Inborn Errors of Metabolism with Hypoglycemia Glycogen Storage Diseases and Inherited Disorders of Gluconeogenesis : Glycogen Storage Diseases and Inherited Disorders of Gluconeogenesis

NARCIS (Netherlands)

Weinstein, David A.; Steuerwald, Ulrike; De Souza, Carolina F. M.; Derks, Terry G. J.

Although hyperinsulinism is the predominant inherited cause of hypoglycemia in the newborn period, inborn errors of metabolism are the primary etiologies after 1 month of age. Disorders of carbohydrate metabolism often present with hypoglycemia when fasting occurs. The presentation, diagnosis, and

/sup 1/H-NMR urinalysis. Simultaneous screening of inborn errors of metabolism of amino acid and organic acid disorders

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Yamamoto, Hideaki; Yamaguchi, Shuichi

1988-02-01

In an effort to examine the usefulness of /sup 1/H-nuclear magnetic resonance (NMR) urinalysis in the diagnosis of congenital metabolic disorders, 70 kinds of urinary metabolites were analysed in relation to the diagnosis of inborn errors of amino acid and organic acid disorders. Homogated decoupling (HMG) method failed to analyze six metabolites within the undetectable range. When non-decoupling method (NON), in which the materials are dissolved in dimethyl sulfoxide, was used, the identification of signals became possible. The combination of HMG and NON methods was, therefore, considered to identify all of the metabolites. When the urine samples, which were obtained from patients with hyperglycerolemia, hyperornithinemia, glutaric acidemia type II, or glycerol kinase deficiency, were analysed by using both HMG and NON methods, abnormally increased urinary metabolites were detected. /sup 1/H-NMR urinalysis, if used in the combination of HMG and NON methods, may allow simultanenous screening of inborn errors of metabolism of amino acid and organic acid disorders. (Namekawa, K.).

Gene therapy for the circumvention of inborn errors of metabolism (IEM) caused by single-nucleotide-polymorphisms (SNPs).

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Wiseman, Alan

2004-01-01

Single nucleotide polymorphisms (SNPs) are the result of point mutations in nuclear (and mitochondrial) DNA. Such localised damage to DNA (and its replicative mechanisms) may not be excised fully by the DNA repair mechanism in the genome: and therefore can become inheritable; subsequently to manifest later as an inborn error of metabolism (IEM). Causes of mutagenic damage to the DNA can include background radiation (such as emitted by radon gas), and by reactive oxygen species (ROS): and also by mutagenic chemicals that occur naturally (inter alia in the diet). Other causes of DNA damage are variable environmental hazards such as solar-derived short wave ultraviolet light A. Gene therapy involves the placement of missing genes into particular tissues by the harnessing of suitable vectors (originally these were animal viruses such as SV40). For example, gene therapy in the rat for diabetes has succeeded by liver-production of insulin (using genes obtained from pancreatic Islets of Langerhans cells). Many inborn errors of metabolism could be treated in this way: examples may include 100 haemoglobinopathies (such as sickle cell anaemia), phenylketonuria; and other diseases caused by lack of tissue-production of a particular enzyme (in its catalytically-active conformation).

Tratamento de erros inatos do metabolismo Treatment of inborn errors of metabolism

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Ida Vanessa Schwartz

2008-08-01

metabolism, priority was given to the most important methods for managing intoxication, in view of the importance for pediatricians to treat acute and life-threatening cases. The article also provides a general overview of the treatment for lysosomal and peroxisomal diseases, with emphasis on enzyme replacement therapy, which is a treatment modality that is growing in use and with which pediatricians should make themselves familiar. SUMMARY OF THE FINDINGS: The most important measures used to manage the intoxication present in many inborn errors of intermediate metabolism were presented (restriction of substrate build-up by means of diet or enzymatic inhibition, removal of toxic products, stimulation of residual enzyme activity, replacement of the deficient product. The section on treatment for lysosomal and peroxisomal diseases includes tables providing information on the treatments available. CONCLUSIONS: Treating inborn errors of metabolism is a complex task that should be performed by a multidisciplinary team of which the pediatrician is the key member. This article provides practical information relating to the management of some inborn errors of metabolism and provides pediatricians with a general overview of recent developments in this area of medicine.

In vivo enzyme activity in inborn errors of metabolism

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Thompson, G.N.; Walter, J.H.; Leonard, J.V.; Halliday, D. (Clinical Research Centre, Harrow (England))

1990-08-01

Low-dose continuous infusions of (2H5)phenylalanine, (1-13C)propionate, and (1-13C)leucine were used to quantitate phenylalanine hydroxylation in phenylketonuria (PKU, four subjects), propionate oxidation in methylmalonic acidaemia (MMA, four subjects), and propionic acidaemia (PA, four subjects) and leucine oxidation in maple syrup urine disease (MSUD, four subjects). In vivo enzyme activity in PKU, MMA, and PA subjects was similar to or in excess of that in adult controls (range of phenylalanine hydroxylation in PKU, 3.7 to 6.5 mumol/kg/h, control 3.2 to 7.9, n = 7; propionate oxidation in MMA, 15.2 to 64.8 mumol/kg/h, and in PA, 11.1 to 36.0, control 5.1 to 19.0, n = 5). By contrast, in vivo leucine oxidation was undetectable in three of the four MSUD subjects (less than 0.5 mumol/kg/h) and negligible in the remaining subject (2 mumol/kg/h, control 10.4 to 15.7, n = 6). These results suggest that significant substrate removal can be achieved in some inborn metabolic errors either through stimulation of residual enzyme activity in defective enzyme systems or by activation of alternate metabolic pathways. Both possibilities almost certainly depend on gross elevation of substrate concentrations. By contrast, only minimal in vivo oxidation of leucine appears possible in MSUD.

In vivo enzyme activity in inborn errors of metabolism

International Nuclear Information System (INIS)

Thompson, G.N.; Walter, J.H.; Leonard, J.V.; Halliday, D.

1990-01-01

Low-dose continuous infusions of [2H5]phenylalanine, [1-13C]propionate, and [1-13C]leucine were used to quantitate phenylalanine hydroxylation in phenylketonuria (PKU, four subjects), propionate oxidation in methylmalonic acidaemia (MMA, four subjects), and propionic acidaemia (PA, four subjects) and leucine oxidation in maple syrup urine disease (MSUD, four subjects). In vivo enzyme activity in PKU, MMA, and PA subjects was similar to or in excess of that in adult controls (range of phenylalanine hydroxylation in PKU, 3.7 to 6.5 mumol/kg/h, control 3.2 to 7.9, n = 7; propionate oxidation in MMA, 15.2 to 64.8 mumol/kg/h, and in PA, 11.1 to 36.0, control 5.1 to 19.0, n = 5). By contrast, in vivo leucine oxidation was undetectable in three of the four MSUD subjects (less than 0.5 mumol/kg/h) and negligible in the remaining subject (2 mumol/kg/h, control 10.4 to 15.7, n = 6). These results suggest that significant substrate removal can be achieved in some inborn metabolic errors either through stimulation of residual enzyme activity in defective enzyme systems or by activation of alternate metabolic pathways. Both possibilities almost certainly depend on gross elevation of substrate concentrations. By contrast, only minimal in vivo oxidation of leucine appears possible in MSUD

Errores innatos del metabolismo de las purinas y otras enfermedades relacionadas Inborn purine metabolism errors and other related diseases

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Jiovanna Contreras Roura

2012-06-01

Full Text Available Los errores innatos en el metabolismo de las purinas son trastornos hereditarios complejos de gran impacto clínico, que presentan síntomas variables de acuerdo con el tipo de enfermedad. Pueden presentarse problemas renales de origen desconocido, retardo mental con manifestaciones neurológicas, retardo del crecimiento, infecciones recurrentes, automutilación, inmunodeficiencias, anemia hemolítica inexplicable, artritis gotosa, historia familiar, consanguinidad y reacciones adversas a fármacos que son análogos de las purinas. Las investigaciones de estas enfermedades comienzan generalmente con la cuantificación del ácido úrico en suero y en orina, por ser el producto final del metabolismo de las purinas en humanos. La dieta y el consumo de medicamentos, entre otras condiciones patológicas, fisiológicas y clínicas, también pueden modificar los niveles de este compuesto. Esta revisión pretende divulgar información de los errores innatos en el metabolismo de las purinas, y facilitar la interpretación de los niveles del ácido úrico y otros marcadores bioquímicos útiles en el diagnóstico de estas enfermedades. Se incluyen tablas que relacionan estas enfermedades con los niveles de excreción de ácido úrico y otros marcadores bioquímicos, las enzimas alteradas, los síntomas clínicos, el modo de herencia y, en algunos casos, el tratamiento propuesto. Este trabajo nos permite afirmar que las variaciones en los niveles del ácido úrico y la presencia de otros marcadores bioquímicos en orina, constituyen una herramienta importante en la pesquisa de algunos errores innatos en el metabolismo de las purinas, así como de otras condiciones patológicas relacionadas.Inborn purine metabolism errors are complex inherited disorders of great clinical impact that present with variable symptoms according to the type of disease. It might occur renal problems of unknown origin, metal retardation with neurological manifestations, retarded

Simultaneous analysis of amino acid and organic acid by NMR spectrometry, 2. Diagnostic aids for inborn error of metabolism

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Koda, Naoya; Yamaguchi, Shuichi; Mori, Takeshi.

1987-09-01

Analysis of urine from patients with inborn error of metabolism were studied by /sup 1/H-nuclear magnetic resonance (NMR) spectrometry. Diseases studied were as follows; phenylketonuria, biotin responsive multiple carboxylase deficiency, non-ketotic hyperglycinemia, 3-ketothiolase deficiency, alkaptonuria, methylmalonic acidemia, isovaleric acidemia, glutaric aciduria, argininosuccinic aciduria and hyperornithinemia. In each disease, specific metabolites in urine were recognized by NMR spectrometry. This method is accomplished within 10 minutes with non-treated small volume of urine and will be successfully available for the screening andor diagnosis of inherited metabolic diseases of amino acid and organic acid.

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

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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

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

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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.

Insight on the impacts of free amino acids and their metabolites on the immune system from a perspective of inborn errors of amino acid metabolism.

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Pakula, Malgorzata M; Maier, Thorsten J; Vorup-Jensen, Thomas

2017-06-01

Amino acids (AAs) support a broad range of functions in living organisms, including several that affect the immune system. The functions of the immune system are affected when free AAs are depleted or in excess because of external factors, such as starvation, or because of genetic factors, such as inborn errors of metabolism. Areas covered: In this review, we discuss the current insights into how free AAs affect immune responses. When possible, we make comparisons to known disease states resulting from inborn errors of metabolism, in which changed levels of AAs or AA metabolites provide insight into the impact of AAs on the human immune system in vivo. We also explore the literature describing how changes in AA levels might provide pharmaceutical targets for safe immunomodulatory treatment. Expert opinion: The impact of free AAs on the immune system is a neglected topic in most immunology textbooks. That neglect is undeserved, because free AAs have both direct and indirect effects on the immune system. Consistent choices of pre-clinical models and better strategies for creating formulations are required to gain clinical impact.

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

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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.

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

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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

The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: Report from the SSIEM Adult Metabolic Physicians Group.

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Sirrs, S; Hollak, C; Merkel, M; Sechi, A; Glamuzina, E; Janssen, M C; Lachmann, R; Langendonk, J; Scarpelli, M; Ben Omran, T; Mochel, F; Tchan, M C

2016-01-01

There are few centres which specialise in the care of adults with inborn errors of metabolism (IEM). To anticipate facilities and staffing needed at these centres, it is of interest to know the distribution of the different disorders. A survey was distributed through the list-serve of the SSIEM Adult Metabolic Physicians group asking clinicians for number of patients with confirmed diagnoses, types of diagnoses and age at diagnosis. Twenty-four adult centres responded to our survey with information on 6,692 patients. Of those 6,692 patients, 510 were excluded for diagnoses not within the IEM spectrum (e.g. bone dysplasias, hemochromatosis) or for age less than 16 years, leaving 6,182 patients for final analysis. The most common diseases followed by the adult centres were phenylketonuria (20.6%), mitochondrial disorders (14%) and lysosomal storage disorders (Fabry disease (8.8%), Gaucher disease (4.2%)). Amongst the disorders that can present with acute metabolic decompensation, the urea cycle disorders, specifically ornithine transcarbamylase deficiency, were most common (2.2%), followed by glycogen storage disease type I (1.5%) and maple syrup urine disease (1.1%). Patients were frequently diagnosed as adults, particularly those with mitochondrial disease and lysosomal storage disorders. A wide spectrum of IEM are followed at adult centres. Specific knowledge of these disorders is needed to provide optimal care including up-to-date knowledge of treatments and ability to manage acute decompensation.

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

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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.

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

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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

Application of nuclear magnetic resonance spectroscopy combined with principal component analysis in detecting inborn errors of metabolism using blood spots: a metabonomic approach

International Nuclear Information System (INIS)

Constantinou, M.A.; Papakonstantinou, E.; Benaki, D.; Spraul, M.; Shulpis, K.; Koupparis, M.A.; Mikros, E.

2004-01-01

NMR spectra of extracted blood spots were used to investigate the possibility for the development of a new method for mass screening concerning the diagnosis of inborn errors of metabolism (IEM). Blood spots were collected on filter papers from normal, phenylketonuric (PKU) and maple syrup urine disease (MSUD) subjects and their Carr-Purcell-Meiboom-Gill (CPMG) 1 H NMR spectra were acquired. The spectra were reduced to a number of spectral descriptors and principal component analysis (PCA) was performed. The scores plot showed that PKU and MSUD samples were well discriminated from the main cluster of points

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

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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.

Inborn errors of metabolism and expanded newborn screening: review and update.

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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

Quality of Life and Associated Factors in Japanese Children With Inborn Errors of Metabolism and Their Families

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Keiko Yamaguchi RN, PHN

2018-02-01

Full Text Available To reveal the associated factors of quality of life (QoL in children with inborn errors of metabolism (IEM, their siblings, and their primary caregivers and partners, we conducted an anonymous questionnaire survey in Japan. Descriptive, correlation, and multiple regression analyses were performed. Fifty-six children with IEM, 35 siblings, 143 primary caregivers, and 86 partners completed our questionnaires. There were significant positive correlations between higher QoL in children with IEM and lower disease influence ( r = 0.46 and higher perceived emotional support ( r = 0.67. We could not find any associated factor of siblings’ QoL. Lower parental distress, higher family empowerment, and higher household income contributed to higher QoL in primary caregivers (adjusted R 2 = 0.636. Higher household income, lower anxiety about childrearing, and higher satisfaction in the relationship with the child and entire family contributed to higher QoL of partners (adjusted R 2 = 0.398. We concluded that developing effective interventions to improve QoL is needed for the entire family in future outpatient settings.

Clinical characteristics of adult patients with inborn errors of metabolism in Spain: A review of 500 cases from university hospitals

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J. Pérez-López

2017-03-01

Full Text Available Patients with inborn errors of metabolism (IEMs have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification. The most prevalent group of IEMs was amino acid disorders, with 108 (21.6% patients diagnosed with phenylketonuria. Lysosomal storage disorders were the second group, in which 32 (6.4% and 25 (5% patients had Fabry disease and Gaucher disease respectively. The great clinical heterogeneity, the significant delay in diagnosis after symptom onset, the existence of some degree of physical dependence in a great number of patients, the need for a multidisciplinary and coordinated approach, and the lack of specific drug treatment are common features in this group of conditions.

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

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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.

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

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Abdellah Tebani

2016-09-01

Full Text Available 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.

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

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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.

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

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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.

Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population

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Kejian Guo

2018-04-01

Full Text Available The incidence of inborn errors of metabolisms (IEMs varies dramatically in different countries and regions. Expanded newborn screening for IEMs by tandem mass spectrometry (MS/MS is an efficient approach for early diagnosis and presymptomatic treatment to prevent severe permanent sequelae and death. To determine the characteristics of IEMs and IEMs-associated mutations in newborns in Jining area, China, 48,297 healthy neonates were recruited for expanded newborn screening by MS/MS. The incidence of IEMs was 1/1178 in Jining, while methylmalonic acidemia, phenylketonuria, and primary carnitine deficiency ranked the top 3 of all detected IEMs. Thirty mutations in nine IEMs-associated genes were identified in 28 confirmed cases. As 19 cases with the mutations in phenylalanine hydroxylase (PAH, solute carrier family 22 member 5 (SLC22A5, and methylmalonic aciduria (cobalamin deficiency cblC type with homocystinuria (MMACHC genes, respectively, it suggested that mutations in the PAH, SLC22A5, and MMACHC genes are the predominant causes of IEMs, leading to the high incidence of phenylketonuria, primary carnitine deficiency, and methylmalonic acidemia, respectively. Our work indicated that the overall incidence of IEMs is high and the mutations in PAH, SLC22A5, and MMACHC genes are the leading causes of IEMs in Jining area. Therefore, it is critical to increase the coverage of expanded newborn screening by MS/MS and prenatal genetic consulting in Jining area.

Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy

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2017-08-31

Metabolism, Inborn Errors; Lipid Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency; Glycogenin-1 Deficiency (Glycogen Storage Disease Type XV); Carnitine Palmitoyl Transferase 2 Deficiency; VLCAD Deficiency; Medium-chain Acyl-CoA Dehydrogenase Deficiency; Multiple Acyl-CoA Dehydrogenase Deficiency; Carnitine Transporter Deficiency; Neutral Lipid Storage Disease; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Muscle Phosphofructokinase Deficiency; Phosphoglucomutase 1 Deficiency; Phosphoglycerate Mutase Deficiency; Phosphoglycerate Kinase Deficiency; Phosphorylase Kinase Deficiency; Beta Enolase Deficiency; Lactate Dehydrogenase Deficiency; Glycogen Synthase Deficiency

Severe infectious diseases of childhood as monogenic inborn errors of immunity.

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Casanova, Jean-Laurent

2015-12-22

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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

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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.

Incidence of Inborn Errors of Metabolism by Expanded Newborn Screening in a Mexican Hospital

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Consuelo Cantú-Reyna MD

2016-09-01

Full Text Available Newborn screening for the detection of inborn errors of metabolism (IEM, endocrinopathies, hemoglobinopathies, and other disorders is a public health initiative aimed at identifying specific diseases in a timely manner. Mexico initiated newborn screening in 1973, but the national incidence of this group of diseases is unknown or uncertain due to the lack of large sample sizes of expanded newborn screening (ENS programs and lack of related publications. The incidence of a specific group of IEM, endocrinopathies, hemoglobinopathies, and other disorders in newborns was obtained from a Mexican hospital. These newborns were part of a comprehensive ENS program at Ginequito (a private hospital in Mexico, from January 2012 to August 2014. The retrospective study included the examination of 10 000 newborns’ results obtained from the ENS program (comprising the possible detection of more than 50 screened disorders. The findings were the following: 34 newborns were confirmed with an IEM, endocrinopathies, hemoglobinopathies, or other disorders and 68 were identified as carriers. Consequently, the estimated global incidence for those disorders was 3.4 in 1000 newborns; and the carrier prevalence was 6.8 in 1000. Moreover, a 0.04% false-positive rate was unveiled as soon as diagnostic testing revealed negative results. The most frequent diagnosis was glucose-6-phosphate dehydrogenase deficiency; and in the case of carriers, it was hemoglobinopathies. The benefit of the ENS is clear as it offers prompt treatment on the basis of an early diagnosis including proper genetic counseling. Furthermore, these results provide a good estimation of the frequencies of different forms of newborn IEM, endocrinopathies, hemoglobinopathies, and other disorders at Ginequito.

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Science.gov (United States)

Casanova, Jean-Laurent

2015-01-01

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications. PMID:26621750

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

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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.

Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD

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Martha eSpilioti

2013-12-01

Full Text Available We screened for the presence of inborn errors of metabolism (IEM in 187 children (105 males; 82 females, ages 4 -14 years old who presented with confirmed features of ASD. Twelve patients (7% manifested increased 3-hydroxyisovaleric acid (3-OH-IVA excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2, succinic semialdehyde dehydrogenase (SSADH deficiency (2 and phenylketonuria (1 (2.7%. Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet. Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated nonspecific MRI pathology, while 25/187 had abnormal EEG findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA and novel treatment approaches in ASD patients.Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of autismspectrum disorder (ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b in 7% (13/187 of patients for whom biotin supplementation or institution of a ketogenic diet resulted in mild to significant clinical improvement in autistic features.

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

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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.

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

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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.

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.

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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 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.

Child and family experiences with inborn errors of metabolism: a qualitative interview study with representatives of patient groups.

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Khangura, Sara D; Tingley, Kylie; Chakraborty, Pranesh; Coyle, Doug; Kronick, Jonathan B; Laberge, Anne-Marie; Little, Julian; Miller, Fiona A; Mitchell, John J; Prasad, Chitra; Siddiq, Shabnaz; Siriwardena, Komudi; Sparkes, Rebecca; Speechley, Kathy N; Stockler, Sylvia; Trakadis, Yannis; Wilson, Brenda J; Wilson, Kumanan; Potter, Beth K

2016-01-01

Patient-centered health care for children with inborn errors of metabolism (IEM) and their families is important and requires an understanding of patient experiences, needs, and priorities. IEM-specific patient groups have emerged as important voices within these rare disease communities and are uniquely positioned to contribute to this understanding. We conducted qualitative interviews with IEM patient group representatives to increase understanding of patient and family experiences, needs, and priorities and inform patient-centered research and care. We developed a sampling frame of patient groups representing IEM disease communities from Canada, the United States, and United Kingdom. With consent, we interviewed participants to explore their views on experiences, needs, and outcomes that are most important to children with IEM and their families. We analyzed the data using a qualitative descriptive approach to identify key themes and sub-themes. We interviewed 18 organizational representatives between February 28 and September 17, 2014, representing 16 IEMs and/or disease categories. Twelve participants voluntarily self-identified as parents and/or were themselves patients. Three key themes emerged from the coded data: managing the uncertainty associated with raising and caring for a child with a rare disease; challenges associated with the affected child's life transitions, and; the collective struggle for improved outcomes and interventions that rare disease communities navigate. Health care providers can support children with IEM and their families by acknowledging and reducing uncertainty, supporting families through children's life transitions, and contributing to rare disease communities' progress toward improved interventions, experiences, and outcomes.

Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis : Results of a European Survey

NARCIS (Netherlands)

Jahnel, Jörg; Zöhrer, Evelyn; Fischler, Björn; D'Antiga, Lorenzo; Debray, Dominique; Dezsofi, Antal; Haas, Dorothea; Hadzic, Nedim; Jacquemin, Emmanuel; Lamireau, Thierry; Maggiore, Giuseppe; McKiernan, Pat J; Calvo, Pier Luigi; Verkade, Henkjan J; Hierro, Loreto; McLin, Valerie; Baumann, Ulrich; Gonzales, Emmanuel

2017-01-01

Objective: Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to

Inborn errors of metabolism for the diagnostic radiologist

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Hendriksz, Chris J. [Birmingham Children' s Hospital NHS Foundation Trust, Department of Clinical Inherited Metabolic Disorders, Birmingham (United Kingdom)

2009-03-15

Inherited metabolic disorders are becoming more important with the increasing availability of diagnostic methods and therapies for these conditions. The radiologist has become an important link in making the diagnosis or collaborating with the specialist centre to diagnose these disorders and monitor effects of therapy. The modes of presentation, disease-specific groups, classic radiological features and investigations are explored in this article to try and give the general radiologist some crucial background knowledge. The following presentations are covered: acute intoxication, hypoglycaemia, developmental delay and storage features. Specific groups of disorders covered are the abnormalities of intermediary metabolism, disorders of fatty acid oxidation and ketogenesis, mitochondrial disorders, lysosomal storage disorders, and, briefly, other groups such as peroxisomal disorders, disorders of glycosylation, and creatine synthesis disorders. New advances and the demands for monitoring are also briefly explored. (orig.)

Inborn errors of metabolism for the diagnostic radiologist

International Nuclear Information System (INIS)

Hendriksz, Chris J.

2009-01-01

Inherited metabolic disorders are becoming more important with the increasing availability of diagnostic methods and therapies for these conditions. The radiologist has become an important link in making the diagnosis or collaborating with the specialist centre to diagnose these disorders and monitor effects of therapy. The modes of presentation, disease-specific groups, classic radiological features and investigations are explored in this article to try and give the general radiologist some crucial background knowledge. The following presentations are covered: acute intoxication, hypoglycaemia, developmental delay and storage features. Specific groups of disorders covered are the abnormalities of intermediary metabolism, disorders of fatty acid oxidation and ketogenesis, mitochondrial disorders, lysosomal storage disorders, and, briefly, other groups such as peroxisomal disorders, disorders of glycosylation, and creatine synthesis disorders. New advances and the demands for monitoring are also briefly explored. (orig.)

Quality of life, psychological adjustment, and adaptive functioning of patients with intoxication-type inborn errors of metabolism - a systematic review.

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Zeltner, Nina A; Huemer, Martina; Baumgartner, Matthias R; Landolt, Markus A

2014-10-25

In recent decades, considerable progress in diagnosis and treatment of patients with intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders (UCD), organic acidurias (OA), maple syrup urine disease (MSUD), or tyrosinemia type 1 (TYR 1) has resulted in a growing group of long-term survivors. However, IT-IEM still require intense patient and caregiver effort in terms of strict dietetic and pharmacological treatment, and the threat of metabolic crises is always present. Furthermore, crises can affect the central nervous system (CNS), leading to cognitive, behavioural and psychiatric sequelae. Consequently, the well-being of the patients warrants consideration from both a medical and a psychosocial viewpoint by assessing health-related quality of life (HrQoL), psychological adjustment, and adaptive functioning. To date, an overview of findings on these topics for IT-IEM is lacking. We therefore aimed to systematically review the research on HrQoL, psychological adjustment, and adaptive functioning in patients with IT-IEM. Relevant databases were searched with predefined keywords. Study selection was conducted in two steps based on predefined criteria. Two independent reviewers completed the selection and data extraction. Eleven articles met the inclusion criteria. Studies were of varying methodological quality and used different assessment measures. Findings on HrQoL were inconsistent, with some showing lower and others showing higher or equal HrQoL for IT-IEM patients compared to norms. Findings on psychological adjustment and adaptive functioning were more consistent, showing mostly either no difference or worse adjustment of IT-IEM patients compared to norms. Single medical risk factors for HrQoL, psychological adjustment, or adaptive functioning have been addressed, while psychosocial risk factors have not been addressed. Data on HrQoL, psychological adjustment, and adaptive functioning for IT-IEM are sparse. Studies are inconsistent in

Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

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Bustamante, Jacinta; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent

2014-01-01

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity. PMID:25453225

Critical Newborn Screens in Double Heterozygotes of Inborn Errors of Metabolism—A Clinical Report and Recommendations

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Katherine G. Langley

2016-11-01

Full Text Available The practice of newborn screening has been in place in the USA since the 1960s, with individual states initially screening for different numbers of disorders. In the early 2000s many efforts were made to standardize the various disorders being screened. Currently, there are at least 34 disorders that each state is mandated to include on their screening panel. Of those 34 disorders, the majority are inborn errors of metabolism (IEM which include urea cycle disorders (UCD, citrullinemia (CIT and argininosuccinic aciduria (ASA, as well as a number of fatty acid oxidation disorders. We present here four cases of infants who had critical newborn screens (NBS in the Commonwealth of Virginia and underwent genetic testing because their clinical presentation and follow-up laboratory studies were not consistent with the disorder that was flagged by NBS. These newborns were found to be carriers for two different IEMs (in three cases or compound heterozygotes (in one case. Currently no guidelines exist with respect to the appropriate way to manage these children who may or may not be symptomatic in the newborn period. We propose some general recommendations for management based on our experience with these four probands, and discuss the necessity for further conversation and collaboration between physicians encountering these not-so-infrequent presentations.

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

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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.

Assessment of a pioneer metabolic information service in Brazil.

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Brustolin, Silvia; Souza, Carolina; Puga, Ana Cristina; Refosco, Lilia; Pires, Ricardo; Peres, Rossana; Giugliani, Roberto

2006-01-01

The Information Service on Inborn Errors of Metabolism (SIEM), a pioneer toll-free service in both Brazil and South America, is based in Porto Alegre, Southern Brazil. SIEM has been operating since October 2001 providing support to health care professionals involved in the diagnosis and management of suspected metabolic diseases. We analyzed the demographic and clinical characteristics of the 376 consults received and followed in the first two and half years of SIEM. Our results show that the suspicion of a metabolic disease was most often associated with neurological symptoms. Among the consults, 24.4% were eventually confirmed as inborn errors of metabolism (IEM), with organic acidurias and amino acid disorders being the two most frequent diagnostic groups. Our conclusion shows this kind of service to provide helpful support to the diagnosis and acute management of IEM, especially to health professionals working in developing countries who are often far from reference centers.

Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: neuroimaging in the more common or recognizable disorders.

Science.gov (United States)

Krishna, Shri H; McKinney, Alexander M; Lucato, Leandro T

2014-04-01

Numerous congenital-genetic inborn errors of metabolism (CIEMs) have been identified and characterized in detail within recent decades, with promising therapeutic options. Neuroimaging is becoming increasingly utilized in earlier stages of CIEMs, and even in asymptomatic relatives of patients with a CIEM, so as to monitor disease progress and treatment response. This review attempts to summarize in a concise fashion the neuroimaging findings of various CIEMs that may present in adulthood, as well as those that may persist into adulthood, whether because of beneficial therapy or a delay in diagnosis. Notably, some of these disorders have neuroimaging findings that differ from their classic infantile or early childhood forms, whereas others are identical to their early pediatric forms. The focus of this review is their appearance on routine magnetic resonance imaging sequences, with some basic attention to the findings of such CIEMs on specialized neuroimaging, based on recent or preliminary research. The general classes of disorders covered in this complex review are: peroxisomal disorders (adrenoleukodystrophy), lysosomal storage disorders (including metachromatic leukodystrophy, Krabbe or globoid cell leukodystrophy, Fabry, Niemann-Pick, GM1, GM2, Gaucher, mucopolysaccharidoses, and Salla diseases), mitochondrial disorders (including mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes, myoclonic epilepsy with ragged red fibers, Leigh disease, and Kearns-Sayre syndrome), urea cycle disorders, several organic acidemias (including phenylketonuria, maple syrup urine disease, 3-hydroxy-3-methylglutaryl colyase deficiency, glutaric acidurias, methylmalonic academia, proprionic academia, 3-methylglucatonic aciduria, and 2-hydroxyglutaric acidurias), cytoskeletal or transporter molecule defects (including Alexander or fibrinoid leukodystrophy, proteolipid protein-1 defect or Pelizaeus Merzbacher, Wilson, and Huntington diseases), and several

Fifteen years experience: Egyptian metabolic lab

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Ekram M. Fateen

2014-10-01

Conclusion: This study illustrates the experience of the reference metabolic lab in Egypt over 15 years. The lab began metabolic disorder screening by using simple diagnostic techniques like thin layer chromatography and colored tests in urine which by time updated and upgraded the methods to diagnose a wide range of disorders. This study shows the most common diagnosed inherited inborn errors of metabolism among the Egyptian population.

Clinical approach to inherited metabolic disorders in neonates

NARCIS (Netherlands)

Saudubray, J. M.; Narcy, C.; Lyonnet, L.; Bonnefont, J. P.; Poll The, B. T.; Munnich, A.

1990-01-01

Most inborn errors of intermediary metabolism presenting in the neonatal period fall schematically into three clinical categories: (1) those which lead to a neurological distress 'intoxication type' with a symptom-free interval, vomiting, comas, hypertonia, abnormal movements and frequent humoral

Risk factors and birth prevalence of birth defects and inborn errors of ...

