syndrome.

Qualitative analysis of factors affecting adherence to the phenylketonuria diet in adolescents.

PubMed

Sharman, Rachael; Mulgrew, Kate; Katsikitis, Mary

2013-01-01

Phenylketonuria (PKU) is an inborn error of metabolism that is primarily treated with a severely restricted, low-protein diet to prevent permanent neurological damage. Despite the recognition of the importance of strict dietary adherence in the prevention of intellectual impairment in individuals with PKU, apathy and attrition from diet, especially during adolescence, remain a threat to normal development in this population. This study's aim was to examine adolescents' perception of factors that encourage or inhibit their dietary adherence. This was a qualitative study, with the authors using thematic analysis to interpret the findings. The study was conducted as part of a Metabolic Disorders Association conference. Eight adolescents with PKU were recruited through convenience sampling. A focus group was conducted with the adolescents to gather information about factors that encourage and discourage dietary adherence. Thematic analysis revealed that the adolescents encountered problems explaining the nature and food requirements of their condition to other people. Friends, family, and wanting to maintain "normal" cognitive abilities were identified as factors that encouraged dietary adherence. Adolescents with PKU appear to share several barriers and incentives for maintaining the strict dietary regimen. Considering such perceptions may aid future interventions aiming to reduce diet attrition rates among adolescents.

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

PubMed

Taurisano, Roberta; Maiorana, Arianna; De Benedetti, Fabrizio; Dionisi-Vici, Carlo; Boldrini, Renata; Deodato, Federica

2014-10-01

The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher's disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.

The galactose-induced decrease in phosphate levels leads to toxicity in yeast models of galactosemia.

PubMed

Machado, Caio M; De-Souza, Evandro A; De-Queiroz, Ana Luiza F V; Pimentel, Felipe S A; Silva, Guilherme F S; Gomes, Fabio M; Montero-Lomelí, Mónica; Masuda, Claudio A

2017-06-01

Classic galactosemia is an inborn error of metabolism caused by deleterious mutations in the GALT gene. A number of evidences indicate that the galactose-1-phosphate accumulation observed in patient cells is a cause of toxicity in this disease. Nevertheless, the consequent molecular events caused by the galactose-1-phosphate accumulation remain elusive. Here we show that intracellular inorganic phosphate levels decreased when yeast models of classic galactosemia were exposed to galactose. The decrease in phosphate levels is probably due to the trapping of phosphate in the accumulated galactose-1-phosphate since the deletion of the galactokinase encoding gene GAL1 suppressed this phenotype. Galactose-induced phosphate depletion caused an increase in glycogen content, an expected result since glycogen breakdown by the enzyme glycogen phosphorylase is dependent on inorganic phosphate. Accordingly, an increase in intracellular phosphate levels suppressed the galactose effect on glycogen content and conferred galactose tolerance to yeast models of galactosemia. These results support the hypothesis that the galactose-induced decrease in phosphate levels leads to toxicity in galactosemia and opens new possibilities for the development of better treatments for this disease. Copyright © 2017 Elsevier B.V. All rights reserved.

A Critical Review on Clinical Application of Separation Techniques for Selective Recognition of Uracil and 5-Fluorouracil.

PubMed

Pandey, Khushaboo; Dubey, Rama Shankar; Prasad, Bhim Bali

2016-03-01

The most important objectives that are frequently found in bio-analytical chemistry involve applying tools to relevant medical/biological problems and refining these applications. Developing a reliable sample preparation step, for the medical and biological fields is another primary objective in analytical chemistry, in order to extract and isolate the analytes of interest from complex biological matrices. Since, main inborn errors of metabolism (IEM) diagnosable through uracil analysis and the therapeutic monitoring of toxic 5-fluoruracil (an important anti-cancerous drug) in dihydropyrimidine dehydrogenase deficient patients, require an ultra-sensitive, reproducible, selective, and accurate analytical techniques for their measurements. Therefore, keeping in view, the diagnostic value of uracil and 5-fluoruracil measurements, this article refines several analytical techniques involved in selective recognition and quantification of uracil and 5-fluoruracil from biological and pharmaceutical samples. The prospective study revealed that implementation of molecularly imprinted polymer as a solid-phase material for sample preparation and preconcentration of uracil and 5-fluoruracil had proven to be effective as it could obviates problems related to tedious separation techniques, owing to protein binding and drastic interferences, from the complex matrices in real samples such as blood plasma, serum samples.

Two novel mutations in the homogentisate-1,2-dioxygenase gene identified in Chinese Han Child with Alkaptonuria.

PubMed

Li, Hongying; Zhang, Kaihui; Xu, Qun; Ma, Lixia; Lv, Xin; Sun, Ruopeng

2015-03-01

Alkaptonuria (AKU) is an autosomal recessive disorder of tyrosine metabolism, which is caused by a defect in the enzyme homogentisate 1,2-dioxygenase (HGD) with subsequent accumulation of homogentisic acid. Presently, more than 100 HGD mutations have been identified as the cause of the inborn error of metabolism across different populations worldwide. However, the HGD mutation is very rarely reported in Asia, especially China. In this study, we present mutational analyses of HGD gene in one Chinese Han child with AKU, which had been identified by gas chromatography-mass spectrometry detection of organic acids in urine samples. PCR and DNA sequencing of the entire coding region as well as exon-intron boundaries of HGD have been performed. Two novel mutations were identified in the HGD gene in this AKU case, a frameshift mutation of c.115delG in exon 3 and the splicing mutation of IVS5+3 A>C, a donor splice site of the exon 5 and exon-intron junction. The identification of these mutations in this study further expands the spectrum of known HGD gene mutations and contributes to prenatal molecular diagnosis of AKU.

Determination of the absolute configuration of 2-hydroxyglutaric acid and 5-oxoproline in urine samples by high-resolution NMR spectroscopy in the presence of chiral lanthanide complexes.

PubMed

Bal, Dominika; Gradowska, Wanda; Gryff-Keller, Adam

2002-06-15

Determination of the absolute configuration of some metabolites in body fluids is important for the diagnosis of some inborn errors of metabolism. Presently available methods of such determinations are tedious and usually require highly specialized instrumentation. In this work, an alternative method, based on high-resolution nuclear magnetic resonance spectroscopy in the presence of the chiral lanthanide shift reagent as an auxiliary additive, has been proposed (NMR/LSR). The method involves the lineshape analysis of a chosen multiplet of the one-dimensional 1H NMR spectrum or application of the two-dimensional 1H-13C correlation spectroscopy (HSQC). In order to confirm the resonance assignments and to boost the signal-noise ratio, the addition of an amount of racemic analyte to the urine sample is recommended. The entire procedure is simple in application and demands minimal or no preprocessing of urine samples. The effectiveness of the method has been confirmed by finding the expected forms of 2-hydroxyglutaric acid and 5-oxoproline in the urine samples of an independently diagnosed patient with 2-D-hydroxyglutaric aciduria and 5-L-oxoprolinuria, respectively.

Clinical findings and effect of sodium hydrogen carbonate in patients with glutathione synthetase deficiency.

PubMed

Gündüz, Mehmet; Ünal, Özlem; Kavurt, Sumru; Türk, Emrecan; Mungan, Neslihan Önenli

2016-04-01

Glutathione synthetase (GS) deficiency is a rare inborn error of glutathione (GSH) metabolism manifested by severe metabolic acidosis, hemolytic anemia, neurological problems and massive excretion of pyroglutamic acid (5-oxoproline) in the urine. The disorder has mild, moderate, and severe clinical variants. We aimed to report clinical and laboratory findings of four patients, effect of sodium hydrogen carbonate treatment and long-term follow up of three patients. Urine organic acid analysis was performed with gas chromatography-mass spectrometry. Molecular genetic analysis was performed in three patients, mutation was found in two of them. Enzyme analysis was performed in one patient. Clinical and laboratory findings of four patients were evaluated. One patient died at 4 months old, one patient's growth and development are normal, two patients have developed intellectual disability and seizures in the long term follow up period. Three patients benefited from sodium hydrogen carbonate treatment. The clinical picture varies from patient to patient, so it is difficult to predict the prognosis and the effectiveness of treatment protocols. We reported long term follow up of four patients and demonstrated that sodium hydrogen carbonate is effective for treatment of chronic metabolic acidosis in GS deficieny.

Investigating host-pathogen behavior and their interaction using genome-scale metabolic network models.

PubMed

Sadhukhan, Priyanka P; Raghunathan, Anu

2014-01-01

Genome Scale Metabolic Modeling methods represent one way to compute whole cell function starting from the genome sequence of an organism and contribute towards understanding and predicting the genotype-phenotype relationship. About 80 models spanning all the kingdoms of life from archaea to eukaryotes have been built till date and used to interrogate cell phenotype under varying conditions. These models have been used to not only understand the flux distribution in evolutionary conserved pathways like glycolysis and the Krebs cycle but also in applications ranging from value added product formation in Escherichia coli to predicting inborn errors of Homo sapiens metabolism. This chapter describes a protocol that delineates the process of genome scale metabolic modeling for analysing host-pathogen behavior and interaction using flux balance analysis (FBA). The steps discussed in the process include (1) reconstruction of a metabolic network from the genome sequence, (2) its representation in a precise mathematical framework, (3) its translation to a model, and (4) the analysis using linear algebra and optimization. The methods for biological interpretations of computed cell phenotypes in the context of individual host and pathogen models and their integration are also discussed.

Late diagnosis of primary hyperoxaluria after failed kidney transplantation.

PubMed

Spasovski, Goce; Beck, Bodo B; Blau, Nenad; Hoppe, Bernd; Tasic, Velibor

2010-09-01

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.

Disorders of metal metabolism

PubMed Central

Ferreira, Carlos R.; Gahl, William A.

2017-01-01

Trace elements are chemical elements needed in minute amounts for normal physiology. Some of the physiologically relevant trace elements include iodine, copper, iron, manganese, zinc, selenium, cobalt and molybdenum. Of these, some are metals, and in particular, transition metals. The different electron shells of an atom carry different energy levels, with those closest to the nucleus being lowest in energy. The number of electrons in the outermost shell determines the reactivity of such an atom. The electron shells are divided in sub-shells, and in particular the third shell has s, p and d sub-shells. Transition metals are strictly defined as elements whose atom has an incomplete d sub-shell. This incomplete d sub-shell makes them prone to chemical reactions, particularly redox reactions. Transition metals of biologic importance include copper, iron, manganese, cobalt and molybdenum. Zinc is not a transition metal, since it has a complete d sub-shell. Selenium, on the other hand, is strictly speaking a nonmetal, although given its chemical properties between those of metals and nonmetals, it is sometimes considered a metalloid. In this review, we summarize the current knowledge on the inborn errors of metal and metalloid metabolism. PMID:29354481

Intellectual, Adaptive, and Behavioral Functioning in Children with Urea Cycle Disorders

PubMed Central

Krivitzky, Lauren; Babikian, Talin; Lee, HyeSeung; Thomas, Nina Hattiangadi; Burk-Paull, Karen L.; Batshaw, Mark L.

2009-01-01

Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain, and result in high rates of mortality and neurodevelopmental disability. The current study seeks to characterize the cognitive, adaptive, and emotional/behavioral functioning of children with Urea Cycle Disorders (UCDs). These domains were measured through testing and parent questionnaires in 92 children with UCDs (33 neonatal onset, 59 late onset). Results indicate that children who present with neonatal onset have poorer outcome than those who present later in childhood. Approximately half of the children with neonatal onset performed in the range of intellectual disability (ID), including a substantial number (~30%) who were severely impaired. In comparison, only a quarter of the late onset group were in the range of ID. There is also evidence that the UCD group has difficulties in aspects of emotional/behavioral and executive skills domains. In conclusion, children with UCDs present with a wide spectrum of cognitive outcomes. Children with neonatal onset disease have a much higher likelihood of having an intellectual disability, which becomes even more evident with increasing age. However, even children with late onset UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning. PMID:19287347

Differentiating food allergies from food intolerances.