African Journals Online (AJOL)

Children with any birth defect or metabolic errors of metabolism at birth or in the neonatology section were our sample for study. Control group was randomly selected from the cases with normal live births. Blood tests were performed for children suspected to suffer from genetic blood disorders. The principal BD as per the ...

Modeling congenital disease and inborn errors of development in Drosophila melanogaster

Science.gov (United States)

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

Clinical neurogenetics: neurologic presentations of metabolic disorders.

Science.gov (United States)

Kwon, Jennifer M; D'Aco, Kristin E

2013-11-01

This article reviews aspects of the neurologic presentations of selected treatable inborn errors of metabolism within the category of small molecule disorders caused by defects in pathways of intermediary metabolism. Disorders that are particularly likely to be seen by neurologists include those associated with defects in amino acid metabolism (organic acidemias, aminoacidopathies, urea cycle defects). Other disorders of small molecule metabolism are discussed as additional examples in which early treatments have the potential for better outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?

Science.gov (United States)

Alcaïs, Alexandre; Quintana-Murci, Lluis; Thaler, David S; Schurr, Erwin; Abel, Laurent; Casanova, Jean-Laurent

2010-12-01

The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably among diseases and among studies. A coherent genetic architecture of infectious diseases is lacking. We suggest here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline; (ii) theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age; (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults; (iv) current knowledge of immunity to primary and secondary or latent infections; (v) the state of the art in the clinical genetics of noninfectious pediatric and adult diseases; and (vi) evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe pediatric infectious diseases is experimentally testable. © 2010 New York Academy of Sciences.

Selective screening of 650 high risk Iranian patients for detection of inborn error of metabolism

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Narges Pishva

2015-02-01

Full Text Available Objective: Although metabolic diseases individually are rare ,but overall have an incidence of 1/2000 and can cause devastating and irreversible effect if not diagnosed early and treated promptly. selective screening is an acceptable method for detection of these multi presentation diseases.Method: using panel neonatal screening for detection of metabolic diseases in 650 high risk Iranian patients in Fars province. The following clinical features were used as inclusion criteria for investigation of the patients.Lethargy, poor feeding ,persistent vomiting, cholestasis, intractable seizure ,decreased level of consciousness ,persistent hypoglycemia, unexplained acid base disturbance and unexplained neonatal death.Result: Organic acidemia with 40 cases (42% was the most frequent disorder diagnosed in our high risk populations, followed by disorder of galactose metabolism(30%, 15 patient had classic galactosemia(GALT

Selective screening of 650 high risk Iranian patients for detection of inborn error of metabolism

Directory of Open Access Journals (Sweden)

Narges Pishva

2015-02-01

Full Text Available Objective: Although metabolic diseases individually are rare ,but overall have an incidence of 1/2000 and can cause devastating and irreversible effect if not diagnosed early and treated promptly. selective screening is an acceptable method for detection of these multi presentation diseases. Method: using panel neonatal screening for detection of metabolic diseases in 650 high risk Iranian patients in Fars province. The following clinical features were used as inclusion criteria for investigation of the patients. Lethargy, poor feeding ,persistent vomiting, cholestasis, intractable seizure ,decreased level of consciousness ,persistent hypoglycemia, unexplained acid base disturbance and unexplained neonatal death. Result: Organic acidemia with 40 cases (42% was the most frequent disorder diagnosed in our high risk populations, followed by disorder of galactose metabolism(30%, 15 patient had classic galactosemia(GALT

Toxigenic and metabolic causes of ketosis and ketoacidotic syndromes.

Science.gov (United States)

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.

Phenylketonuria screening in the Republic of Macedonia.

Science.gov (United States)

Kocova, Mirjana; Anastasovska, Violeta

2016-08-05

Phenylketonuria is an autosomal recessive inborn error of metabolism which can be prevented by early and continuous treatment. Therefore newborn screening for phenylketonuria has been introduced in many countries. We present here the results of the selective newborn screening for inborn errors of metabolism, including PKU, performed by tandem mass spectrometry which has been introduced in Macedonia since 2011.

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

Science.gov (United States)

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.

Therapeutic Approaches Using Riboflavin in Mitochondrial Energy Metabolism Disorders.

Science.gov (United States)

Henriques, Bárbara J; Lucas, Tânia G; Gomes, Cláudio M

2016-01-01

Riboflavin, or vitamin B2, plays an important role in the cell as biological precursor of FAD and FMN, two important flavin cofactors which are essential for the structure and function of flavoproteins. Riboflavin has been used in therapeutic approaches of various inborn errors of metabolism, notably in metabolic disorders resulting either from defects in proteins involved in riboflavin metabolism and transport or from defects in flavoenzymes. The scope of this review is to provide an updated perspective of clinical cases in which riboflavin was used as a potential therapeutic agent in disorders affecting mitochondrial energy metabolism. In particular, we discuss available mechanistic insights on the role of riboflavin as a pharmacological chaperone for the recovery of misfolded metabolic flavoenzymes.

Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.

Science.gov (United States)

Quintana, Anita M; Yu, Hung-Chun; Brebner, Alison; Pupavac, Mihaela; Geiger, Elizabeth A; Watson, Abigail; Castro, Victoria L; Cheung, Warren; Chen, Shu-Huang; Watkins, David; Pastinen, Tomi; Skovby, Flemming; Appel, Bruce; Rosenblatt, David S; Shaikh, Tamim H

2017-08-01

CblX (MIM309541) is an X-linked recessive disorder characterized by defects in cobalamin (vitamin B12) metabolism and other developmental defects. Mutations in HCFC1, a transcriptional co-regulator which interacts with multiple transcription factors, have been associated with cblX. HCFC1 regulates cobalamin metabolism via the regulation of MMACHC expression through its interaction with THAP11, a THAP domain-containing transcription factor. The HCFC1/THAP11 complex potentially regulates genes involved in diverse cellular functions including cell cycle, proliferation, and transcription. Thus, it is likely that mutation of THAP11 also results in biochemical and other phenotypes similar to those observed in patients with cblX. We report a patient who presented with clinical and biochemical phenotypic features that overlap cblX, but who does not have any mutations in either MMACHC or HCFC1. We sequenced THAP11 by Sanger sequencing and discovered a potentially pathogenic, homozygous variant, c.240C > G (p.Phe80Leu). Functional analysis in the developing zebrafish embryo demonstrated that both THAP11 and HCFC1 regulate the proliferation and differentiation of neural precursors, suggesting important roles in normal brain development. The loss of THAP11 in zebrafish embryos results in craniofacial abnormalities including the complete loss of Meckel's cartilage, the ceratohyal, and all of the ceratobranchial cartilages. These data are consistent with our previous work that demonstrated a role for HCFC1 in vertebrate craniofacial development. High throughput RNA-sequencing analysis reveals several overlapping gene targets of HCFC1 and THAP11. Thus, both HCFC1 and THAP11 play important roles in the regulation of cobalamin metabolism as well as other pathways involved in early vertebrate development. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cystinuria: an inborn cause of urolithiasis

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Eggermann Thomas

2012-04-01

Full Text Available Abstract Cystinuria (OMIM 220100 is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21 encodes the heavy subunit rBAT of a renal b0,+ transporter while SLC7A9 (chromosome 19q12 encodes its interacting light subunit b0,+AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

Newborn screening of inherited metabolic disorders by tandem mass spectrometry: past, present and future

Directory of Open Access Journals (Sweden)

G. Scaturro

2013-04-01

Full Text Available Inborn errors of metabolism are inherited biochemical disorders caused by lack of a functional enzyme, transmembrane transporter, or similar protein, which then results in blockage of the corresponding metabolic pathway. Taken individually, inborn errors of metabolism are rare. However, as a group these diseases are relatively frequent and they may account for most of neonatal mortality and need of health resources. The detection of genetic metabolic disorders should occur in a pre-symptomatic phase. Recently, the introduction of the tandem mass spectrometric methods for metabolite analysis has changed our ability to detect intermediates of metabolism in smaller samples and provides the means to detect a large number of metabolic disorders in a single analytical run. Screening panels now include a large number of disorders that may not meet all the criteria that have been used as a reference for years. The rationale behind inclusion or exclusion of a respective disorder is difficult to understand in most cases and it may impose an ethical dilemma. The current organization is an important tool of secondary preventive medicine, essential for children’s healthcare, but the strong inhomogeneity of the regional models of screening applied today create in the Italian neonatal population macroscopic differences with regards to healthcare, which is in effect mainly diversified by the newborn’s place of birth, in possible violation of the universal criterion of the equality of all citizens. Carefully weighed arguments are urgently needed since patient organizations, opinion leaders and politicians are pressing to proceed with expansion of neonatal population screening.

Exome sequencing and the management of neurometabolic disorders

OpenAIRE

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

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, ...

Exome Sequencing and the Management of Neurometabolic Disorders

OpenAIRE

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

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 c...

Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

Science.gov (United States)

Boisson-Dupuis, Stephanie; Kong, Xiao-Fei; Okada, Satoshi; Cypowyj, Sophie; Puel, Anne; Abel, Laurent; Casanova, Jean-Laurent

2012-01-01

The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes. PMID:22651901

Stem Cell Transplant for Inborn Errors of Metabolism

Science.gov (United States)

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

Investigation of metabolic encephalopathy

African Journals Online (AJOL)

cycle defects is the X-linked recessive disorder, ornithine ... life, or if the child is fed the compounds that they are unable .... as learning difficulties, drowsiness and avoidance of ... Table 2. Laboratory investigation of suspected metabolic encephalopathy. Laboratory .... Clinical approach to treatable inborn metabolic diseases:.

In vivo neuro MR spectroscopy: a non-invasive insight into cerebral metabolism

International Nuclear Information System (INIS)

Rose, S.; De Zubicaray, G.; Wang, D.; Galloway, G.; Doddrell, D.; Chalk, J.; University of Queensland, Brisbane, QLD; Eagle, S.; Semple, J.

1999-01-01

In addition to conventional magnetic resonance imaging (MRI) for examining anatomical structure, in vivo proton magnetic resonance spectroscopy (MRS) is currently being used as a non-invasive clinical tool for monitoring altered brain metabolism. Conditions such as head injury, dementia, multiple sclerosis, tumour, stroke, epilepsy and inborn errors of metabolism are all presently being investigated with MRS. At the Centre for Magnetic Resonance, we are currently undertaking a longitudinal study of dementia progression in Alzheimer's disease (AD) utilising both MRS and volumetric MRI techniques. The aim is to identify metabolic differences between this patient group and normal older adults and to correlate these measures with cognitive function. Cerebral artrophy, or loss of brain matter, together with ventricular enlargement , or enlargement of normally occuring cavities, is clearly present on MRI exams in patients with moderate and severe AD

Inherited metabolic disorders in Thailand.

Science.gov (United States)

Wasant, Pornswan; Svasti, Jisnuson; Srisomsap, Chantragan; Liammongkolkul, Somporn

2002-08-01

The study of inborn errors of metabolism (IEM) in Thailand is in its infancy. The majority are clinically diagnosed since there are only a handful of clinicians and scientists with expertise in inherited metabolic disorders, shortage of well-equipped laboratory facilities and lack of governmental financial support. Genetic metabolic disorders are usually not considered a priority due to prevalence of infectious diseases and congenital infections. From a retrospective study at the Medical Genetics Unit, Department of Pediatrics, Siriraj Hospital; estimated pediatrics patients with suspected IEM were approximately 2-3 per cent of the total pediatric admissions of over 5,000 annually. After more than 10 years of research and accumulated clinical experiences, a genetic metabolic center is being established in collaboration with expert laboratories both in Bangkok (Chulabhorn Research Institute) and abroad (Japan and the United States). Numerous inherited metabolic disorders were identified--carbohydrate, amino acids, organic acids, mitochondrial fatty acid oxidation, peroxisomal, mucopolysaccharidoses etc. This report includes the establishment of genetic metabolic center in Thailand, research and pilot studies in newborn screening in Thailand and a multicenter study from 5 institutions (Children's National Center, King Chulalongkorn Memorial Hospital, Pramongkutklao Hospital, Ramathibodi and Siriraj Hospitals). Inherited metabolic disorders reported are fructose-1,6-bisphosphatase deficiency, phenylketonuria, homocystinuria, nonketotic hyperglycinemia, urea cycle defect (arginino succinate lyase deficiency, argininosuccinate synthetase deficiency), Menkes disease, propionic acidemia and mucopolysaccharidoses (Hurler, Hurler-Scheie).

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

Directory of Open Access Journals (Sweden)

Julie Thompson Legault

2015-11-01

Full Text Available 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.

Adherence issues in inherited metabolic disorders treated by low natural protein diets

DEFF Research Database (Denmark)

MaCdonald, A; van Rijn, M; Feillet, F

2012-01-01

Common inborn errors of metabolism treated by low natural protein diets [amino acid (AA) disorders, organic acidemias and urea cycle disorders] are responsible for a collection of diverse clinical symptoms, each condition presenting at different ages with variable severity. Precursor......-free or essential L-AAs are important in all these conditions. Optimal long-term outcome depends on early diagnosis and good metabolic control, but because of the rarity and severity of conditions, randomized controlled trials are scarce. In all of these disorders, it is commonly described that dietary adherence...... on their neuropsychological profile. There are little data about their ability to self-manage their own diet or the success of any formal educational programs that may have been implemented. Trials conducted in non-phenylketonuria (PKU) patients are rare, and the development of specialist L-AAs for non-PKU AA disorders has...

Secondary psychosis induced by metabolic disorders

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Olivier eBonnot

2015-05-01

Full Text Available Metabolic disorders are not well recognized by psychiatrists as a possible source of secondary psychoses. Inborn errors of metabolism (IEMs are not frequent. Although, their prompt diagnosis may lead to suitable treatments. IEMs are well known to paediatricians, in particular for their most serious forms, having an early expression most of the time. Recent years discoveries have unveiled later expression forms, and sometimes, very discreet first physical signs. There is a growing body of evidence that supports the hypothesis that IEMs can manifest as atypical psychiatric symptoms, even in the absence of clear neurological symptoms. In the present review, we propose a detailed overview at schizophrenia-like and autism-like symptoms that can lead practitioners to bear in mind an IEM. Other psychiatric manifestations are also found, as behavioral., cognitive, learning and mood disorders. However, they are less frequent. Ensuring an accurate IEM diagnosis, in front of these psychiatric symptoms should be a priority, in order to grant suitable and valuable treatment for these pathologies.

Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach

Directory of Open Access Journals (Sweden)

Swati Chaturvedi

2016-01-01

Full Text Available One of the extreme challenges in biology is to ameliorate the understanding of the mechanisms which emphasize metabolic enzyme deficiency (MED and how these pretend to have influence on human health. However, it has been manifested that MED could be either inherited as inborn error of metabolism (IEM or acquired, which carries a high risk of interrupted biochemical reactions. Enzyme deficiency results in accumulation of toxic compounds that may disrupt normal organ functions and cause failure in producing crucial biological compounds and other intermediates. The MED related disorders cover widespread clinical presentations and can involve almost any organ system. To sum up the causal factors of almost all the MED-associated disorders, we decided to embark on a less traveled but nonetheless relevant direction, by focusing our attention on associated gene family products, regulation of their expression, genetic mutation, and mutation types. In addition, the review also outlines the clinical presentations as well as diagnostic and therapeutic approaches.

Selective screening in neonates suspected to have inborn errors of ...

African Journals Online (AJOL)

Rabah M. Shawky

2015-02-16

Feb 16, 2015 ... Objective: The aim of this work was to detect the prevalence of IEM among neonates ... defect, mitochondrial disease, and galactosemia were diagnosed in one patient each (7.7%). ... relation of symptoms to feeding, similar cases in the family, ... The extended metabolic screening test showed high leucine,.

Peripheral Neuropathy, Episodic Rhabdomyolysis, and Hypoparathyroidism in a Patient with Mitochondrial Trifunctional Protein Deficiency

NARCIS (Netherlands)

van Vliet, Peter; Berden, Annelies E.; van Schie, Mojca K. M.; Bakker, Jaap A.; Heringhaus, Christian; de Coo, Irenaeus F. M.; Langeveld, Mirjam; Schroijen, Marielle A.; Arbous, M. Sesmu

2017-01-01

A combination of unexplained peripheral neuropathy, hypoparathyroidism, and the inability to cope with metabolic stress could point to a rare inborn error of metabolism, such as mitochondrial trifunctional protein (MTP) deficiency.Here, we describe a 20-year-old woman who was known since childhood

Disease: H00182 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available eSH: C535408 OMIM: 219500 PMID:16702350 ... AUTHORS ... Finkelstein JD ... TITLE ... Inborn errors of sulfur-containing amino acid metabolism. ... JOURNAL ... J Nutr 136:1750S-1754S (2006) ...

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.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome.

Science.gov (United States)

Choe, Chi-un; Nabuurs, Christine; Stockebrand, Malte C; Neu, Axel; Nunes, Patricia; Morellini, Fabio; Sauter, Kathrin; Schillemeit, Stefan; Hermans-Borgmeyer, Irm; Marescau, Bart; Heerschap, Arend; Isbrandt, Dirk

2013-01-01

Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l-arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus.

Cerebellar involvement in metabolic disorders: a pattern-recognition approach

International Nuclear Information System (INIS)

Steinlin, M.; Boltshauser, E.; Blaser, S.

1998-01-01

Inborn errors of metabolism can affect the cerebellum during development, maturation and later during life. We have established criteria for pattern recognition of cerebellar abnormalities in metabolic disorders. The abnormalities can be divided into four major groups: cerebellar hypoplasia (CH), hyperplasia, cerebellar atrophy (CA), cerebellar white matter abnormalities (WMA) or swelling, and involvement of the dentate nuclei (DN) or cerebellar cortex. CH can be an isolated typical finding, as in adenylsuccinase deficiency, but is also occasionally seen in many other disorders. Differentiation from CH and CA is often difficult, as in carbohydrate deficient glycoprotein syndrome or 2-l-hydroxyglutaric acidaemia. In cases of atrophy the relationship of cerebellar to cerebral atrophy is important. WMA may be diffuse or patchy, frequently predominantly around the DN. Severe swelling of white matter is present during metabolic crisis in maple syrup urine disease. The DN can be affected by metabolite deposition, necrosis, calcification or demyelination. Involvement of cerebellar cortex is seen in infantile neuroaxonal dystrophy. Changes in DN and cerebellar cortex are rather typical and therefore most helpful; additional features should be sought as they are useful in narrowing down the differential diagnosis. (orig.)

Selective screening in neonates suspected to have inborn errors of metabolism

Directory of Open Access Journals (Sweden)

Rabah M. Shawky

2015-04-01

Conclusion: IEM represent a high percent (32.5% of neonates who had sepsis like symptoms, and when diagnosed, patients showed marked improvement after therapy. IEM should be considered in differential diagnosis of the sick neonates, and investigations, and management should be started rapidly to decrease morbidity, and mortality till nationwide screen for IEM is applied in Egypt.

Biochemical screening of 504,049 newborns in Denmark, the Faroe Islands and Greenland--experience and development of a routine program for expanded newborn screening

DEFF Research Database (Denmark)

Lund, Allan Meldgaard; Hougaard, David Michael; Simonsen, Henrik

2012-01-01

Expanded newborn screening for selected inborn errors of metabolism (IEM) in Denmark, the Faroe Islands and Greenland was introduced in 2002. We now present clinical, biochemical, and statistical results of expanded screening (excluding PKU) of 504,049 newborns during nine years as well as diagno......Expanded newborn screening for selected inborn errors of metabolism (IEM) in Denmark, the Faroe Islands and Greenland was introduced in 2002. We now present clinical, biochemical, and statistical results of expanded screening (excluding PKU) of 504,049 newborns during nine years as well...... as a pilot study during the first seven years, and the experience obtained during these years was used in the development of the routine neonatal screening program introduced in 2009. Methods for screening included tandem mass spectrometry and an assay for determination of biotinidase activity. A total...

Late-onset ornithine transcarbamylase deficiency: An under recognized cause of metabolic encephalopathy

Directory of Open Access Journals (Sweden)

Eric T Rush

2014-07-01

Full Text Available Introduction: Ornithine transcarbamylase deficiency is the most common inherited disorder of the urea cycle, has a variable phenotype, and is caused by mutations in the OTC gene. We report three cases of ornithine transcarbamylase deficiency to illustrate the late-onset presentation of this disorder and provide strategies for diagnosis and treatment. The patients were maternal first cousins, presenting with hyperammonemia and obtundation. Urea cycle disorder was not initially suspected in the first patient, delaying diagnosis. Results: Sequencing of the OTC gene showed a novel missense mutation, c.563G > C (p.G188A. Numerous family members were found to carry this mutation, which shows a trend toward later onset. Each urea cycle disorder has its own unique pattern of biochemical abnormalities, which differ from non-metabolic causes of critical illness. Conclusion: Regardless of age, clinical suspicion of a urea cycle disorder is important in encephalopathic patients to ensure quick diagnosis and definitive treatment of the underlying inborn error of metabolism.

Genetics Home Reference: methylmalonic acidemia

Science.gov (United States)

... Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens ... patients with the cblD inborn error of cobalamin metabolism. J Pediatr. 2009 Apr;154(4):551-6. ...

BOOK REVIEWS BOEKRESENSIES

African Journals Online (AJOL)

Berylliosis, and Leprosy. 12. The. Treponematoses and Nonspirocbetal Venerial Diseases. ... later section on inborn errors of metabolism. Unusual, too, is ... Within the last 5 years, however, the introduction of canine rabies across the Limpopo ...

MRI of neonatal encephalopathy

International Nuclear Information System (INIS)

Khong, P.L.; Lam, B.C.C.; Tung, H.K.S.; Wong, V.; Chan, F.L.; Ooi, G.C.

2003-01-01

We present the magnetic resonance imaging (MRI) findings in neonatal encephalopathy, including hypoxic-ischaemic encephalopathy, perinatal/neonatal stroke, metabolic encephalopathy from inborn errors of metabolism, congenital central nervous system infections and birth trauma. The applications of advanced MRI techniques, such as diffusion-weighted imaging and magnetic resonance spectroscopy are emphasized

Cytogenetics In Medical Practice

African Journals Online (AJOL)

1974-08-03

Aug 3, 1974 ... inborn error of metabolism may be studied. Information supplied by ... family data to complement chromosomal findings. Department of Hnman ... baby with Down's syndrome is reaching a significant level, or women who have ...

Wolman disease in patients with familial hemophagocytic ...

African Journals Online (AJOL)

Solaf Elsayed

2015-09-26

Sep 26, 2015 ... Marine Gil b ... many inborn errors of metabolism and lysosomal storage diseases in which hemophagocytic ... The diagnosis of secondary HLH is usually made in association with infection by viruses, bacteria, fungi, or para-.

Investigating host-pathogen behavior and their interaction using genome-scale metabolic network models.

Science.gov (United States)

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.

L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome

NARCIS (Netherlands)

Choe, C.U.; Nabuurs, C.I.H.C.; Stockebrand, M.C.; Neu, A.; Nunes, P.M.; Morellini, F.; Sauter, K.; Schillemeit, S.; Hermans-Borgmeyer, I.; Marescau, B.; Heerschap, A.; Isbrandt, D.

2013-01-01

Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine

Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral disruption

NARCIS (Netherlands)

van Straaten, H. L. M.; van Tintelen, J. P.; Trijbels, J. M. F.; van den Heuvel, L. P.; Troost, D.; Rozemuller, J. M.; Duran, M.; de Vries, L. S.; Schuelke, M.; Barth, P. G.

2005-01-01

Cerebral developmental abnormalities occur in various inborn errors of metabolism including peroxisomal deficiencies, pyruvate dehydrogenase complex deficiency and others. Associations with abnormalities of the respiratory chain are rare. Here we report male and female siblings with microcephaly, a

Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral disruption

NARCIS (Netherlands)

van Straaten, HLM; van Tintelen, JP; Trijbels, JMF; van den Heuvel, LP; Troost, D; Rozemuller, JM; Duran, M; de Vries, LS; Schuelke, M; Barth, PG

Cerebral developmental abnormalities occur in various inborn errors of metabolism including peroxisomal deficiencies, pyruvate dehydrogenase complex deficiency and others. Associations with abnormalities of the respiratory chain are rare. Here we report male and female siblings with microcephaly, a

Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral disruption.

NARCIS (Netherlands)

Straaten, H.L.M. van; Tintelen, J.P. van; Trijbels, J.M.F.; Heuvel, L.P.W.J. van den; Troost, D.; Rozemuller, J.M.; Duran, M.; Vries, L.S. de; Schuelke, M.; Barth, P.G.

2005-01-01

Cerebral developmental abnormalities occur in various inborn errors of metabolism including peroxisomal deficiencies, pyruvate dehydrogenase complex deficiency and others. Associations with abnormalities of the respiratory chain are rare. Here we report male and female siblings with microcephaly, a

Activity-based protein profiling of glucosidases, fucosidases and glucuronidases

NARCIS (Netherlands)

Jiang, J.

2016-01-01

Glycoside hydrolases (GHs), enzymes that catalyze the hydrolytic cleavage of glycosidic bonds, receive continuing interest both in fundamental and applied biology and biomedicine. Lysosomal storage disorders (LSDs) are caused by inborn metabolic errors due to deficiency in specific lysosomal

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

Science.gov (United States)

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

Effect of inborn versus outborn delivery on clinical outcomes in ventilated preterm neonates: secondary results from the NEOPAIN trial.

Science.gov (United States)

Palmer, Kristine G; Kronsberg, Shari S; Barton, Bruce A; Hobbs, Charlotte A; Hall, Richard W; Anand, K J S

2005-04-01

The objective of this study was to evaluate the effect of birth center (inborn versus outborn) on morbidity and mortality for preterm neonates (23 to 32 weeks) using data collected prospectively within a uniform protocol. Secondary analyses of data from the NEurologic Outcomes and Pre-emptive Analgesia In Neonates (NEOPAIN) trial (n=898) were performed to evaluate the effect of inborn versus outborn delivery on neonatal outcomes, including the occurrence of severe intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), chronic lung disease (CLD), and mortality. Outborn babies were more likely to have severe IVH (p=0.0005); this increased risk persisted after controlling for severity of illness. When adjustments for antenatal steroids were added, the effect of birth center was no longer significant. Neither the occurrences of PVL or CLD nor mortality were significantly different between the inborn and outborn infants. Outborn babies are more likely to have severe IVH than inborn babies, perhaps because their mothers are less likely to receive antenatal steroids. Improvements in antenatal steroid administration to high-risk women may substantially reduce neonatal morbidity.

Diagnostiek van het cerebro-hepato-renale syndroom van Zellweger

NARCIS (Netherlands)

Schutgens, R. B.; Heymans, H. S.; Purvis, R.; Wanders, R. J.; Schrakamp, G.; van den Bosch, H.

1984-01-01

The cerebro-hepato-renal syndrome of Zellweger is an autosomal recessive inborn error of metabolism. Clinically the disease is characterised by craniofacial malformations, a lack of muscle tone, disturbances in liver function, renal cysts and mental retardation. The disease is characterised

External quality assurance programme for enzymatic analysis of lysosomal storage diseases : A pilot study

NARCIS (Netherlands)

Ruijter, G.J.G.; Boer, M.; Weykamp, C. W.; de Vries, R.; van den Berg, I.; Janssens-Puister, J.; Niezen-Koning, K.; Wevers, R. A.; Poorthuis, B. J. H. M.; van Diggelen, O. P.

2005-01-01

Inborn errors of metabolism are rare and laboratories performing diagnostic tests in this field must participate in external quality assurance (EQA) schemes to demonstrate their competence and also to maintain sufficient experience with patient material. EQA schemes for metabolite analyses are

Tandem Mass Neonatal Screening in Taiwan—Report from One Center

Directory of Open Access Journals (Sweden)

Hsiang-Po Huang

2006-01-01

Conclusion: We found that MS/MS neonatal screening was valuable in the early diagnosis of severe and treatable inborn errors of metabolism such as organic acidemias and urea cycle disorders. It also detected less severe disorders that required only observation.

When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription

NARCIS (Netherlands)

Ferri, L.; Dionisi-Vici, C.; Taurisano, R.; Vaz, F. M.; Guerrini, R.; Morrone, A.

2016-01-01

Barth syndrome (BTHS) is an X-linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3-methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical

Wolman disease in patients with familial hemophagocytic ...

African Journals Online (AJOL)

Major signs and symptoms include hepatomegaly, splenomegaly, anemia, leucopenia or thrombocytopenias which resemble many inborn errors of metabolism and lysosomal storage diseases in which hemophagocytic lymphohistiocytosis has also been reported as a secondary association. Case reports: We report three ...

Cerebral ketone body metabolism.

Science.gov (United States)

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.

Outline of metabolic diseases in adult neurology.

Science.gov (United States)

Mochel, F

2015-01-01

Inborn errors of metabolism (IEM) are traditionally defined by enzymatic deficiencies or defects in proteins involved in cellular metabolism. Historically discovered and characterized in children, a growing number of IEM are described in adults, and especially in the field of neurology. In daily practice, it is important to recognize emergency situations as well as neurodegenerative diseases for which a metabolic disease is likely, especially when therapeutic interventions are available. Here, the goal is to provide simple clinical, imaging and biochemical tools that can first orientate towards and then confirm the diagnosis of IEM. General guidelines are presented to treat the most common IEM during metabolic crises - acute encephalopathies with increased plasma ammonia, lactate or homocystein, as well as rhabdomyolysis. Examples of therapeutic strategies currently applied to chronic neurometabolic diseases are also provided - GLUT1 deficiency, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Niemann-Pick type C and Wilson disease. Genetic counseling is mandatory in some X-linked diseases - ornithine transcarbamylase deficiency and adrenoleukodystrophy - and recommended in maternally inherited mitochondrial diseases - mutations of mitochondrial DNA. Besides these practical considerations, the contribution of metabolism to the field of adult neurology and neurosciences is much greater: first, with the identification of blood biomarkers that are progressively changing our diagnostic strategies thanks to lipidomic approaches, as illustrated in the field of spastic paraplegia and atypical psychiatric presentations; and second, through the understanding of pathophysiological mechanisms involved in common neurological diseases thanks to the study of these rare diseases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Galactose Epimerase Deficiency: Expanding the Phenotype

NARCIS (Netherlands)

Dias Costa, Filipa; Ferdinandusse, Sacha; Pinto, Carla; Dias, Andrea; Keldermans, Liesbeth; Quelhas, Dulce; Matthijs, Gert; Mooijer, Petra A.; Diogo, Luísa; Jaeken, Jaak; Garcia, Paula

2017-01-01

Galactose epimerase deficiency is an inborn error of metabolism due to uridine diphosphate-galactose-4'-epimerase (GALE) deficiency. We report the clinical presentation, genetic and biochemical studies in two siblings with generalized GALE deficiency.Patient 1: The first child was born with a

Timelines of the “free-particle” and “fixed-particle” models of stone-formation: theoretical and experimental investigations

NARCIS (Netherlands)

Kok, D.J.; W.P.A. Boellaard (Willem); Y. Ridwan (Yanto); Levchenko, V.A.

2017-01-01

textabstractTwo major theories on renal stone formation will be reviewed, the “free-particle” and “fixed-particle” mechanisms. These theories combine data on intrinsic factors (inborn metabolic errors), extrinsic factors (diet), renal cell responses and the physico-chemistry and biochemistry of

Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia.

NARCIS (Netherlands)

Mudd, S.H.; Cerone, R.; Schiaffino, M.C.; Fantasia, A.R.; Minniti, G.; Caruso, U.; Lorini, R.; Watkins, D.; Matiaszuk, N.; Rosenblatt, D.S.; Schwahn, B.; Rozen, R.; Gros, L. Le; Kotb, M.; Capdevila, A.; Luka, Z.; Finkelstein, J.; Tangerman, A.; Stabler, S.P.; Allen, R.; Wagner, C.

2001-01-01

This paper reports clinical and metabolic studies of two Italian siblings with a novel form of persistent isolated hypermethioninaemia, i.e. abnormally elevated plasma methionine that lasted beyond the first months of life and is not due to cystathionine beta-synthase deficiency, tyrosinaemia I or

The impact of consanguinity on the frequency of inborn errors of metabolism

DEFF Research Database (Denmark)

Afzal, Raja Majid; Lund, Allan Meldgaard; Skovby, Flemming

2018-01-01

for selected IEM with autosomal recessive mode of inheritance, a national screening program of newborns covering the period from 2002 until April 2017. Among the 838,675 newborns from Denmark, the Faroe Islands and Greenland, a total of 196 newborns had an IEM of whom 155 from Denmark were included...... children. The data indicate a strong association between consanguinity and IEM. These figures could be useful to health professionals providing antenatal, pediatric, and clinical genetic services....

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

Science.gov (United States)

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.

ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism

NARCIS (Netherlands)

Peters, Heidi; Buck, Nicole; Wanders, Ronald; Ruiter, Jos; Waterham, Hans; Koster, Janet; Yaplito-Lee, Joy; Ferdinandusse, Sacha; Pitt, James

2014-01-01

Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this

D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK)

DEFF Research Database (Denmark)

Sass, Jörn Oliver; Fischer, Kathleen; Wang, Raymond

2010-01-01

D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficienc...

Hepatocytes in the development of liver support systems

NARCIS (Netherlands)

I.H.M. Borel Rinkes (Inne)

1993-01-01

textabstractThis thesis focuses on the development of alternative strategies in the treatment of patients with acute fulminant hepatic failure and inborn errors of metabolism, using hepatocytes as the basis of liver support. When compared with transplantation of the liver as an organ, the

High activity of fatty acid oxidation enzymes in human placenta: implications for fetal-maternal disease

NARCIS (Netherlands)

Oey, N. A.; den Boer, M. E. J.; Ruiter, J. P. N.; Wanders, R. J. A.; Duran, M.; Waterham, H. R.; Boer, K.; van der Post, J. A. M.; Wijburg, F. A.

2003-01-01

As the human fetus and placenta are considered to be primarily dependent on glucose oxidation for energy metabolism, the cause of the remarkable association between severe maternal pregnancy complications and the carriage of a fetus with an inborn error of mitochondrial long-chain fatty acid

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

Science.gov (United States)

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.

OPPORTUNITIES OF TRANSVAGINAL ECHOCARDIOGRAPHY FOR EARLY PRENATAL DIAGNOSIS OF INBORN HEART DISEASES IN FETUS

Directory of Open Access Journals (Sweden)

E.A. Shevchenko

2008-01-01

Full Text Available According to the literature data, transvaginal echocardiography (Echocg is the method, used for the doppler diagnostics in early terms of pregnancy (if principles of safety are observed. This method allows detecting about 70–97% of all prognostic cally significant inborn heart diseases in fetus, beginning at 12 week of pregnancy. a scheme of research includes estimation of four chamber cut of fetus heart, and study of state of its main arteries. This is an expert investigation, because it needs special grounding of specialist, high resolution ultrasonic equipment, and considerable expense of time. Wile parameters are estimated, it is necessary to use normative rates of sizes of ventricles and main arteries of fetus, developed by Russian experts, taking into account individual variations.Key words: transvaginal echocardiography, diagnosis, inborn heart disease.

Clinical variability in 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency

NARCIS (Netherlands)

Ensenauer, Regina; Niederhoff, Helmut; Ruiter, Jos P. N.; Wanders, Ronald J. A.; Schwab, K. Otfried; Brandis, Matthias; Lehnert, Willy

2002-01-01

We report the identification of two new 7-year-old patients with 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency, a recently described inborn error of isoleucine metabolism. The defect is localized one step above 3-ketothiolase, resulting in a urinary metabolite pattern similar to that seen

Defining the phenotype and diagnostic considerations in adults with congenital disorders of N-linked glycosylation

NARCIS (Netherlands)

Wolthuis, D.F.; Janssen, M.C.H.; Cassiman, D.; Lefeber, D.J.; Morava-Kozicz, E.

2014-01-01

Congenital disorders of N-glycosylation (CDG) form a rapidly growing group of more than 20 inborn errors of metabolism. Most patients are identified at the pediatric age with multisystem disease. There is no systematic review on the long-term outcome and clinical presentation in adult patients.

Management of Newborn Infants with Phenylketonuria.

Science.gov (United States)

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…

Autism in patients with propionic acidemia

NARCIS (Netherlands)

Witters, P.; Debbold, E.; Crivelly, K.; Kerckhove, K. Vande; Corthouts, K.; Debbold, B.; Andersson, H.; Vannieuwenborg, L.; Geuens, S.; Baumgartner, M.; Kozicz, L.T.; Settles, L.; Morava, E.

2016-01-01

Certain inborn errors of metabolism have been suggested to increase the risk of autistic behavior. In an animal model, propionic acid ingestion triggered abnormal behavior resembling autism. So far only a few cases were reported with propionic acidemia and autistic features. From a series of twelve

Effects of β-alanine administration on selected parameters of oxidative stress and phosphoryltransfer network in cerebral cortex and cerebellum of rats

NARCIS (Netherlands)

Gemelli, Tanise; de Andrade, Rodrigo Binkowski; Rojas, Denise Bertin; Bonorino, Nariélle Ferner; Mazzola, Priscila Nicolao; Tortorelli, Lucas Silva; Funchal, Cláudia; Filho, Carlos Severo Dutra; Wannmacher, Clovis Milton Duval

β-Alanine is a β-amino acid derivative of the degradation of pyrimidine uracil and precursor of the oxidative substrate acetyl-coenzyme A (acetyl-CoA). The accumulation of β-alanine occurs in β-alaninemia, an inborn error of metabolism. Patients with β-alaninemia may develop neurological

Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency

NARCIS (Netherlands)

Grünert, Sarah Catharina; Schmitt, Robert Niklas; Schlatter, Sonja Marina; Gemperle-Britschgi, Corinne; Balci, Mehmet Cihan; Berg, Volker; Çoker, Mahmut; Das, Anibh M; Demirkol, Mübeccel; Derks, Terry G J; Gökçay, Gülden; Uçar, Sema Kalkan; Konstantopoulou, Vassiliki; Christoph Korenke, G.; Lotz-Havla, Amelie Sophia; Schlune, Andrea; Staufner, Christian; Tran, Christel; Visser, Gepke; Schwab, Karl Otfried; Fukao, Toshiyuki; Sass, Jörn Oliver

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more

Biomarker for Glycogen Storage Diseases

Science.gov (United States)

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

Rapid quantification of underivatized amino acids in plasma by hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass-spectrometry

NARCIS (Netherlands)

Prinsen, Hubertus C M T; Schiebergen-Bronkhorst, B. G M; Roeleveld, M. W.; Jans, J. J M; de Sain-van der Velden, M. G M; Visser, G.; van Hasselt, P. M.; Verhoeven-Duif, N. M.

Background: Amino acidopathies are a class of inborn errors of metabolism (IEM) that can be diagnosed by analysis of amino acids (AA) in plasma. Current strategies for AA analysis include cation exchange HPLC with post-column ninhydrin derivatization, GC-MS, and LC-MS/MS-related methods. Major

1H-NMR urinalysis

International Nuclear Information System (INIS)

Yamamoto, Hideaki; Yamaguchi, Shuichi

1988-01-01

In an effort to examine the usefulness of 1 H-nuclear magnetic resonance (NMR) urinalysis in the diagnosis of congenital metabolic disorders, 70 kinds of urinary metabolites were analysed in relation to the diagnosis of inborn errors of amino acid and organic acid disorders. Homogated decoupling (HMG) method failed to analyze six metabolites within the undetectable range. When non-decoupling method (NON), in which the materials are dissolved in dimethyl sulfoxide, was used, the identification of signals became possible. The combination of HMG and NON methods was, therefore, considered to identify all of the metabolites. When the urine samples, which were obtained from patients with hyperglycerolemia, hyperornithinemia, glutaric acidemia type II, or glycerol kinase deficiency, were analysed by using both HMG and NON methods, abnormally increased urinary metabolites were detected. 1 H-NMR urinalysis, if used in the combination of HMG and NON methods, may allow simultanenous screening of inborn errors of metabolism of amino acid and organic acid disorders. (Namekawa, K.)

Clinical and laboratorial study of 19 cases of mucopolysaccharidoses

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Albano Lilian M. J.

2000-01-01

Full Text Available The mucopolysaccharidoses (MPS are a heterogeneous group of inborn errors of lysosomal glycosaminoglycan (GAG metabolism. The importance of this group of disorders among the inborn errors of metabolism led us to report 19 cases. METHOD: We performed clinical, radiological, and biochemical evaluations of the suspected patients, which allowed us to establish a definite diagnosis in 19 cases. RESULTS: Not all patients showed increased GAG levels in urine; enzyme assays should be performed in all cases with strong clinical suspicion. The diagnosis was made on average at the age of 48 months, and the 19 MPS cases, after a full clinical, radiological, and biochemical study, were classified as follows: Hurler -- MPS I (1 case; Hunter -- MPS II (2 cases; Sanfilippo -- MPS III (2 cases; Morquio -- MPS IV (4 cases; Maroteaux-Lamy -- MPS VI (9 cases; and Sly -- MPS VII (1 case. DISCUSSION: The high relative frequency of Maroteaux-Lamy disease contrasts with most reports in the literature and could express a population variability.

Author Details

African Journals Online (AJOL)

Gouda, A. Vol 10, No 2 (2009) - Articles Screening for phenylketonuria and galactosemia among Egyptian newborns in Menoufiya governorate. Abstract PDF · Vol 10, No 2 (2009) - Articles Inborn errors of metabolism revealed by organic acid profile analysis in high risk Egyptian patients: Six years experience. Abstract PDF.

Enzymatic Preparation of Low-Phenylalanine Formula Derived from ...

African Journals Online (AJOL)

Background: Phenylketonuria (PKU) is one of the most common inborn errors of amino acids metabolism. WHO guidelines introduced in 1979 and revised 1988 for breast-feeding infants with PKU included a formula containing low amounts of phenylalanine as a part of dietary prescription. Mental retardation can be ...

International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up

NARCIS (Netherlands)

Welling, Lindsey; Bernstein, Laurie E.; Berry, Gerard T.; Burlina, Alberto B.; Eyskens, François; Gautschi, Matthias; Grünewald, Stephanie; Gubbels, Cynthia S.; Knerr, Ina; Labrune, Philippe; van der Lee, Johanna H.; MacDonald, Anita; Murphy, Elaine; Portnoi, Pat A.; Õunap, Katrin; Potter, Nancy L.; Rubio-Gozalbo, M. Estela; Spencer, Jessica B.; Timmers, Inge; Treacy, Eileen P.; van Calcar, Sandra C.; Waisbren, Susan E.; Bosch, Annet M.

2017-01-01

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care,

Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan.

Science.gov (United States)

Niu, Dau-Ming; Chien, Yin-Hsiu; Chiang, Chuan-Chi; Ho, Hui-Chen; Hwu, Wuh-Liang; Kao, Shu-Min; Chiang, Szu-Hui; Kao, Chuan-Hong; Liu, Tze-Tze; Chiang, Hung; Hsiao, Kwang-Jen

2010-10-01

In Taiwan, during the period March 2000 to June 2009, 1,495,132 neonates were screened for phenylketonuria (PKU) and homocystinuria (HCU), and 1,321,123 neonates were screened for maple syrup urine disease (MSUD), methylmalonic academia (MMA), medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency, isovaleric academia (IVA), and glutaric aciduria type 1 (GA-1) using tandem mass spectrometry (MS/MS). In a pilot study, 592,717 neonates were screened for citrullinemia, 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC) and other fatty acid oxidation defects in the MS/MS newborn screening. A total of 170 newborns and four mothers were confirmed to have inborn errors of metabolism. The overall incidence was approximately 1/5,882 (1/6,219 without mothers). The most common inborn errors were defects of phenylalanine metabolism [five classic PKU, 20 mild PKU, 40 mild hyperphenylalaninemia (HPA), and 13 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency]. MSUD was the second most common amino acidopathy and, significantly, most MSUD patients (10/13) belonged to the Austronesian aboriginal tribes of southern Taiwan. The most frequently detected among organic acid disorders was 3-MCC deficiency (14 newborns and four mothers). GA-1 and MMA were the second most common organic acid disorders (13 and 13 newborns, respectively). In fatty acid disorders, five carnitine transport defect (CTD), five short-chain acyl-CoA dehydrogenase deficiency (SCAD), and two medium-chain acyl-CoA dehydrogenase (MCAD) deficiency were confirmed. This is the largest case of MS/MS newborn screening in an East-Asian population to date. We hereby report the incidences and outcomes of metabolic inborn error diseases found in our nationwide MS/MS newborn screening program.

Pyridoxine-dependent epilepsy owing to antiquitin deficiency - mutation in the ALDH7A1 gene

NARCIS (Netherlands)

Jagadeesh, S.; Suresh, B.; Murugan, V.; Suresh, S.; Salomons, G.S.; Struys, E.A.; Jacobs, C.

2013-01-01

Pyridoxine-dependent epilepsy (PDE) is an inborn error of metabolism resulting from antiquitin deficiency. There is marked elevation of a-amino adipic semi-aldehyde (aAASA), piperidine-6-carboxylate (P6C) and pipecolic acid. The diagnosis can be confirmed by identifying the mutation in the ALDH7A1

Study of amino acid disorders among a high risk group of Egyptian ...

African Journals Online (AJOL)

Aim of the work: The present work aimed at investigating infants (In neonatal and post neonatal period) and children suspected of having inborn errors of metabolism with unexplained mental retardation. The frequency pattern of the various amino acid disorders, in a group of selected infants and children was done to ...

Beta-ureidopropionase deficiency presenting with febrile status epilepticus

NARCIS (Netherlands)

Assmann, Birgit E.; van Kuilenburg, Andre B. P.; Distelmaier, Felix; Abeling, Nico G. G. M.; Rosenbaum, Thorsten; Schaper, Jörg; Duran, Marinus; Mayatepek, Ertan

2006-01-01

Beta-ureidopropionase is the third enzyme in the catabolic pathway of uracil and thymine. To date, only three other patients are reported with this inborn error of metabolism. We report the clinical presentation of a male patient who presented at the age of 4 months after an ALTE-like event (ALTE =

Errores innatos del metabolismo: Enfermedades lisosomales

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Caridad Menéndez Saínz

2002-03-01

Full Text Available Dentro de los errores innatos del metabolismo se encuentran las enfermedades de almacenamiento lisosomal o enzimopatías lisosomales, las cuáles se caracterizan por un déficit enzimático específico, la excreción de metabolitos por la orina y la acumulación de los compuestos no degradados en diferentes órganos y tejidos que ocasionan la disfución de éstos. Tienen un patrón de herencia autosómico recesivo, excepto para la enfermedad de Fabry y la enfermedad de Hunter en las que el patrón de herencia está ligado al cromosoma X. Estas enfermedades tienen una baja incidencia en general, aunque hay poblaciones donde algunas de ellas tienen una alta incidencia. Su importancia radica en la magnitud que representan como problema de salud, por la pobre calidad de vida de esos pacientes, así como su fallecimiento prematuro, motivo por el cual hay que evitar los nacimientos de nuevos niños afectados.Among the metabolism inborn errors, there are the lysosomal storage diseases or lysosomal enzymopathies that are characterized by an specific enzymatic deficiency, excretion of metabollites in urine and accumulation of non-degraded compounds in various organs and tissues causing their dysfunction. These diseases have a recessive autosomal heredity, except for Fabry´s disease and Hunter’s disease in which the pattern of heredity is chromosome X-linked. These diseases have a low incidence in general although there are populations where they show a high incidence. Their importance lies in what they represent as a health problem because of the poor quality of life of these patients and their early death, therefore, it is necessary to prevent the birth of new infants affected with these diseases.

MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation

Energy Technology Data Exchange (ETDEWEB)

Jan, Wajanat; Wang, Zhiyue J. [Department of Radiology, University of Pennsylvania School of Medicine, Children' s Hospital of Philadelphia, Pennsylvania (United States); Zimmerman, Robert A. [Department of Radiology, University of Pennsylvania School of Medicine, Children' s Hospital of Philadelphia, Pennsylvania (United States); Department of Radiology, Children' s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, PA 19104, Philadelphia (United States); Berry, Gerard T.; Kaplan, Paige B.; Kaye, Edward M. [Department of Pediatrics, University of Pennsylvania School of Medicine, The Children' s Hospital of Philadelphia, Philadelphia, Pennsylvania (United States)

2003-06-01

Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism, which affects the brain tissue resulting in impairment or death if untreated. Imaging studies have shown reversible brain edema during acute metabolic decompensation. The purpose of this paper is to describe the diffusion-weighted imaging (DWI) and spectroscopy findings during metabolic decompensation and to assess the value of these findings in the prediction of patient outcome. Six patients with the diagnosis of MSUD underwent conventional MR imaging with DWI during acute presentation with metabolic decompensation. Spectroscopy with long TE was performed in four of the six patients. Follow-up examinations were performed after clinical and metabolic recovery. DWI demonstrated marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter and the cerebral cortex. This was accompanied by the presence of an abnormal branched-chain amino acids (BCAA) and branched-chain alpha-keto acids (BCKA) peak at 0.9 ppm as well as elevated lactate on proton spectroscopy in all four patients. The changes in all six patients were reversed with treatment without evidence of volume loss or persistent tissue damage. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply imminent cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction. (orig.)

MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation

International Nuclear Information System (INIS)

Jan, Wajanat; Wang, Zhiyue J.; Zimmerman, Robert A.; Berry, Gerard T.; Kaplan, Paige B.; Kaye, Edward M.

2003-01-01

Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism, which affects the brain tissue resulting in impairment or death if untreated. Imaging studies have shown reversible brain edema during acute metabolic decompensation. The purpose of this paper is to describe the diffusion-weighted imaging (DWI) and spectroscopy findings during metabolic decompensation and to assess the value of these findings in the prediction of patient outcome. Six patients with the diagnosis of MSUD underwent conventional MR imaging with DWI during acute presentation with metabolic decompensation. Spectroscopy with long TE was performed in four of the six patients. Follow-up examinations were performed after clinical and metabolic recovery. DWI demonstrated marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter and the cerebral cortex. This was accompanied by the presence of an abnormal branched-chain amino acids (BCAA) and branched-chain alpha-keto acids (BCKA) peak at 0.9 ppm as well as elevated lactate on proton spectroscopy in all four patients. The changes in all six patients were reversed with treatment without evidence of volume loss or persistent tissue damage. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply imminent cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction. (orig.)

Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose.

Science.gov (United States)

Amaral, Ana I

2013-07-01

Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes.

Protein and leucine metabolism in maple syrup urine disease

International Nuclear Information System (INIS)

Thompson, G.N.; Bresson, J.L.; Pacy, P.J.; Bonnefont, J.P.; Walter, J.H.; Leonard, J.V.; Saudubray, J.M.; Halliday, D.

1990-01-01

Constant infusions of [13C]leucine and [2H5]phenylalanine were used to trace leucine and protein kinetics, respectively, in seven children with maple syrup urine disease (MSUD) and eleven controls matched for age and dietary protein intake. Despite significant elevations of plasma leucine (mean 351 mumol/l, range 224-477) in MSUD subjects, mean whole body protein synthesis [3.78 +/- 0.42 (SD) g.kg-1. 24 h-1] and catabolism (4.07 +/- 0.46) were similar to control values (3.69 +/- 0.50 and 4.09 +/- 0.50, respectively). The relationship between phenylalanine and leucine fluxes was also similar in MSUD subjects (mean phenylalanine-leucine flux ratio 0.35 +/- 0.07) and previously reported adult controls (0.33 +/- 0.02). Leucine oxidation was undetectable in four of the MSUD subjects and very low in the other three (less than 4 mumol.kg-1.h-1; controls 13-20). These results show that persistent elevation in leucine concentration has no effect on protein synthesis. The marked disturbance in leucine metabolism in MSUD did not alter the relationship between rates of catabolism of protein to phenylalanine and leucine, which provides further support for the validity of the use of a single amino acid to trace whole body protein metabolism. The minimal leucine oxidation in MSUD differs from findings in other inborn metabolic errors and indicates that in patients with classical MSUD there is no significant route of leucine disposal other than through protein synthesis

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

Science.gov (United States)

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.

Neonatal seizures: the overlap between diagnosis of metabolic disorders and structural abnormalities. Case report

Directory of Open Access Journals (Sweden)

Freitas Alessandra

2003-01-01

Full Text Available Inborn metabolic errors (IME and cortical developmental malformations are uncommon etiologies of neonatal seizures, however they may represent treatable causes of refractory epilepsy and for this reason must be considered as possible etiological factors. This case report aims to demonstrate the importance of neuroimaging studies in one patient with neonatal seizures, even when there are clues pointing to a metabolic disorder. CASE REPORT: A previously healthy 14 day-old child started presenting reiterated focal motor seizures (FMS which evolved to status epilepticus. Exams showed high serum levels of ammonia and no other abnormalities. A metabolic investigation was conducted with normal results. During follow-up, the patient presented developmental delay and left side hemiparesia. Seizures remained controlled with anti-epileptic drugs for four months, followed by relapse with repetitive FMS on the left side. Temporary improvement was obtained with anti-epileptic drug adjustment. At the age of 6 months, during a new episode of status epilepticus, high ammonia levels were detected. Other metabolic exams remained normal. The child was referred to a video-electroencephalographic monitoring and continuous epileptiform discharges were recorded over the right parasagittal and midline regions, with predominance over the posterior quadrant. A new neuroimaging study was performed and displayed a malformation of cortical development. Our case illustrates that because newborns are prone to present metabolic disarrangement, an unbalance such as hyperammonemia may be a consequence of acute events and conduct to a misdiagnosis of IME.

Carrier detection in X-linked ocular albinism of the Nettleship-Falls type by DNA analysis

NARCIS (Netherlands)

Bergen, A. A.; Schuurman, E. J.; van den Born, L. I.; Samanns, C.; van Dorp, D. B.; Pinckers, A. J.; Bakker, E.; van Ommen, G. J.; Gal, A.; Bleeker-Wagemakers, E. M.

1992-01-01

X-linked ocular albinism (XOA) is characterized by anomalies of the eyes and hypopigmentation or absence of pigment in skin, hair and eyes due to a hereditary inborn error of metabolism affecting the pigment cells. The gene of XOA of the Nettleship-Falls type (OA1) has been mapped to Xp22.3, and

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

Science.gov (United States)

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.

Black aorta in a patient with alkaptonuria (ochronosis).

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Newborn screening: need of the hour in India.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Phenylketonuria: central nervous system and microbiome interaction

Directory of Open Access Journals (Sweden)

Demian Arturo Herrera Morban

2017-06-01

Full Text Available Phenylketonuria (PKU is an autosomal recessive inborn error of metabolism characterized by increased phenylalanine (Phe levels causing an inadequate neurodevelopment; the treatment of PKU is a Phe-restricting diet, and as such it can modulate the intestinal microbiome of the individual, generating central nervous system secondary disturbances that, added to the baseline disturbance, can influence the outcome of the disease.

Neurological images in phenylketonuria (PKU

Directory of Open Access Journals (Sweden)

Juan Francisco Cabello

2014-07-01

Full Text Available Phenylketonuria is an inborn error of metabolism that causes structural abnormalities in the white matter of the brain. In untreated patients demyelization can be observed, and there is evidence of intramyelin edema even in some treated patients. Imaging studies especially magnetic resonance imaging are useful for the study of patients with phenylketonuria, but their benefit as monitoring tools is controversial.

Viral symbiosis and the holobiontic nature of the human genome.

Science.gov (United States)

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.

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

Science.gov (United States)

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

Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities

DEFF Research Database (Denmark)

Quintana, Anita M; Yu, Hung-Chun; Brebner, Alison

2017-01-01

roles in normal brain development. The loss of THAP11 in zebrafish embryos results in craniofacial abnormalities including the complete loss of Meckel's cartilage, the ceratohyal, and all of the ceratobranchial cartilages. These data are consistent with our previous work that demonstrated a role...

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.

Science.gov (United States)

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.

Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency

Directory of Open Access Journals (Sweden)

Peter J. McGuire

2014-02-01

types of inborn errors of metabolism.

Neuropsychiatric manifestations in late-onset urea cycle disorder patients

OpenAIRE

Serrano Mercedes L.; Martins Cecilia E.; Pérez-Dueñas Belén; Gómez-López Lilian; Murgui Empar; Fons Carmen; García-Cazorla Ángels; Artuch Rafael M D; Jara Fernando; Arranz José Antonio; Häberle Johannes; Briones Paz; Campistol Jaume M D; Pineda Mercè; Vilaseca María Antònia Antonia

2010-01-01

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 hyper...

Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress

OpenAIRE

Merritt II, J Lawrence; Sun,Angela

2015-01-01

Angela Sun, J Lawrence Merritt II Department of Pediatrics, University of Washington, Seattle, WA, USA Abstract: Fatty acid oxidation disorders are inborn errors of metabolism resulting in failure of ß-oxidation within or transport of fatty acids into the mitochondria. The long-chain fatty acid oxidation disorders are characterized by variable presentations ranging from newborn cardiomyopathy, to infantile hypoketotic hypoglycemia resulting from liver involvement, to skeletal myopa...

Tay-Sach disease with "cherry-red spot"--first reported case in Malaysia.

Science.gov (United States)

Chan, L Y; Balasubramaniam, S; Sunder, R; Jamalia, R; Karunakar, T V N; Alagaratnam, J

2011-12-01

We present a rare case of Tay-Sachs disease with retinal 'cherry-red spots' in a 19-month-old Malay child. Molecular genetic studies confirmed the diagnosis. The case highlights that 'cherry-red spot' is a useful clinical clue in Tay-Sachs disease and several other lysosomal storage disorders. It serves as an ideal illustration of the eye as a window to inborn error of metabolism.

Alkaptonuria: A case report.

Science.gov (United States)

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.

Inhibition of mitochondrial complex I in cerebral cortex of immature rats following seizures induced by homocysteic acid

Czech Academy of Sciences Publication Activity Database

Ješina, P.; Folbergrová, Jaroslava; Drahota, Zdeněk; Haugvicová, Renata; Lisá, Věra; Pecinová, Alena; Houštěk, Josef

2008-01-01

Roč. 31, Suppl.1 (2008), s. 60-60 ISSN 0141-8955. [Annual Symposium of the Society for the Study of Inborn Errors of Metabolism . 02.09.2008-05.09.2008, Lisboa] R&D Projects: GA ČR GA309/08/0292 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * immature rats * homocysteic acid-induced seizures * mitochondrial complex I inhibition Subject RIV: CE - Biochemistry

Determination of the spectrum of low molecular mass organic acids in urine by capillary electrophoresis with contactless conductivity and ultraviolet photometric detection-An efficient tool for monitoring of inborn metabolic disorders

Energy Technology Data Exchange (ETDEWEB)

Tuma, Petr, E-mail: petr.tuma@lf3.cuni.cz [Institute of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague 10 (Czech Republic); Samcova, Eva [Institute of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague 10 (Czech Republic); Stulik, Karel [Department of Analytical Chemistry, Charles University, Albertov 2030, 128 43 Prague 2 (Czech Republic)

2011-01-24

A mixture of 29 organic acids (OAs) occurring in urine was analyzed by capillary electrophoresis (CE) with capacitively coupled contactless conductivity detection (C{sup 4}D) and UV photometric detection. The optimized analytical system involved a 100 cm long polyacrylamide-coated capillary (50 {mu}m i.d.) and the background electrolyte of 20 mM 2-morpholinoethanesulfonic acid (MES)/NaOH + 10% (v/v) methanol, pH 6.0 (pH is related to the 20 mM MES/NaOH buffer in water). The LOD values obtained by C{sup 4}D for the OAs which do not absorb UV radiation range from 0.6 {mu}M (oxalic acid) to 6.8 {mu}M (pyruvic acid); those obtained by UV photometry for the remaining OAs range from 2.9 {mu}M (5-hydroxy-3-indoleacetic acid) to 10.2 {mu}M (uric acid). The repeatability of the procedure developed is characterized by the coefficients of variation, which vary between 0.3% (tartaric acid) and 0.6% (5-hydroxy-3-indoleacetic acid) for the migration time and between 1.3% (tartaric acid) and 3.5% (lactic acid) for the peak area. The procedure permitted quantitation of 20 OAs in a real urine sample and was applied to monitoring of the occurrence of the inborn metabolic fault of methylmalonic aciduria.

Pesquisaje neonatal y selectivo para algunos errores congénitos del metabolismo en Villa Clara Neonatal and selective screening for some congenital errors of metabolism in Villa Clara

Directory of Open Access Journals (Sweden)

Carmelo Gilberto Soto Villasante

2007-03-01

Full Text Available Los errores congénitos del metabolismo integran un grupo muy heterogéneo de enfermedades de causa genética que afectan fundamentalmente a la población infantil. El diagnóstico puede ser realizado en el período neonatal temprano o en los niños que tienen riesgos de padecer esta dolencia. En el trabajo se presentan los resultados obtenidos en nuestro laboratorio a lo largo de 15 años. Se investigaron 6 158 recién nacidos con el objeto de detectar galactosemia y deficiencia de biotinidasa. Se pensó que un niño tenía una variante de galactosemia conocida como variante Duarte. Se realizó un estudio selectivo de 920 niños con presuntos errores congénitos del metabolismo y se detectó un 3,36 % de casos positivos. Entre ellos, la enfermedad más frecuente fue la mucopolisacaridosis. Se evidenció que el empleo de la tecnología convencional con una buena cooperación del médico permite el diagnóstico de un elevado número de niños que padecen algún error congénito del metabolismo.The congenital errors of metabolism integrate a very heterogeneous group of diseases of genetic cause affecting mainly the infantile population. The diagnosis may be made in the early neonatal period or in children at risk for suffering from this disease. The results obtained in our lab during 15 years are presented in this paper. 6 159 newborns were studied in order to detect galactosemia and biotinidase deficiency. It was thought that a child had a variant of galactosemia known as Duarte. A selective study of 920 children with presumptive congenital errors of metabolism was conducted, and 3.36 % of positive cases were found. The most frequent disease among them was mucopolysacharidosis. It was proved that the use of the conventional technology and a good cooperation of the physician allowed to make the diagnosis in a great number of children with some congenital error of metabolism.

Cellular disturbance in the rats retina after irradiation and metabolic errors during the postnatal period

International Nuclear Information System (INIS)

Lierse, W.; Franke, H.D.

1982-01-01

During the first five days of the postnatal period the retina has been vulnerable following administration of DNA blocking drugs and irradiation with conventional X-rays and fast neutrons. During this period the disturbance of lamination accompanied with pycnosis of neurons and neuroblasts has been the important morphologic reaction. During the same phase metabolic errors, like experimental phenylketonuria, have produced a swelling of photoreceptor cells and pigmentepithelium cells. The other neurons of the retina were pycnotic. Structural alterations like rosettes persisted during the rest of life. The relative minor error during the first phase of rats life may result in a persistent disease. (orig.)