PubMed

Guandalini, Stefano; Newland, Catherine

2011-10-01

Adverse reactions to foods are extremely common, and generally they are attributed to allergy. However, clinical manifestations of various degrees of severity related to ingestion of foods can arise as a result of a number of disorders, only some of which can be defined as allergic, implying an immune mechanism. Recent epidemiological data in North America showed that the prevalence of food allergy in children has increased. The most common food allergens in the United States include egg, milk, peanut, tree nuts, wheat, crustacean shellfish, and soy. This review examines the various forms of food intolerances (immunoglobulin E [IgE] and non-IgE mediated), including celiac disease and gluten sensitivity. Immune mediated reactions can be either IgE mediated or non-IgE mediated. Among the first group, Immediate GI hypersensitivity and oral allergy syndrome are the best described. Often, but not always, IgE-mediated food allergies are entities such as eosinophilic esophagitis and eosinophilic gastroenteropathy. Non IgE-mediated immune mediated food reactions include celiac disease and gluten sensitivity, two increasingly recognized disorders. Finally, non-immune mediated reactions encompass different categories such as disorders of digestion and absorption, inborn errors of metabolism, as well as pharmacological and toxic reactions.

Skin Lesions Associated with Nutritional Management of Maple Syrup Urine Disease

PubMed Central

Uaariyapanichkul, Jaraspong; Saengpanit, Puthita; Damrongphol, Ponghatai; Suphapeetiporn, Kanya

2017-01-01

Introduction Maple syrup urine disease (MSUD) is an inborn error of branched chain amino acids (BCAAs) metabolism. We report an infant with MSUD who developed 2 episodes of cutaneous lesions as a result of isoleucine deficiency and zinc deficiency, respectively. Case Presentation A 12-day-old male infant was presented with poor milk intake and lethargy. The diagnosis of MSUD was made based on clinical and biochemical data. Management and Outcome Specific dietary restriction of BCAAs was given. Subsequently, natural protein was stopped as the patient developed hospital-acquired infections which resulted in an elevation of BCAAs. Acrodermatitis dysmetabolica developed and was confirmed to be from isoleucine deficiency. At the age of 6 months, the patient developed severe lethargy and was on natural protein exclusion for an extended period. Despite enteral supplementation of zinc sulfate, cutaneous manifestations due to zinc deficiency occurred. Discussion Skin lesions in MSUD patients could arise from multiple causes. Nutritional deficiency including isoleucine and zinc deficiencies can occur and could complicate the treatment course as a result of malabsorption, even while on enteral supplementation. Parenteral nutrition should be considered and initiated accordingly. Clinical status, as well as BCAA levels, should be closely monitored in MSUD patients. PMID:29209542

The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers.

PubMed

Caterino, Marianna; Chandler, Randy J; Sloan, Jennifer L; Dorko, Kenneth; Cusmano-Ozog, Kristina; Ingenito, Laura; Strom, Stephen C; Imperlini, Esther; Scolamiero, Emanuela; Venditti, Charles P; Ruoppolo, Margherita

2016-02-01

Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder.

Severe hypertriglyceridemia-related acute pancreatitis.

PubMed

Stefanutti, Claudia; Labbadia, Giancarlo; Morozzi, Claudia

2013-04-01

Acute pancreatitis is a potentially life-threatening complication of severe hypertriglyceridemia. In some cases, inborn errors of metabolism such as lipoprotein lipase deficiency, apoprotein C-II deficiency, and familial hypertriglyceridemia have been reported as causes of severe hypertriglyceridemia. More often, severe hypertriglyceridemia describes various clinical conditions characterized by high plasma levels of triglycerides (>1000 mg/dL), chylomicron remnants, or intermediate density lipoprotein like particles, and/or chylomicrons. International guidelines on the management of acute pancreatitis are currently available. Standard therapeutic measures are based on the use of lipid-lowering agents (fenofibrate, gemfibrozil, niacin, Ω-3 fatty acids), low molecular weight heparin, and insulin in diabetic patients. However, when standard medical therapies have failed, non-pharmacological approaches based upon the removal of triglycerides with therapeutic plasma exchange can also provide benefit to patients with severe hypertriglyceridemia and acute pancreatitis. Plasma exchange could be very helpful in reducing triglycerides levels during the acute phase of hyperlipidemic pancreatitis, and in the prevention of recurrence. The current evidence on management of acute pancreatitis and severe hypertriglyceridemia, focusing on symptoms, treatment and potential complications is reviewed herein. © 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.

T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome

PubMed Central

Gaballa, Ahmed; Sundin, Mikael; Stikvoort, Arwen; Abumaree, Muhamed; Uzunel, Mehmet; Sairafi, Darius; Uhlin, Michael

2016-01-01

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T cells are responsible for both the beneficial graft-versus-leukemia (GVL) effect against malignant cells and protection against infections. The immune recovery of T cells relies initially on peripheral expansion of mature cells from the graft and later on the differentiation and maturation from donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released upon rearrangement of the T cell receptor. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. Here, we discuss the role of TREC analysis in the prediction of clinical outcome after allogeneic HSCT. Due to the pivotal role of T cell reconstitution we propose that TREC analysis should be included as a key indicator in the post-HSCT follow-up. PMID:27727179

Gaucher disease: clinical profile and therapeutic developments.

PubMed

Cox, Timothy M

2010-12-06

Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme(®)), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV(®) (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential 'niche busters'. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide - a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized - with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.

Gaucher disease: clinical profile and therapeutic developments

PubMed Central

Cox, Timothy M

2010-01-01

Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme®), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV® (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential ‘niche busters’. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed. PMID:21209725

Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System

PubMed Central

Cruz-Muñoz, Mario E.; Fuentes-Pananá, Ezequiel M.

2018-01-01

Viruses are the most abundant and diverse biological entities in the planet. Historically, our main interest in viruses has focused on their pathogenic role, recognized by pandemics that have decimated the world population. However, viral infections have also played a major role in the evolution of cellular organisms, both through interchanging of genes with novel functions and shaping the immune system. Examples abound of infections that seriously compromise the host integrity, but evidence of plant and insect viruses mutualistic relationships have recently surfaced in which infected hosts are better suited for survival, arguing that virus-host interactions are initially parasitic but become mutualistic over years of co-evolution. A similar mutual help scenario has emerged with commensal gut bacteria. EBV is a herpesvirus that shares more than a hundred million years of co-evolution with humans, today successfully infecting close to 100% of the adult world population. Infection is usually acquired early in childhood persisting for the host lifetime mostly without apparent clinical symptoms. Disturbance of this homeostasis is rare and results in several diseases, of which the best understood are infectious mononucleosis and several EBV-associated cancers. Less understood are recently found inborn errors of the immune system that result in primary immunodeficiencies with an increased predisposition almost exclusive to EBV-associated diseases. Puzzling to these scenarios of broken homeostasis is the co-existence of immunosuppression, inflammation, autoimmunity and cancer. Homologous to EBV, HCMV, HHV-6 and HHV-7 are herpesviruses that also latently infect most individuals. Several lines of evidence support a mutualistic equilibrium between HCMV/EBV and hosts, that when altered trigger diseases in which the immune system plays a critical role. Interestingly, these beta and gamma herpesviruses persistently infect all immune lineages and early precursor cells. In this review, we will discuss the evidence of the benefits that infection of immune cells with these herpesviruses brings to the host. Also, the circumstances in which this positive relationship is broken, predisposing the host to diseases characterized by an abnormal function of the host immune system. PMID:29354096

Stochastic Models of Human Errors

NASA Technical Reports Server (NTRS)

Elshamy, Maged; Elliott, Dawn M. (Technical Monitor)

2002-01-01

Humans play an important role in the overall reliability of engineering systems. More often accidents and systems failure are traced to human errors. Therefore, in order to have meaningful system risk analysis, the reliability of the human element must be taken into consideration. Describing the human error process by mathematical models is a key to analyzing contributing factors. Therefore, the objective of this research effort is to establish stochastic models substantiated by sound theoretic foundation to address the occurrence of human errors in the processing of the space shuttle.

Operational Interventions to Maintenance Error

NASA Technical Reports Server (NTRS)

Kanki, Barbara G.; Walter, Diane; Dulchinos, VIcki

1997-01-01

A significant proportion of aviation accidents and incidents are known to be tied to human error. However, research of flight operational errors has shown that so-called pilot error often involves a variety of human factors issues and not a simple lack of individual technical skills. In aircraft maintenance operations, there is similar concern that maintenance errors which may lead to incidents and accidents are related to a large variety of human factors issues. Although maintenance error data and research are limited, industry initiatives involving human factors training in maintenance have become increasingly accepted as one type of maintenance error intervention. Conscientious efforts have been made in re-inventing the team7 concept for maintenance operations and in tailoring programs to fit the needs of technical opeRAtions. Nevertheless, there remains a dual challenge: 1) to develop human factors interventions which are directly supported by reliable human error data, and 2) to integrate human factors concepts into the procedures and practices of everyday technical tasks. In this paper, we describe several varieties of human factors interventions and focus on two specific alternatives which target problems related to procedures and practices; namely, 1) structured on-the-job training and 2) procedure re-design. We hope to demonstrate that the key to leveraging the impact of these solutions comes from focused interventions; that is, interventions which are derived from a clear understanding of specific maintenance errors, their operational context and human factors components.

Reduction of Maintenance Error Through Focused Interventions

NASA Technical Reports Server (NTRS)

Kanki, Barbara G.; Walter, Diane; Rosekind, Mark R. (Technical Monitor)

1997-01-01

It is well known that a significant proportion of aviation accidents and incidents are tied to human error. In flight operations, research of operational errors has shown that so-called "pilot error" often involves a variety of human factors issues and not a simple lack of individual technical skills. In aircraft maintenance operations, there is similar concern that maintenance errors which may lead to incidents and accidents are related to a large variety of human factors issues. Although maintenance error data and research are limited, industry initiatives involving human factors training in maintenance have become increasingly accepted as one type of maintenance error intervention. Conscientious efforts have been made in re-inventing the "team" concept for maintenance operations and in tailoring programs to fit the needs of technical operations. Nevertheless, there remains a dual challenge: to develop human factors interventions which are directly supported by reliable human error data, and to integrate human factors concepts into the procedures and practices of everyday technical tasks. In this paper, we describe several varieties of human factors interventions and focus on two specific alternatives which target problems related to procedures and practices; namely, 1) structured on-the-job training and 2) procedure re-design. We hope to demonstrate that the key to leveraging the impact of these solutions comes from focused interventions; that is, interventions which are derived from a clear understanding of specific maintenance errors, their operational context and human factors components.

Human Factors Process Task Analysis: Liquid Oxygen Pump Acceptance Test Procedure at the Advanced Technology Development Center

NASA Technical Reports Server (NTRS)

Diorio, Kimberly A.; Voska, Ned (Technical Monitor)

2002-01-01

This viewgraph presentation provides information on Human Factors Process Failure Modes and Effects Analysis (HF PFMEA). HF PFMEA includes the following 10 steps: Describe mission; Define System; Identify human-machine; List human actions; Identify potential errors; Identify factors that effect error; Determine likelihood of error; Determine potential effects of errors; Evaluate risk; Generate solutions (manage error). The presentation also describes how this analysis was applied to a liquid oxygen pump acceptance test.

A theory of human error

NASA Technical Reports Server (NTRS)

Mcruer, D. T.; Clement, W. F.; Allen, R. W.

1981-01-01

Human errors tend to be treated in terms of clinical and anecdotal descriptions, from which remedial measures are difficult to derive. Correction of the sources of human error requires an attempt to reconstruct underlying and contributing causes of error from the circumstantial causes cited in official investigative reports. A comprehensive analytical theory of the cause-effect relationships governing propagation of human error is indispensable to a reconstruction of the underlying and contributing causes. A validated analytical theory of the input-output behavior of human operators involving manual control, communication, supervisory, and monitoring tasks which are relevant to aviation, maritime, automotive, and process control operations is highlighted. This theory of behavior, both appropriate and inappropriate, provides an insightful basis for investigating, classifying, and quantifying the needed cause-effect relationships governing propagation of human error.

Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome.

PubMed

Vanlander, A V; Jorens, P G; Smet, J; De Paepe, B; Verbrugghe, W; Van den Eynden, G G; Meire, F; Pauwels, P; Van der Aa, N; Seneca, S; Lissens, W; Okun, J G; Van Coster, R

2012-04-01

Propofol is an anesthetic agent widely used for induction and maintenance of anesthesia, and sedation in children. Although generally considered as reliable and safe, administration of propofol can occasionally induce a potentially fatal complication known as propofol infusion syndrome (PRIS). Mitochondrial dysfunction has been implicated in the pathogenesis of PRIS. We report on an adult patient with Leber hereditary optic neuropathy (LHON) who developed PRIS. He was a carrier of the m.3460G>A mutation, one of the major three pathogenic point mutations associated with LHON. The propositus was blind and underwent propofol sedation after severe head injury. Five days after start of propofol infusion, the patient died. The activity of complex I of the oxidative phosphorylation (OXPHOS) system was severely deficient in skeletal muscle. Our observation indicates that fulminate PRIS can occur in an adult patient with an inborn OXPHOS defect and corroborates the hypothesis that PRIS is caused by inhibition of the OXPHOS system. © 2012 The Authors. Acta Anaesthesiologica Scandinavica © 2012 The Acta Anaesthesiologica Scandinavica Foundation.

Hospital outcomes of extremely low birth weight infants after introduction of donor milk to supplement mother's milk.

PubMed

Verd, Sergio; Porta, Roser; Botet, Francesc; Gutiérrez, Antonio; Ginovart, Gemma; Barbero, Ana Herranz; Ciurana, Anna; Plata, Isabel Iglesias

2015-04-01

This study evaluated the impact of an exclusive human milk diet to nourish extremely low birth weight infants in the neonatal intensive care unit. This multicenter pre-post retrospective study included all inborn infants <1,000 g admitted to four Level IV neonatal intensive care units either before or after implementing a donor human milk policy. The feeding protocol was unchanged in both periods. Collected data included maternal/infant demographics, infant clinical data, and enteral intake as mother's own milk, donor milk, and formula. Two hundred one infants were enrolled. Infant growth and other clinical outcomes were similar in both groups. Exposure to mother's own milk at discharge was not different. Median time in oxygen and duration of mechanical ventilation were significantly higher among formula-fed infants (63 versus 192 hours [p=0.046] and 24 versus 60 hours [p=0.016], respectively). Our results add evidence supporting the safety of donor milk. This study also found an association between exposure to formula in preterm infants and the requirement for respiratory support, a finding that warrants further investigation.

The contributions of human factors on human error in Malaysia aviation maintenance industries

NASA Astrophysics Data System (ADS)

Padil, H.; Said, M. N.; Azizan, A.

2018-05-01

Aviation maintenance is a multitasking activity in which individuals perform varied tasks under constant pressure to meet deadlines as well as challenging work conditions. These situational characteristics combined with human factors can lead to various types of human related errors. The primary objective of this research is to develop a structural relationship model that incorporates human factors, organizational factors, and their impact on human errors in aviation maintenance. Towards that end, a questionnaire was developed which was administered to Malaysian aviation maintenance professionals. Structural Equation Modelling (SEM) approach was used in this study utilizing AMOS software. Results showed that there were a significant relationship of human factors on human errors and were tested in the model. Human factors had a partial effect on organizational factors while organizational factors had a direct and positive impact on human errors. It was also revealed that organizational factors contributed to human errors when coupled with human factors construct. This study has contributed to the advancement of knowledge on human factors effecting safety and has provided guidelines for improving human factors performance relating to aviation maintenance activities and could be used as a reference for improving safety performance in the Malaysian aviation maintenance companies.

A theory of human error

NASA Technical Reports Server (NTRS)

Mcruer, D. T.; Clement, W. F.; Allen, R. W.

1980-01-01

Human error, a significant contributing factor in a very high proportion of civil transport, general aviation, and rotorcraft accidents is investigated. Correction of the sources of human error requires that one attempt to reconstruct underlying and contributing causes of error from the circumstantial causes cited in official investigative reports. A validated analytical theory of the input-output behavior of human operators involving manual control, communication, supervisory, and monitoring tasks which are relevant to aviation operations is presented. This theory of behavior, both appropriate and inappropriate, provides an insightful basis for investigating, classifying, and quantifying the needed cause-effect relationships governing propagation of human error.

Human Reliability and the Cost of Doing Business

NASA Technical Reports Server (NTRS)

DeMott, Diana

2014-01-01

Most businesses recognize that people will make mistakes and assume errors are just part of the cost of doing business, but does it need to be? Companies with high risk, or major consequences, should consider the effect of human error. In a variety of industries, Human Errors have caused costly failures and workplace injuries. These have included: airline mishaps, medical malpractice, administration of medication and major oil spills have all been blamed on human error. A technique to mitigate or even eliminate some of these costly human errors is the use of Human Reliability Analysis (HRA). Various methodologies are available to perform Human Reliability Assessments that range from identifying the most likely areas for concern to detailed assessments with human error failure probabilities calculated. Which methodology to use would be based on a variety of factors that would include: 1) how people react and act in different industries, and differing expectations based on industries standards, 2) factors that influence how the human errors could occur such as tasks, tools, environment, workplace, support, training and procedure, 3) type and availability of data and 4) how the industry views risk & reliability influences ( types of emergencies, contingencies and routine tasks versus cost based concerns). The Human Reliability Assessments should be the first step to reduce, mitigate or eliminate the costly mistakes or catastrophic failures. Using Human Reliability techniques to identify and classify human error risks allows a company more opportunities to mitigate or eliminate these risks and prevent costly failures.

Human Reliability and the Cost of Doing Business

NASA Technical Reports Server (NTRS)

DeMott, D. L.

2014-01-01

Human error cannot be defined unambiguously in advance of it happening, it often becomes an error after the fact. The same action can result in a tragic accident for one situation or a heroic action given a more favorable outcome. People often forget that we employ humans in business and industry for the flexibility and capability to change when needed. In complex systems, operations are driven by their specifications of the system and the system structure. People provide the flexibility to make it work. Human error has been reported as being responsible for 60%-80% of failures, accidents and incidents in high-risk industries. We don't have to accept that all human errors are inevitable. Through the use of some basic techniques, many potential human error events can be addressed. There are actions that can be taken to reduce the risk of human error.

Inborn errors of metabolism and expanded newborn screening: review and update.

PubMed

Mak, Chloe Miu; Lee, Han-Chih Hencher; Chan, Albert Yan-Wo; Lam, Ching-Wan

2013-11-01

Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.

Human Error Analysis in a Permit to Work System: A Case Study in a Chemical Plant

PubMed Central

Jahangiri, Mehdi; Hoboubi, Naser; Rostamabadi, Akbar; Keshavarzi, Sareh; Hosseini, Ali Akbar

2015-01-01

Background A permit to work (PTW) is a formal written system to control certain types of work which are identified as potentially hazardous. However, human error in PTW processes can lead to an accident. Methods This cross-sectional, descriptive study was conducted to estimate the probability of human errors in PTW processes in a chemical plant in Iran. In the first stage, through interviewing the personnel and studying the procedure in the plant, the PTW process was analyzed using the hierarchical task analysis technique. In doing so, PTW was considered as a goal and detailed tasks to achieve the goal were analyzed. In the next step, the standardized plant analysis risk-human (SPAR-H) reliability analysis method was applied for estimation of human error probability. Results The mean probability of human error in the PTW system was estimated to be 0.11. The highest probability of human error in the PTW process was related to flammable gas testing (50.7%). Conclusion The SPAR-H method applied in this study could analyze and quantify the potential human errors and extract the required measures for reducing the error probabilities in PTW system. Some suggestions to reduce the likelihood of errors, especially in the field of modifying the performance shaping factors and dependencies among tasks are provided. PMID:27014485

Unmasking the Terror.

ERIC Educational Resources Information Center

Chambers, Jamie C.

2000-01-01

Author recounts his personal experiences growing up as a youth of color and subsequent work as a youth counselor. Argues that all young people choose purposive behavior based on competing inborn motivational systems. Fear in any degree is an innate protective mechanism, but racism is an irrational fear. Provides strategies for confronting…

Even Geniuses Work Hard

ERIC Educational Resources Information Center

Dweck, Carol S.

2010-01-01

In her well-known research, Carol Dweck has documented how individuals' attitudes about intelligence affect their behavior and achievement. People with a fixed mindset, she writes, believe that intelligence is inborn and unchangeable, whereas those with a growth mindset believe that intelligence can grow through practice and effort. In this…

Managing human fallibility in critical aerospace situations

NASA Astrophysics Data System (ADS)

Tew, Larry

2014-11-01

Human fallibility is pervasive in the aerospace industry with over 50% of errors attributed to human error. Consider the benefits to any organization if those errors were significantly reduced. Aerospace manufacturing involves high value, high profile systems with significant complexity and often repetitive build, assembly, and test operations. In spite of extensive analysis, planning, training, and detailed procedures, human factors can cause unexpected errors. Handling such errors involves extensive cause and corrective action analysis and invariably schedule slips and cost growth. We will discuss success stories, including those associated with electro-optical systems, where very significant reductions in human fallibility errors were achieved after receiving adapted and specialized training. In the eyes of company and customer leadership, the steps used to achieve these results lead to in a major culture change in both the workforce and the supporting management organization. This approach has proven effective in other industries like medicine, firefighting, law enforcement, and aviation. The roadmap to success and the steps to minimize human error are known. They can be used by any organization willing to accept human fallibility and take a proactive approach to incorporate the steps needed to manage and minimize error.

Prediction of human errors by maladaptive changes in event-related brain networks.

PubMed

Eichele, Tom; Debener, Stefan; Calhoun, Vince D; Specht, Karsten; Engel, Andreas K; Hugdahl, Kenneth; von Cramon, D Yves; Ullsperger, Markus

2008-04-22

Humans engaged in monotonous tasks are susceptible to occasional errors that may lead to serious consequences, but little is known about brain activity patterns preceding errors. Using functional MRI and applying independent component analysis followed by deconvolution of hemodynamic responses, we studied error preceding brain activity on a trial-by-trial basis. We found a set of brain regions in which the temporal evolution of activation predicted performance errors. These maladaptive brain activity changes started to evolve approximately 30 sec before the error. In particular, a coincident decrease of deactivation in default mode regions of the brain, together with a decline of activation in regions associated with maintaining task effort, raised the probability of future errors. Our findings provide insights into the brain network dynamics preceding human performance errors and suggest that monitoring of the identified precursor states may help in avoiding human errors in critical real-world situations.

Prediction of human errors by maladaptive changes in event-related brain networks

PubMed Central

Eichele, Tom; Debener, Stefan; Calhoun, Vince D.; Specht, Karsten; Engel, Andreas K.; Hugdahl, Kenneth; von Cramon, D. Yves; Ullsperger, Markus

2008-01-01

Humans engaged in monotonous tasks are susceptible to occasional errors that may lead to serious consequences, but little is known about brain activity patterns preceding errors. Using functional MRI and applying independent component analysis followed by deconvolution of hemodynamic responses, we studied error preceding brain activity on a trial-by-trial basis. We found a set of brain regions in which the temporal evolution of activation predicted performance errors. These maladaptive brain activity changes started to evolve ≈30 sec before the error. In particular, a coincident decrease of deactivation in default mode regions of the brain, together with a decline of activation in regions associated with maintaining task effort, raised the probability of future errors. Our findings provide insights into the brain network dynamics preceding human performance errors and suggest that monitoring of the identified precursor states may help in avoiding human errors in critical real-world situations. PMID:18427123

Defining the Relationship Between Human Error Classes and Technology Intervention Strategies

NASA Technical Reports Server (NTRS)

Wiegmann, Douglas A.; Rantanen, Eas M.