Association Between Newborn Metabolic Profiles and Pediatric Kidney Disease

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Manish M. Sood

2018-05-01

Full Text Available Introduction: Metabolomics offers considerable promise in early disease detection. We set out to test the hypothesis that routine newborn metabolic profiles at birth, obtained through screening for inborn errors of metabolism, would be associated with kidney disease and add incremental information to known clinical risk factors. Methods: We conducted a population-level cohort study in Ontario, Canada, using metabolic profiles from 1,288,905 newborns from 2006 to 2015. The primary outcome was chronic kidney disease (CKD or dialysis. Individual metabolites and their ratio combinations were examined by logistic regression after adjustment for established risk factors for kidney disease and incremental risk prediction measured. Results: CKD occurred in 2086 (0.16%, median time 612 days and dialysis in 641 (0.05%, median time 99 days infants and children. Individual metabolites consisted of amino acids, acylcarnitines, markers of fatty acid oxidation, and others. Base models incorporating clinical risk factors only provided c-statistics of 0.61 for CKD and 0.70 for dialysis. The addition of identified metabolites to risk prediciton models resulted in significant incremental improvement in the performance of both models (CKD model: c-statistic 0.66 NRI 0.36 IDI 0.04, dialysis model: c-statistic 0.77 NRI 0.57 IDI 0.09. This was consistent after internal validation using bootstrapping and a sensitivity analysis excluding outcomes within the first 30 days. Conclusion: Routinely collected screening metabolites at birth are associated with CKD and the need for dialytic therapies in infants and children, and add incremental information to traditional clinical risk factors. Keywords: chronic kidney disease, dialysis, end-stage kidney disease, metabolomics, newborn screening, pediatric, renal failure

Clinical, Biochemical, and Molecular Spectrum of Hyperargininemia Due to Arginase I Deficiency

OpenAIRE

Scaglia, Fernando; Lee, Brendan

2006-01-01

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Urea cycle disorders are a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia and hyperglutaminemia. Deficiencies of all of the enzymes of the cycle have been described and although each specific disorder results in the accumulation of different precursors, hyperammonemia and hyperglutaminemia are common biochemical hallmarks of these disorders. ...

Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies

OpenAIRE

Wajner, Moacir; Amaral, Alexandre?Umpierrez

2016-01-01

Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in maintaining body energy homoeostasis mainly during catabolic states. Oxidation of fatty acids requires approximately 25 proteins. Inherited defects of FAO have been identified in the majority of these proteins and constitute an important group of inborn errors of metabolism. Affected patients usually present with severe hepatopathy, cardiomyopathy and skeletal myopathy, whereas some patients may suffer acute and/or progressive e...

Alkaptonuria: A case report

Directory of Open Access Journals (Sweden)

Nirupama Damarla

2017-01-01

Full Text Available 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.

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

Science.gov (United States)

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.

Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment

NARCIS (Netherlands)

Bosch, A.M.; Abeling, N.G.G.M.; Ijlst, L.; Knoester, H.; van der Pol, W.L.; Stroomer, A.E.M.; Wanders, R.J.; Visser, G.; Wijburg, F.A.; Duran, M.; Waterham, H.R.

2011-01-01

We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and urine organic acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation

Gestational dating by metabolic profile at birth: a California cohort study.

Science.gov (United States)

Jelliffe-Pawlowski, Laura L; Norton, Mary E; Baer, Rebecca J; Santos, Nicole; Rutherford, George W

2016-04-01

Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications. We sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset. When considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care. Copyright © 2016 The Authors. Published

Biotin deprivation impairs mitochondrial structure and function and has implications for inherited metabolic disorders.

Science.gov (United States)

Ochoa-Ruiz, Estefanía; Díaz-Ruiz, Rodrigo; Hernández-Vázquez, Alaín de J; Ibarra-González, Isabel; Ortiz-Plata, Alma; Rembao, Daniel; Ortega-Cuéllar, Daniel; Viollet, Benoit; Uribe-Carvajal, Salvador; Corella, José Ahmed; Velázquez-Arellano, Antonio

2015-11-01

Certain inborn errors of metabolism result from deficiencies in biotin containing enzymes. These disorders are mimicked by dietary absence or insufficiency of biotin, ATP deficit being a major effect,whose responsible mechanisms have not been thoroughly studied. Here we show that in rats and cultured cells it is the result of reduced TCA cycle flow, partly due to deficient anaplerotic biotin-dependent pyruvate carboxylase. This is accompanied by diminished flow through the electron transport chain, augmented by deficient cytochrome c oxidase (complex IV) activity with decreased cytochromes and reduced oxidative phosphorylation. There was also severe mitochondrial damage accompanied by decrease of mitochondria, associated with toxic levels of propionyl CoA as shown by carnitine supplementation studies, which explains the apparently paradoxical mitochondrial diminution in the face of the energy sensor AMPK activation, known to induce mitochondria biogenesis. This idea was supported by experiments on AMPK knockout mouse embryonic fibroblasts (MEFs). The multifactorial ATP deficit also provides a plausible basis for the cardiomyopathy in patients with propionic acidemia, and other diseases.Additionally, systemic inflammation concomitant to the toxic state might explain our findings of enhanced IL-6, STAT3 and HIF-1α, associated with an increase of mitophagic BNIP3 and PINK proteins, which may further increase mitophagy. Together our results imply core mechanisms of energy deficit in several inherited metabolic disorders.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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

Metabolic encephalopathy and lipid storage myopathy associated with a presumptive mitochondrial fatty acid oxidation defect in a dog

Directory of Open Access Journals (Sweden)

Vanessa R Biegen

2015-11-01

Full Text Available A 1-year-old spayed female Shih Tzu presented for episodic abnormalities of posture and mentation. Neurologic 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 neurologic 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.

Endocrine manifestations related to inherited metabolic diseases in adults

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Vantyghem Marie-Christine

2012-01-01

Full Text Available Abstract Most inborn errors of metabolism (IEM are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.. IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects, and metal (hemochromatosis and storage disorders (cystinosis. Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes, whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure, congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last. This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.

Digital subtraction angiography in patients with Marfan's syndrome

Energy Technology Data Exchange (ETDEWEB)

Rauber, K; Riemann, H

1987-06-01

Marfan's syndrome is a rare inborn error of metabolism. Marfan patients are prone to aneurysms of the ascending aorta and run a high risk of rupture of the aortic arch. The diameter of the aneurysm is the most important predictor of the risk and therefore the leading point for surgical interventions. IV and IA-DSA according to our experiences are simple and effective methods in pre- and postoperative evaluation of patients with the syndrome.

Pathogenic Cascades in Lysosomal Disease – Why so Complex?

OpenAIRE

Walkley, Steven U.

2009-01-01

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, as well as signaling. More than two-thirds of lys...

Gestational dating by metabolic profile at birth: a California cohort study

Science.gov (United States)

Jelliffe-Pawlowski, Laura L.; Norton, Mary E.; Baer, Rebecca J.; Santos, Nicole; Rutherford, George W.

2016-01-01

Background Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications. Objective We sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset. Conclusion When considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care. PMID

Co-existence of Phenylketonuria and Fabry disease on a 3 year-old boy: case report

Directory of Open Access Journals (Sweden)

Bonapace Giuseppe

2010-05-01

Full Text Available Abstract Background The co-existence of two genetically distinct metabolic disorders in the same patient has rarely been reported. Phenylketonuria (PKU is an inborn error of the metabolism resulting from a phenylalanine hydroxylase deficiency. Fabry disease (FD is an X-linked lysosomal storage disorder due to a deficiency of the enzyme alpha-galactosidase A. Case presentation We report a case of a 3 year- old boy affected by classic PKU and FD, both confirmed by molecular data. The FD was suspected at the age of 21 months on the presence of non-specific GI symptoms (severe abdominal pain and periodically appearance of not specific episodes of gastroenteritis apparently non related to PKU. Conclusion This is the first report of co-existence of FD and PKU, two different congenital inborn of metabolism and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of this diseases made very difficult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specific gastroenteritis episodes. Furthermore, this case report helps to define the early clinical phenotype of FD.

Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response.

Science.gov (United States)

Watson, Emma; MacNeil, Lesley T; Arda, H Efsun; Zhu, Lihua Julie; Walhout, Albertha J M

2013-03-28

Expression profiles are tailored according to dietary input. However, the networks that control dietary responses remain largely uncharacterized. Here, we combine forward and reverse genetic screens to delineate a network of 184 genes that affect the C. elegans dietary response to Comamonas DA1877 bacteria. We find that perturbation of a mitochondrial network composed of enzymes involved in amino acid metabolism and the TCA cycle affects the dietary response. In humans, mutations in the corresponding genes cause inborn diseases of amino acid metabolism, most of which are treated by dietary intervention. We identify several transcription factors (TFs) that mediate the changes in gene expression upon metabolic network perturbations. Altogether, our findings unveil a transcriptional response system that is poised to sense dietary cues and metabolic imbalances, illustrating extensive communication between metabolic networks in the mitochondria and gene regulatory networks in the nucleus. Copyright © 2013 Elsevier Inc. All rights reserved.

Urea cycle disorder--argininosuccinic lyase deficiency.

Science.gov (United States)

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.

Simultaneous analysis of amino acid and organic acid by NMR spectrometry, 2

International Nuclear Information System (INIS)

Koda, Naoya; Yamaguchi, Shuichi; Mori, Takeshi.

1987-01-01

Analysis of urine from patients with inborn error of metabolism were studied by 1 H-nuclear magnetic resonance (NMR) spectrometry. Diseases studied were as follows; phenylketonuria, biotin responsive multiple carboxylase deficiency, non-ketotic hyperglycinemia, 3-ketothiolase deficiency, alkaptonuria, methylmalonic acidemia, isovaleric acidemia, glutaric aciduria, argininosuccinic aciduria and hyperornithinemia. In each disease, specific metabolites in urine were recognized by NMR spectrometry. This method is accomplished within 10 minutes with non-treated small volume of urine and will be successfully available for the screening and/or diagnosis of inherited metabolic diseases of amino acid and organic acid. (author)

Digital subtraction angiography in patients with Marfan's syndrome

International Nuclear Information System (INIS)

Rauber, K.; Riemann, H.

1987-01-01

Marfan's syndrome is a rare inborn error of metabolism. Marfan patients are prone to aneurysms of the ascending aorta and run a high risk of rupture of the aortic arch. The diameter of the aneurysm is the most important predictor of the risk and therefore the leading point for surgical interventions. IV and IA-DSA according to our experiences are simple and effective methods in pre- and postoperative evaluation of patients with the syndrome. (orig.) [de

Digital subtraction angiography in patients with Marfan's syndrome

Energy Technology Data Exchange (ETDEWEB)

Rauber, K.; Riemann, H.

1987-06-01

Marfan's syndrome is a rare inborn error of metabolism. Marfan patients are prone to aneurysms of the ascending aorta and run a high risk of rupture of the aortic arch. The diameter of the aneurysm is the most important predictor of the risk and therefore the leading point for surgical interventions. IV and IA-DSA according to our experiences are simple and effective methods in pre- and postoperative evaluation of patients with the syndrome.

Disease: H00849 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available e deficiency; Guanidinoacetate methyltransferase deficiency [DS:H00834]; X-linked creatine deficiency syndrome (XL-CDS) The creatin...e deficiency syndrome is a group of inborn errors of creatine metabolism, that includ...transferase (AGAT) deficiency, and X-linked creatine deficiency syndrome (XL-CDS). Intellectual disability a...nd seizures are common to all three disorders. GAMT deficiency and AGAT deficiency are creatine biosynthesis... disorders and inherited in an autosomal recessive manner. XL-CDS is the creatine

Non-decussating retinal-fugal fibre syndrome. An inborn achiasmatic malformation associated with visuotopic misrouting, visual evoked potential ipsilateral asymmetry and nystagmus

NARCIS (Netherlands)

Apkarian, P.; Bour, L. J.; Barth, P. G.; Wenniger-Prick, L.; Verbeeten, B.

1995-01-01

We report a newly identified syndrome in which nasal retinal fibres fail to decussate due to the inborn absence of an optic chiasm. Visual evoked potential (VEP) assessment and neuro-opththalmic evaluation in two unrelated, non-albino children revealed the unusual visual pathway anomaly in the form

Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis.

Science.gov (United States)

Ivanovski, Ivan; Ješić, Miloš; Ivanovski, Ana; Garavelli, Livia; Ivanovski, Petar

2017-11-28

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.

Exome Sequencing and the Management of Neurometabolic Disorders.

Science.gov (United States)

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.).

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

NARCIS (Netherlands)

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

2018-01-01

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

Substrate kinetics in patients with disorders of skeletal muscle metabolism.

Science.gov (United States)

Ørngreen, Mette Cathrine

2016-07-01

The main purpose of the following studies was to investigate pathophysiological mechanisms in fat and carbohydrate metabolism and effect of nutritional interventions in patients with metabolic myopathies and in patients with severe muscle wasting. Yet there is no cure for patients with skeletal muscle disorders. The group of patients is heterozygous and this thesis is focused on patients with metabolic myopathies and low muscle mass due to severe muscle wasting. Disorders of fatty acid oxidation (FAO) are, along with myophosphorylase deficiency (McArdle disease), the most common inborn errors of metabolism leading to recurrent episodes of rhabdomyolysis in adults. Prolonged exercise, fasting, and fever are the main triggering factors for rhabdomyolysis in these conditions, and can be complicated by acute renal failure. Patients with low muscle mass are in risk of loosing their functional skills and depend on a wheel chair and respiratory support. We used nutritional interventions and metabolic studies with stable isotope technique and indirect calorimetry in patients with metabolic myopathies and patients with low muscle mass to get information of the metabolism of the investigated diseases, and to gain knowledge of the biochemical pathways of intermediary metabolism in human skeletal muscle. We have shown that patients with fat metabolism disorders in skeletal muscle affecting the transporting enzyme of fat into the mitochondria (carnitine palmitoyltransferase II deficiency) and affecting the enzyme responsible for breakdown of the long-chain fatty acids (very long chain acyl-CoA dehydrogenase deficiency) have a normal fatty acid oxidation at rest, but enzyme activity is too low to increase fatty acid oxidation during exercise. Furthermore, these patients benefit from a carbohydrate rich diet. Oppositely is exercise capacity worsened by a fat-rich diet in these patients. The patients also benefit from IV glucose, however, when glucose is given orally just before

Mass spectrometry in clinical chemistry

International Nuclear Information System (INIS)

Pettersen, J.E.

1977-01-01

A brief description is given of the functional elements of a mass spectrometer and of some currently employed mass spectrometric techniques, such as combined gas chromatography-mass spectrometry, mass chromatography, and selected ion monitoring. Various areas of application of mass spectrometry in clinical chemistry are discussed, such as inborn errors of metabolism and other metabolic disorders, intoxications, quantitative determinations of drugs, hormones, gases, and trace elements, and the use of isotope dilution mass spectrometry as a definitive method for the establishment of true values for concentrations of various compounds in reference sera. It is concluded that mass spectrometry is of great value in clinical chemistry. (Auth.)

Isovaleric acidaemia: cranial CT and MRI findings

International Nuclear Information System (INIS)

Sogut, Ayhan; Acun, Ceyda; Tomsac, Nazan; Demirel, Fatma; Aydin, Kubilay; Aktuglu, Cigdem

2004-01-01

Isovaleric acidaemia is an inborn error of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase, which results in accumulation of isovaleric acid in body fluids. There are acute and chronic-intermittent forms of the disease. We present the cranial CT and MRI findings of a 19-month-old girl with the chronic-intermittent form of isovaleric acidaemia. She presented with severe metabolic acidosis, hyperglycaemia, glycosuria, ketonuria and acute encephalopathy. Cranial CT revealed bilateral hypodensity of the globi pallidi. MRI showed signal changes in the globi pallidi and corticospinal tracts of the mesencephalon, which were hypointense on T1-weighted and hyperintense on T2-weighted images. (orig.)

Isovaleric acidaemia: cranial CT and MRI findings

Energy Technology Data Exchange (ETDEWEB)

Sogut, Ayhan; Acun, Ceyda; Tomsac, Nazan; Demirel, Fatma [Department of Paediatrics, Karaelmas University, Zonguldak (Turkey); Aydin, Kubilay [Department of Radiology, Istanbul Medical School, Istanbul University, Camlikyolu, B. mehmetpasa sokak yavuz apt. No:10/10, Etiler, Istanbul (Turkey); Aktuglu, Cigdem [Department of Paediatrics, Cerrahpasa Medical School, Istanbul University, Istanbul (Turkey)

2004-02-01

Isovaleric acidaemia is an inborn error of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase, which results in accumulation of isovaleric acid in body fluids. There are acute and chronic-intermittent forms of the disease. We present the cranial CT and MRI findings of a 19-month-old girl with the chronic-intermittent form of isovaleric acidaemia. She presented with severe metabolic acidosis, hyperglycaemia, glycosuria, ketonuria and acute encephalopathy. Cranial CT revealed bilateral hypodensity of the globi pallidi. MRI showed signal changes in the globi pallidi and corticospinal tracts of the mesencephalon, which were hypointense on T1-weighted and hyperintense on T2-weighted images. (orig.)

Clinical and radiological pictures of two newborn babies with manifestations of chondrodysplasia punctata and review of available literature

International Nuclear Information System (INIS)

Jurkiewicz, Elżbieta; Marcinska, Beata; Bothur-Nowacka, Joanna; Dobrzanska, Anna

2013-01-01

Chondrodysplasia punctata (CDP) is a rare, heterogeneous congenital skeletal dysplasia, characterized by punctate or dot-like calcium deposits in cartilage observed on neonatal radiograms. A number of inborn metabolic diseases are associated with CDP, including peroxisomal and cholesterol biosynthesis dysfunction and other inborn errors of metabolism such as: mucolipidosis type II, mucopolysacharidosis type III, GM1 gangliosidosis. CDP is also related to disruption of vitamin K-dependent metabolism, causing secondary effects on the embryo, as well as fetal alcohol syndrome (FAS), chromosomal abnormalities that include trisomies 18 and 21, Turner syndrome. This article presents clinical data and diagnostic imaging findings of two newborn babies with chondrodysplasia punctata. Children presented with skeletal and cartilage anomalies, dysmorphic facial feature, muscles tone abnormalities, skin changes and breathing difficulties. One of the patients demonstrated critical stenosis of spinal canal with anterior subluxation of C1 vertebra relative to C2. The aim of this article is to present cases and briefly describe current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases coexisting with CDP. Radiological diagnostic imaging allows for visualization of punctate focal mineralization in bone epiphyses during neonatal age and infancy. Determining the etiology of chondrodysplasia punctata requires performing various basic as well as additional examinations, including genetic studies

Genetics of alkaptonuria – an overview

Directory of Open Access Journals (Sweden)

Zatkova Andrea

2015-12-01

Full Text Available Alkaptonuria (AKU is the first described inborn error of metabolism and a classical example of rare autosomal recessive disease. AKU patients carry homozygous or compound heterozygous mutations of the gene coding for enzyme homogentisate dioxygenase (HGD involved in metabolism of tyrosine. The metabolic block in AKU causes accumulation of homogentisic acid (HGA that, with advancing age of the patient, leads to severe and painful ochronotic arthropathy. HGD gene was mapped to chromosome 3q13.3 and is composed of 14 exons. In about 400 patients, 142 pathogenic variants were reported that are listed in HGD mutations database (http://hgddatabase.cvtisr.sk/. In this review, we summarise different aspects of AKU genetics and impact of the HGD variants on enzyme function.

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

Science.gov (United States)

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.

Scintigraphic appearances of Gaucher's disease

International Nuclear Information System (INIS)

Okada, Junichi; Uchiyama, Guio; Hayakawa, Kazushige; Araki, Tsutomu; Hayashi, Sanshin; Yamada, Kayoko; Seto, Kazuhiko

1985-01-01

Gaucher's disease is an inborn error of metabolism in which glucocerebroside accumlates within reticuloendotherial cells of spleen, liver and bone marrow. The scintigraphic appearances are described in a 19-year-old man with Gaucher's disease. The colloid scan showed increased uptake in the lung and bone marrow of legs where the reticuloendotherial system was activated. The bone scan demonstrated increased activity in the metaphyseal and diaphyseal region infiltrated by Gaucher's cell. Ga-67 was thought to be accumlated in the progressive focus of the disease. (author)

First report of alkaptonuria in Peru

OpenAIRE

Guillén-Mendoza, Daniel; Facultad de Medicina, Universidad Peruana Cayetano Heredia. Lima, Perú.; Quiroga de Michelena, María; Facultad de Medicina, Universidad Peruana Cayetano Heredia. Lima, Perú. Genética. Instituto de Medicina Genética. Lima, Perú.

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 intens...

Sudden unexpected infant death (SUDI in a newborn due to medium chain acyl CoA dehydrogenase (MCAD deficiency with an unusual severe genotype

Directory of Open Access Journals (Sweden)

Lovera Cristina

2012-10-01

Full Text Available Abstract Medium chain acyl CoA dehydrogenase deficiency (MCAD is the most common inborn error of fatty acid oxidation. This condition may lead to cellular energy shortage and cause severe clinical events such as hypoketotic hypoglycemia, Reye syndrome and sudden death. MCAD deficiency usually presents around three to six months of life, following catabolic stress as intercurrent infections or prolonged fasting, whilst neonatal-onset of the disease is quite rare. We report the case of an apparently healthy newborn who suddenly died at the third day of life, in which the diagnosis of MCAD deficiency was possible through peri-mortem blood-spot acylcarnitine analysis that showed very high concentrations of octanoylcarnitine. Genetic analysis at the ACADM locus confirmed the biochemical findings by demonstrating the presence in homozygosity of the frame-shift c.244dup1 (p.Trp82LeufsX23 mutation, a severe genotype that may explain the unusual and very early fatal outcome in this newborn. This report confirms that inborn errors of fatty acid oxidation represent one of the genetic causes of sudden unexpected deaths in infancy (SUDI and underlines the importance to include systematically specific metabolic screening in any neonatal unexpected death.

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis

Energy Technology Data Exchange (ETDEWEB)

Rossi, Massimiliano; Edery, Patrick [Hospices Civils de Lyon, Genetic Department, Referral Centre for Developmental Abnormalities, Femme-Mere-Enfant Hospital, Bron (France); INSERM U1028 UMR CNRS 5,292, UCBL, CRNL TIGER Team, CH le Vinater, Bron (France); Hall, Christine M. [Retired from Department of Radiology, Great Ormond Street Hospital, London (United Kingdom); Bouvier, Raymonde; Collardeau-Frachon, Sophie [Hospices Civils de Lyon, Department of Pathology, CBPE, Bron (France); Le Breton, Frederique [Hospices Civils de Lyon, Department of Pathology, Croix-Rousse Hospital, Lyon (France); Bucourt, Martine [AP-HP, Foetopathology Unit, Jean Verdier Hospital, Bondy (France); Cordier, Marie Pierre [Hospices Civils de Lyon, Genetic Department, Referral Centre for Developmental Abnormalities, Femme-Mere-Enfant Hospital, Bron (France); Vianey-Saban, Christine [Hospices Civils de Lyon, Department of Inborn Errors of Metabolism and Neonatal Screening, CBPE, Bron (France); Parenti, Giancarlo; Andria, Generoso [Federico II University, Department of Translational Medical Sciences, Section of Pediatrics, Naples (Italy); Le Merrer, Martine [AP-HP, Genetic Department, Referal Centre for Skeletal Dysplasias, Institut Imagine, Necker-Enfants Malades Hospital, Paris (United Kingdom); Offiah, Amaka C. [Stephenson Wing Sheffield Children' s NHS Foundation Trust Western Bank, Radiology Department, Children' s Hospital, Academic Unit of Child Health Room C4, Sheffield (United Kingdom)

2015-07-15

Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis. (orig.)

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis

International Nuclear Information System (INIS)

Rossi, Massimiliano; Edery, Patrick; Hall, Christine M.; Bouvier, Raymonde; Collardeau-Frachon, Sophie; Le Breton, Frederique; Bucourt, Martine; Cordier, Marie Pierre; Vianey-Saban, Christine; Parenti, Giancarlo; Andria, Generoso; Le Merrer, Martine; Offiah, Amaka C.

2015-01-01

Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis. (orig.)

Neurometabolic diseases of childhood

International Nuclear Information System (INIS)

Patay, Zoltan; Blaser, Susan I.; Poretti, Andrea; Huisman, Thierry A.G.M.

2015-01-01

Metabolic diseases affecting the pediatric brain are complex conditions, the underlying mechanisms leading to structural damage are diverse and the diagnostic imaging manifestations are often non-specific; hence early, sensitive and specific diagnosis can be challenging for the radiologist. However, misdiagnosis or a delayed diagnosis can result in a devastating, irreversible injury to the developing brain. Based upon the inborn error, neurometabolic diseases can be subdivided in various groups depending on the predominantly involved tissue (e.g., white matter in leukodystrophies or leukoencephalopathies), the involved metabolic processes (e.g., organic acidurias and aminoacidopathies) and primary age of the child at presentation (e.g., neurometabolic disorders of the newborn). This manuscript summarizes these topics. (orig.)

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

DEFF Research Database (Denmark)

Baumgartner, Matthias R; Hörster, Friederike; Dionisi-Vici, Carlo

2014-01-01

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~...... recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.......:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA...

Neurometabolic diseases of childhood

Energy Technology Data Exchange (ETDEWEB)

Patay, Zoltan [St. Jude Children' s Research Hospital, Section of Neuroradiology, Division of Radiology, Department of Radiological Sciences, Memphis, TN (United States); Blaser, Susan I. [The Hospital for Sick Children, Division of Neuroradiology, Department of Diagnostic Imaging, Toronto (Canada); Poretti, Andrea; Huisman, Thierry A.G.M. [Charlotte R. Bloomberg Children' s Center, Pediatric Radiology and Pediatric Neuroradiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Baltimore, MD (United States)

2015-09-15

Metabolic diseases affecting the pediatric brain are complex conditions, the underlying mechanisms leading to structural damage are diverse and the diagnostic imaging manifestations are often non-specific; hence early, sensitive and specific diagnosis can be challenging for the radiologist. However, misdiagnosis or a delayed diagnosis can result in a devastating, irreversible injury to the developing brain. Based upon the inborn error, neurometabolic diseases can be subdivided in various groups depending on the predominantly involved tissue (e.g., white matter in leukodystrophies or leukoencephalopathies), the involved metabolic processes (e.g., organic acidurias and aminoacidopathies) and primary age of the child at presentation (e.g., neurometabolic disorders of the newborn). This manuscript summarizes these topics. (orig.)

Primary hyperoxaluria: spectrum of clinical and imaging findings

Energy Technology Data Exchange (ETDEWEB)

Strauss, Sara B.; Levin, Terry L. [Children' s Hospital of Montefiore Medical Center, Division of Pediatric Radiology, Department of Radiology, Bronx, NY (United States); Waltuch, Temima; Kaskel, Frederick [Children' s Hospital at Montefiore Medical Center, Division of Pediatric Nephrology, Bronx, NY (United States); Bivin, William [Allegheny General Hospital, Department of Pathology, Pittsburgh, PA (United States)

2017-01-15

Primary hyperoxaluria is a rare autosomal recessive inborn error of metabolism with three known subtypes. In primary hyperoxaluria type 1, the most common of the subtypes, a deficiency in the hepatic enzymes responsible for the metabolism of glycoxylate to glycine, leads to excessive levels of glyoxylate, which is converted to oxalate. The resultant elevation in serum and urinary oxalate that characterizes primary hyperoxaluria leads to calcium oxalate crystal deposition in multiple organ systems (oxalosis). We review the genetics, pathogenesis, variable clinical presentation and course of this disease as well as its treatment. Emphasis is placed on the characteristic imaging findings before and after definitive treatment with combined liver and renal transplantation. (orig.)

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

Science.gov (United States)

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.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Inborn anemias in mice

International Nuclear Information System (INIS)

Bernstein, S.E.; Barker, J.E.; Russell, E.S.

1981-06-01

hereditary anemias of mice have been the chief objects of investigation. At present under study are four macrocytic anemias, five hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an α-thalassemia, and a new target-cell anemia. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus our wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: (a) characterization of peripheral blood values, (b) determinations of radiosensitivity under a variety of conditions, (c) measurements of iron metabolism and heme synthesis, (d) histological and biochemical study of blood-forming tissue, (e) functional tests of the stem cell component, (f) examination of responses to erythroid stimuli, and (g) transplantation of tissue between individuals of differently affected genotypes

Exercising with blocked muscle glycogenolysis

DEFF Research Database (Denmark)

Nielsen, Tue L; Pinós, Tomàs; Brull, Astrid

2018-01-01

BACKGROUND: McArdle disease (glycogen storage disease type V) is an inborn error of skeletal muscle metabolism, which affects glycogen phosphorylase (myophosphorylase) activity leading to an inability to break down glycogen. Patients with McArdle disease are exercise intolerant, as muscle glycogen......-derived glucose is unavailable during exercise. Metabolic adaptation to blocked muscle glycogenolysis occurs at rest in the McArdle mouse model, but only in highly glycolytic muscle. However, it is unknown what compensatory metabolic adaptations occur during exercise in McArdle disease. METHODS: In this study, 8......-week old McArdle and wild-type mice were exercised on a treadmill until exhausted. Dissected muscles were compared with non-exercised, age-matched McArdle and wild-type mice for histology and activation and expression of proteins involved in glucose uptake and glycogenolysis. RESULTS: Investigation...

Crystals hold the clue

Directory of Open Access Journals (Sweden)

Asha K Varghese

2017-01-01

Full Text Available A 21-day-old male infant, born as the first child to a nonconsanguineous couple, presented with nonspecific symptoms, signs, and superimposed infection. Investigations conducted were not conclusive to arrive at a diagnosis. In 6 days, the infant succumbed to his condition. Postmortem samples were analyzed for metabolic substances, and liver biopsy was done. Urine metabolic screening showed the presence of amino acids and reducing substance. Further analysis proved the presence of galactose, generalized aminoaciduria, and liver biopsy with features of inborn error of metabolism. Further samples for higher investigations were not available, which draws attention to the need of being able to diagnose the condition early enough to save lives. We are suggesting a helpful, easy to perform, and cheap diagnostic test algorithm for diagnosing galactosemia in resource-poor settings.

Framing the inborn aging process and longevity science.

Science.gov (United States)

Farrelly, Colin

2010-06-01

The medical sciences are currently dominated by the "disease-model" approach to health extension, an approach that prioritizes the study of pathological mechanisms with the goal of discovering treatment modalities for specific diseases. This approach has marginalized research on the aging process itself, research that could lead to an intervention that retards aging, thus conferring health dividends that would far exceed what could be expected by eliminating any specific disease of aging. This paper offers a diagnosis of how this sub-optimal approach to health extension arose and some general prescriptions concerning how progress could be made in terms of adopting a more rational approach to health extension. Drawing on empirical findings from psychology and economics, "prospect theory" is applied to the challenges of "framing" the inborn aging process given the cognitive capacities of real (rather than rational) decision-makers under conditions of risk and uncertainty. Prospect theory reveals that preferences are in fact dependent on whether particular outcomes of a choice are regarded as "a loss" or "a gain", relative to a reference point (or "aspiration level for survival"). And this has significant consequences for the way biogerontologists ought to characterise the central aspirations of the field (i.e. to prevent disease versus extend lifespan). Furthermore, it reveals the importance of shifting the existing reference point of the medical sciences to one that is shaped by the findings of evolutionary biology and biodemography.

Tamiz metabólico neonatal por espectrometría de masas en tándem: dos años de experiencia en Nuevo León, México Expand newborn screening using tandem mass spectrometry: two years' experience in Nuevo León, Mexico

Directory of Open Access Journals (Sweden)

María del Rosario Torres-Sepúlveda

2008-06-01

Full Text Available OBJETIVO: Instituir un programa estatal de tamizaje neonatal ampliado para identificar errores innatos del metabolismo y determinar su prevalencia en la población de recién nacidos del estado de Nuevo León. MATERIAL Y MÉTODOS: Entre marzo de 2002 y febrero de 2004 se incluyeron neonatos consecutivos nacidos en hospitales públicos del estado. Se colectaron muestras de sangre en papel filtro entre las 24 y 48 horas de vida y se las sometió a tamiz metabólico mediante espectrometría de masas en tándem. RESULTADOS: Se analizaron 42 264 primeras muestras y se detectaron siete casos, uno de cada padecimiento: homocistinuria, fenilcetonuria, citrulinemia, tirosinemia/transitoria, deficiencia de 3-metilcrotonil-CoA carboxilasa, deficiencia de 3-hidroxi-3-metilglutaril-CoA liasa y galactosemia típica. CONCLUSIONES: La incidencia acumulada de defectos metabólicos en la población fue de 1:5 000 con 0.22% de casos falso-positivos. El programa permitió identificar y tratar con oportunidad los trastornos metabólicos al nacimiento con una efectiva prevención secundaria del retraso mental.OBJECTIVE: To initiate a statewide expanded metabolic screening program in neonates with the purpose of identifying the most common inborn errors of metabolism. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: The estimated incidence of inborn errors of metabolism is 1:5 000, with a false positive rate

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

Science.gov (United States)

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.

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

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Ben Pode-Shakked

2014-01-01

Full Text Available 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.

Role of Mass Spectrometry in Clinical Endocrinology.

Science.gov (United States)

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.

Creatine Transporter Deficiency in Two Brothers with Autism Spectrum Disorder.

Science.gov (United States)

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.

Early infantile form of galactosialidosis in a female baby with a prenatal diagnosis of fetal ascites: First case in Brazil

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Santos Cláudia Maria Carvalho dos

1998-01-01

Full Text Available We present the first case of an early infantile form of galactosialidosis among Brazilians. This very rare and severe lysosomal storage disease has only a dozen patients clearly diagnosed worldwide. Clinical, pathological and biochemical features were consistent with previously published findings. We detected the disorder in a 7-month-old female baby with prenatal diagnosis of ascites. Evolution of the storage disease was monitored through routine thin-layer chromatography (TLC for urinary oligosaccharides as part of a screening program for inborn errors of metabolism (IEM in high-risk children, carried out in Rio de Janeiro.

Dental care of patients after surgical therapy of inborn oro-facial clefts 3D technologies in diagnostics and therapy of cleft patients

OpenAIRE

Kašparová, Magdaléna

2015-01-01

Patients with orofacial defects, inborn or acquired, isolated or in combination with other handicaps in syndroms, suffer from various problems including psychological problems. Morphological changes within these handicaps burden not only the patients themselves, but also their families. Among the main problems are difficulties with feeding, speech or breathing. Anomalies in number or position of deciduous and permanent teeth, development of jaws and dental arches are often present. Multidisci...

Hypoglycaemia related to inherited metabolic diseases in adults

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Douillard Claire

2012-05-01

Full Text Available Abstract In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family. Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD, ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency].

Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients.

Science.gov (United States)

Scaglia, Fernando; Carter, Susan; O'Brien, William E; Lee, Brendan

2004-04-01

Urea cycle disorders (UCDs) are a group of inborn errors of hepatic metabolism caused by the loss of enzymatic activities that mediate the transfer of nitrogen from ammonia to urea. These disorders often result in life-threatening hyperammonemia and hyperglutaminemia. A combination of sodium phenylbutyrate and sodium phenylacetate/benzoate is used in the clinical management of children with urea cycle defects as a glutamine trap, diverting nitrogen from urea synthesis to alternatives routes of excretion. We have observed that patients treated with these compounds have selective branched chain amino acid (BCAA) deficiency despite adequate dietary protein intake. However, the direct effect of alternative therapy on the steady state levels of plasma branched chain amino acids has not been well characterized. We have measured steady state plasma branched chain and other essential non-branched chain amino acids in control subjects, untreated ornithine transcarbamylase deficiency females and treated null activity urea cycle disorder patients in the fed steady state during the course of stable isotope studies. Steady-state leucine levels were noted to be significantly lower in treated urea cycle disorder patients when compared to either untreated ornithine transcarbamylase deficiency females or control subjects (Purea cycle disorder patients. These findings suggest that better titration of protein restriction could be achieved with branched chain amino acid supplementation in patients with UCDs who are on alternative route therapy.

Effect of changes in fat availability on exercise capacity in McArdle disease

DEFF Research Database (Denmark)

Andersen, S.T.; Jeppesen, T.D.; Taivassalo, T.

2009-01-01

for oxidation during exercise. DESIGN: Randomized, placebo-controlled, crossover trial. SETTING: Hospitalized care. PATIENTs: Ten patients (8 men and 2 women) with McArdle disease. INTERVENTIONS: Patients cycled at a constant workload corresponding to 70% of their maximum oxygen consumption. In random order......Ardle disease, but maximal rates of fat oxidation seem limited and cannot be increased above physiologically normal rates during exercise. This limitation is probably caused by a metabolic bottleneck in the tricarboxylic acid cycle due to impaired glycolytic flux in McArdle disease. Therapies aimed at enhancing......BACKGROUND: The major fuel for exercising muscle at low exercise intensities is fat. OBJECTIVE: To investigate the role of fat metabolism in McArdle disease (also known as glycogen storage disease type V), an inborn error of muscle glycogenolysis, by manipulating free fatty acid availability...

Exercise in muscle glycogen storage diseases

DEFF Research Database (Denmark)

Preisler, Nicolai Rasmus; Haller, Ronald G; Vissing, John

2015-01-01

exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs. We review the studies...... that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise.......Glycogen storage diseases (GSD) are inborn errors of glycogen or glucose metabolism. In the GSDs that affect muscle, the consequence of a block in skeletal muscle glycogen breakdown or glucose use, is an impairment of muscular performance and exercise intolerance, owing to 1) an increase...

Inherited metabolic liver diseases in infants and children: an overview

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Ivo Barić

2013-10-01

Full Text Available Inborn errors of metabolism, which affect the liver are a large, continuously increasing group of diseases. Their clinical onset can occur at any age, from intrauterine period presenting as liver failure already at birth to late adulthood. Inherited metabolic disorders must be considered in differential diagnosis of every unexplained liver disease. Specific diagnostic work-up for either their confirmation or exclusion should start immediately since any postponing can result in delayed diagnosis and death or irreversible disability. This can be particularly painful while many inherited metabolic liver diseases are relatively easily treatable if diagnosed on time, for instance galactosemia or hereditary fructose intolerance by simple dietary means. Any unexplained liver disease, even one looking initially benign, should be considered as a potential liver failure and therefore should deserve proper attention. Diagnosis in neonates is additionally complicated because of the factors which can mask liver disease, such as physiological neonatal jaundice, normally relatively enlarged liver and increased transaminases at that age. In everyday practice, in order to reveal the etiology, it is useful to classify and distinguish some clinical patterns which, together with a few routine, widely available laboratory tests (aminotransferases, prothrombine time, albumin, gammaGT, total and conjugated bilirubin, ammonia, alkaline phosphatase and glucose make the search for the cause much easier. These patterns are isolated hyperbilirubinemia, syndrome of cholestasis in early infancy, hepatocellular jaundice, Reye syndrome, portal cirrhosis and isolated hepatomegaly. Despite the fact that some diseases can present with more than one pattern (for instance, alpha-1-antitrypsin deficiency as infantile cholestasis, but also as hepatocellular jaundice, and that in some disesases one pattern can evolve into another (for instance, Wilson disease from hepatocellular

Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *

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Mengel Eugen

2011-06-01

Full Text Available Abstract Background National newborn screening programmes based on tandem-mass spectrometry (MS/MS and other newborn screening (NBS technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome. Methods In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated. Results Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in

Phenylketonuria

International Nuclear Information System (INIS)

Pearsen, K.D.; Gean-Marton, A.D.; Levy, H.L.; Davis, K.R.

1989-01-01

Phenylketonuria (PKU) is an autosomal, recessive, inborn error of phenylalanine metabolism. Without diet treatment, PKU leads to mental retardation as well as demyelimation, gliosis, and spongiosis of the white matter. This paper reports cerebral MR imaging prospectively performed on 16 PKU patients (ages, 8-35; IQ levels, 20-120; diet-history range, treated since infancy to no treatment). MR images revealed a spectrum of subtle to advanced demyelination of the posterior periventricular white matter, with frontal lobe involvement in severe cases, but no structural or posterior fossa abnormalities in any cases. No reliable correlation was found, either between MR abnormalities and intelligence or between MR abnormalities and diet history

An Adult Form of Gaucher Disease Associated with Portal Hypertension: A Case

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Ahmet Dulger

2013-04-01

Full Text Available Gaucher disease (GD is an inborn error of metabolism that affects the recycling of cellular glycolipids. Glucosylceramide (also called glucocerebroside accumulate within the lysosomes of cells. Gaucher%u2019s disease is most common lysosomal storage disease and its incidence is 1/75.000. Three types of this disease have been defined. During the course of disease, it was reported that hepatosplenomegaly, portal hypertension, hyperferritinemia, splenic infarcts and splenic nodules might develop. Therefore, as in our case; Gaucher%u2019s disease must be remembered in the setting of hepatosplenomegaly, portal hypertension, hyperferritinemia, splenic infarcts and splenic nodules of unknown etiology.

Mutational analysis of the HGO gene in Finnish alkaptonuria patients

Science.gov (United States)

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

Clinical neurogenetics: neuropathic lysosomal storage disorders.

Science.gov (United States)

Pastores, Gregory M; Maegawa, Gustavo H B

2013-11-01

The lysosomal storage disorders are a clinically heterogeneous group of inborn errors of metabolism, associated with the accumulation of incompletely degraded macromolecules within several cellular sites. Affected individuals present with a broad range of clinical problems, including hepatosplenomegaly and skeletal dysplasia. Onset of symptoms may range from birth to adulthood. Most are associated with neurologic features. Later-onset forms are often misdiagnosed as symptoms, which might include psychiatric manifestations, are slowly progressive, and may precede other neurologic or systemic features. Symptomatic care, which remains the mainstay for most subtypes, can lead to significant improvement in quality of life. Copyright © 2013 Elsevier Inc. All rights reserved.

Atypical Vitamin B-6 Deficiency A Rare Cause of Unexplained Neonatal and Infantile Epilepsies

DEFF Research Database (Denmark)

Baumgart, A.; von Spiczak, S.; Verhoeven-Duif, N. M.

2014-01-01

ALDH7A1 and PNPO deficiencies are rare inborn errors of vitamin B-6 metabolism causing perinatal seizure disorders. The phenotypic variability, however, is broad. To assess the frequency of these deficiencies in unexplained infantile epilepsy, we screened 113 patients for mutations in both genes...... pyridoxine treatment. "Hidden" vitamin B-6 deficiencies might be rare but treatable causes of unexplained epilepsy extending beyond the classical phenotypes........ We identified 1 patient with an epilepsy phenotype resembling Dravet syndrome and likely pathogenic mutations in ALDH7A1. Presenting features were highly atypical of pyridoxine-dependent epilepsy, including febrile seizures, response to anticonvulsive drugs, and periods of seizure freedom without...

Compound heterozygosity with a novel S222N GALT mutation leads to atypical galactosemia with loss of GALT activity in erythrocytes but little evidence of clinical disease

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Benjamin Cocanougher

2015-03-01

Full Text Available Galactosemia is an inborn error of galactose metabolism caused by mutations in the GALT gene. Though early detection and galactose restriction prevent severe liver disease, affected individuals have persistently elevated biomarkers and often neuro-developmental symptoms. We present a teenage compound heterozygote for a known pathogenic mutation (H132Q and a novel variant of unknown significance (S222N, with nearly absent erythrocyte GALT enzyme activity but normal biomarkers and only mild anxiety despite diet non-adherence. This case is similar to a previously reported S135L mutation. In this report we investigate the novel S222N variant and critically evaluate a clinically puzzling case.

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

Science.gov (United States)

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.

TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State.

Science.gov (United States)

Cardaci, Simone; Ciriolo, Maria Rosa

2012-01-01

Inborn defects of the tricarboxylic acid (TCA) cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH), pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology.

TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State

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Simone Cardaci

2012-01-01

Full Text Available Inborn defects of the tricarboxylic acid (TCA cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH, fumarate hydratase (FH, and isocitrate dehydrogenase (IDH, pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology.

GALACTOSEMIA IN NEWBORN CHILDREN

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G.V. Yatsyk

2007-01-01

Full Text Available Galactosemia is a hereditary disease, the pathogenetic treatment of which is based on dietotherapy. Early diagnosing and the adequate choice of the diet improve the development forecasts for the ill child. The article describes a classical galactosemia case in a newborn. It is shown that despite diagnosing the disease on the second month of life, the adequate selection of etiopathogenetic dietotherapy and etiotropic therapy of the concurrent diseases helped compensate the inborn galactose metabolism defect and optimize the long-term forecast for the child.Key words: inborn metabolism dysfunctions, alactosemia, dietotherapy, newborn children.

Necropsy findings in lysinuric protein intolerance.

Science.gov (United States)

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

A case of severe glutathione synthetase deficiency with novel GSS mutations

Science.gov (United States)

Xia, H.; Ye, J.; Wang, L.; Zhu, J.; He, Z.

2018-01-01

Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old. PMID:29340523

A case of severe glutathione synthetase deficiency with novel GSS mutations

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H. Xia

2018-01-01

Full Text Available Glutathione synthetase deficiency (GSSD is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.

Selective screening in neonates suspected to have inborn errors of ...

African Journals Online (AJOL)

Results: 13 patients (32.5%) were diagnosed as having IEM, 7 of them (53.8%) had urea cycle defect, 2 (15.4%) had maple syrup urine disease, while methylmalonic acidemia, fatty acid oxidation defect, mitochondrial disease, and galactosemia were diagnosed in one patient each (7.7%). Out of these patients, 12 patients ...

Rare inborn errors associated with chronic hepatitis B virus infection

DEFF Research Database (Denmark)

Zhao, Qiang; Peng, Liang; Huang, Weijun

2012-01-01

further studied its expression by immunohistochemistry, real-time polymerase chain reaction, and western blotting. Our results showed that it was strongly expressed by healthy hepatocytes, but its expression was reduced in liver tissues with CHB, hepatitis B viral (HBV) genome-containing HepG2.2.15 cells......, as compared with healthy liver tissues and non-HBV genome-containing HepG2 cells (P = 0.022 and 0.0036, respectively)....

Progress toward cell-directed therapy for phenylketonuria

Science.gov (United States)

Harding, CO

2009-01-01

Phenylketonuria (PKU) is one of the most common inborn errors of metabolism with an annual incidence of approximately 1:16,000 live births in North America. Contemporary therapy relies upon lifelong dietary protein restriction and supplementation with phenylalanine-free medical foods. This therapy is expensive and unpalatable; dietary compliance is difficult to maintain throughout life. Non-adherence to the diet is associated with learning disabilities, adult-onset neurodegenerative disease, and maternal PKU syndrome. The fervent dream of many individuals with PKU is a more permanent cure for this disease. This paper will review ongoing efforts to develop viable cell-directed therapies, in particular cell transplantation and gene therapy, for the treatment of PKU. PMID:18498375

Assessment of brain phenylalanine dynamics in phenylketonuria patients

International Nuclear Information System (INIS)

Bik-Multanowski, M.; Pietrzyk, J. J.; Pasowicz, M.; Banys, R.P.

2006-01-01

Phenylketonuria (PKU) is the most common inborn error of metabolism in man. Brain phenylalanine kinetics can determine neurological treatment outcome in phenylketonuria. The aim of our study wa sto test a simplified magnetic resonance spectroscopy method for assessment of brain phenylalanine dynamics in PKU patients. Brain phenylalanine concentration (measured by means of magnetic resonance spectroscopy) and blood phenylalanine concentrations changes occurring within 24 hours after oral phenylalanine loading were analyzed in 5 PKU patients. The brain/blood phenylalanine ratio in 3 persons with normal intelligence was lower than in 2 with borderline intelligence or mild mental retardation. In our opinion the proposed method could be useful for assessment of brain phenylalanine dynamics in PKU patients. (author)

Radiobiological studies with a series of human cell lines of varying glutathione content

Energy Technology Data Exchange (ETDEWEB)

Astor, M.B. (Columbia Univ., New York (USA). Radiological Research Lab.)

1984-08-01

The effect of decreased levels of intracellular glutathione (GSH) on the radiosensitivity of aerated and hypoxic cells was studied using human skin fibroblasts obtained from patients affected with the inborn error of metabolism, 5-oxoprolinuria. The oxygen enhancement ratios (OER) were determined for four cell lines obtained from a single family, SR and SUR (heterozygous parents) and GM3877 and GM3878 (affected homozygous siblings). Glutathione values ranged from 7.4 to 130% of control values. Only GM3877 with a GSH value 7.4% of control exhibited a reduced OER of 1.9 compared with a control value of 3. These results suggest that a reduction in OER is observed only when GSH levels reach extremely low values.

Ketogenic Diet: An Early Option for Epilepsy Treatment, Instead of A Last Choice Only

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Huei-Shyong Wang

2012-02-01

Full Text Available Ketogenic diet (KD was usually tried as a last resort in the treatment of intractable epilepsy after failure of many antiepileptics and even epilepsy surgery. Glucose transporter-1 deficiency and pyruvate dehydrogenase deficiency must be treated with KD as the first choice because of inborn errors of glucose metabolism. Infantile spasms, tuberous sclerosis complex, Rett syndrome, Doose syndrome, Dravet syndrome, etc., appear to respond to KD, and it has been suggested by the international consensus statement to use KD early. We believe that all patients with epilepsy, except those with contraindicated situations such as pyruvate carboxylase deficiency, porphyria, β-oxidation defects, primary carnitine deficiency, etc., may try KD before trying other regimens.

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet.

Science.gov (United States)

Cappuccio, Gerarda; Pinelli, Michele; Alagia, Marianna; Donti, Taraka; Day-Salvatore, Debra-Lynn; Veggiotti, Pierangelo; De Giorgis, Valentina; Lunghi, Simona; Vari, Maria Stella; Striano, Pasquale; Brunetti-Pierri, Nicola; Kennedy, Adam D; Elsea, Sarah H

2017-01-01

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.

Filter paper saturated by urine sample in metabolic disorders detection by proton magnetic resonance spectroscopy.

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Blasco, Hélène; Garrigue, Marie-Ange; De Vos, Aymeric; Antar, Catherine; Labarthe, François; Maillot, François; Andres, Christian R; Nadal-Desbarats, Lydie

2010-02-01

NMR spectroscopy of urine samples is able to diagnose many inborn errors of metabolism (IEM). However, urinary metabolites have a poor stability, requiring special care for routine analysis (storage of urine at -20 or -80 degrees C, fast transport). The aim of our study was to investigate the reliability of dried urine filter paper for urine storage and transport and to evaluate the ability of NMR to detect several IEM using this method. Urine samples from five healthy subjects were analyzed by (1)H NMR following different storage conditions (-20 vs 4 degrees C vs dried on filter paper) and at different time points (24 h, 48 h, 96 h, and 7 days). Urine pattern of fresh urine was considered as a reference. We analyzed the conservation of some amino acids and organic acids using Bland and Altman plot with intraclass correlation coefficient determination. Then, we evaluated the use of filter paper to detect four different IEM (methylmalonic and isovaleric acidurias, ornithine transcarbamylase deficiency, and cystinuria). Analysis of urine samples from healthy subjects revealed a high stability of studied molecules (ICC > 0.8) even after 7 days of storage on filter paper. Moreover, an excellent preservation of metabolites specifically accumulated in IEM was observed when analysis of dried urine filter paper was compared to fresh urine (coefficient of variation storage of dried urine on filter paper is reliable for (1)H NMR spectroscopy analysis. Preservation of urine molecules over time using that method is convenient for routine clinical practice.

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

Science.gov (United States)

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.

In-Born Radio Frequency Identification Devices for Safeguards Use at Gas-Centrifuge Enrichment Plants

International Nuclear Information System (INIS)

Ward, R.; Rosenthal, M.

2009-01-01

Global expansion of nuclear power has made the need for improved safeguards measures at Gas Centrifuge Enrichment Plants (GCEPs) imperative. One technology under consideration for safeguards applications is Radio Frequency Identification Devices (RFIDs). RFIDs have the potential to increase IAEA inspector's efficiency and effectiveness either by reducing the number of inspection visits necessary or by reducing inspection effort at those visits. This study assesses the use of RFIDs as an integral component of the 'Option 4' safeguards approach developed by Bruce Moran, U.S. Nuclear Regulatory Commission (NRC), for a model GCEP [1]. A previous analysis of RFIDs was conducted by Jae Jo, Brookhaven National Laboratory (BNL), which evaluated the effectiveness of an RFID tag applied by the facility operator [2]. This paper presents a similar evaluation carried out in the framework of Jo's paper, but it is predicated on the assumption that the RFID tag is applied by the manufacturer at the birth of the cylinder, rather than by the operator. Relevant diversion scenarios are examined to determine if RFIDs increase the effectiveness and/ or efficiency of safeguards in these scenarios. Conclusions on the benefits offered to inspectors by using in-born RFID tagging are presented.

Glutaric aciduria type I

International Nuclear Information System (INIS)

Mandel, H.; Berant, M.; Braun, J.; Technion-Israel Inst. of Tech., Haifa; El-Peleg, O.; Christensen, E.

1991-01-01

Serial CT findings in an infant with glutaric aciduria type I (GA-I) are reported. The major CT features were dilatation of the insular cisterns, regression of the temporal lobes, with 'bat wings' dilatation of the Sylvian fissures and hypodensity of the lenticular nuclei. CT changes preceded the onset of symptoms by 3 months. An improvement in the temporal lobe atrophy was seen after a period of treatment, coinciding with marked clinical improvement. A peculiar feature was the presence of external hydrocephalus, which diverted the attention from manifestations of the primary disease and thus constituted a diagnostic pitfall. The delineation and recognition of the characteristic radiologic manifestations of GA-I are essential for allowing an adequate radiologist/clinician interaction in diagnosing this inborn error of metabolism. (orig.)

Radiobiological studies with a series of human cell lines of varying glutathione content

International Nuclear Information System (INIS)

Astor, M.B.

1984-01-01

The effect of decreased levels of intracellular glutathione (GSH) on the radiosensitivity of aerated and hypoxic cells was studied using human skin fibroblasts obtained from patients affected with the inborn error of metabolism, 5-oxoprolinuria. The oxygen enhancement ratios (OER) were determined for four cell lines obtained from a single family, SR and SUR (heterozygous parents) and GM3877 and GM3878 (affected homozygous siblings). Glutathione values ranged from 7.4 to 130% of control values. Only GM3877 with a GSH value 7.4% of control exhibited a reduced OER of 1.9 compared with a control value of 3. These results suggest that a reduction in OER is observed only when GSH levels reach extremely low values. (author)

High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, Triple H syndrome and OTC deficiency.

Science.gov (United States)

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 screening for inherited disorders by biochemical laboratories. Copyright © 2014 Elsevier B.V. All rights reserved.

Amyloidosis in alkaptonuria.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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.

New secondary metabolites of phenylbutyrate in humans and rats.

Science.gov (United States)

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.

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

Science.gov (United States)

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

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

Science.gov (United States)

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.

New mechanisms of disease and parasite-host interactions.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Genetics Home Reference: sialuria

Science.gov (United States)

... 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 ...

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

Science.gov (United States)

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.

Prenatal diagnosis in adenylosuccinate lyase deficiency

NARCIS (Netherlands)

Marie, S.; Flipsen, J. W.; Duran, M.; Poll-The, B. T.; Beemer, F. A.; Bosschaart, A. N.; Vincent, M. F.; van den Berghe, G.

2000-01-01

Adenylosuccinate lyase deficiency, an autosomal recessive inborn error of purine synthesis, provokes accumulation in body fluids of succinylaminoimidazolecarboxamide riboside and succinyladenosine, the dephosphorylated derivatives of the two substrates of the enzyme. Most patients display severe

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

Science.gov (United States)

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

[High plasma folate in patients with phenylketonuria].

Science.gov (United States)

Zielińska, Magdalena; Żółkowska, Joanna; Przybylska-Kruszewska, Amanda; Gładysz, Dominika; Korycińska-Chaaban, Dorota; Nowacka, Maria; Hozyasz, Kamil K

2016-04-01

Phenylketonuria is an inborn error of metabolism treated with a closely monitored low phenylalanine diet. Protein substitutes used for treatment are supplemented with vitamins and micronutrients. The aim of this study was to investigate plasma folic acid concentrations in children with phenylketonuria. Retrospective analysis of medical records of 73 patients with phenylketonuria and 28 with mild hyperphenylalaninemia (on normal diet) was carried out. Intake of folic acid was calculated on the basis of protein substitute intake. Folate concentrations were analyzed according to their intake, and concentration of homocysteine and phenylalanine. In 76.7% patients with phenylketonuria intake of folic acid exceeded recommended dietary allowance. Serum folic acid concentrations above upper reference level were detected in 75.3% patients with phenylketonuria and only in 25% patients with hyperphenylalaninemia (pphenylketonuria requires further detailed research. © 2016 MEDPRESS.

Evaluating Innovations in Transition From Pediatric to Adult Care - The Transition Navigator Trial

Science.gov (United States)

2017-11-21

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

Clinical findings and effect of sodium hydrogen carbonate in patients with glutathione synthetase deficiency.

Science.gov (United States)

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.

Error-related brain activity and error awareness in an error classification paradigm.

Science.gov (United States)

Di Gregorio, Francesco; Steinhauser, Marco; Maier, Martin E

2016-10-01

Error-related brain activity has been linked to error detection enabling adaptive behavioral adjustments. However, it is still unclear which role error awareness plays in this process. Here, we show that the error-related negativity (Ne/ERN), an event-related potential reflecting early error monitoring, is dissociable from the degree of error awareness. Participants responded to a target while ignoring two different incongruent distractors. After responding, they indicated whether they had committed an error, and if so, whether they had responded to one or to the other distractor. This error classification paradigm allowed distinguishing partially aware errors, (i.e., errors that were noticed but misclassified) and fully aware errors (i.e., errors that were correctly classified). The Ne/ERN was larger for partially aware errors than for fully aware errors. Whereas this speaks against the idea that the Ne/ERN foreshadows the degree of error awareness, it confirms the prediction of a computational model, which relates the Ne/ERN to post-response conflict. This model predicts that stronger distractor processing - a prerequisite of error classification in our paradigm - leads to lower post-response conflict and thus a smaller Ne/ERN. This implies that the relationship between Ne/ERN and error awareness depends on how error awareness is related to response conflict in a specific task. Our results further indicate that the Ne/ERN but not the degree of error awareness determines adaptive performance adjustments. Taken together, we conclude that the Ne/ERN is dissociable from error awareness and foreshadows adaptive performance adjustments. Our results suggest that the relationship between the Ne/ERN and error awareness is correlative and mediated by response conflict. Copyright © 2016 Elsevier Inc. All rights reserved.

High myopia and congenital myopathy with partial pachygyria in cutis laxa syndrome.

NARCIS (Netherlands)

Morava, E.; Willemsen, M.A.A.P.; Wopereis, S.; Laak, H.J. ter; Lefeber, D.J.; Wevers, R.A.; Cruysberg, J.R.M.

2006-01-01

PURPOSE: Several types of inborn errors of the O-glycan biosynthesis are known, leading to clinically very distinct phenotypes. Children with O-mannosyl glycan biosynthesis defects commonly present as a severe form of congenital muscular dystrophy with decreased alpha-dystroglycan staining,

Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood

NARCIS (Netherlands)

Zeharia, Avraham; Shaag, Avraham; Houtkooper, Riekelt H.; Hindi, Tareq; de Lonlay, Pascale; Erez, Gilli; Hubert, Laurence; Saada, Ann; de Keyzer, Yves; Eshel, Gideon; Vaz, Frédéric M.; Pines, Ophry; Elpeleg, Orly

2008-01-01

Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using

Molybdenum-cofactor deficiency: an easily missed cause of neonatal convulsions

NARCIS (Netherlands)

Slot, H. M.; Overweg-Plandsoen, W. C.; Bakker, H. D.; Abeling, N. G.; Tamminga, P.; Barth, P. G.; van Gennip, A. H.

1993-01-01

Intractable seizures in the neonatal period may be caused by molybdenum-cofactor deficiency, an inborn error which combines the deficiencies of sulphite oxidase and xanthine dehydrogenase. The neurological symptoms of molybdenum cofactor and isolated sulphite oxidase deficiencies are identical. Two

Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E.

Science.gov (United States)

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.

Sequential magnetic resonance spectroscopic changes in a patient with nonketotic hyperglycinemia

Directory of Open Access Journals (Sweden)

Ji Hun Shin

2012-08-01

Full Text Available Nonketotic hyperglycinemia (NKH is a rare inborn error of amino acid metabolism. A defect in the glycine cleavage enzyme system results in highly elevated concentrations of glycine in the plasma, urine, cerebrospinal fluid, and brain, resulting in glycine-induced encephalopathy and neuropathy. The prevalence of NKH in Korea is very low, and no reports of surviving patients are available, given the scarcity and poor prognosis of this disease. In the current study, we present a patient with NKH diagnosed on the basis of clinical features, biochemical profiles, and genetic analysis. Magnetic resonance spectroscopy (MRS allowed the measurement of absolute glycine concentrations in different parts of the brain that showed a significantly increased glycine peak, consolidating the diagnosis of NKH. In additional, serial MRS follow-up showed changes in the glycine/creatinine ratios in different parts of the brain. In conclusion, MRS is an effective, noninvasive diagnostic tool for NKH that can be used to distinguish this disease from other glycine metabolism disorders. It may also be useful for monitoring NKH treatment.

Risk factors and birth prevalence of birth defects and inborn errors of ...

African Journals Online (AJOL)

raoul

2011-02-23

Feb 23, 2011 ... methylmalonic aciduria, and maple syrup urine disease (MSUD) had their diagnoses confirmed by enzyme assay. The diagnosis of all ... Personal information like date of birth, sex, area of residence, mother's age at birth, father's age, order of birth, birth weight, gestational age on birth, medical history and ...

Exercise in muscle glycogen storage diseases.

Science.gov (United States)

Preisler, Nicolai; Haller, Ronald G; Vissing, John

2015-05-01

Glycogen storage diseases (GSD) are inborn errors of glycogen or glucose metabolism. In the GSDs that affect muscle, the consequence of a block in skeletal muscle glycogen breakdown or glucose use, is an impairment of muscular performance and exercise intolerance, owing to 1) an increase in glycogen storage that disrupts contractile function and/or 2) a reduced substrate turnover below the block, which inhibits skeletal muscle ATP production. Immobility is associated with metabolic alterations in muscle leading to an increased dependence on glycogen use and a reduced capacity for fatty acid oxidation. Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal muscle substrate metabolism in ways that are beneficial for patients with GSD, such as improving exercise tolerance and increasing fatty acid oxidation. In addition, a regular exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs. We review the studies that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise.

B-12 vitamin metabolism disorders

International Nuclear Information System (INIS)

Fabriciova, K.; Bzduch, V.; Behulova, D.; Skodova, J.; Holesova, D.; Ostrozlikova, M.; Schmidtova, K.; Kozich, V.

2012-01-01

Vitamin B-12 – cobalamin (Cbl) is a water soluble vitamin, which is synthesized by lower organisms. It cannot be synthesized by plants and higher organisms. Problem in the metabolic pathway of Cbl can be caused by its deficiency or by the deficiency of its last metabolites – adenosylcobalamin and methylcobalamin. Both reasons are presented by errors in the homocysteine and methylmalonyl-coenzyme A metabolism. Clinical symptoms of the Cbl metabolism disorders are: different neurological disorders, changes in haematological status (megaloblastic anemia, pancytopenia), symptoms of gastrointestinal tract (glossitis, loss of appetite, diarrhea) and changes in the immune system. In the article the authors describe the causes of Cbl metabolism disorders, its different diagnosis and treatment. They introduce the group of patients with these disorders, who were taken care of in the I st Paediatric Department of University Children Hospital for the last 5 years. (author)

Modeling human Coenzyme A synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism

Directory of Open Access Journals (Sweden)

Camilla Ceccatelli Berti

2015-04-01

Full Text Available Mutations in nuclear genes associated with defective coenzyme A biosynthesis have been identified as responsible for some forms of neurodegeneration with brain iron accumulation (NBIA, namely PKAN and CoPAN. PKAN are defined by mutations in PANK2, encoding the pantothenate kinase 2 enzyme, that account for about 50% of cases of NBIA, whereas mutations in CoA synthase COASY have been recently reported as the second inborn error of CoA synthesis leading to CoPAN. As reported previously, yeast cells expressing the pathogenic mutation exhibited a temperature-sensitive growth defect in the absence of pantothenate and a reduced CoA content. Additional characterization revealed decreased oxygen consumption, reduced activities of mitochondrial respiratory complexes, higher iron content, increased sensitivity to oxidative stress and reduced amount of lipid droplets, thus partially recapitulating the phenotypes found in patients and establishing yeast as a potential model to clarify the pathogenesis underlying PKAN and CoPAN diseases.

Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry

DEFF Research Database (Denmark)

Matern, Dietrich; He, Miao; Berry, Susan A

2003-01-01

but asymptomatic. METHODS: We report 8 additional patients identified by prospective newborn screening using tandem mass spectrometry. RESULTS: Molecular genetic analysis performed for 3 of these patients revealed that all are homozygous for an 1165A>G mutation that causes skipping of exon 10 of the SBCAD gene....... Although there was no obvious consanguinity, all patients belong to the Hmong, an ancient ethnic group that originated in China and constitutes only 0.8% and 0.6% of the Minnesota and Wisconsin population, respectively. Dietary treatment was initiated in the neonatal period. Except for 1 patient who...... developed mild muscle hypotonia, all patients remain asymptomatic at ages ranging from 3 to 14 months of age. CONCLUSIONS: These cases suggest that SBCAD deficiency is another inborn error of metabolism detectable by newborn screening using tandem mass spectrometry. The continued efficacy of long...

How Darwinian reductionism refutes genetic determinism.

Science.gov (United States)

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.

Hereditary Causes of Kidney Stones and Chronic Kidney Disease

Science.gov (United States)

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].

Science.gov (United States)

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.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Prediction of lithium-ion battery capacity with metabolic grey model

International Nuclear Information System (INIS)

Chen, Lin; Lin, Weilong; Li, Junzi; Tian, Binbin; Pan, Haihong

2016-01-01

Given the popularity of Lithium-ion batteries in EVs (electric vehicles), predicting the capacity quickly and accurately throughout a battery's full life-time is still a challenging issue for ensuring the reliability of EVs. This paper proposes an approach in predicting the varied capacity with discharge cycles based on metabolic grey theory and consider issues from two perspectives: 1) three metabolic grey models will be presented, including MGM (metabolic grey model), MREGM (metabolic Residual-error grey model), and MMREGM (metabolic Markov-residual-error grey model); 2) the universality of these models will be explored under different conditions (such as various discharge rates and temperatures). Furthermore, the research findings in this paper demonstrate the excellent performance of the prediction depending on the three models; however, the precision of the MREGM model is inferior compared to the others. Therefore, we have obtained the conclusion in which the MGM model and the MMREGM model have excellent performances in predicting the capacity under a variety of load conditions, even using few data points for modeling. Also, the universality of the metabolic grey prediction theory is verified by predicting the capacity of batteries under different discharge rates and different temperatures. - Highlights: • The metabolic mechanism is introduced in a grey system for capacity prediction. • Three metabolic grey models are presented and studied. • The universality of these models under different conditions is assessed. • A few data points are required for predicting the capacity with these models.

Gap-filling analysis of the iJO1366 Escherichia coli metabolic network reconstruction for discovery of metabolic functions

Directory of Open Access Journals (Sweden)

Orth Jeffrey D

2012-05-01

Full Text Available Abstract Background The iJO1366 reconstruction of the metabolic network of Escherichia coli is one of the most complete and accurate metabolic reconstructions available for any organism. Still, because our knowledge of even well-studied model organisms such as this one is incomplete, this network reconstruction contains gaps and possible errors. There are a total of 208 blocked metabolites in iJO1366, representing gaps in the network. Results A new model improvement workflow was developed to compare model based phenotypic predictions to experimental data to fill gaps and correct errors. A Keio Collection based dataset of E. coli gene essentiality was obtained from literature data and compared to model predictions. The SMILEY algorithm was then used to predict the most likely missing reactions in the reconstructed network, adding reactions from a KEGG based universal set of metabolic reactions. The feasibility of these putative reactions was determined by comparing updated versions of the model to the experimental dataset, and genes were predicted for the most feasible reactions. Conclusions Numerous improvements to the iJO1366 metabolic reconstruction were suggested by these analyses. Experiments were performed to verify several computational predictions, including a new mechanism for growth on myo-inositol. The other predictions made in this study should be experimentally verifiable by similar means. Validating all of the predictions made here represents a substantial but important undertaking.

Flavin Adenine Dinucleotide Status and the Effects of High-Dose Riboflavin Treatment in Short-Chain Acyl-CoA Dehydrogenase Deficiency

NARCIS (Netherlands)

van Maldegem, Bianca T.; Duran, Marinus; Wanders, Ronald J. A.; Waterham, Hans R.; Wijburg, Frits A.

2010-01-01

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inborn error, biochemically characterized by increased plasma butyrylcarnitine (C4-C) concentration and increased ethylmalonic acid (EMA) excretion and caused by rare mutations and/or common gene variants in the SCAD encoding gene. Although

Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency

NARCIS (Netherlands)

Maldegem, B.T.; Wanders, R.J.A.; Wijburg, F.A.

2010-01-01

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing

Transaldolase deficiency in a two-year-old boy with cirrhosis

NARCIS (Netherlands)

Wamelink, M.M.; Struijs, E.A.; Salomons, G.S.; Fowler, D.; Jakobs, C.A.J.M.; Clayton, P.T.

2008-01-01

Transaldolase (TALDO) deficiency is a rare inborn error of the pentose phosphate pathway. We report the clinical presentation and laboratory findings of a new patient with TALDO deficiency. The two-year-old Arabic boy presented with neonatal onset of anemia and thrombocytopenia, tubulopathy, and

Perinatal and early infantile symptoms in congenital disorders of glycosylation

NARCIS (Netherlands)

Funke, S.; Gardeitchik, T.; Kouwenberg, D.; Mohamed, M.; Wortmann, S.B.; Korsch, E.; Adamowicz, M.; Al-Gazali, L.; Wevers, R.A.; Horvath, A.; Lefeber, D.J.; Morava, E.

2013-01-01

Congenital disorders of glycosylation (CDG) are a rapidly growing family of inborn errors. Screening for CDG in suspected cases is usually performed in the first year of life by serum transferrin isoelectric focusing or mass spectrometry. Based on the transferrin analysis patients can be

Action errors, error management, and learning in organizations.

Science.gov (United States)

Frese, Michael; Keith, Nina

2015-01-03

Every organization is confronted with errors. Most errors are corrected easily, but some may lead to negative consequences. Organizations often focus on error prevention as a single strategy for dealing with errors. Our review suggests that error prevention needs to be supplemented by error management--an approach directed at effectively dealing with errors after they have occurred, with the goal of minimizing negative and maximizing positive error consequences (examples of the latter are learning and innovations). After defining errors and related concepts, we review research on error-related processes affected by error management (error detection, damage control). Empirical evidence on positive effects of error management in individuals and organizations is then discussed, along with emotional, motivational, cognitive, and behavioral pathways of these effects. Learning from errors is central, but like other positive consequences, learning occurs under certain circumstances--one being the development of a mind-set of acceptance of human error.

Modeling coherent errors in quantum error correction

Science.gov (United States)

Greenbaum, Daniel; Dutton, Zachary

2018-01-01

Analysis of quantum error correcting codes is typically done using a stochastic, Pauli channel error model for describing the noise on physical qubits. However, it was recently found that coherent errors (systematic rotations) on physical data qubits result in both physical and logical error rates that differ significantly from those predicted by a Pauli model. Here we examine the accuracy of the Pauli approximation for noise containing coherent errors (characterized by a rotation angle ɛ) under the repetition code. We derive an analytic expression for the logical error channel as a function of arbitrary code distance d and concatenation level n, in the small error limit. We find that coherent physical errors result in logical errors that are partially coherent and therefore non-Pauli. However, the coherent part of the logical error is negligible at fewer than {ε }-({dn-1)} error correction cycles when the decoder is optimized for independent Pauli errors, thus providing a regime of validity for the Pauli approximation. Above this number of correction cycles, the persistent coherent logical error will cause logical failure more quickly than the Pauli model would predict, and this may need to be combated with coherent suppression methods at the physical level or larger codes.

Errors in causal inference: an organizational schema for systematic error and random error.

Science.gov (United States)

Suzuki, Etsuji; Tsuda, Toshihide; Mitsuhashi, Toshiharu; Mansournia, Mohammad Ali; Yamamoto, Eiji

2016-11-01

To provide an organizational schema for systematic error and random error in estimating causal measures, aimed at clarifying the concept of errors from the perspective of causal inference. We propose to divide systematic error into structural error and analytic error. With regard to random error, our schema shows its four major sources: nondeterministic counterfactuals, sampling variability, a mechanism that generates exposure events and measurement variability. Structural error is defined from the perspective of counterfactual reasoning and divided into nonexchangeability bias (which comprises confounding bias and selection bias) and measurement bias. Directed acyclic graphs are useful to illustrate this kind of error. Nonexchangeability bias implies a lack of "exchangeability" between the selected exposed and unexposed groups. A lack of exchangeability is not a primary concern of measurement bias, justifying its separation from confounding bias and selection bias. Many forms of analytic errors result from the small-sample properties of the estimator used and vanish asymptotically. Analytic error also results from wrong (misspecified) statistical models and inappropriate statistical methods. Our organizational schema is helpful for understanding the relationship between systematic error and random error from a previously less investigated aspect, enabling us to better understand the relationship between accuracy, validity, and precision. Copyright © 2016 Elsevier Inc. All rights reserved.

Ethylmalonic aciduria is associated with an amino acid variant of short chain acyl-coenzyme A dehydrogenase

DEFF Research Database (Denmark)

Corydon, M J; Gregersen, N; Lehnert, W

1996-01-01

Ethylmalonic aciduria is a common biochemical finding in patients with inborn errors of short chain fatty acid beta-oxidation. The urinary excretion of ethylmalonic acid (EMA) may stem from decreased oxidation by short chain acyl-CoA dehydrogenase (SCAD) of butyryl-CoA, which is alternatively...

5FU and oxaliplatin-containing chemotherapy in two dihydropyrimidine dehydrogenase-deficient patients

NARCIS (Netherlands)

Reerink, O; Mulder, NH; Szabo, BG; Hospers, GAP

2004-01-01

Patients with a germline mutation leading to a deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme are at risk from developing severe toxicity on the administration of 5FU-containing chemotherapy. We report on the implications of this inborn genetic error in two patients who received 5FU

Clinical approach to inherited metabolic diseases in the neonatal period: a 20-year survey

NARCIS (Netherlands)

Saudubray, J. M.; Ogier, H.; Bonnefont, J. P.; Munnich, A.; Lombes, A.; Hervé, F.; Mitchel, G.; Poll The, B.; Specola, N.; Parvy, P.

1989-01-01

Every newborn with unexplained neurological deterioration, ketosis, metabolic acidosis or hypoglycaemia should be suspected of having an inherited error of intermediary metabolism. Many of these conditions can be diagnosed clinically with the aid of simple laboratory investigations. Since a

Error begat error: design error analysis and prevention in social infrastructure projects.

Science.gov (United States)

Love, Peter E D; Lopez, Robert; Edwards, David J; Goh, Yang M

2012-09-01

Design errors contribute significantly to cost and schedule growth in social infrastructure projects and to engineering failures, which can result in accidents and loss of life. Despite considerable research that has addressed their error causation in construction projects they still remain prevalent. This paper identifies the underlying conditions that contribute to design errors in social infrastructure projects (e.g. hospitals, education, law and order type buildings). A systemic model of error causation is propagated and subsequently used to develop a learning framework for design error prevention. The research suggests that a multitude of strategies should be adopted in congruence to prevent design errors from occurring and so ensure that safety and project performance are ameliorated. Copyright © 2011. Published by Elsevier Ltd.

Cardiac magnetic resonance spectroscopy : applications in a mouse model of fatty acid oxidation deficiency

NARCIS (Netherlands)

Bakermans, A.J.

2013-01-01

Under normal, well-fed conditions, the primary source of energy for the healthy heart are long-chain fatty acids that fuel the mitochondrial fatty acid ß-oxidation (FAO) pathway. Patients with an inborn error in long-chain FAO may present with hypoketotic hypoglycemia and liver disease, and/or a

Analysis of pyrimidine synthesis "de novo" intermediates in urine and dried urine filter- paper strips with HPLC-electrospray tandem mass spectrometry

NARCIS (Netherlands)

van Kuilenburg, André B. P.; van Lenthe, Henk; Löffler, Monika; van Gennip, Albert H.

2004-01-01

BACKGROUND: The concentrations of the pyrimidine "de novo" metabolites and their degradation products in urine are useful indicators for the diagnosis of an inborn error of the pyrimidine de novo pathway or a urea-cycle defect. Until now, no procedure was available that allowed the analysis of all

Hyperamonemia in children. Study of 72 cases

Directory of Open Access Journals (Sweden)

Jiménez Pérez Mario

2014-07-01

Full Text Available Hyperammonemia (HA is a metabolic emergency, and when not diagnosed and treated in a timely manner leads to severe neuro- logical damage and/ or death. HA may have multiple origins, but the EIM are one of the causes that should always be suspected. The objective of this work is to make a clinical description of the causes of HA in a sample of patients from the National Institute of Pediatrics (INP, to know the proportion of patients with HA in which could confirm the presence of an inborn error of metabolism (IEM. We found 72 patients with HA in the past 10 years, of whom 11 were patients already known to have an IEM and 61 with unknown cause; Of the latter, 46% of patients underwent metabolic studies (amino acids quantification, organic acids analysis and orotic acid quantification and in 14 cases (30% an IEM was diagnosed. The clinical symptoms most frequently observed were neurological (seizures, drowsiness, lethargy, irritability, developmental delay, and hypotonia stupor, etc., followed by digestive disturbances such as vomiting and refusal to eat. Urea cycle disorders, aminoacidopathies and organic acidemias were diagnosed, so the management and treatment of these should be known by the pediatricians, especially those dedicated to emergencies.

Good laboratory practices for biochemical genetic testing and newborn screening for inherited metabolic disorders.

Science.gov (United States)

2012-04-06

Biochemical genetic testing and newborn screening are essential laboratory services for the screening, detection, diagnosis, and monitoring of inborn errors of metabolism or inherited metabolic disorders. Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized on the basis of the level of testing complexity as either waived (i.e., from routine regulatory oversight) or nonwaived testing (which includes tests of moderate and high complexity). Laboratories that perform biochemical genetic testing are required by CLIA regulations to meet the general quality systems requirements for nonwaived testing and the personnel requirements for high-complexity testing. Laboratories that perform public health newborn screening are subject to the same CLIA regulations and applicable state requirements. As the number of inherited metabolic diseases that are included in state-based newborn screening programs continues to increase, ensuring the quality of performance and delivery of testing services remains a continuous challenge not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories. To help ensure the quality of laboratory testing, CDC collaborated with the Centers for Medicare & Medicaid Services, the Food and Drug Administration, the Health Resources and Services Administration, and the National Institutes of Health to develop guidelines for laboratories to meet CLIA requirements and apply additional quality assurance measures for these areas of genetic testing. This report provides recommendations for good laboratory practices that were developed based on recommendations from the Clinical Laboratory Improvement Advisory Committee, with additional input from the Secretary's Advisory Committee on Genetics, Health, and Society; the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; and representatives of newborn

Metabolic network prediction through pairwise rational kernels.

Science.gov (United States)

Roche-Lima, Abiel; Domaratzki, Michael; Fristensky, Brian

2014-09-26

Metabolic networks are represented by the set of metabolic pathways. Metabolic pathways are a series of biochemical reactions, in which the product (output) from one reaction serves as the substrate (input) to another reaction. Many pathways remain incompletely characterized. One of the major challenges of computational biology is to obtain better models of metabolic pathways. Existing models are dependent on the annotation of the genes. This propagates error accumulation when the pathways are predicted by incorrectly annotated genes. Pairwise classification methods are supervised learning methods used to classify new pair of entities. Some of these classification methods, e.g., Pairwise Support Vector Machines (SVMs), use pairwise kernels. Pairwise kernels describe similarity measures between two pairs of entities. Using pairwise kernels to handle sequence data requires long processing times and large storage. Rational kernels are kernels based on weighted finite-state transducers that represent similarity measures between sequences or automata. They have been effectively used in problems that handle large amount of sequence information such as protein essentiality, natural language processing and machine translations. We create a new family of pairwise kernels using weighted finite-state transducers (called Pairwise Rational Kernel (PRK)) to predict metabolic pathways from a variety of biological data. PRKs take advantage of the simpler representations and faster algorithms of transducers. Because raw sequence data can be used, the predictor model avoids the errors introduced by incorrect gene annotations. We then developed several experiments with PRKs and Pairwise SVM to validate our methods using the metabolic network of Saccharomyces cerevisiae. As a result, when PRKs are used, our method executes faster in comparison with other pairwise kernels. Also, when we use PRKs combined with other simple kernels that include evolutionary information, the accuracy

Follow-up findings in regional cerebral blood flow (r-CBF)-SPECT in a case of idiopathic childhood hemidystonia. Functional neuroimaging and pathophysiological implications

International Nuclear Information System (INIS)

Fiedler, A.; Aderbauer, J.; Segerer, H.; Marienhagen, J.; Bock, E.; Eilles, C.

1999-01-01

A 9 1/2-year-old girl suffered from intermitting tremor and jitteriness of her left hand and oral muscles every 4 to 6 weeks with long lasting episodes. Clinically myoclonias and dystonic positioning of the left arm, hand and facial muscles were seen. No evidence of trauma, infection or inborn errors of metabolism was found. Successful therapy with carbamazepine was initiated while L-DOPA failed. An ictal 99m-Tc-HMPAO-SPECT showed severe asymmetry with focal hyperperfusion of the contralateral right thalamus and basal ganglia as well as of the bifrontal cortex, whereas no anatomical lesions were found by MRI. In contrast, an interictally performed 99m-Tc-HMPAO SPECT showed hypoperfusion or the right thalamus and normalisation of the frontal perfusion under medical treatment. These 99m-Tc-HMPAO-SPECT findings may provide new insights into the localisation and pathophysiological pathways of idiopathic childhood dystonia. (orig.) [de

ENT manifestations of alkaptonuria: report on a case series.

Science.gov (United States)

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.

Nutritional Therapies in Congenital Disorders of Glycosylation (CDG

Directory of Open Access Journals (Sweden)

Peter Witters

2017-11-01

Full Text Available Congenital disorders of glycosylation (CDG are a group of more than 130 inborn errors of metabolism affecting N-linked, O-linked protein and lipid-linked glycosylation. The phenotype in CDG patients includes frequent liver involvement, especially the disorders belonging to the N-linked protein glycosylation group. There are only a few treatable CDG. Mannose-Phosphate Isomerase (MPI-CDG was the first treatable CDG by high dose mannose supplements. Recently, with the successful use of d-galactose in Phosphoglucomutase 1 (PGM1-CDG, other CDG types have been trialed on galactose and with an increasing number of potential nutritional therapies. Current mini review focuses on therapies in glycosylation disorders affecting liver function and dietary intervention in general in N-linked glycosylation disorders. We also emphasize now the importance of early screening for CDG in patients with mild hepatopathy but also in cholestasis.

Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency

DEFF Research Database (Denmark)

Pedersen, Christina Bak; Bross, P.; Winter, V.S.

2003-01-01

and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate...... proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.......Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding...

Program for PET image alignment: Effects on calculated differences in cerebral metabolic rates for glucose

International Nuclear Information System (INIS)

Phillips, R.L.; London, E.D.; Links, J.M.; Cascella, N.G.

1990-01-01

A program was developed to align positron emission tomography images from multiple studies on the same subject. The program allowed alignment of two images with a fineness of one-tenth the width of a pixel. The indications and effects of misalignment were assessed in eight subjects from a placebo-controlled double-blind crossover study on the effects of cocaine on regional cerebral metabolic rates for glucose. Visual examination of a difference image provided a sensitive and accurate tool for assessing image alignment. Image alignment within 2.8 mm was essential to reduce variability of measured cerebral metabolic rates for glucose. Misalignment by this amount introduced errors on the order of 20% in the computed metabolic rate for glucose. These errors propagate to the difference between metabolic rates for a subject measured in basal versus perturbed states

Errors, error detection, error correction and hippocampal-region damage: data and theories.

Science.gov (United States)

MacKay, Donald G; Johnson, Laura W

2013-11-01

This review and perspective article outlines 15 observational constraints on theories of errors, error detection, and error correction, and their relation to hippocampal-region (HR) damage. The core observations come from 10 studies with H.M., an amnesic with cerebellar and HR damage but virtually no neocortical damage. Three studies examined the detection of errors planted in visual scenes (e.g., a bird flying in a fish bowl in a school classroom) and sentences (e.g., I helped themselves to the birthday cake). In all three experiments, H.M. detected reliably fewer errors than carefully matched memory-normal controls. Other studies examined the detection and correction of self-produced errors, with controls for comprehension of the instructions, impaired visual acuity, temporal factors, motoric slowing, forgetting, excessive memory load, lack of motivation, and deficits in visual scanning or attention. In these studies, H.M. corrected reliably fewer errors than memory-normal and cerebellar controls, and his uncorrected errors in speech, object naming, and reading aloud exhibited two consistent features: omission and anomaly. For example, in sentence production tasks, H.M. omitted one or more words in uncorrected encoding errors that rendered his sentences anomalous (incoherent, incomplete, or ungrammatical) reliably more often than controls. Besides explaining these core findings, the theoretical principles discussed here explain H.M.'s retrograde amnesia for once familiar episodic and semantic information; his anterograde amnesia for novel information; his deficits in visual cognition, sentence comprehension, sentence production, sentence reading, and object naming; and effects of aging on his ability to read isolated low frequency words aloud. These theoretical principles also explain a wide range of other data on error detection and correction and generate new predictions for future test. Copyright © 2013 Elsevier Ltd. All rights reserved.

Web-based newborn screening system for metabolic diseases: machine learning versus clinicians.

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Chen, Wei-Hsin; Hsieh, Sheau-Ling; Hsu, Kai-Ping; Chen, Han-Ping; Su, Xing-Yu; Tseng, Yi-Ju; Chien, Yin-Hsiu; Hwu, Wuh-Liang; Lai, Feipei

2013-05-23

A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets collected in year 2011 were used as

Learning time-dependent noise to reduce logical errors: real time error rate estimation in quantum error correction

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Huo, Ming-Xia; Li, Ying

2017-12-01

Quantum error correction is important to quantum information processing, which allows us to reliably process information encoded in quantum error correction codes. Efficient quantum error correction benefits from the knowledge of error rates. We propose a protocol for monitoring error rates in real time without interrupting the quantum error correction. Any adaptation of the quantum error correction code or its implementation circuit is not required. The protocol can be directly applied to the most advanced quantum error correction techniques, e.g. surface code. A Gaussian processes algorithm is used to estimate and predict error rates based on error correction data in the past. We find that using these estimated error rates, the probability of error correction failures can be significantly reduced by a factor increasing with the code distance.

[Liver transplantation].

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Pompili, Maurizio; Mirante, Vincenzo Giorgio; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni

2004-01-01

Liver transplantation represents the first choice treatment for patients with fulminant acute hepatitis and for patients with chronic liver disease and advanced functional failure. Patients in the waiting list for liver transplantation are classified according to the severity of their clinical conditions (evaluated using staging systems mostly based on hematochemical parameters related to liver function). This classification, together with the blood group and the body size compatibility, remains the main criterion for organ allocation. The main indications for liver transplantation are cirrhosis (mainly HCV-, HBV- and alcohol-related) and hepatocellular carcinoma emerging in cirrhosis in adult patients, biliary atresia and some inborn errors of metabolism in pediatric patients. In adults the overall 5-year survival ranges between 60 and 70%, in both American and European series. Even better results have been reported for pediatric patients: in fact, the 5-year survival rate for children ranges between 70 and 80% in the main published series. In this study we evaluated the main medical problems correlated with liver transplantation such as immunosuppressive treatment, acute and chronic rejection, infectious complications, the recurrence of the liver disease leading to transplantation, and cardiovascular and metabolic complications.

Two novel mutations in the homogentisate-1,2-dioxygenase gene identified in Chinese Han Child with Alkaptonuria.

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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.

Premature Calcifications of Costal Cartilages: A New Perspective Premature Calcifications of Costal Cartilages: A New Perspective

International Nuclear Information System (INIS)

Rhomberg, W.; Schuster, A.

2014-01-01

Calcifications of the costal cartilages occur, as a rule, not until the age of 30 years. The knowledge of the clinical significance of early and extensive calcifications is still incomplete. Materials and Methods. A search was made to find patients below the age of 30 years who showed distinct calcifications of their lower costal cartilages by viewing 360 random samples of intravenous pyelograms and abdominal plain films. The histories, and clinical and laboratory findings of these patients were analyzed. Results. Nineteen patients fulfilled the criteria of premature calcifications of costal cartilages (CCCs). The patients had in common that they were frequently referred to a hospital and were treated by several medical disciplines. Nevertheless many complaints of the patients remained unsolved. Premature CCCs were often associated with rare endocrine disorders, inborn errors of metabolism, and abnormal hematologic findings. Among the metabolic disorders there were 2 proven porphyrias and 7 patients with a suspected porphyria but with inconclusive laboratory findings. Conclusion. Premature CCCs are unlikely to be a normal variant in skeletal radiology. The findings in this small group of patients call for more intensive studies, especially in regard to the putative role of a porphyria

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

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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.

Temporal expression-based analysis of metabolism.

Directory of Open Access Journals (Sweden)

Sara B Collins

Full Text Available Metabolic flux is frequently rerouted through cellular metabolism in response to dynamic changes in the intra- and extra-cellular environment. Capturing the mechanisms underlying these metabolic transitions in quantitative and predictive models is a prominent challenge in systems biology. Progress in this regard has been made by integrating high-throughput gene expression data into genome-scale stoichiometric models of metabolism. Here, we extend previous approaches to perform a Temporal Expression-based Analysis of Metabolism (TEAM. We apply TEAM to understanding the complex metabolic dynamics of the respiratorily versatile bacterium Shewanella oneidensis grown under aerobic, lactate-limited conditions. TEAM predicts temporal metabolic flux distributions using time-series gene expression data. Increased predictive power is achieved by supplementing these data with a large reference compendium of gene expression, which allows us to take into account the unique character of the distribution of expression of each individual gene. We further propose a straightforward method for studying the sensitivity of TEAM to changes in its fundamental free threshold parameter θ, and reveal that discrete zones of distinct metabolic behavior arise as this parameter is changed. By comparing the qualitative characteristics of these zones to additional experimental data, we are able to constrain the range of θ to a small, well-defined interval. In parallel, the sensitivity analysis reveals the inherently difficult nature of dynamic metabolic flux modeling: small errors early in the simulation propagate to relatively large changes later in the simulation. We expect that handling such "history-dependent" sensitivities will be a major challenge in the future development of dynamic metabolic-modeling techniques.

Quantum chemical approach to estimating the thermodynamics of metabolic reactions.

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Jinich, Adrian; Rappoport, Dmitrij; Dunn, Ian; Sanchez-Lengeling, Benjamin; Olivares-Amaya, Roberto; Noor, Elad; Even, Arren Bar; Aspuru-Guzik, Alán

2014-11-12

Thermodynamics plays an increasingly important role in modeling and engineering metabolism. We present the first nonempirical computational method for estimating standard Gibbs reaction energies of metabolic reactions based on quantum chemistry, which can help fill in the gaps in the existing thermodynamic data. When applied to a test set of reactions from core metabolism, the quantum chemical approach is comparable in accuracy to group contribution methods for isomerization and group transfer reactions and for reactions not including multiply charged anions. The errors in standard Gibbs reaction energy estimates are correlated with the charges of the participating molecules. The quantum chemical approach is amenable to systematic improvements and holds potential for providing thermodynamic data for all of metabolism.

Medication errors: prescribing faults and prescription errors.

Science.gov (United States)

Velo, Giampaolo P; Minuz, Pietro

2009-06-01

1. Medication errors are common in general practice and in hospitals. Both errors in the act of writing (prescription errors) and prescribing faults due to erroneous medical decisions can result in harm to patients. 2. Any step in the prescribing process can generate errors. Slips, lapses, or mistakes are sources of errors, as in unintended omissions in the transcription of drugs. Faults in dose selection, omitted transcription, and poor handwriting are common. 3. Inadequate knowledge or competence and incomplete information about clinical characteristics and previous treatment of individual patients can result in prescribing faults, including the use of potentially inappropriate medications. 4. An unsafe working environment, complex or undefined procedures, and inadequate communication among health-care personnel, particularly between doctors and nurses, have been identified as important underlying factors that contribute to prescription errors and prescribing faults. 5. Active interventions aimed at reducing prescription errors and prescribing faults are strongly recommended. These should be focused on the education and training of prescribers and the use of on-line aids. The complexity of the prescribing procedure should be reduced by introducing automated systems or uniform prescribing charts, in order to avoid transcription and omission errors. Feedback control systems and immediate review of prescriptions, which can be performed with the assistance of a hospital pharmacist, are also helpful. Audits should be performed periodically.

What is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure?

Science.gov (United States)

Liss, D B; Paden, M S; Schwarz, E S; Mullins, M E

2013-11-01

Paracetamol (acetaminophen) ingestion is the most frequent pharmaceutical overdose in the developed world. Metabolic acidosis sometimes occurs, but the acidosis is infrequently persistent or severe. A growing number of case reports and case series describe high anion gap metabolic acidosis (HAGMA) following paracetamol exposure with subsequent detection or measurement of 5-oxoproline (also called pyroglutamic acid) in blood, urine, or both. Typically 5-oxoprolinuria or 5-oxoprolinemia occurs in the setting of inborn genetic errors in glutathione metabolism. It is unknown whether 5-oxoprolinemia in the setting of paracetamol exposure reflects an acquired or transient derangement of glutathione metabolism or previously unrecognized genetic defects. We reviewed the published cases of 5-oxoprolinemia or 5-oxoprolinuria among patients with HAGMA in the setting of paracetamol exposure. Our goal was to identify any consistent features that might increase our understanding of the pathophysiology, diagnosis, and treatment of similar cases. We searched the medical literature using PUBMED and EMBASE from inception to 28 August 2013 applying search terms ("oxoproline" OR "pyroglutamic acid" AND "paracetamol" OR "acetaminophen"). The intersection of these two searches returned 77 articles, of which 64 involved human subjects and were in English. Two articles, one each in Spanish and Dutch, were reviewed. An additional Google Scholar search was done with the same terms. We manually searched the reference lists of retrieved articles to identify additional four relevant articles. We focused on articles including measured 5-oxoproline concentrations in urine or blood. Twenty-two articles included quantified 5-oxoproline concentrations. Several additional articles mentioned only qualitative detection of 5-oxoproline in urine or blood without concentrations being reported. Our manual reference search yielded four additional articles for a total of 24 articles describing 43 patients

Radio-immuno-assay for trypsin in newborn-screening for cystic fibrosis

International Nuclear Information System (INIS)

Sander, J.; Niehaus, C.