2003-01-01

The modus operandi in addressing human error in aviation systems is predominantly that of technological interventions or fixes. Such interventions exhibit considerable variability both in terms of sophistication and application. Some technological interventions address human error directly while others do so only indirectly. Some attempt to eliminate the occurrence of errors altogether whereas others look to reduce the negative consequences of these errors. In any case, technological interventions add to the complexity of the systems and may interact with other system components in unforeseeable ways and often create opportunities for novel human errors. Consequently, there is a need to develop standards for evaluating the potential safety benefit of each of these intervention products so that resources can be effectively invested to produce the biggest benefit to flight safety as well as to mitigate any adverse ramifications. The purpose of this project was to help define the relationship between human error and technological interventions, with the ultimate goal of developing a set of standards for evaluating or measuring the potential benefits of new human error fixes.

Applying lessons learned to enhance human performance and reduce human error for ISS operations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nelson, W.R.

1999-01-01

A major component of reliability, safety, and mission success for space missions is ensuring that the humans involved (flight crew, ground crew, mission control, etc.) perform their tasks and functions as required. This includes compliance with training and procedures during normal conditions, and successful compensation when malfunctions or unexpected conditions occur. A very significant issue that affects human performance in space flight is human error. Human errors can invalidate carefully designed equipment and procedures. If certain errors combine with equipment failures or design flaws, mission failure or loss of life can occur. The control of human error during operation ofmore » the International Space Station (ISS) will be critical to the overall success of the program. As experience from Mir operations has shown, human performance plays a vital role in the success or failure of long duration space missions. The Department of Energy{close_quote}s Idaho National Engineering and Environmental Laboratory (INEEL) is developing a systematic approach to enhance human performance and reduce human errors for ISS operations. This approach is based on the systematic identification and evaluation of lessons learned from past space missions such as Mir to enhance the design and operation of ISS. This paper will describe previous INEEL research on human error sponsored by NASA and how it can be applied to enhance human reliability for ISS. {copyright} {ital 1999 American Institute of Physics.}« less

Applying lessons learned to enhance human performance and reduce human error for ISS operations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nelson, W.R.

1998-09-01

A major component of reliability, safety, and mission success for space missions is ensuring that the humans involved (flight crew, ground crew, mission control, etc.) perform their tasks and functions as required. This includes compliance with training and procedures during normal conditions, and successful compensation when malfunctions or unexpected conditions occur. A very significant issue that affects human performance in space flight is human error. Human errors can invalidate carefully designed equipment and procedures. If certain errors combine with equipment failures or design flaws, mission failure or loss of life can occur. The control of human error during operation ofmore » the International Space Station (ISS) will be critical to the overall success of the program. As experience from Mir operations has shown, human performance plays a vital role in the success or failure of long duration space missions. The Department of Energy`s Idaho National Engineering and Environmental Laboratory (INEEL) is developed a systematic approach to enhance human performance and reduce human errors for ISS operations. This approach is based on the systematic identification and evaluation of lessons learned from past space missions such as Mir to enhance the design and operation of ISS. This paper describes previous INEEL research on human error sponsored by NASA and how it can be applied to enhance human reliability for ISS.« less

Structured methods for identifying and correcting potential human errors in aviation operations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nelson, W.R.

1997-10-01

Human errors have been identified as the source of approximately 60% of the incidents and accidents that occur in commercial aviation. It can be assumed that a very large number of human errors occur in aviation operations, even though in most cases the redundancies and diversities built into the design of aircraft systems prevent the errors from leading to serious consequences. In addition, when it is acknowledged that many system failures have their roots in human errors that occur in the design phase, it becomes apparent that the identification and elimination of potential human errors could significantly decrease the risksmore » of aviation operations. This will become even more critical during the design of advanced automation-based aircraft systems as well as next-generation systems for air traffic management. Structured methods to identify and correct potential human errors in aviation operations have been developed and are currently undergoing testing at the Idaho National Engineering and Environmental Laboratory (INEEL).« less

Human errors and violations in computer and information security: the viewpoint of network administrators and security specialists.

PubMed

Kraemer, Sara; Carayon, Pascale

2007-03-01

This paper describes human errors and violations of end users and network administration in computer and information security. This information is summarized in a conceptual framework for examining the human and organizational factors contributing to computer and information security. This framework includes human error taxonomies to describe the work conditions that contribute adversely to computer and information security, i.e. to security vulnerabilities and breaches. The issue of human error and violation in computer and information security was explored through a series of 16 interviews with network administrators and security specialists. The interviews were audio taped, transcribed, and analyzed by coding specific themes in a node structure. The result is an expanded framework that classifies types of human error and identifies specific human and organizational factors that contribute to computer and information security. Network administrators tended to view errors created by end users as more intentional than unintentional, while errors created by network administrators as more unintentional than intentional. Organizational factors, such as communication, security culture, policy, and organizational structure, were the most frequently cited factors associated with computer and information security.

Intervention strategies for the management of human error

NASA Technical Reports Server (NTRS)

Wiener, Earl L.

1993-01-01

This report examines the management of human error in the cockpit. The principles probably apply as well to other applications in the aviation realm (e.g. air traffic control, dispatch, weather, etc.) as well as other high-risk systems outside of aviation (e.g. shipping, high-technology medical procedures, military operations, nuclear power production). Management of human error is distinguished from error prevention. It is a more encompassing term, which includes not only the prevention of error, but also a means of disallowing an error, once made, from adversely affecting system output. Such techniques include: traditional human factors engineering, improvement of feedback and feedforward of information from system to crew, 'error-evident' displays which make erroneous input more obvious to the crew, trapping of errors within a system, goal-sharing between humans and machines (also called 'intent-driven' systems), paperwork management, and behaviorally based approaches, including procedures, standardization, checklist design, training, cockpit resource management, etc. Fifteen guidelines for the design and implementation of intervention strategies are included.

Treatment in Fabry disease.

PubMed

López Rodríguez, M

2018-04-13

Fabry disease is an X-linked inborn disease caused by deficit of alpha-galactosidaseA. This results in accumulation of glycosphingolipids in all cells and tissues. All males should receive enzyme replacement treatment in case of very low or undetectable levels of alpha-galactosidaseA. Female carriers and males with marginally levels of alpha-galactosidaseA should be treated in case of renal, neurologic o cardiac manifestations. There are two intravenous formulations of human recombinant enzyme, agalsidase alpha and agalsidase beta, showing similar efficacy and safety. Patients with amenable mutations of alpha-galactosidase can be treated with oral migalastat hydrochloride. Migalastat hydrochloride is a pharmacological chaperone that facilitates trafficking of alpha-galactosidaseA to lysosomes increasing enzyme activity. Patients treated with migalastat hydrochloride had significant improvements in left ventricular mass and gastrointestinal symptoms. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Exploring Reactions to Pilot Reliability Certification and Changing Attitudes on the Reduction of Errors

ERIC Educational Resources Information Center

Boedigheimer, Dan

2010-01-01

Approximately 70% of aviation accidents are attributable to human error. The greatest opportunity for further improving aviation safety is found in reducing human errors in the cockpit. The purpose of this quasi-experimental, mixed-method research was to evaluate whether there was a difference in pilot attitudes toward reducing human error in the…

Evaluating a medical error taxonomy.

PubMed

Brixey, Juliana; Johnson, Todd R; Zhang, Jiajie

2002-01-01

Healthcare has been slow in using human factors principles to reduce medical errors. The Center for Devices and Radiological Health (CDRH) recognizes that a lack of attention to human factors during product development may lead to errors that have the potential for patient injury, or even death. In response to the need for reducing medication errors, the National Coordinating Council for Medication Errors Reporting and Prevention (NCC MERP) released the NCC MERP taxonomy that provides a standard language for reporting medication errors. This project maps the NCC MERP taxonomy of medication error to MedWatch medical errors involving infusion pumps. Of particular interest are human factors associated with medical device errors. The NCC MERP taxonomy of medication errors is limited in mapping information from MEDWATCH because of the focus on the medical device and the format of reporting.

An Evaluation of Departmental Radiation Oncology Incident Reports: Anticipating a National Reporting System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Terezakis, Stephanie A., E-mail: stereza1@jhmi.edu; Harris, Kendra M.; Ford, Eric

Purpose: Systems to ensure patient safety are of critical importance. The electronic incident reporting systems (IRS) of 2 large academic radiation oncology departments were evaluated for events that may be suitable for submission to a national reporting system (NRS). Methods and Materials: All events recorded in the combined IRS were evaluated from 2007 through 2010. Incidents were graded for potential severity using the validated French Nuclear Safety Authority (ASN) 5-point scale. These incidents were categorized into 7 groups: (1) human error, (2) software error, (3) hardware error, (4) error in communication between 2 humans, (5) error at the human-software interface,more » (6) error at the software-hardware interface, and (7) error at the human-hardware interface. Results: Between the 2 systems, 4407 incidents were reported. Of these events, 1507 (34%) were considered to have the potential for clinical consequences. Of these 1507 events, 149 (10%) were rated as having a potential severity of ≥2. Of these 149 events, the committee determined that 79 (53%) of these events would be submittable to a NRS of which the majority was related to human error or to the human-software interface. Conclusions: A significant number of incidents were identified in this analysis. The majority of events in this study were related to human error and to the human-software interface, further supporting the need for a NRS to facilitate field-wide learning and system improvement.« less

Sleep quality, posttraumatic stress, depression, and human errors in train drivers: a population-based nationwide study in South Korea.

PubMed

Jeon, Hong Jin; Kim, Ji-Hae; Kim, Bin-Na; Park, Seung Jin; Fava, Maurizio; Mischoulon, David; Kang, Eun-Ho; Roh, Sungwon; Lee, Dongsoo

2014-12-01

Human error is defined as an unintended error that is attributable to humans rather than machines, and that is important to avoid to prevent accidents. We aimed to investigate the association between sleep quality and human errors among train drivers. Cross-sectional. Population-based. A sample of 5,480 subjects who were actively working as train drivers were recruited in South Korea. The participants were 4,634 drivers who completed all questionnaires (response rate 84.6%). None. The Pittsburgh Sleep Quality Index (PSQI), the Center for Epidemiologic Studies Depression Scale (CES-D), the Impact of Event Scale-Revised (IES-R), the State-Trait Anxiety Inventory (STAI), and the Korean Occupational Stress Scale (KOSS). Of 4,634 train drivers, 349 (7.5%) showed more than one human error per 5 y. Human errors were associated with poor sleep quality, higher PSQI total scores, short sleep duration at night, and longer sleep latency. Among train drivers with poor sleep quality, those who experienced severe posttraumatic stress showed a significantly higher number of human errors than those without. Multiple logistic regression analysis showed that human errors were significantly associated with poor sleep quality and posttraumatic stress, whereas there were no significant associations with depression, trait and state anxiety, and work stress after adjusting for age, sex, education years, marital status, and career duration. Poor sleep quality was found to be associated with more human errors in train drivers, especially in those who experienced severe posttraumatic stress. © 2014 Associated Professional Sleep Societies, LLC.

Analyzing human errors in flight mission operations

NASA Technical Reports Server (NTRS)

Bruno, Kristin J.; Welz, Linda L.; Barnes, G. Michael; Sherif, Josef

1993-01-01

A long-term program is in progress at JPL to reduce cost and risk of flight mission operations through a defect prevention/error management program. The main thrust of this program is to create an environment in which the performance of the total system, both the human operator and the computer system, is optimized. To this end, 1580 Incident Surprise Anomaly reports (ISA's) from 1977-1991 were analyzed from the Voyager and Magellan projects. A Pareto analysis revealed that 38 percent of the errors were classified as human errors. A preliminary cluster analysis based on the Magellan human errors (204 ISA's) is presented here. The resulting clusters described the underlying relationships among the ISA's. Initial models of human error in flight mission operations are presented. Next, the Voyager ISA's will be scored and included in the analysis. Eventually, these relationships will be used to derive a theoretically motivated and empirically validated model of human error in flight mission operations. Ultimately, this analysis will be used to make continuous process improvements continuous process improvements to end-user applications and training requirements. This Total Quality Management approach will enable the management and prevention of errors in the future.