1982-01-01

In 4,956 infants the concentration of immunoreactive trypsin was measured in dried blood on filter paper using a double antibody radioimmuno assay. About 90% of all results were below 40 ng/ml. In 13 infants the concentration of immunoreactive trypsin exceeded 80 ng/ml. These infants were examined clinically, including sweationtophoresis. We found three children suffering from cystic fibrosis. One further child showing an elevated concentration of chloride in the sweat (60 mval/ml) could not be reexamined. The concentration of immunoreactive trypsin in the cystic fibrosis children was 230, 297, and in one case 108 ng/ml at the 76th day of life, whereas the values for the 9 other children were between 80 and 154 ng/ml. We believe these results justify to use this test for a much higher number of infants, especially because it is inexpensive and can easily be added to existing newborn screening programs for inborn errors of metabolism. (orig.) [de

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

Science.gov (United States)

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.

Molecular studies of deletions at the human steroid sulfatase locus

International Nuclear Information System (INIS)

Shapiro, L.J.; Yen, P.; Pomerantz, D.; Martin, E.; Rolewic, L.; Mohandas, T.

1989-01-01

The human steroid sulfatase gene (STS) is located on the distal X chromosome short arm close to the pseudoautosomal region but in a segment of DNA that is unique to the X chromosome. In contrast to most X chromosome-encoded genes, STS expression is not extinguished during the process of X chromosome inactivation. Deficiency of STS activity produced the syndrome of X chromosome-linked ichthyosis, which is one of the most common inborn errors of metabolism in man. Approximately 90% of STS - individuals have large deletions at the STS locus. The authors and others have found that the end points of such deletions are heterogeneous in their location. One recently ascertained subject was observed to have a 40-kilobase deletion that is entirely intragenic, permitting the cloning and sequencing of the deletion junction. Studies of this patient and of other X chromosome sequences in other subjects permit some insight into the mechanism(s) responsible for generating frequent deletions on the short arm of the X chromosome

Acute treatment of hyperammonemia by continuous renal replacement therapy in a newborn patient with ornithine transcarbamylase deficiency

Directory of Open Access Journals (Sweden)

Hyo Jeong Kim

2011-10-01

Full Text Available Ornithine transcarbamylase (OTC deficiency is well known as the most common inherited disorder of the urea cycle, and 1 of the most common causes of hyperammonemia in newborns. We experienced a case of a 3-day-old boy with OTC deficiency who appeared healthy in the first 2 days of life but developed lethargy and seizure soon afterwards. His serum ammonia level was measured as &gt;1700 μg/dL (range, 0 to 45 μg/dL. Continuous renal replacement therapy (CRRT in the mode of continuous venovenous hemodiafiltration was immediately applied to correct the raised ammonia level. No seizure occurred after the elevated ammonia level was reduced. Therefore, CRRT should be included as 1 of the treatment modalities for newborns with inborn errors of metabolism, especially hyperammonemia. Here, we report 1 case of successful treatment of hyperammonemia by CRRT in a neonate with OTC deficiency.

Neuropsychiatric manifestations in late-onset urea cycle disorder patients.

Science.gov (United States)

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.

Mesenchymal stem cell treatment for hemophilia: a review of current knowledge.

Science.gov (United States)

Sokal, E M; Lombard, C; Mazza, G

2015-06-01

Hemophilia remains a non-curative disease, and patients are constrained to undergo repeated injections of clotting factors. In contrast, the sustained production of endogenous factors VIII (FVIII) or IX (FIX) by the patient's own cells could represent a curative treatment. Gene therapy has thus provided new hope for these patients. However, the issues surrounding the durability of expression and immune responses against gene transfer vectors remain. Cell therapy, involving stem cells expanded in vitro, can provide de novo protein synthesis and, if implanted successfully, could induce a steady-state production of low quantities of factors, which may keep the patient above the level required to prevent spontaneous bleeding. Liver-derived stem cells are already being assessed in clinical trials for inborn errors of metabolism and, in view of their capacity to produce FVIII and FIX in cell culture, they are now also being considered for clinical application in hemophilia patients. © 2015 International Society on Thrombosis and Haemostasis.

Acute intermittent porphyria: A single-base deletion and a nonsense mutation in the human hydroxymethylbilane synthase gene, predicting truncations of the enzyme polypeptide

Energy Technology Data Exchange (ETDEWEB)

Lee, G.L.; Astrin, K.H.; Desnick, R.J. [Mount Sinai School of Medicine, New York, NY (United States)

1995-08-28

Acute intermittent porphyria (AIP) is an autosomal-dominant inborn error of metabolism that results from the half-normal activity of the third enzyme in the heme biosynthetic pathway, hydroxymethylbilane synthase (HMB-synthase). AIP is an ecogenetic condition, since the life-threatening acute attacks are precipitated by various factors, including drugs, alcohol, fasting, and certain hormones. Biochemical diagnosis is problematic, and the identification of mutations in the HMB-synthase gene provides accurate detection of presymptomatic heterozygotes, permitting avoidance of the acute precipitating factors. By direct solid-phase sequencing, two mutations causing AIP were identified, an adenine deletion at position 629 in exon 11(629delA), which alters the reading frame and predicts premature truncation of the enzyme protein after amino acid 255, and a nonsense mutation in exon 12 (R225X). These mutations were confirmed by either restriction enzyme analysis or family studies of symptomatic patients, permitting accurate presymptomatic diagnosis of affected relatives. 29 refs., 2 figs.

Ochronotic Arthropathy: Two Case Reports from a Developing Country

Directory of Open Access Journals (Sweden)

Farooq A. Rathore

2016-01-01

Full Text Available 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.

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

Directory of Open Access Journals (Sweden)

Angel L. Pey

2013-01-01

Full Text Available 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.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Challenge and Error: Critical Events and Attention-Related Errors

Science.gov (United States)

Cheyne, James Allan; Carriere, Jonathan S. A.; Solman, Grayden J. F.; Smilek, Daniel

2011-01-01

Attention lapses resulting from reactivity to task challenges and their consequences constitute a pervasive factor affecting everyday performance errors and accidents. A bidirectional model of attention lapses (error [image omitted] attention-lapse: Cheyne, Solman, Carriere, & Smilek, 2009) argues that errors beget errors by generating attention…

A method to deal with installation errors of wearable accelerometers for human activity recognition

International Nuclear Information System (INIS)

Jiang, Ming; Wang, Zhelong; Shang, Hong; Li, Hongyi; Wang, Yuechao

2011-01-01

Human activity recognition (HAR) by using wearable accelerometers has gained significant interest in recent years in a range of healthcare areas, including inferring metabolic energy expenditure, predicting falls, measuring gait parameters and monitoring daily activities. The implementation of HAR relies heavily on the correctness of sensor fixation. The installation errors of wearable accelerometers may dramatically decrease the accuracy of HAR. In this paper, a method is proposed to improve the robustness of HAR to the installation errors of accelerometers. The method first calculates a transformation matrix by using Gram–Schmidt orthonormalization in order to eliminate the sensor's orientation error and then employs a low-pass filter with a cut-off frequency of 10 Hz to eliminate the main effect of the sensor's misplacement. The experimental results showed that the proposed method obtained a satisfactory performance for HAR. The average accuracy rate from ten subjects was 95.1% when there were no installation errors, and was 91.9% when installation errors were involved in wearable accelerometers

Error forecasting schemes of error correction at receiver

International Nuclear Information System (INIS)

Bhunia, C.T.

2007-08-01

To combat error in computer communication networks, ARQ (Automatic Repeat Request) techniques are used. Recently Chakraborty has proposed a simple technique called the packet combining scheme in which error is corrected at the receiver from the erroneous copies. Packet Combining (PC) scheme fails: (i) when bit error locations in erroneous copies are the same and (ii) when multiple bit errors occur. Both these have been addressed recently by two schemes known as Packet Reversed Packet Combining (PRPC) Scheme, and Modified Packet Combining (MPC) Scheme respectively. In the letter, two error forecasting correction schemes are reported, which in combination with PRPC offer higher throughput. (author)

Operator errors

International Nuclear Information System (INIS)

Knuefer; Lindauer

1980-01-01

Besides that at spectacular events a combination of component failure and human error is often found. Especially the Rasmussen-Report and the German Risk Assessment Study show for pressurised water reactors that human error must not be underestimated. Although operator errors as a form of human error can never be eliminated entirely, they can be minimized and their effects kept within acceptable limits if a thorough training of personnel is combined with an adequate design of the plant against accidents. Contrary to the investigation of engineering errors, the investigation of human errors has so far been carried out with relatively small budgets. Intensified investigations in this field appear to be a worthwhile effort. (orig.)

Determination of fructose metabolic pathways in normal and fructose-intolerant children: A 13C NMR study using [U-13C]fructose

International Nuclear Information System (INIS)

Gopher, A.; Lapidot, A.; Vaisman, N.; Mandel, H.

1990-01-01

An inborn deficiency in the ability of aldolase B to split fructose 1-phosphate is found in humans with hereditary fructose intolerance (HFI). A stable isotope procedure to elucidate the mechanism of conversion of fructose to glucose in normal children and in HFI children has been developed. A constant infusion of D-[U- 13 C]fructose was given nasogastrically to control and to HFI children. Hepatic fructose conversion to glucose was estimated by examination of 13 C NMR spectra of plasma glucose. Significantly lower values (∼3-fold) for fructose conversion to glucose were obtained for the HFI patients as compared to the controls. A quantitative determination of the metabolic pathways of fructose conversion to glucose was derived from 13 C NMR measurement of plasma [ 13 C]glucose isotopomer populations. The finding of isotopomer populations of three adjacent 13 C atoms at glucose C-4 ( 13 C 3 - 13 C 4 - 13 C 5 ) suggests that there is a direct pathway from fructose, by-passing fructose-1-phosphate aldolase, to fructose 1,6-bisphosphate. The metabolism of fructose by fructose-1-phosphate aldolase activity accounts for only ∼50% of the total amount of hepatic fructose conversion to glucose. In view of the marked decline by 67% in synthesis of glucose from fructose in HFI subjects found in this study, the extent of [ 13 C]glucose formation from a trace amount of [U- 13 C]fructose infused into the patient can be used as a safe and noninvasive diagnostic test for inherent faulty fructose metabolism

Rapid quantification of underivatized amino acids in plasma by hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass-spectrometry.

Science.gov (United States)

Prinsen, Hubertus C M T; Schiebergen-Bronkhorst, B G M; Roeleveld, M W; Jans, J J M; de Sain-van der Velden, M G M; Visser, G; van Hasselt, P M; Verhoeven-Duif, N M

2016-09-01

Amino acidopathies are a class of inborn errors of metabolism (IEM) that can be diagnosed by analysis of amino acids (AA) in plasma. Current strategies for AA analysis include cation exchange HPLC with post-column ninhydrin derivatization, GC-MS, and LC-MS/MS-related methods. Major drawbacks of the current methods are time-consuming procedures, derivative problems, problems with retention, and MS-sensitivity. The use of hydrophilic interaction liquid chromatography (HILIC) columns is an ideal separation mode for hydrophilic compounds like AA. Here we report a HILIC-method for analysis of 36 underivatized AA in plasma to detect defects in AA metabolism that overcomes the major drawbacks of other methods. A rapid, sensitive, and specific method was developed for the analysis of AA in plasma without derivatization using HILIC coupled with tandem mass-spectrometry (Xevo TQ, Waters). Excellent separation of 36 AA (24 quantitative/12 qualitative) in plasma was achieved on an Acquity BEH Amide column (2.1×100 mm, 1.7 μm) in a single MS run of 18 min. Plasma of patients with a known IEM in AA metabolism was analyzed and all patients were correctly identified. The reported method analyzes 36 AA in plasma within 18 min and provides baseline separation of isomeric AA such as leucine and isoleucine. No separation was obtained for isoleucine and allo-isoleucine. The method is applicable to study defects in AA metabolism in plasma.

How Do Simulated Error Experiences Impact Attitudes Related to Error Prevention?

Science.gov (United States)

Breitkreuz, Karen R; Dougal, Renae L; Wright, Melanie C

2016-10-01

The objective of this project was to determine whether simulated exposure to error situations changes attitudes in a way that may have a positive impact on error prevention behaviors. Using a stratified quasi-randomized experiment design, we compared risk perception attitudes of a control group of nursing students who received standard error education (reviewed medication error content and watched movies about error experiences) to an experimental group of students who reviewed medication error content and participated in simulated error experiences. Dependent measures included perceived memorability of the educational experience, perceived frequency of errors, and perceived caution with respect to preventing errors. Experienced nursing students perceived the simulated error experiences to be more memorable than movies. Less experienced students perceived both simulated error experiences and movies to be highly memorable. After the intervention, compared with movie participants, simulation participants believed errors occurred more frequently. Both types of education increased the participants' intentions to be more cautious and reported caution remained higher than baseline for medication errors 6 months after the intervention. This study provides limited evidence of an advantage of simulation over watching movies describing actual errors with respect to manipulating attitudes related to error prevention. Both interventions resulted in long-term impacts on perceived caution in medication administration. Simulated error experiences made participants more aware of how easily errors can occur, and the movie education made participants more aware of the devastating consequences of errors.

Cobalamin C deficiency in an adolescent with altered mental status and anorexia.

Science.gov (United States)

Rahmandar, Maria H; Bawcom, Amanda; Romano, Mary E; Hamid, Rizwan

2014-12-01

Although cobalamin (cbl) C deficiency is the most common inherited disorder of vitamin B12 metabolism, the late-onset form of the disease can be difficult to recognize because it has a broad phenotypic spectrum. In this report, we describe an adolescent female exposed to unknown illicit substances and sexual abuse who presented with psychosis, anorexia, seizures, and ataxia. The patient's diagnosis was delayed until a metabolic workup was initiated, revealing hyperhomocysteinemia, low normal plasma methionine, and methylmalonic aciduria. Ultimately, cblC deficiency was confirmed when molecular testing showed compound heterozygosity for mutations (c.271dupA and c.482G>A) in the MMACHC gene. This diagnosis led to appropriate treatment with hydroxocobalamin, betaine, and folate, which resulted in improvement of her clinical symptoms and laboratory values. This patient demonstrates a previously unrecognized presentation of late-onset cblC deficiency. Although neuropsychiatric symptoms are common in late-onset disease, seizures and cerebellar involvement are not. Furthermore, anorexia has not been previously described in these patients. This case emphasizes that inborn errors of metabolism should be part of the differential diagnosis for a teenager presenting with altered mental status, especially when the diagnosis is challenging or neurologic symptoms are unexplained. Correct diagnosis of this condition is important because treatment is available and can result in clinical improvement.(1.) Copyright © 2014 by the American Academy of Pediatrics.

Statistical errors in Monte Carlo estimates of systematic errors

Energy Technology Data Exchange (ETDEWEB)

Roe, Byron P. [Department of Physics, University of Michigan, Ann Arbor, MI 48109 (United States)]. E-mail: byronroe@umich.edu

2007-01-01

For estimating the effects of a number of systematic errors on a data sample, one can generate Monte Carlo (MC) runs with systematic parameters varied and examine the change in the desired observed result. Two methods are often used. In the unisim method, the systematic parameters are varied one at a time by one standard deviation, each parameter corresponding to a MC run. In the multisim method (see ), each MC run has all of the parameters varied; the amount of variation is chosen from the expected distribution of each systematic parameter, usually assumed to be a normal distribution. The variance of the overall systematic error determination is derived for each of the two methods and comparisons are made between them. If one focuses not on the error in the prediction of an individual systematic error, but on the overall error due to all systematic errors in the error matrix element in data bin m, the number of events needed is strongly reduced because of the averaging effect over all of the errors. For simple models presented here the multisim model was far better if the statistical error in the MC samples was larger than an individual systematic error, while for the reverse case, the unisim model was better. Exact formulas and formulas for the simple toy models are presented so that realistic calculations can be made. The calculations in the present note are valid if the errors are in a linear region. If that region extends sufficiently far, one can have the unisims or multisims correspond to k standard deviations instead of one. This reduces the number of events required by a factor of k{sup 2}.

Statistical errors in Monte Carlo estimates of systematic errors

International Nuclear Information System (INIS)

Roe, Byron P.

2007-01-01

For estimating the effects of a number of systematic errors on a data sample, one can generate Monte Carlo (MC) runs with systematic parameters varied and examine the change in the desired observed result. Two methods are often used. In the unisim method, the systematic parameters are varied one at a time by one standard deviation, each parameter corresponding to a MC run. In the multisim method (see ), each MC run has all of the parameters varied; the amount of variation is chosen from the expected distribution of each systematic parameter, usually assumed to be a normal distribution. The variance of the overall systematic error determination is derived for each of the two methods and comparisons are made between them. If one focuses not on the error in the prediction of an individual systematic error, but on the overall error due to all systematic errors in the error matrix element in data bin m, the number of events needed is strongly reduced because of the averaging effect over all of the errors. For simple models presented here the multisim model was far better if the statistical error in the MC samples was larger than an individual systematic error, while for the reverse case, the unisim model was better. Exact formulas and formulas for the simple toy models are presented so that realistic calculations can be made. The calculations in the present note are valid if the errors are in a linear region. If that region extends sufficiently far, one can have the unisims or multisims correspond to k standard deviations instead of one. This reduces the number of events required by a factor of k 2

Intracellular trafficking of the free cholesterol derived from LDL cholesteryl ester is defective in vivo in Niemann-Pick C disease: insights on normal metabolism of HDL and LDL gained from the NP-C mutation.

Science.gov (United States)

Shamburek, R D; Pentchev, P G; Zech, L A; Blanchette-Mackie, J; Carstea, E D; VandenBroek, J M; Cooper, P S; Neufeld, E B; Phair, R D; Brewer, H B; Brady, R O; Schwartz, C C

1997-12-01

Niemann-Pick C disease (NP-C) is a rare inborn error of metabolism with hepatic involvement and neurological sequelae that usually manifest in childhood. Although in vitro studies have shown that the lysosomal distribution of LDL-derived cholesterol is defective in cultured cells of NP-C subjects, no unusual characteristics mark the plasma lipoprotein profiles. We set out to determine whether anomalies exist in vivo in the cellular distribution of newly synthesized, HDL-derived or LDL-derived cholesterol under physiologic conditions in NP-C subjects. Three affected and three normal male subjects were administered [14C]mevalonate as a tracer of newly synthesized cholesterol and [3H]cholesteryl linoleate in either HDL or LDL to trace the distribution of lipoprotein-derived free cholesterol. The rate of appearance of free [14C]- and free [3H]cholesterol in the plasma membrane was detected indirectly by monitoring their appearance in plasma and bile. The plasma disappearance of [3H]cholesteryl linoleate was slightly faster in NP-C subjects regardless of its lipoprotein origin. Appearance of free [14C] cholesterol ill the plasma (and in bile) was essentially identical in normal and affected individuals as was the initial appearance of free [3H]cholesterol derived from HDL, observed before extensive exchange occurred of the [3H]cholesteryl linoleate among lipoproteins. In contrast, the rate of appearance of LDL-derived free [3H]cholesterol in the plasma membrane of NP-C subjects, as detected in plasma and bile, was retarded to a similar extent that LDL cholesterol metabolism was defective in cultured fibroblasts of these affected subjects. These findings show that intracellular distribution of both newly synthesized and HDL-derived cholesterol are essentially unperturbed by the NP-C mutation, and therefore occur by lysosomal-independent paths. In contrast, in NP-C there is defective trafficking of LDL-derived cholesterol to the plasma membrane in vivo as well as in vitro

Field error lottery

Energy Technology Data Exchange (ETDEWEB)

Elliott, C.J.; McVey, B. (Los Alamos National Lab., NM (USA)); Quimby, D.C. (Spectra Technology, Inc., Bellevue, WA (USA))

1990-01-01

The level of field errors in an FEL is an important determinant of its performance. We have computed 3D performance of a large laser subsystem subjected to field errors of various types. These calculations have been guided by simple models such as SWOOP. The technique of choice is utilization of the FELEX free electron laser code that now possesses extensive engineering capabilities. Modeling includes the ability to establish tolerances of various types: fast and slow scale field bowing, field error level, beam position monitor error level, gap errors, defocusing errors, energy slew, displacement and pointing errors. Many effects of these errors on relative gain and relative power extraction are displayed and are the essential elements of determining an error budget. The random errors also depend on the particular random number seed used in the calculation. The simultaneous display of the performance versus error level of cases with multiple seeds illustrates the variations attributable to stochasticity of this model. All these errors are evaluated numerically for comprehensive engineering of the system. In particular, gap errors are found to place requirements beyond mechanical tolerances of {plus minus}25{mu}m, and amelioration of these may occur by a procedure utilizing direct measurement of the magnetic fields at assembly time. 4 refs., 12 figs.

Errors in clinical laboratories or errors in laboratory medicine?

Science.gov (United States)

Plebani, Mario

2006-01-01

Laboratory testing is a highly complex process and, although laboratory services are relatively safe, they are not as safe as they could or should be. Clinical laboratories have long focused their attention on quality control methods and quality assessment programs dealing with analytical aspects of testing. However, a growing body of evidence accumulated in recent decades demonstrates that quality in clinical laboratories cannot be assured by merely focusing on purely analytical aspects. The more recent surveys on errors in laboratory medicine conclude that in the delivery of laboratory testing, mistakes occur more frequently before (pre-analytical) and after (post-analytical) the test has been performed. Most errors are due to pre-analytical factors (46-68.2% of total errors), while a high error rate (18.5-47% of total errors) has also been found in the post-analytical phase. Errors due to analytical problems have been significantly reduced over time, but there is evidence that, particularly for immunoassays, interference may have a serious impact on patients. A description of the most frequent and risky pre-, intra- and post-analytical errors and advice on practical steps for measuring and reducing the risk of errors is therefore given in the present paper. Many mistakes in the Total Testing Process are called "laboratory errors", although these may be due to poor communication, action taken by others involved in the testing process (e.g., physicians, nurses and phlebotomists), or poorly designed processes, all of which are beyond the laboratory's control. Likewise, there is evidence that laboratory information is only partially utilized. A recent document from the International Organization for Standardization (ISO) recommends a new, broader definition of the term "laboratory error" and a classification of errors according to different criteria. In a modern approach to total quality, centered on patients' needs and satisfaction, the risk of errors and mistakes

ERF/ERFC, Calculation of Error Function, Complementary Error Function, Probability Integrals

International Nuclear Information System (INIS)

Vogel, J.E.

1983-01-01

1 - Description of problem or function: ERF and ERFC are used to compute values of the error function and complementary error function for any real number. They may be used to compute other related functions such as the normal probability integrals. 4. Method of solution: The error function and complementary error function are approximated by rational functions. Three such rational approximations are used depending on whether - x .GE.4.0. In the first region the error function is computed directly and the complementary error function is computed via the identity erfc(x)=1.0-erf(x). In the other two regions the complementary error function is computed directly and the error function is computed from the identity erf(x)=1.0-erfc(x). The error function and complementary error function are real-valued functions of any real argument. The range of the error function is (-1,1). The range of the complementary error function is (0,2). 5. Restrictions on the complexity of the problem: The user is cautioned against using ERF to compute the complementary error function by using the identity erfc(x)=1.0-erf(x). This subtraction may cause partial or total loss of significance for certain values of x

Successful recovery from iatrogenic severe hypernatremia and severe metabolic acidosis resulting from accidental use of inappropriate bicarbonate concentrate for hemodialysis treatment

Directory of Open Access Journals (Sweden)

Guruprasad P Bhosale

2015-01-01

Full Text Available Bicarbonate dialysis is the treatment modality of choice for correction of metabolic acidosis in chronic renal failure. However, improper selection of dialysate concentrate can result in life-threatening human errors. We report a case of iatrogenic severe hypernatremia (sodium 207 mEq/L and severe metabolic acidosis (pH 6.65 that resulted due to accidental use of inappropriate bicarbonate concentrate for hemodialysis treatment. There was successful recovery in this patient with no neurological sequelae. To the best of our knowledge, this is the first case report in adults of severe hypernatremia along with severe metabolic acidosis due to error in the preparation of dialysis fluid.

A methodology for translating positional error into measures of attribute error, and combining the two error sources

Science.gov (United States)

Yohay Carmel; Curtis Flather; Denis Dean

2006-01-01

This paper summarizes our efforts to investigate the nature, behavior, and implications of positional error and attribute error in spatiotemporal datasets. Estimating the combined influence of these errors on map analysis has been hindered by the fact that these two error types are traditionally expressed in different units (distance units, and categorical units,...

Statistical errors in Monte Carlo estimates of systematic errors

Science.gov (United States)

Roe, Byron P.

2007-01-01

For estimating the effects of a number of systematic errors on a data sample, one can generate Monte Carlo (MC) runs with systematic parameters varied and examine the change in the desired observed result. Two methods are often used. In the unisim method, the systematic parameters are varied one at a time by one standard deviation, each parameter corresponding to a MC run. In the multisim method (see ), each MC run has all of the parameters varied; the amount of variation is chosen from the expected distribution of each systematic parameter, usually assumed to be a normal distribution. The variance of the overall systematic error determination is derived for each of the two methods and comparisons are made between them. If one focuses not on the error in the prediction of an individual systematic error, but on the overall error due to all systematic errors in the error matrix element in data bin m, the number of events needed is strongly reduced because of the averaging effect over all of the errors. For simple models presented here the multisim model was far better if the statistical error in the MC samples was larger than an individual systematic error, while for the reverse case, the unisim model was better. Exact formulas and formulas for the simple toy models are presented so that realistic calculations can be made. The calculations in the present note are valid if the errors are in a linear region. If that region extends sufficiently far, one can have the unisims or multisims correspond to k standard deviations instead of one. This reduces the number of events required by a factor of k2. The specific terms unisim and multisim were coined by Peter Meyers and Steve Brice, respectively, for the MiniBooNE experiment. However, the concepts have been developed over time and have been in general use for some time.

Medication Errors - A Review

OpenAIRE

Vinay BC; Nikhitha MK; Patel Sunil B

2015-01-01

In this present review article, regarding medication errors its definition, medication error problem, types of medication errors, common causes of medication errors, monitoring medication errors, consequences of medication errors, prevention of medication error and managing medication errors have been explained neatly and legibly with proper tables which is easy to understand.

Error Patterns

NARCIS (Netherlands)

Hoede, C.; Li, Z.

2001-01-01

In coding theory the problem of decoding focuses on error vectors. In the simplest situation code words are $(0,1)$-vectors, as are the received messages and the error vectors. Comparison of a received word with the code words yields a set of error vectors. In deciding on the original code word,

The error in total error reduction.

Science.gov (United States)

Witnauer, James E; Urcelay, Gonzalo P; Miller, Ralph R

2014-02-01

Most models of human and animal learning assume that learning is proportional to the discrepancy between a delivered outcome and the outcome predicted by all cues present during that trial (i.e., total error across a stimulus compound). This total error reduction (TER) view has been implemented in connectionist and artificial neural network models to describe the conditions under which weights between units change. Electrophysiological work has revealed that the activity of dopamine neurons is correlated with the total error signal in models of reward learning. Similar neural mechanisms presumably support fear conditioning, human contingency learning, and other types of learning. Using a computational modeling approach, we compared several TER models of associative learning to an alternative model that rejects the TER assumption in favor of local error reduction (LER), which assumes that learning about each cue is proportional to the discrepancy between the delivered outcome and the outcome predicted by that specific cue on that trial. The LER model provided a better fit to the reviewed data than the TER models. Given the superiority of the LER model with the present data sets, acceptance of TER should be tempered. Copyright © 2013 Elsevier Inc. All rights reserved.

Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease.

Science.gov (United States)

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.

Characteristics of pediatric chemotherapy medication errors in a national error reporting database.

Science.gov (United States)

Rinke, Michael L; Shore, Andrew D; Morlock, Laura; Hicks, Rodney W; Miller, Marlene R

2007-07-01

Little is known regarding chemotherapy medication errors in pediatrics despite studies suggesting high rates of overall pediatric medication errors. In this study, the authors examined patterns in pediatric chemotherapy errors. The authors queried the United States Pharmacopeia MEDMARX database, a national, voluntary, Internet-accessible error reporting system, for all error reports from 1999 through 2004 that involved chemotherapy medications and patients aged error reports, 85% reached the patient, and 15.6% required additional patient monitoring or therapeutic intervention. Forty-eight percent of errors originated in the administering phase of medication delivery, and 30% originated in the drug-dispensing phase. Of the 387 medications cited, 39.5% were antimetabolites, 14.0% were alkylating agents, 9.3% were anthracyclines, and 9.3% were topoisomerase inhibitors. The most commonly involved chemotherapeutic agents were methotrexate (15.3%), cytarabine (12.1%), and etoposide (8.3%). The most common error types were improper dose/quantity (22.9% of 327 cited error types), wrong time (22.6%), omission error (14.1%), and wrong administration technique/wrong route (12.2%). The most common error causes were performance deficit (41.3% of 547 cited error causes), equipment and medication delivery devices (12.4%), communication (8.8%), knowledge deficit (6.8%), and written order errors (5.5%). Four of the 5 most serious errors occurred at community hospitals. Pediatric chemotherapy errors often reached the patient, potentially were harmful, and differed in quality between outpatient and inpatient areas. This study indicated which chemotherapeutic agents most often were involved in errors and that administering errors were common. Investigation is needed regarding targeted medication administration safeguards for these high-risk medications. Copyright (c) 2007 American Cancer Society.

Inborn anemias in mice. Progress report, 1 August 1979-15 July 1980

Energy Technology Data Exchange (ETDEWEB)

Bernstein, S.E.; Russell, E.S.

1980-08-01

Four macrocytic anemias, four hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia are under investigation in mice. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus the wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: (a) characterization of peripheral blood values; (b) determinations of radiosensitivity under a variety of conditions; (c) measurements of iron metabolism and heme synthesis; (d) histological and biochemical study of blood-forming tissue; (e) functional tests of the stem cell component; (f) examination of responses to erythroid stimuli; and (g) transplantation of tissue between individuals of differently affected genotypes.

Genetic and bibliographic information: ASAH1 [GenLibi

Lifescience Database Archive (English)

Full Text Available System (C10.228.140.163.100.435) > Sphingolipidoses (C10.228.140.163.100.435.825) > Farber Lipogranulomatosi...ain Diseases, Metabolic, Inborn (C16.320.565.189) > Lysosomal Storage Diseases, Nervous System (C16.320.565.189.435) > Sphingolipidos...16.320.565.398) > Lipidoses (C16.320.565.398.641) > Sphingolipidoses (C16.320.565.398.641.803) > Farber Lipo...rage Diseases, Nervous System (C18.452.132.100.435) > Sphingolipidoses (C18.452.132.100.435.825) > Farber Li... (C18) > Metabolic Diseases (C18.452) > Lipid Metabolism Disorders (C18.452.584) > Lipidoses (C18.452.584.687) > Sphingolipidos

Error studies for SNS Linac. Part 1: Transverse errors

International Nuclear Information System (INIS)

Crandall, K.R.

1998-01-01

The SNS linac consist of a radio-frequency quadrupole (RFQ), a drift-tube linac (DTL), a coupled-cavity drift-tube linac (CCDTL) and a coupled-cavity linac (CCL). The RFQ and DTL are operated at 402.5 MHz; the CCDTL and CCL are operated at 805 MHz. Between the RFQ and DTL is a medium-energy beam-transport system (MEBT). This error study is concerned with the DTL, CCDTL and CCL, and each will be analyzed separately. In fact, the CCL is divided into two sections, and each of these will be analyzed separately. The types of errors considered here are those that affect the transverse characteristics of the beam. The errors that cause the beam center to be displaced from the linac axis are quad displacements and quad tilts. The errors that cause mismatches are quad gradient errors and quad rotations (roll)

Two-dimensional errors

International Nuclear Information System (INIS)

Anon.