Human Error and the International Space Station: Challenges and Triumphs in Science Operations

NASA Technical Reports Server (NTRS)

Harris, Samantha S.; Simpson, Beau C.

2016-01-01

Any system with a human component is inherently risky. Studies in human factors and psychology have repeatedly shown that human operators will inevitably make errors, regardless of how well they are trained. Onboard the International Space Station (ISS) where crew time is arguably the most valuable resource, errors by the crew or ground operators can be costly to critical science objectives. Operations experts at the ISS Payload Operations Integration Center (POIC), located at NASA's Marshall Space Flight Center in Huntsville, Alabama, have learned that from payload concept development through execution, there are countless opportunities to introduce errors that can potentially result in costly losses of crew time and science. To effectively address this challenge, we must approach the design, testing, and operation processes with two specific goals in mind. First, a systematic approach to error and human centered design methodology should be implemented to minimize opportunities for user error. Second, we must assume that human errors will be made and enable rapid identification and recoverability when they occur. While a systematic approach and human centered development process can go a long way toward eliminating error, the complete exclusion of operator error is not a reasonable expectation. The ISS environment in particular poses challenging conditions, especially for flight controllers and astronauts. Operating a scientific laboratory 250 miles above the Earth is a complicated and dangerous task with high stakes and a steep learning curve. While human error is a reality that may never be fully eliminated, smart implementation of carefully chosen tools and techniques can go a long way toward minimizing risk and increasing the efficiency of NASA's space science operations.

Modeling human response errors in synthetic flight simulator domain

NASA Technical Reports Server (NTRS)

Ntuen, Celestine A.

1992-01-01

This paper presents a control theoretic approach to modeling human response errors (HRE) in the flight simulation domain. The human pilot is modeled as a supervisor of a highly automated system. The synthesis uses the theory of optimal control pilot modeling for integrating the pilot's observation error and the error due to the simulation model (experimental error). Methods for solving the HRE problem are suggested. Experimental verification of the models will be tested in a flight quality handling simulation.

Homo imitans? Seven reasons why imitation couldn't possibly be associative

PubMed Central

Heyes, Cecilia

2016-01-01

Many comparative and developmental psychologists believe that we are Homo imitans; humans are more skilled and prolific imitators than other animals, because we have a special, inborn ‘intermodal matching’ mechanism that integrates representations of others with representations of the self. In contrast, the associative sequence learning (ASL) model suggests that human infants learn to imitate using mechanisms that they share with other animals, and the rich resources provided by their sociocultural environments. This article answers seven objections to the ASL model: (i) it presents evidence that newborns do not imitate; (ii) argues that infants receive a plentiful supply of the kind of experience necessary for learning to imitate; (iii) suggests that neither infants nor adults can imitate elementally novel actions; (iv) explains why non-human animals have a limited capacity for imitation; (v) discusses the goal-directedness of imitation; (vi) presents evidence that improvement in imitation depends on visual feedback; and (vii) reflects on the view that associative theories steal ‘the soul of imitation’. The empirical success of the ASL model indicates that the mechanisms which make imitation possible, by aligning representations of self with representations of others, have been tweaked by cultural evolution, not built from scratch by genetic evolution. PMID:26644604

Homo imitans? Seven reasons why imitation couldn't possibly be associative.

PubMed

Heyes, Cecilia

2016-01-19

Many comparative and developmental psychologists believe that we are Homo imitans; humans are more skilled and prolific imitators than other animals, because we have a special, inborn 'intermodal matching' mechanism that integrates representations of others with representations of the self. In contrast, the associative sequence learning (ASL) model suggests that human infants learn to imitate using mechanisms that they share with other animals, and the rich resources provided by their sociocultural environments. This article answers seven objections to the ASL model: (i) it presents evidence that newborns do not imitate; (ii) argues that infants receive a plentiful supply of the kind of experience necessary for learning to imitate; (iii) suggests that neither infants nor adults can imitate elementally novel actions; (iv) explains why non-human animals have a limited capacity for imitation; (v) discusses the goal-directedness of imitation; (vi) presents evidence that improvement in imitation depends on visual feedback; and (vii) reflects on the view that associative theories steal 'the soul of imitation'. The empirical success of the ASL model indicates that the mechanisms which make imitation possible, by aligning representations of self with representations of others, have been tweaked by cultural evolution, not built from scratch by genetic evolution. © 2015 The Author(s).

Defining the Relationship Between Human Error Classes and Technology Intervention Strategies

NASA Technical Reports Server (NTRS)

Wiegmann, Douglas A.; Rantanen, Esa; Crisp, Vicki K. (Technical Monitor)

2002-01-01

One of the main factors in all aviation accidents is human error. The NASA Aviation Safety Program (AvSP), therefore, has identified several human-factors safety technologies to address this issue. Some technologies directly address human error either by attempting to reduce the occurrence of errors or by mitigating the negative consequences of errors. However, new technologies and system changes may also introduce new error opportunities or even induce different types of errors. Consequently, a thorough understanding of the relationship between error classes and technology "fixes" is crucial for the evaluation of intervention strategies outlined in the AvSP, so that resources can be effectively directed to maximize the benefit to flight safety. The purpose of the present project, therefore, was to examine the repositories of human factors data to identify the possible relationship between different error class and technology intervention strategies. The first phase of the project, which is summarized here, involved the development of prototype data structures or matrices that map errors onto "fixes" (and vice versa), with the hope of facilitating the development of standards for evaluating safety products. Possible follow-on phases of this project are also discussed. These additional efforts include a thorough and detailed review of the literature to fill in the data matrix and the construction of a complete database and standards checklists.

Development and implementation of a human accuracy program in patient foodservice.

PubMed

Eden, S H; Wood, S M; Ptak, K M

1987-04-01

For many years, industry has utilized the concept of human error rates to monitor and minimize human errors in the production process. A consistent quality-controlled product increases consumer satisfaction and repeat purchase of product. Administrative dietitians have applied the concepts of using human error rates (the number of errors divided by the number of opportunities for error) at four hospitals, with a total bed capacity of 788, within a tertiary-care medical center. Human error rate was used to monitor and evaluate trayline employee performance and to evaluate layout and tasks of trayline stations, in addition to evaluating employees in patient service areas. Long-term employees initially opposed the error rate system with some hostility and resentment, while newer employees accepted the system. All employees now believe that the constant feedback given by supervisors enhances their self-esteem and productivity. Employee error rates are monitored daily and are used to counsel employees when necessary; they are also utilized during annual performance evaluation. Average daily error rates for a facility staffed by new employees decreased from 7% to an acceptable 3%. In a facility staffed by long-term employees, the error rate increased, reflecting improper error documentation. Patient satisfaction surveys reveal satisfaction, for tray accuracy increased from 88% to 92% in the facility staffed by long-term employees and has remained above the 90% standard in the facility staffed by new employees.

Reflections on human error - Matters of life and death

NASA Technical Reports Server (NTRS)

Wiener, Earl L.

1989-01-01

The last two decades have witnessed a rapid growth in the introduction of automatic devices into aircraft cockpits, and eleswhere in human-machine systems. This was motivated in part by the assumption that when human functioning is replaced by machine functioning, human error is eliminated. Experience to date shows that this is far from true, and that automation does not replace humans, but changes their role in the system, as well as the types and severity of the errors they make. This altered role may lead to fewer, but more critical errors. Intervention strategies to prevent these errors, or ameliorate their consequences include basic human factors engineering of the interface, enhanced warning and alerting systems, and more intelligent interfaces that understand the strategic intent of the crew and can detect and trap inconsistent or erroneous input before it affects the system.

A stochastic dynamic model for human error analysis in nuclear power plants

NASA Astrophysics Data System (ADS)

Delgado-Loperena, Dharma

Nuclear disasters like Three Mile Island and Chernobyl indicate that human performance is a critical safety issue, sending a clear message about the need to include environmental press and competence aspects in research. This investigation was undertaken to serve as a roadmap for studying human behavior through the formulation of a general solution equation. The theoretical model integrates models from two heretofore-disassociated disciplines (behavior specialists and technical specialists), that historically have independently studied the nature of error and human behavior; including concepts derived from fractal and chaos theory; and suggests re-evaluation of base theory regarding human error. The results of this research were based on comprehensive analysis of patterns of error, with the omnipresent underlying structure of chaotic systems. The study of patterns lead to a dynamic formulation, serving for any other formula used to study human error consequences. The search for literature regarding error yielded insight for the need to include concepts rooted in chaos theory and strange attractors---heretofore unconsidered by mainstream researchers who investigated human error in nuclear power plants or those who employed the ecological model in their work. The study of patterns obtained from the rupture of a steam generator tube (SGTR) event simulation, provided a direct application to aspects of control room operations in nuclear power plant operations. In doing so, the conceptual foundation based in the understanding of the patterns of human error analysis can be gleaned, resulting in reduced and prevent undesirable events.

Cystathionine beta-synthase deficiency alters hepatic phospholipid and choline metabolism: Post-translational repression of phosphatidylethanolamine N-methyltransferase is a consequence rather than a cause of liver injury in homocystinuria.

PubMed

Jacobs, René L; Jiang, Hua; Kennelly, John P; Orlicky, David J; Allen, Robert H; Stabler, Sally P; Maclean, Kenneth N

2017-04-01

Classical homocystinuria (HCU) due to inactivating mutation of cystathionine β-synthase (CBS) is a poorly understood life-threatening inborn error of sulfur metabolism. A previously described cbs-/- mouse model exhibits a semi-lethal phenotype due to neonatal liver failure. The transgenic HO mouse model of HCU exhibits only mild liver injury and recapitulates multiple aspects of the disease as it occurs in humans. Disruption of the methionine cycle in HCU has the potential to impact multiple aspect of phospholipid (PL) metabolism by disruption of both the Kennedy pathway and phosphatidylethanolamine N-methyltransferase (PEMT) mediated synthesis of phosphatidylcholine (PC). Comparative metabolomic analysis of HO mouse liver revealed decreased levels of choline, and choline phosphate indicating disruption of the Kennedy pathway. Alterations in the relative levels of multiple species of PL included significant increases in PL degradation products consistent with enhanced membrane PL turnover. A significant decrease in PC containing 20:4n6 which primarily formed by the methylation of phosphatidylethanolamine to PC was consistent with decreased flux through PEMT. Hepatic expression of PEMT in both the cbs-/- and HO models is post-translationally repressed with decreased levels of PEMT protein and activity that inversely-correlates with the scale of liver injury. Failure to induce further repression of PEMT in HO mice by increased homocysteine, methionine and S-adenosylhomocysteine or depletion of glutathione combined with examination of multiple homocysteine-independent models of liver injury indicated that repression of PEMT in HCU is a consequence rather than a cause of liver injury. Collectively, our data show significant alteration of a broad range of hepatic PL and choline metabolism in HCU with the potential to contribute to multiple aspects of pathogenesis in this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

The Study of Carbamoyl Phosphate Synthetase 1 Deficiency Sheds Light on the Mechanism for Switching On/Off the Urea Cycle.

PubMed

Díez-Fernández, Carmen; Gallego, José; Häberle, Johannes; Cervera, Javier; Rubio, Vicente

2015-05-20

Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is an inborn error of the urea cycle having autosomal (2q34) recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-kDa C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS1, N-acetyl-L-glutamate (NAG), is bound or is not bound to it. To carry out the present studies, we exploited a novel system that allows the expression in vitro and the purification of human CPS1, thus permitting site-directed mutagenesis. These studies have clarified disease causation by individual mutations, identifying functionally important residues, and revealing that a number of mutations decrease the affinity of the enzyme for NAG. Patients with NAG affinity-decreasing mutations might benefit from NAG site saturation therapy with N-carbamyl-L-glutamate (a registered drug, the analog of NAG). Our results, together with additional present and prior site-directed mutagenesis data for other residues mapping in this domain, suggest an NAG-triggered conformational change in the β4-α4 loop of the C-terminal domain of this enzyme. This change might be an early event in the NAG activation process. Molecular dynamics simulations that were restrained according to the observed effects of the mutations are consistent with this hypothesis, providing further backing for this structurally plausible signaling mechanism by which NAG could trigger urea cycle activation via CPS1. Copyright © 2015 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin

PubMed Central

Molloy, Anne M.; Pangilinan, Faith; Mills, James L.; Shane, Barry; O’Neill, Mary B.; McGaughey, David M.; Velkova, Aneliya; Abaan, Hatice Ozel; Ueland, Per M.; McNulty, Helene; Ward, Mary; Strain, J.J.; Cunningham, Conal; Casey, Miriam; Cropp, Cheryl D.; Kim, Yoonhee; Bailey-Wilson, Joan E.; Wilson, Alexander F.; Brody, Lawrence C.

2016-01-01

Methylmalonic acid (MMA) is a by-product of propionic acid metabolism through the vitamin B12 (cobalamin)-dependent enzyme methylmalonyl CoA mutase. Elevated MMA concentrations are a hallmark of several inborn errors of metabolism and indicators of cobalamin deficiency in older persons. In a genome-wide analysis of 2,210 healthy young Irish adults (median age 22 years) we identified a strong association of plasma MMA with SNPs in 3-hydroxyisobutyryl-CoA hydrolase (HIBCH, p = 8.42 × 10−89) and acyl-CoA synthetase family member 3 (ACSF3, p = 3.48 × 10−19). These loci accounted for 12% of the variance in MMA concentration. The most strongly associated SNP (HIBCH rs291466; c:2T>C) causes a missense change of the initiator methionine codon (minor-allele frequency = 0.43) to threonine. Surprisingly, the resulting variant, p.Met1?, is associated with increased expression of HIBCH mRNA and encoded protein. These homozygotes had, on average, 46% higher MMA concentrations than methionine-encoding homozygotes in young adults with generally low MMA concentrations (0.17 [0.14–0.21] μmol/L; median [25th–75th quartile]). The association between MMA levels and HIBCH rs291466 was highly significant in a replication cohort of 1,481 older individuals (median age 79 years) with elevated plasma MMA concentrations (0.34 [0.24–0.51] μmol/L; p = 4.0 × 10−26). In a longitudinal study of 185 pregnant women and their newborns, the association of this SNP remained significant across the gestational trimesters and in newborns. HIBCH is unique to valine catabolism. Studies evaluating flux through the valine catabolic pathway in humans should account for these variants. Furthermore, this SNP could help resolve equivocal clinical tests where plasma MMA values have been used to diagnose cobalamin deficiency. PMID:27132595

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation, function and EBV immunity.

PubMed

Edwards, Emily S J; Bier, Julia; Cole, Theresa S; Wong, Melanie; Hsu, Peter; Berglund, Lucinda J; Boztug, Kaan; Lau, Anthony; Gostick, Emma; Price, David A; O'Sullivan, Michael; Meyts, Isabelle; Choo, Sharon; Gray, Paul; Holland, Steven M; Deenick, Elissa K; Uzel, Gulbu; Tangye, Stuart G

2018-05-22

Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphatidylinositol-3 kinase, result in hyperactivation of the PI3K-AKT-mTOR pathway and underlie a novel inborn error of immunity. Affected individuals exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or CMV infection, and an increased incidence of B-cell lymphoproliferation and/or lymphoma. Mechanisms underlying disease pathogenesis remain unknown. Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in individuals with PIK3CD GOF mutations, identify key molecules required for cell mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this as well as other EBV-opathies. We studied the consequences of PIK3CD GOF mutations on the generation, differentiation and function of CD8 + T cells and NK cells, which are implicated in host defense against infection with herpesviruses including EBV. PIK3CD GOF total and EBV-specific CD8 + T cells were skewed towards an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion, and increased susceptibility to re-activation induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF. NK cells in PIK3CD GOF individuals also exhibited perturbed expression of differentiation-associated molecules. Both CD8 + T cells and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, PDL-1/2 and CD70. PIK3CD GOF mutations aberrantly induce exhaustion and/or senescence and impair cytotoxicity of CD8+ T and NK cells. These defects may contribute to clinical features of affected individuals, such as impaired immunity to herpesviruses and tumor surveillance. Copyright © 2018. Published by Elsevier Inc.

Communication Apprehension and Resting Alpha Range Asymmetry in the Anterior Cortex

ERIC Educational Resources Information Center

Beatty, Michael J.; Heisel, Alan D.; Lewis, Robert J.; Pence, Michelle E.; Reinhart, Amber; Tian, Yan

2011-01-01

In this study, we examined the relationship between trait-like communication apprehension (CA) and resting alpha range asymmetry in the anterior cortex (AC). Although theory and research in cognitive neuroscience suggest that asymmetry in the AC constitutes a relatively stable, inborn, substrate of emotion, some studies indicate that asymmetry can…

Who Has an Artistic Temperament? Relationships between Creativity and Temperament among Artists and Bank Officers

ERIC Educational Resources Information Center

Necka, Edward; Hlawacz, Teresa

2013-01-01

In contrast to vast literature devoted to the relationships between creativity and personality, relatively few studies addressed the question of the creativity-temperament link. Temperament is conceptualized as the biologically rooted, mostly inborn, foundations for personality and other individual traits. Sixty artists and 60 bank officers…

The Big Picture. Spotlight: Gender Differences.

ERIC Educational Resources Information Center

Turner, Joy

1995-01-01

Examines the influence of prenatal sex hormones on later behavior and social learning that results from differential treatment of boys and girls by parents and peers. Also explores differences in academic achievement between boys and girls. Concludes that, contrary to the views of some parents and teachers in the 1970s and 1980s, inborn gender…

Attention Deficit Disorder and Hyperactivity. Second Edition.

ERIC Educational Resources Information Center

Friedman, Ronald J.; Doyal, Guy T.

This book is designed for parents and teachers of children with Attention Deficit Disorder (ADD) and hyperactivity. Chapter 1 describes the symptoms, diagnosis, and causes of ADD, its effect on parents and families, inborn temperament characteristics of children with ADD, and tests and rating scales used to diagnose and treat the disorder. The…

Human factors process failure modes and effects analysis (HF PFMEA) software tool

NASA Technical Reports Server (NTRS)

Chandler, Faith T. (Inventor); Relvini, Kristine M. (Inventor); Shedd, Nathaneal P. (Inventor); Valentino, William D. (Inventor); Philippart, Monica F. (Inventor); Bessette, Colette I. (Inventor)

2011-01-01

Methods, computer-readable media, and systems for automatically performing Human Factors Process Failure Modes and Effects Analysis for a process are provided. At least one task involved in a process is identified, where the task includes at least one human activity. The human activity is described using at least one verb. A human error potentially resulting from the human activity is automatically identified, the human error is related to the verb used in describing the task. A likelihood of occurrence, detection, and correction of the human error is identified. The severity of the effect of the human error is identified. The likelihood of occurrence, and the severity of the risk of potential harm is identified. The risk of potential harm is compared with a risk threshold to identify the appropriateness of corrective measures.

Air Force Academy Homepage

Science.gov Websites

Chaplain Corps Cadet Chapel Community Center Chapel Institutional Review Board Not Human Subjects Research Requirements 7 Not Human Subjects Research Form 8 Researcher Instructions - Activities Submitted to DoD IRB 9 Review 18 Not Human Subjects Errors 19 Exempt Research Most Frequent Errors 20 Most Frequent Errors for

Development of an FAA-EUROCONTROL technique for the analysis of human error in ATM : final report.

DOT National Transportation Integrated Search

2002-07-01

Human error has been identified as a dominant risk factor in safety-oriented industries such as air traffic control (ATC). However, little is known about the factors leading to human errors in current air traffic management (ATM) systems. The first s...

Human Error: The Stakes Are Raised.

ERIC Educational Resources Information Center

Greenberg, Joel

1980-01-01

Mistakes related to the operation of nuclear power plants and other technologically complex systems are discussed. Recommendations are given for decreasing the chance of human error in the operation of nuclear plants. The causes of the Three Mile Island incident are presented in terms of the human error element. (SA)

Avoiding Human Error in Mission Operations: Cassini Flight Experience

NASA Technical Reports Server (NTRS)

Burk, Thomas A.

2012-01-01

Operating spacecraft is a never-ending challenge and the risk of human error is ever- present. Many missions have been significantly affected by human error on the part of ground controllers. The Cassini mission at Saturn has not been immune to human error, but Cassini operations engineers use tools and follow processes that find and correct most human errors before they reach the spacecraft. What is needed are skilled engineers with good technical knowledge, good interpersonal communications, quality ground software, regular peer reviews, up-to-date procedures, as well as careful attention to detail and the discipline to test and verify all commands that will be sent to the spacecraft. Two areas of special concern are changes to flight software and response to in-flight anomalies. The Cassini team has a lot of practical experience in all these areas and they have found that well-trained engineers with good tools who follow clear procedures can catch most errors before they get into command sequences to be sent to the spacecraft. Finally, having a robust and fault-tolerant spacecraft that allows ground controllers excellent visibility of its condition is the most important way to ensure human error does not compromise the mission.

Good people who try their best can have problems: recognition of human factors and how to minimise error.

PubMed

Brennan, Peter A; Mitchell, David A; Holmes, Simon; Plint, Simon; Parry, David

2016-01-01

Human error is as old as humanity itself and is an appreciable cause of mistakes by both organisations and people. Much of the work related to human factors in causing error has originated from aviation where mistakes can be catastrophic not only for those who contribute to the error, but for passengers as well. The role of human error in medical and surgical incidents, which are often multifactorial, is becoming better understood, and includes both organisational issues (by the employer) and potential human factors (at a personal level). Mistakes as a result of individual human factors and surgical teams should be better recognised and emphasised. Attitudes and acceptance of preoperative briefing has improved since the introduction of the World Health Organization (WHO) surgical checklist. However, this does not address limitations or other safety concerns that are related to performance, such as stress and fatigue, emotional state, hunger, awareness of what is going on situational awareness, and other factors that could potentially lead to error. Here we attempt to raise awareness of these human factors, and highlight how they can lead to error, and how they can be minimised in our day-to-day practice. Can hospitals move from being "high risk industries" to "high reliability organisations"? Copyright © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Using a Delphi Method to Identify Human Factors Contributing to Nursing Errors.

PubMed

Roth, Cheryl; Brewer, Melanie; Wieck, K Lynn

2017-07-01

The purpose of this study was to identify human factors associated with nursing errors. Using a Delphi technique, this study used feedback from a panel of nurse experts (n = 25) on an initial qualitative survey questionnaire followed by summarizing the results with feedback and confirmation. Synthesized factors regarding causes of errors were incorporated into a quantitative Likert-type scale, and the original expert panel participants were queried a second time to validate responses. The list identified 24 items as most common causes of nursing errors, including swamping and errors made by others that nurses are expected to recognize and fix. The responses provided a consensus top 10 errors list based on means with heavy workload and fatigue at the top of the list. The use of the Delphi survey established consensus and developed a platform upon which future study of nursing errors can evolve as a link to future solutions. This list of human factors in nursing errors should serve to stimulate dialogue among nurses about how to prevent errors and improve outcomes. Human and system failures have been the subject of an abundance of research, yet nursing errors continue to occur. © 2016 Wiley Periodicals, Inc.

Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance.

PubMed

Habib, Anasufiza; Md Yunus, Zabedah; Azize, Nor Azimah; Ch'ng, Gaik-Siew; Ong, Winnie Peitee; Chen, Bee-Chin; Hsu, Ho-Torng; Wong, Ke-Juin; Pitt, James; Ngu, Lock-Hock

2013-09-01

Lysinuric protein intolerance (LPI; MIM 222700) is an inherited aminoaciduria with an autosomal recessive mode of inheritance. Biochemically, affected patients present with increased excretion of the cationic amino acids: lysine, arginine, and ornithine. We report the first case of LPI diagnosed in Malaysia presented with excessive excretion of homocitrulline. The patient was a 4-year-old male who presented with delayed milestones, recurrent diarrhea, and severe failure to thrive. He developed hyperammonemic coma following a forced protein-rich diet. Plasma amino acid analysis showed increased glutamine, alanine, and citrulline but decreased lysine, arginine and ornithine. Urine amino acids showed a marked excretion of lysine and ornithine together with a large peak of unknown metabolite which was subsequently identified as homocitrulline by tandem mass spectrometry. Molecular analysis confirmed a previously unreported homozygous mutation at exon 1 (235 G > A, p.Gly79Arg) in the SLC7A7 gene. This report demonstrates a novel mutation in the SLC7A7 gene in this rare inborn error of diamino acid metabolism. It also highlights the importance of early and efficient treatment of infections and dehydration in these patients. The diagnosis of LPI is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis.

Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.

PubMed

Comeaux, Matthew S; Wang, Jing; Wang, Guoli; Kleppe, Soledad; Zhang, Victor Wei; Schmitt, Eric S; Craigen, William J; Renaud, Deborah; Sun, Qin; Wong, Lee-Jun

2013-07-01

Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing. Copyright © 2013 Elsevier Inc. All rights reserved.

High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, Triple H syndrome and OTC deficiency.

PubMed

Auray-Blais, Christiane; Maranda, Bruno; Lavoie, Pamela

2014-09-25

Creatine synthesis and transport disorders, Triple H syndrome and ornithine transcarbamylase deficiency are treatable inborn errors of metabolism. Early screening of patients was found to be beneficial. Mass spectrometry analysis of specific urinary biomarkers might lead to early detection and treatment in the neonatal period. We developed a high-throughput mass spectrometry methodology applicable to newborn screening using dried urine on filter paper for these aforementioned diseases. A high-throughput methodology was devised for the simultaneous analysis of creatine, guanidineacetic acid, orotic acid, uracil, creatinine and respective internal standards, using both positive and negative electrospray ionization modes, depending on the compound. The precision and accuracy varied by <15%. Stability during storage at different temperatures was confirmed for three weeks. The limits of detection and quantification for each biomarker varied from 0.3 to 6.3 μmol/l and from 1.0 to 20.9 μmol/l, respectively. Analyses of urine specimens from affected patients revealed abnormal results. Targeted biomarkers in urine were detected in the first weeks of life. This rapid, simple and robust liquid chromatography/tandem mass spectrometry methodology is an efficient tool applicable to urine screening for inherited disorders by biochemical laboratories. Copyright © 2014 Elsevier B.V. All rights reserved.

In Vivo Selection of Transplanted Hepatocytes by Pharmacological Inhibition of Fumarylacetoacetate Hydrolase in Wild-type Mice

PubMed Central

Paulk, Nicole K; Wursthorn, Karsten; Haft, Annelise; Pelz, Carl; Clarke, Gregory; Newell, Amy H; Olson, Susan B; Harding, Cary O; Finegold, Milton J; Bateman, Raymond L; Witte, John F; McClard, Ronald; Grompe, Markus

2012-01-01

Genetic fumarylacetoacetate hydrolase (Fah) deficiency is unique in that healthy gene-corrected hepatocytes have a strong growth advantage and can repopulate the diseased liver. Unfortunately, similar positive selection of gene-corrected cells is absent in most inborn errors of liver metabolism and it is difficult to reach the cell replacement index required for therapeutic benefit. Therefore, methods to transiently create a growth advantage for genetically modified hepatocytes in any genetic background would be advantageous. To mimic the selective pressure of Fah deficiency in normal animals, an efficient in vivo small molecule inhibitor of FAH, 4-[(2-carboxyethyl)-hydroxyphosphinyl]-3-oxobutyrate (CEHPOBA) was developed. Microarray analysis demonstrated that pharmacological inhibition of FAH produced highly similar gene expression changes to genetic deficiency. As proof of principle, hepatocytes lacking homogentisic acid dioxygenase (Hgd) and hence resistant to FAH inhibition were transplanted into sex-mismatched wild-type recipients. Time course analyses of 4–6 weeks of CEHPOBA administration after transplantation showed a linear relationship between treatment length and replacement index. Compared to controls, recipients treated with the FAH-inhibitor had 20–100-fold increases in liver repopulation. We conclude that pharmacological inhibition of FAH is a promising approach to in vivo selection of hepatocytes. PMID:22871666

Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease.

PubMed

Fuller, Maria; Rozaklis, Tina; Lovejoy, Melanie; Zarrinkalam, Krystyna; Hopwood, John J; Meikle, Peter J

2008-04-01

Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme beta-glucosidase leading to the accumulation of glucosylceramide (GC) in lysosomes of affected cells. In order to determine the effect of GC accumulation on intracellular lipid content in fibroblasts from patients with GD, we measured individual species of ceramide, di- and trihexosylceramide, sphingomyelin, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol using electrospray ionisation-tandem mass spectrometry. The different subspecies of each lipid class correlated with each other and were summed to give total lipid concentrations. In addition to GC, we also noted secondary elevations in other lipids, especially in type 2 GD. Sub-cellular fractionation showed that GC was not confined to the lysosome but increased throughout the cell. The sequelae of extra-lysosomal accumulation may have implications in the pathogenic mechanisms of GD by interaction with biochemical and metabolic pathways located outside the lysosome. The elevation of ceramide in confluent type 2 GD fibroblasts redistributed from its primary site of accumulation in the lysosome to the endosomal region at four-weeks post-confluence. The accumulation of lipids in the endosome and lysosome suggests both impaired trafficking of lipids and reduced capacity of the lysosome to degrade lipids.

Physical therapy management of infants and children with hypophosphatasia.

PubMed

Phillips, Dawn; Case, Laura E; Griffin, Donna; Hamilton, Kim; Lara, Sergio Lerma; Leiro, Beth; Monfreda, Jessica; Westlake, Elaine; Kishnani, Priya S

2016-09-01

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities. Recent clinical trials of enzyme replacement therapy have begun to offer an opportunity for improvement in survival and function. The role of physical therapy in the treatment of the underlying musculoskeletal dysfunction in HPP is underrecognized. It is important for physical therapists to understand the disease characteristics of the natural history of a rare disease like HPP and how the impairment and activity limitations may change in response to medical interventions. An understanding of when and how to intervene is also important in order to optimally impact body function, lessen structural impairment, and facilitate increased functional independence in mobility and activities of daily living. Individualizing treatment to the child's needs, medical fragility, and setting (home/school/hospital), while educating parents, caregivers, and school staff regarding approved activities and therapy frequency, may improve function and development in children with HPP. Copyright © 2016 Elsevier Inc. All rights reserved.

Hyperammonemia associated with distal renal tubular acidosis or urinary tract infection: a systematic review.

PubMed

Clericetti, Caterina M; Milani, Gregorio P; Lava, Sebastiano A G; Bianchetti, Mario G; Simonetti, Giacomo D; Giannini, Olivier

2018-03-01

Hyperammonemia usually results from an inborn error of metabolism or from an advanced liver disease. Individual case reports suggest that both distal renal tubular acidosis and urinary tract infection may also result in hyperammonemia. A systematic review of the literature on hyperammonemia secondary to distal renal tubular acidosis and urinary tract infection was conducted. We identified 39 reports on distal renal tubular acidosis or urinary tract infections in association with hyperammonemia published between 1980 and 2017. Hyperammonemia was detected in 13 children with distal renal tubular acidosis and in one adult patient with distal renal tubular acidosis secondary to primary hyperparathyroidism. In these patients a negative relationship was observed between circulating ammonia and bicarbonate levels (P < 0.05). In 31 patients (19 children, 12 adults), an acute urinary tract infection was complicated by acute hyperammonemia and symptoms and signs of acute neuronal dysfunction, such as an altered level of consciousness, convulsions and asterixis, often associated with signs of brain edema, such as anorexia and vomiting. Urea-splitting bacteria were isolated in 28 of the 31 cases. The urinary tract was anatomically or functionally abnormal in 30 of these patients. This study reveals that both altered distal renal tubular acidification and urinary tract infection may be associated with relevant hyperammonemia in both children and adults.

Pathogenesis, Epidemiology, Diagnosis and Clinical Aspects of Smith-Lemli-Opitz Syndrome

PubMed Central

Bianconi, Simona E.; Cross, Joanna L.; Wassif, Christopher A.; Porter, Forbes D.

2015-01-01

Introduction Smith-Lemli-Opitz Syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability. Areas covered In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients. We then explore the underlying biochemical defect and pathophysiological alterations that may contribute to the many disease manifestations. Subsequently we explore the epidemiology and succinctly discuss population genetics as they relate to SLOS. The next section presents the diagnostic possibilities. Thereafter, the treatment and management as is standard of care are presented. Expert opinion Even though the knowledge of the underlying molecular mutations and the biochemical alterations is being rapidly accumulated, there is currently no efficacious therapy addressing neurological dysfunction. We discuss the difficulty of treating this disorder, which manifests as a combination of a malformation syndrome and an inborn error of metabolism. A very important factor in developing new therapies is the need to rigorously establish efficacy in controlled trials. PMID:25734025

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations.

PubMed

Stephen, Joshi; Vilboux, Thierry; Haberman, Yael; Pri-Chen, Hadass; Pode-Shakked, Ben; Mazaheri, Sina; Marek-Yagel, Dina; Barel, Ortal; Di Segni, Ayelet; Eyal, Eran; Hout-Siloni, Goni; Lahad, Avishay; Shalem, Tzippora; Rechavi, Gideon; Malicdan, May Christine V; Weiss, Batia; Gahl, William A; Anikster, Yair

2016-08-01

Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

Newborn screening 50 years later: access issues faced by adults with PKU

PubMed Central

Berry, Susan A.; Brown, Christine; Grant, Mitzie; Greene, Carol L.; Jurecki, Elaina; Koch, Jean; Moseley, Kathryn; Suter, Ruth; van Calcar, Sandra C.; Wiles, Judy; Cederbaum, Stephen

2013-01-01

Fifty years after the implementation of universal newborn screening programs for phenylketonuria, the first disease identified through newborn screening and considered a success story of newborn screening, a cohort of adults with phenylketonuria treated from birth provides valuable information about effects of long-term treatment for inborn errors of metabolism in general, and phenylketonuria specifically. For phenylketonuria, newborn screening allows early implementation of the phenylalanine-restricted diet, eliminating the severe neurocognitive and neuromotor impairment associated with untreated phenylketonuria. However, executive function impairments and psychiatric problems are frequently reported even for those treated early and continuously with the phenylalanine-restricted diet alone. Moreover, a large percentage of adults with phenylketonuria are reported as lost to follow-up by metabolic clinics. While a group of experts identified by the National Institutes of Health convenes to update treatment guidelines for phenylketonuria, we explore individual patient, social, and economic factors preventing >70% of adult phenylketonuria patients in the United States from accessing treatment. As more conditions are identified through newborn screening, factors affecting access to treatment grow in importance, and we must continue to be vigilant in assessing and addressing factors that affect patient treatment outcomes and not just celebrate amelioration of the most severe manifestations of disease. Genet Med 2013:15(8):591–599 PMID:23470838

Newborn screening 50 years later: access issues faced by adults with PKU.

PubMed

Berry, Susan A; Brown, Christine; Grant, Mitzie; Greene, Carol L; Jurecki, Elaina; Koch, Jean; Moseley, Kathryn; Suter, Ruth; van Calcar, Sandra C; Wiles, Judy; Cederbaum, Stephen

2013-08-01

Fifty years after the implementation of universal newborn screening programs for phenylketonuria, the first disease identified through newborn screening and considered a success story of newborn screening, a cohort of adults with phenylketonuria treated from birth provides valuable information about effects of long-term treatment for inborn errors of metabolism in general, and phenylketonuria specifically. For phenylketonuria, newborn screening allows early implementation of the phenylalanine-restricted diet, eliminating the severe neurocognitive and neuromotor impairment associated with untreated phenylketonuria. However, executive function impairments and psychiatric problems are frequently reported even for those treated early and continuously with the phenylalanine-restricted diet alone. Moreover, a large percentage of adults with phenylketonuria are reported as lost to follow-up by metabolic clinics. While a group of experts identified by the National Institutes of Health convenes to update treatment guidelines for phenylketonuria, we explore individual patient, social, and economic factors preventing >70% of adult phenylketonuria patients in the United States from accessing treatment. As more conditions are identified through newborn screening, factors affecting access to treatment grow in importance, and we must continue to be vigilant in assessing and addressing factors that affect patient treatment outcomes and not just celebrate amelioration of the most severe manifestations of disease.

d-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence.

PubMed

Swanson, Michael A; Garcia, Stephanie M; Spector, Elaine; Kronquist, Kathryn; Creadon-Swindell, Geralyn; Walter, Melanie; Christensen, Ernst; Van Hove, Johan L K; Sass, Jörn Oliver

2017-06-01

Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Mutations in the GLYCTK gene (encoding d-glycerate kinase) causing glyceric aciduria were previously noted. Since glycine changes were not observed in almost all of the subsequently reported cases of d-glyceric aciduria, this theory of NKH as a secondary syndrome of d-glyceric aciduria was revisited in this work. We showed that this historic patient harbored a homozygous missense mutation in AMT c.350C>T, p.Ser117Leu, and enzymatic assay of the expressed mutation confirmed the pathogeneity of the p.Ser117Leu mutation. We conclude that the original d-glyceric aciduria patient also had classic NKH and that this co-occurrence of two inborn errors of metabolism explains the original presentation. We conclude that no evidence remains that d-glyceric aciduria would cause NKH. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolic cutis laxa syndromes.

PubMed

Mohamed, Miski; Kouwenberg, Dorus; Gardeitchik, Thatjana; Kornak, Uwe; Wevers, Ron A; Morava, Eva

2011-08-01

Cutis laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of cutis laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited cutis laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with cutis laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of cutis laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic cutis laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing cutis laxa we offer a practical approach for the differential diagnosis of metabolic cutis laxa syndromes.

Evaluation of oxidative stress markers and cardiovascular risk factors in Fabry Disease patients

PubMed Central

Müller, Karen B.; Galdieri, Luciano C.; Pereira, Vanessa G.; Martins, Ana M.; D’Almeida, Vânia

2012-01-01

Fabry Disease, an X-linked inborn error of metabolism, is characterized by progressive renal insufficiency, with cardio and cerebrovascular involvement. Homocysteine (Hcy) is considered a risk factor for vascular diseases, but the mechanisms by which it produces cardiovascular damage are still poorly understood. Regarding the vascular involvement in FD patients, the analysis of factors related to thromboembolic events could be useful to improving our understanding of the disease. The aim of this study was to evaluate plasma Hcy and other parameters involved in the methionine cycle, as well as oxidative stress markers. The sample consisted of a group of 10 male FD patients and a control group of 8 healthy individuals, paired by age. Venous blood was collected for Hcy determination, molecular analysis, identification of thiobarbituric acid reactive substances, total glutathione and antioxidant enzymes activity, as well as vitamins quantification. Comparative analysis of FD patients versus the control group indicated hyperhomocysteinemia in 8 of the 10 FD patients, as well as a significant increase in overall glutathione levels and catalase activity. It is inferred that FD patients, apart from activation of the antioxidant system, present increased levels of plasma Hcy, although this is probably unrelated to common alterations in the methionine cycle. PMID:22888289

Diagnosis of secondary amyloidosis in alkaptonuria.

PubMed

Millucci, Lia; Ghezzi, Lorenzo; Bernardini, Giulia; Braconi, Daniela; Lupetti, Pietro; Perfetto, Federico; Orlandini, Maurizio; Santucci, Annalisa

2014-09-26

Alkaptonuria (AKU) is an inborn error of catabolism due to a deficient activity of homogentisate 1,2-dioxygenase. Patients suffer from a severe arthropathy, cardiovascular and kidney disease but other organs are affected, too. We found secondary amyloidosis as a life-threatening complication in AKU, thus opening new perspectives for its treatment. We proved that methotrexate and anti-oxidants have an excellent efficacy to inhibit the production of amyloid in AKU model chondrocytes. Owing to the progressive and intractable condition, it seems important to detect amyloid deposits at an early phase in AKU and the choice of specimens for a correct diagnosis is crucial. Ten AKU subjects were examined for amyloidosis; abdominal fat pad aspirates, labial salivary gland, cartilage and synovia specimens were analysed by CR, Th-T, IF, TEM. Amyloid was detected in only one abdominal fat pad specimen. However, all subjects demonstrated amyloid deposition in salivary glands and in other organ biopsies, indicating salivary gland as the ideal specimen for early amyloid detection in AKU. This is, at the best of our knowledge, the first report providing correct indications on the diagnosis of amyloidosis in AKU, thus offering the possibility of treatment of such co-morbidity to AKU patients. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_185.

Genetic polymorphisms of vitamin D receptor (VDR) in Fabry disease.

PubMed

Teitcher, Michael; Weinerman, Sarah; Whybra, Catharina; Beck, Michael; Sharon, Nir; Elstein, Deborah; Altarescu, Gheona

2008-11-01

Fabry disease, an X-linked inborn error of metabolism, is characterized by multi-organ involvement including cardiac signs of left ventricular hypertrophy and abnormal intima-medial (IMT) thickening of arteries, progressive renal failure, neurological involvement, and more. The vitamin D receptor (VDR) and an enzyme producing vitamin D3 result in an autocrine loop with direct effects on blood vessels. The purpose of this study is to assess VDR polymorphisms (BsmI, FokI, ApaI, and TaqI) relative to clinically important disease parameters using a disease-specific severity score (MSSI) and haplotype analysis. There were statistically significant differences between females (43% of 74 patients) and males in MSSI total scores, and in general and neurologic sub-scores. There appears to be a protective effect of the TaqI tt genotype so that there were significantly lower scores in clinical categories between those with the tt genotype versus those with the TT genotype. Multivariate models of haplotypes with MSSI scores reveal that T-A-f-B and t-a-F-b haplotypes of the VDR gene polymorphisms are significantly associated with variation in the Fabry phenotype. Despite the limitations of using the MSSI score as a clinical correlate, these results are provocative and further studies in larger cohorts with more males are recommended.

Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E.

PubMed

Baumgartner, Matthias R

2013-01-01

The catalytic properties of many enzymes depend on the participation of vitamins as obligatory cofactors. Vitamin B12 (cobalamin) and folic acid (folate) deficiencies in infants and children classically present with megaloblastic anemia and are often accompanied by neurological signs. A number of rare inborn errors of cobalamin and folate absorption, transport, cellular uptake, and intracellular metabolism have been delineated and identification of disease-causing mutations has improved our ability to diagnose and treat many of these conditions. Two inherited defects in biotin metabolism are known, holocarboxylase synthetase and biotinidase deficiency. Both lead to multiple carboxylase deficiency manifesting with metabolic acidosis, neurological abnormalities, and skin rash. Thiamine-responsive megaloblastic anemia is characterized by megaloblastic anemia, non-type I diabetes, and sensorineural deafness that responds to pharmacological doses of thiamine (vitamin B1). Individuals affected with inherited vitamin E deficiencies including ataxia with isolated vitamin E deficiency and abetalipoproteinemia present with a spinocerebellar syndrome similar to patients with Friedreich's ataxia. If started early, treatment of these defects by oral or parenteral administration of the relevant vitamin often results in correction of the metabolic defect and reversal of the signs of disease, stressing the importance of early and correct diagnosis in these treatable conditions. Copyright © 2013 Elsevier B.V. All rights reserved.

Transient 5-oxoprolinuria: unusually high anion gap acidosis in an infant.

PubMed

Hulley, Sarah L; Perring, Jeff; Manning, Nigel; Olpin, Simon; Yap, Sufin

2015-12-01

Transient 5-oxoprolinuria is a phenomenon that is well recognised in adults. We illustrate an unusual paediatric case of transient 5-oxoprolinuria presenting during an episode of severe sepsis with concomitant paracetamol use. The 15-month-old patient had an extremely high anion gap metabolic acidosis. Adequate resuscitation failed to correct the biochemical disturbance, and high levels of 5-oxoproline were identified. A combination of haemofiltration, replenishment of glutathione stores with N-acetylcysteine and cessation of paracetamol administration resulted in the resolution of the acidosis. Subsequent testing following treatment of the sepsis revealed no ongoing 5-oxoprolinuria. Transient 5-oxoprolinuria has been previously reported in the adult population during episodes of severe sepsis and various pharmaceutical interventions. This case illustrates that it is a phenomenon that should be considered in paediatric patients where a very high anion gap metabolic acidosis exists that cannot be explained by the biochemical indices. • 5-oxoprolinuria in the paediatric population is usually secondary to an inborn error of metabolism. • Transient 5-oxoprolinuria is well recognised in adults during episodes of severe glutathione depletion. • Transient 5-oxoprolinuria is a phenomenon rarely reported in the paediatric population. • It highlights the importance of investigating a high anion gap such that unusual diagnoses are not missed.

Application of a comprehensive protocol for the identification of Gaucher disease in Brazil.

PubMed

Michelin, Kristiane; Wajner, Alessandro; de Souza, Fernanda T S; de Mello, Alexandre S; Burin, Maira G; Pereira, Maria Luiza S; Pires, Ricardo F; Giugliani, Roberto; Coelho, Janice C

2005-07-01

Gaucher disease (GD) is a sphingolipidosis caused by a genetic defect that leads to glucocerebrosidase (beta-glucosidase) deficiency. Between January 1982 and October 2003, 1,081 blood samples from patients suspected of having GD were referred for biochemical analysis. The activities of the enzymes beta-glucosidase (beta-glu) and chitotriosidase (CT) were measured in these samples. Among the 412 diagnosed cases of GD (38.1%), the great majority were GD type 1. The Brazilian regions with the greatest concentration of these patients were the Southeast, South, and Northeast. The mean age of patients at diagnosis was 19 years. The activity of beta-glu in patients with GD was, on average, 10.7% of that of normal individuals. CT was, on average, 269 times more elevated in this group of patients. Among the 669 cases with no confirmation of GD, there were patients with Niemann-Pick disease types A, B, or C (44 cases), possible heterozygotes for GD (59 cases), patients with other lysosomal storage diseases (LSDs) (19 cases) or with other inborn errors of metabolism (3 cases). In 508 cases, no metabolic disorder was found. This study shows that the biochemical protocol employed was effective for the detection of GD, a disease that is reasonably frequent in Brazil. Copyright (c) 2005 Wiley-Liss, Inc.

Fatal ammonia toxicity in an adult due to an undiagnosed urea cycle defect: under-recognition of ornithine transcarbamylase deficiency.

PubMed

Thurlow, Vanessa R; Asafu-Adjaye, Michelle; Agalou, Stamatina; Rahman, Yusof

2010-05-01

There is a lack of awareness of acutely presenting inborn errors of metabolism in adults, of which the X-linked urea cycle defect ornithine transcarbamylase (OTC) deficiency is an example, many comparatively mild mutations having been identified. In male hemizygotes clinical manifestations and age at presentation vary and depend on the mutation. In female heterozygotes the clinical spectrum depends on the extent to which the abnormal gene is expressed. Milder versions of the defect may not cause clear clinical symptoms and may remain unrecognized until the person is subjected to an unusually high nitrogen load when they develop severe hyperammonaemia. During acute episodes liver enzymes may be normal or only slightly elevated and occasionally accompanied by coagulopathy, but the key finding is hyperammonaemia. Boys with these milder forms may exhibit abnormal behaviour and be diagnosed with attention deficit hyperactivity disorder. This case illustrates how late presentation of OTC deficiency in a non-specialist centre can be difficult to differentiate from drug abuse, psychiatric illness or encephalopathy. Failure to measure blood ammonia in adults with unexplained key symptoms - particularly prolonged vomiting without diarrhoea and altered mental state/hallucinations, or to recognize the significance of elevated blood ammonia without evidence of liver decompensation can lead to delayed or missed diagnosis.