1991-01-01

This chapter addresses the extension of previous work in one-dimensional (linear) error theory to two-dimensional error analysis. The topics of the chapter include the definition of two-dimensional error, the probability ellipse, the probability circle, elliptical (circular) error evaluation, the application to position accuracy, and the use of control systems (points) in measurements

Error-related anterior cingulate cortex activity and the prediction of conscious error awareness

Directory of Open Access Journals (Sweden)

Catherine eOrr

2012-06-01

Full Text Available Research examining the neural mechanisms associated with error awareness has consistently identified dorsal anterior cingulate activity (ACC as necessary but not predictive of conscious error detection. Two recent studies (Steinhauser and Yeung, 2010; Wessel et al. 2011 have found a contrary pattern of greater dorsal ACC activity (in the form of the error-related negativity during detected errors, but suggested that the greater activity may instead reflect task influences (e.g., response conflict, error probability and or individual variability (e.g., statistical power. We re-analyzed fMRI BOLD data from 56 healthy participants who had previously been administered the Error Awareness Task, a motor Go/No-go response inhibition task in which subjects make errors of commission of which they are aware (Aware errors, or unaware (Unaware errors. Consistent with previous data, the activity in a number of cortical regions was predictive of error awareness, including bilateral inferior parietal and insula cortices, however in contrast to previous studies, including our own smaller sample studies using the same task, error-related dorsal ACC activity was significantly greater during aware errors when compared to unaware errors. While the significantly faster RT for aware errors (compared to unaware was consistent with the hypothesis of higher response conflict increasing ACC activity, we could find no relationship between dorsal ACC activity and the error RT difference. The data suggests that individual variability in error awareness is associated with error-related dorsal ACC activity, and therefore this region may be important to conscious error detection, but it remains unclear what task and individual factors influence error awareness.

Errors in otology.

Science.gov (United States)

Kartush, J M

1996-11-01

Practicing medicine successfully requires that errors in diagnosis and treatment be minimized. Malpractice laws encourage litigators to ascribe all medical errors to incompetence and negligence. There are, however, many other causes of unintended outcomes. This article describes common causes of errors and suggests ways to minimize mistakes in otologic practice. Widespread dissemination of knowledge about common errors and their precursors can reduce the incidence of their occurrence. Consequently, laws should be passed to allow for a system of non-punitive, confidential reporting of errors and "near misses" that can be shared by physicians nationwide.

The Impact of Error-Management Climate, Error Type and Error Originator on Auditors’ Reporting Errors Discovered on Audit Work Papers

NARCIS (Netherlands)

A.H. Gold-Nöteberg (Anna); U. Gronewold (Ulfert); S. Salterio (Steve)

2010-01-01

textabstractWe examine factors affecting the auditor’s willingness to report their own or their peers’ self-discovered errors in working papers subsequent to detailed working paper review. Prior research has shown that errors in working papers are detected in the review process; however, such

Learning from Errors

OpenAIRE

Martínez-Legaz, Juan Enrique; Soubeyran, Antoine

2003-01-01

We present a model of learning in which agents learn from errors. If an action turns out to be an error, the agent rejects not only that action but also neighboring actions. We find that, keeping memory of his errors, under mild assumptions an acceptable solution is asymptotically reached. Moreover, one can take advantage of big errors for a faster learning.

Error Detection and Error Classification: Failure Awareness in Data Transfer Scheduling

Energy Technology Data Exchange (ETDEWEB)

Louisiana State University; Balman, Mehmet; Kosar, Tevfik

2010-10-27

Data transfer in distributed environment is prone to frequent failures resulting from back-end system level problems, like connectivity failure which is technically untraceable by users. Error messages are not logged efficiently, and sometimes are not relevant/useful from users point-of-view. Our study explores the possibility of an efficient error detection and reporting system for such environments. Prior knowledge about the environment and awareness of the actual reason behind a failure would enable higher level planners to make better and accurate decisions. It is necessary to have well defined error detection and error reporting methods to increase the usability and serviceability of existing data transfer protocols and data management systems. We investigate the applicability of early error detection and error classification techniques and propose an error reporting framework and a failure-aware data transfer life cycle to improve arrangement of data transfer operations and to enhance decision making of data transfer schedulers.

The glutathione cycle: Glutathione metabolism beyond the γ-glutamyl cycle.

Science.gov (United States)

Bachhawat, Anand Kumar; Yadav, Shambhu

2018-04-17

Glutathione was discovered in 1888, over 125 years ago. Since then, our understanding of various functions and metabolism of this important molecule has grown over these years. But it is only now, in the last decade, that a somewhat complete picture of its metabolism has emerged. Glutathione metabolism has till now been largely depicted and understood by the γ-glutamyl cycle that was proposed in 1970. However, new findings and knowledge particularly on the transport and degradation of glutathione have revealed that many aspects of the γ-glutamyl cycle are incorrect. Despite this, an integrated critical analysis of the cycle has never been undertaken and this has led to the cycle and its errors perpetuating in the literature. This review takes a careful look at the γ-glutamyl cycle and its shortcomings and presents a "glutathione cycle" that captures the current understanding of glutathione metabolism. © 2018 IUBMB Life, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

Generalized Gaussian Error Calculus

CERN Document Server

Grabe, Michael

2010-01-01

For the first time in 200 years Generalized Gaussian Error Calculus addresses a rigorous, complete and self-consistent revision of the Gaussian error calculus. Since experimentalists realized that measurements in general are burdened by unknown systematic errors, the classical, widespread used evaluation procedures scrutinizing the consequences of random errors alone turned out to be obsolete. As a matter of course, the error calculus to-be, treating random and unknown systematic errors side by side, should ensure the consistency and traceability of physical units, physical constants and physical quantities at large. The generalized Gaussian error calculus considers unknown systematic errors to spawn biased estimators. Beyond, random errors are asked to conform to the idea of what the author calls well-defined measuring conditions. The approach features the properties of a building kit: any overall uncertainty turns out to be the sum of a contribution due to random errors, to be taken from a confidence inter...

A Hybrid Unequal Error Protection / Unequal Error Resilience ...

African Journals Online (AJOL)

The quality layers are then assigned an Unequal Error Resilience to synchronization loss by unequally allocating the number of headers available for synchronization to them. Following that Unequal Error Protection against channel noise is provided to the layers by the use of Rate Compatible Punctured Convolutional ...

Inborn anemias in mice. Progress report, 1 May 1977--31 July 1978

Energy Technology Data Exchange (ETDEWEB)

Bernstein, S.E.; Russell, E.S.

1978-08-01

Hereditary anemias of mice have been the chief objects of investigation. At present under study are four macrocytic anemias, four hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, and the autoimmune hemolytic anemia of NZB. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus our wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: characterization of peripheral blood values, determinations of radiosensitivity under a variety of conditions, measurements of iron metabolism and heme synthesis, histological and biochemical study of blood-forming tissue, functional tests of the stem cell component, examination of responses to erythroid stimuli, and transplantation of tissue between individuals of differently affected genotypes. Considerable effort is devoted to perfection of hematologic, cell culture, and transplant methods to make these techniques useful in dealing with special problems associated with abnormal function.

Learning from prescribing errors

OpenAIRE

Dean, B

2002-01-01



 The importance of learning from medical error has recently received increasing emphasis. This paper focuses on prescribing errors and argues that, while learning from prescribing errors is a laudable goal, there are currently barriers that can prevent this occurring. Learning from errors can take place on an individual level, at a team level, and across an organisation. Barriers to learning from prescribing errors include the non-discovery of many prescribing errors, lack of feedback to th...

Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

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Ricardo Schmitt de Bem

2013-08-01

Full Text Available OBJECTIVE: Wilson's disease (WD is an inborn error of metabolism caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in a group of patients living in southern Brazil. METHODS: 36 WD subjects were studied and classified according to their clinical and epidemiological data. In 23 subjects the ATP7B gene was analyzed. RESULTS: Fourteen distinct mutations were detected in at least one of the alleles. The c.3207C>A substitution at exon 14 was the most common mutation (allelic frequency=37.1% followed by the c.3402delC at exon 15 (allelic frequency=11.4%. The mutations c.2018-2030del13 at exon 7 and c.4093InsT at exon 20 are being reported for the first time. CONCLUSION: The c.3207C>A substitution at exon 14, was the most common mutation, with an allelic frequency of 37.1%. This mutation is the most common mutation described in Europe.

Isolated sulfite oxidase deficiency.

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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.

Diagnosis and treatment of urea cycle disorder in Japan.

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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.

Seizure as a presenting manifestation of vitamin D dependent rickets type 1

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P Radha Rani

2013-01-01

Full Text Available There are two types of vitamin D dependent rickets (VDDR that cause rickets in children. VDDR type 1 (VDDR-I is caused by an inborn error of vitamin D metabolism, which interferes with renal conversion of calcidiol (25OHD to calcitriol (1,25(OH 2 D by the enzyme 1-α-hydroxylase. Patients with VDDR-I have mutations of chromosome 12 that affect the gene for the enzyme 1-α-hydroxylase, resulting in decreased levels of 1,25(OH vitamin D. Clinical features include growth failure, hypotonia, weakness, rachitic rosary, convulsions, tetany, open fontanels and pathologic fractures. We report a case of VDDR-I in 14-month-old male child. Establishing an early diagnosis of these genetic forms of rickets is challenging, especially in developing countries where nutritional rickets is the most common variety of the disease where genetic diagnosis is not always possible because of financial constraints. A prompt diagnosis is necessary to initiate adequate treatment, resolve biochemical features and prevent complications, such as severe deformities that may require surgical intervention.

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

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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.

Biochemical Diagnosis of Common Gene Mutations in Galactosemia

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Farzaneh Mirzajani

2005-04-01

Full Text Available Objective: Galactosemia is an inborn error of galactose metabolism that is inherited in an autosomal recessive trait. Classical galactosemia is caused by deficient activity of the galactose-1-phosphate uridyltransferase (GALT enzyme that can result in galactosemia complications. Materials & Methods: 135 unrelated families, clinically suspected to galactosemia, were screened by qualitative measurement of galactose-1-phosphate uridyl transferase (GALT activity in blood RBCs by using Beutler method. Results: Deficient enzyme activity (classical galactosemia were confirmed in 16 families. All of these 16 families were submitted to the diagnosis of six common mutations in GALT gene including Q188R, K285N, S135L, L195P, X380R and Q169K by using PCR-RFLP method which resulted in detection of 68% of the mutated alleles. Eight patients were homozygote for Q188R mutation, while one patient homozygote for S135L mutation and one heterozygote for K285N mutation. Conclusion: Biochemnical diagnosis of Galactosemia in Grand infant hospital is very important and necessary.

Riboflavin-Responsive Multiple Acyl-CoA Dehydrogenase Deficiency Associated with Hepatoencephalomyopathy and White Matter Signal Abnormalities on Brain MRI.

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Vieira, Päivi; Myllynen, Päivi; Perhomaa, Marja; Tuominen, Hannu; Keski-Filppula, Riikka; Rytky, Seppo; Risteli, Leila; Uusimaa, Johanna

2017-06-01

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting both fatty acid and amino acid oxidation. It can manifest at any age, but riboflavin-responsiveness has mainly been described in less severely affected patients. We describe an infant with severe MADD presenting with profound hypotonia and hepatomegaly. Treatment with riboflavin improved his muscle strength, liver size, and biochemical markers. A homozygous mutation of electron transfer flavoprotein dehydrogenase ( ETFDH ) was found. His motor skills continued to progress until a fatal infection-triggered deterioration at the age of 34 months. We show changes in brain magnetic resonance imaging over the course of the disease, with profound white matter abnormalities during the deterioration phase. Aggregates of mitochondria with abnormal cristae in muscle electron microscopy were noticed already in infancy. An unusual lactate dehydrogenase (LDH) isoenzyme pattern with LDH-1 predominance was additionally observed. This case demonstrates riboflavin-responsiveness in a severely affected infant with both muscular and extramuscular involvement and further underlines the variable nature of this disease. Georg Thieme Verlag KG Stuttgart · New York.

Pathogenic cascades in lysosomal disease-Why so complex?

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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.

Quantitative charge-tags for sterol and oxysterol analysis.

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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 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.

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

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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.

Random and Systematic Errors Share in Total Error of Probes for CNC Machine Tools

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Adam Wozniak

2018-03-01

Full Text Available Probes for CNC machine tools, as every measurement device, have accuracy limited by random errors and by systematic errors. Random errors of these probes are described by a parameter called unidirectional repeatability. Manufacturers of probes for CNC machine tools usually specify only this parameter, while parameters describing systematic errors of the probes, such as pre-travel variation or triggering radius variation, are used rarely. Systematic errors of the probes, linked to the differences in pre-travel values for different measurement directions, can be corrected or compensated, but it is not a widely used procedure. In this paper, the share of systematic errors and random errors in total error of exemplary probes are determined. In the case of simple, kinematic probes, systematic errors are much greater than random errors, so compensation would significantly reduce the probing error. Moreover, it shows that in the case of kinematic probes commonly specified unidirectional repeatability is significantly better than 2D performance. However, in the case of more precise strain-gauge probe systematic errors are of the same order as random errors, which means that errors correction or compensation, in this case, would not yield any significant benefits.

Uncorrected refractive errors.

Science.gov (United States)

Naidoo, Kovin S; Jaggernath, Jyoti

2012-01-01

Global estimates indicate that more than 2.3 billion people in the world suffer from poor vision due to refractive error; of which 670 million people are considered visually impaired because they do not have access to corrective treatment. Refractive errors, if uncorrected, results in an impaired quality of life for millions of people worldwide, irrespective of their age, sex and ethnicity. Over the past decade, a series of studies using a survey methodology, referred to as Refractive Error Study in Children (RESC), were performed in populations with different ethnic origins and cultural settings. These studies confirmed that the prevalence of uncorrected refractive errors is considerably high for children in low-and-middle-income countries. Furthermore, uncorrected refractive error has been noted to have extensive social and economic impacts, such as limiting educational and employment opportunities of economically active persons, healthy individuals and communities. The key public health challenges presented by uncorrected refractive errors, the leading cause of vision impairment across the world, require urgent attention. To address these issues, it is critical to focus on the development of human resources and sustainable methods of service delivery. This paper discusses three core pillars to addressing the challenges posed by uncorrected refractive errors: Human Resource (HR) Development, Service Development and Social Entrepreneurship.

Uncorrected refractive errors

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Kovin S Naidoo

2012-01-01

Full Text Available Global estimates indicate that more than 2.3 billion people in the world suffer from poor vision due to refractive error; of which 670 million people are considered visually impaired because they do not have access to corrective treatment. Refractive errors, if uncorrected, results in an impaired quality of life for millions of people worldwide, irrespective of their age, sex and ethnicity. Over the past decade, a series of studies using a survey methodology, referred to as Refractive Error Study in Children (RESC, were performed in populations with different ethnic origins and cultural settings. These studies confirmed that the prevalence of uncorrected refractive errors is considerably high for children in low-and-middle-income countries. Furthermore, uncorrected refractive error has been noted to have extensive social and economic impacts, such as limiting educational and employment opportunities of economically active persons, healthy individuals and communities. The key public health challenges presented by uncorrected refractive errors, the leading cause of vision impairment across the world, require urgent attention. To address these issues, it is critical to focus on the development of human resources and sustainable methods of service delivery. This paper discusses three core pillars to addressing the challenges posed by uncorrected refractive errors: Human Resource (HR Development, Service Development and Social Entrepreneurship.

Basal metabolic rate scaled to body mass within species by the ...

African Journals Online (AJOL)

Basal metabolic rate scaled to body mass within species by the fractal dimension of the vascular system and body composition. ... The postulate bd = c is shown to hold for both these species within the limits of experimental error, with the crucian carp evidence being especially convincing, since b, c and d are estimated from ...

Detected-jump-error-correcting quantum codes, quantum error designs, and quantum computation

International Nuclear Information System (INIS)

Alber, G.; Mussinger, M.; Beth, Th.; Charnes, Ch.; Delgado, A.; Grassl, M.

2003-01-01

The recently introduced detected-jump-correcting quantum codes are capable of stabilizing qubit systems against spontaneous decay processes arising from couplings to statistically independent reservoirs. These embedded quantum codes exploit classical information about which qubit has emitted spontaneously and correspond to an active error-correcting code embedded in a passive error-correcting code. The construction of a family of one-detected-jump-error-correcting quantum codes is shown and the optimal redundancy, encoding, and recovery as well as general properties of detected-jump-error-correcting quantum codes are discussed. By the use of design theory, multiple-jump-error-correcting quantum codes can be constructed. The performance of one-jump-error-correcting quantum codes under nonideal conditions is studied numerically by simulating a quantum memory and Grover's algorithm

Medication Errors: New EU Good Practice Guide on Risk Minimisation and Error Prevention.

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Goedecke, Thomas; Ord, Kathryn; Newbould, Victoria; Brosch, Sabine; Arlett, Peter

2016-06-01

A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. Reducing the risk of medication errors is a shared responsibility between patients, healthcare professionals, regulators and the pharmaceutical industry at all levels of healthcare delivery. In 2015, the EU regulatory network released a two-part good practice guide on medication errors to support both the pharmaceutical industry and regulators in the implementation of the changes introduced with the EU pharmacovigilance legislation. These changes included a modification of the 'adverse reaction' definition to include events associated with medication errors, and the requirement for national competent authorities responsible for pharmacovigilance in EU Member States to collaborate and exchange information on medication errors resulting in harm with national patient safety organisations. To facilitate reporting and learning from medication errors, a clear distinction has been made in the guidance between medication errors resulting in adverse reactions, medication errors without harm, intercepted medication errors and potential errors. This distinction is supported by an enhanced MedDRA(®) terminology that allows for coding all stages of the medication use process where the error occurred in addition to any clinical consequences. To better understand the causes and contributing factors, individual case safety reports involving an error should be followed-up with the primary reporter to gather information relevant for the conduct of root cause analysis where this may be appropriate. Such reports should also be summarised in periodic safety update reports and addressed in risk management plans. Any risk minimisation and prevention strategy for medication errors should consider all stages of a medicinal product's life-cycle, particularly the main sources and types of medication errors during product development. This article

Congenital malformations of hands and feet in Smith-Lemli-Opitz syndrome

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N. A. Kovalenko-Klychkova

2013-01-01

Full Text Available Smith-Lemli-Opitz syndrome is rare genetic disorder with multiple limb malformations and neurological manifestation, caused by inborn defect of cholesterol metabolism. Congenital deformities of feet and hands are most common orthopedic symptoms in this syndrome. Description of a girl with Smith-Lemli-Opitz syndrome demonstrates specific features of this disorder and emphasize the importance of proper interpretation of orthopedic malformations for early diagnosis of genetic conditions.

Perceptual learning eases crowding by reducing recognition errors but not position errors.

Science.gov (United States)

Xiong, Ying-Zi; Yu, Cong; Zhang, Jun-Yun

2015-08-01

When an observer reports a letter flanked by additional letters in the visual periphery, the response errors (the crowding effect) may result from failure to recognize the target letter (recognition errors), from mislocating a correctly recognized target letter at a flanker location (target misplacement errors), or from reporting a flanker as the target letter (flanker substitution errors). Crowding can be reduced through perceptual learning. However, it is not known how perceptual learning operates to reduce crowding. In this study we trained observers with a partial-report task (Experiment 1), in which they reported the central target letter of a three-letter string presented in the visual periphery, or a whole-report task (Experiment 2), in which they reported all three letters in order. We then assessed the impact of training on recognition of both unflanked and flanked targets, with particular attention to how perceptual learning affected the types of errors. Our results show that training improved target recognition but not single-letter recognition, indicating that training indeed affected crowding. However, training did not reduce target misplacement errors or flanker substitution errors. This dissociation between target recognition and flanker substitution errors supports the view that flanker substitution may be more likely a by-product (due to response bias), rather than a cause, of crowding. Moreover, the dissociation is not consistent with hypothesized mechanisms of crowding that would predict reduced positional errors.

Error suppression and error correction in adiabatic quantum computation: non-equilibrium dynamics

International Nuclear Information System (INIS)

Sarovar, Mohan; Young, Kevin C

2013-01-01

While adiabatic quantum computing (AQC) has some robustness to noise and decoherence, it is widely believed that encoding, error suppression and error correction will be required to scale AQC to large problem sizes. Previous works have established at least two different techniques for error suppression in AQC. In this paper we derive a model for describing the dynamics of encoded AQC and show that previous constructions for error suppression can be unified with this dynamical model. In addition, the model clarifies the mechanisms of error suppression and allows the identification of its weaknesses. In the second half of the paper, we utilize our description of non-equilibrium dynamics in encoded AQC to construct methods for error correction in AQC by cooling local degrees of freedom (qubits). While this is shown to be possible in principle, we also identify the key challenge to this approach: the requirement of high-weight Hamiltonians. Finally, we use our dynamical model to perform a simplified thermal stability analysis of concatenated-stabilizer-code encoded many-body systems for AQC or quantum memories. This work is a companion paper to ‘Error suppression and error correction in adiabatic quantum computation: techniques and challenges (2013 Phys. Rev. X 3 041013)’, which provides a quantum information perspective on the techniques and limitations of error suppression and correction in AQC. In this paper we couch the same results within a dynamical framework, which allows for a detailed analysis of the non-equilibrium dynamics of error suppression and correction in encoded AQC. (paper)

Prediction of metabolic flux distribution from gene expression data based on the flux minimization principle.

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Hyun-Seob Song

Full Text Available Prediction of possible flux distributions in a metabolic network provides detailed phenotypic information that links metabolism to cellular physiology. To estimate metabolic steady-state fluxes, the most common approach is to solve a set of macroscopic mass balance equations subjected to stoichiometric constraints while attempting to optimize an assumed optimal objective function. This assumption is justifiable in specific cases but may be invalid when tested across different conditions, cell populations, or other organisms. With an aim to providing a more consistent and reliable prediction of flux distributions over a wide range of conditions, in this article we propose a framework that uses the flux minimization principle to predict active metabolic pathways from mRNA expression data. The proposed algorithm minimizes a weighted sum of flux magnitudes, while biomass production can be bounded to fit an ample range from very low to very high values according to the analyzed context. We have formulated the flux weights as a function of the corresponding enzyme reaction's gene expression value, enabling the creation of context-specific fluxes based on a generic metabolic network. In case studies of wild-type Saccharomyces cerevisiae, and wild-type and mutant Escherichia coli strains, our method achieved high prediction accuracy, as gauged by correlation coefficients and sums of squared error, with respect to the experimentally measured values. In contrast to other approaches, our method was able to provide quantitative predictions for both model organisms under a variety of conditions. Our approach requires no prior knowledge or assumption of a context-specific metabolic functionality and does not require trial-and-error parameter adjustments. Thus, our framework is of general applicability for modeling the transcription-dependent metabolism of bacteria and yeasts.

Team errors: definition and taxonomy

International Nuclear Information System (INIS)

Sasou, Kunihide; Reason, James

1999-01-01

In error analysis or error management, the focus is usually upon individuals who have made errors. In large complex systems, however, most people work in teams or groups. Considering this working environment, insufficient emphasis has been given to 'team errors'. This paper discusses the definition of team errors and its taxonomy. These notions are also applied to events that have occurred in the nuclear power industry, aviation industry and shipping industry. The paper also discusses the relations between team errors and Performance Shaping Factors (PSFs). As a result, the proposed definition and taxonomy are found to be useful in categorizing team errors. The analysis also reveals that deficiencies in communication, resource/task management, excessive authority gradient, excessive professional courtesy will cause team errors. Handling human errors as team errors provides an opportunity to reduce human errors

The Errors of Our Ways: Understanding Error Representations in Cerebellar-Dependent Motor Learning.

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Popa, Laurentiu S; Streng, Martha L; Hewitt, Angela L; Ebner, Timothy J

2016-04-01

The cerebellum is essential for error-driven motor learning and is strongly implicated in detecting and correcting for motor errors. Therefore, elucidating how motor errors are represented in the cerebellum is essential in understanding cerebellar function, in general, and its role in motor learning, in particular. This review examines how motor errors are encoded in the cerebellar cortex in the context of a forward internal model that generates predictions about the upcoming movement and drives learning and adaptation. In this framework, sensory prediction errors, defined as the discrepancy between the predicted consequences of motor commands and the sensory feedback, are crucial for both on-line movement control and motor learning. While many studies support the dominant view that motor errors are encoded in the complex spike discharge of Purkinje cells, others have failed to relate complex spike activity with errors. Given these limitations, we review recent findings in the monkey showing that complex spike modulation is not necessarily required for motor learning or for simple spike adaptation. Also, new results demonstrate that the simple spike discharge provides continuous error signals that both lead and lag the actual movements in time, suggesting errors are encoded as both an internal prediction of motor commands and the actual sensory feedback. These dual error representations have opposing effects on simple spike discharge, consistent with the signals needed to generate sensory prediction errors used to update a forward internal model.

Video Error Correction Using Steganography

Science.gov (United States)

Robie, David L.; Mersereau, Russell M.

2002-12-01

The transmission of any data is always subject to corruption due to errors, but video transmission, because of its real time nature must deal with these errors without retransmission of the corrupted data. The error can be handled using forward error correction in the encoder or error concealment techniques in the decoder. This MPEG-2 compliant codec uses data hiding to transmit error correction information and several error concealment techniques in the decoder. The decoder resynchronizes more quickly with fewer errors than traditional resynchronization techniques. It also allows for perfect recovery of differentially encoded DCT-DC components and motion vectors. This provides for a much higher quality picture in an error-prone environment while creating an almost imperceptible degradation of the picture in an error-free environment.

Rotational error in path integration: encoding and execution errors in angle reproduction.

Science.gov (United States)

Chrastil, Elizabeth R; Warren, William H

2017-06-01

Path integration is fundamental to human navigation. When a navigator leaves home on a complex outbound path, they are able to keep track of their approximate position and orientation and return to their starting location on a direct homebound path. However, there are several sources of error during path integration. Previous research has focused almost exclusively on encoding error-the error in registering the outbound path in memory. Here, we also consider execution error-the error in the response, such as turning and walking a homebound trajectory. In two experiments conducted in ambulatory virtual environments, we examined the contribution of execution error to the rotational component of path integration using angle reproduction tasks. In the reproduction tasks, participants rotated once and then rotated again to face the original direction, either reproducing the initial turn or turning through the supplementary angle. One outstanding difficulty in disentangling encoding and execution error during a typical angle reproduction task is that as the encoding angle increases, so does the required response angle. In Experiment 1, we dissociated these two variables by asking participants to report each encoding angle using two different responses: by turning to walk on a path parallel to the initial facing direction in the same (reproduction) or opposite (supplementary angle) direction. In Experiment 2, participants reported the encoding angle by turning both rightward and leftward onto a path parallel to the initial facing direction, over a larger range of angles. The results suggest that execution error, not encoding error, is the predominant source of error in angular path integration. These findings also imply that the path integrator uses an intrinsic (action-scaled) rather than an extrinsic (objective) metric.

Video Error Correction Using Steganography

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Robie David L

2002-01-01

Full Text Available The transmission of any data is always subject to corruption due to errors, but video transmission, because of its real time nature must deal with these errors without retransmission of the corrupted data. The error can be handled using forward error correction in the encoder or error concealment techniques in the decoder. This MPEG-2 compliant codec uses data hiding to transmit error correction information and several error concealment techniques in the decoder. The decoder resynchronizes more quickly with fewer errors than traditional resynchronization techniques. It also allows for perfect recovery of differentially encoded DCT-DC components and motion vectors. This provides for a much higher quality picture in an error-prone environment while creating an almost imperceptible degradation of the picture in an error-free environment.

Part two: Error propagation

International Nuclear Information System (INIS)

Picard, R.R.

1989-01-01

Topics covered in this chapter include a discussion of exact results as related to nuclear materials management and accounting in nuclear facilities; propagation of error for a single measured value; propagation of error for several measured values; error propagation for materials balances; and an application of error propagation to an example of uranium hexafluoride conversion process

Prediction-error of Prediction Error (PPE)-based Reversible Data Hiding

OpenAIRE

Wu, Han-Zhou; Wang, Hong-Xia; Shi, Yun-Qing

2016-01-01

This paper presents a novel reversible data hiding (RDH) algorithm for gray-scaled images, in which the prediction-error of prediction error (PPE) of a pixel is used to carry the secret data. In the proposed method, the pixels to be embedded are firstly predicted with their neighboring pixels to obtain the corresponding prediction errors (PEs). Then, by exploiting the PEs of the neighboring pixels, the prediction of the PEs of the pixels can be determined. And, a sorting technique based on th...

Diagnostic errors in pediatric radiology

International Nuclear Information System (INIS)

Taylor, George A.; Voss, Stephan D.; Melvin, Patrice R.; Graham, Dionne A.

2011-01-01

Little information is known about the frequency, types and causes of diagnostic errors in imaging children. Our goals were to describe the patterns and potential etiologies of diagnostic error in our subspecialty. We reviewed 265 cases with clinically significant diagnostic errors identified during a 10-year period. Errors were defined as a diagnosis that was delayed, wrong or missed; they were classified as perceptual, cognitive, system-related or unavoidable; and they were evaluated by imaging modality and level of training of the physician involved. We identified 484 specific errors in the 265 cases reviewed (mean:1.8 errors/case). Most discrepancies involved staff (45.5%). Two hundred fifty-eight individual cognitive errors were identified in 151 cases (mean = 1.7 errors/case). Of these, 83 cases (55%) had additional perceptual or system-related errors. One hundred sixty-five perceptual errors were identified in 165 cases. Of these, 68 cases (41%) also had cognitive or system-related errors. Fifty-four system-related errors were identified in 46 cases (mean = 1.2 errors/case) of which all were multi-factorial. Seven cases were unavoidable. Our study defines a taxonomy of diagnostic errors in a large academic pediatric radiology practice and suggests that most are multi-factorial in etiology. Further study is needed to define effective strategies for improvement. (orig.)

The role of brain magnetic resonance imaging in the diagnosis of pantothenate kinase deficiency (previously Hallervorden-Spatz disease): case report; Znaczenie badania tomografii rezonansu magnetycznego mozgowia w diagnostyce deficytu kinazy pantotenowej (dawniej choroby Hallervordena-Spatza) - opis przypadku

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Gizewska, M; Bieleninik, A; Adamczyk, T; Walczak, M [II Klinika Chorob Dzieci Pomorskiej Akademii Medycznej, Szczecin (Poland); Cyrylowski, L [Zaklad Diagnostyki Obrazowej i Radiologii Interwencyjnej Pomorskiej Akademii Medycznej, Szczecin (Poland); Abramczyk, G [Oddzial Noworodkow, Patologii i Intensywnej Terapii, Samodzielnego Publicznego Specjalistycznego ZOZ ' ' Zdroje ' ' , Szczecin (Poland); Nowacki, P [Klinika Neurologii Pomorskiej Akademii Medycznej, Szczecin (Poland)

2005-07-01

Panthotenate kinase deficiency is a rare metabolic disorder from the group of neuroaxonal dystrophy. It is characterized by symptoms of extrapiramidal system impairment, general dystonia, progressive gait disturbances, limbs rigidity, dyskinesias, choreoatetotic movements, dysarthria and progressive dementia. On the brain MRI, T2 - weighted images demonstrate typical, symmetrical '' eye of the tiger '' sign with hyperintensive signals from the central parts of the pallidum, surrounded by low signals in the pallidum and accompanied by hypointensity in substantia nigra resulting from iron deposition. We present a case of 13.5 year old boy with gait disturbances, increase muscles tone, dysartria, aggressive behavior and learning difficulties progressing from the early childhood. In the differential diagnosis a number of inborn errors of metabolism was excluded. Finding on the brain MRI in T2- weighted images typical picture of '' eye of the tiger '' led to a diagnosis of panthotenate kinase deficiency. In subsequent years of observation, despite attempts of baclofen and calcium panthotenate treatment, progression of pyramidal-extrapyramidal syndrome is observed. In children with symptoms of progressive extrapyramidal tract impairment, a sign of '' eye of the tiger '' with hyperintensive signals from the central parts of the pallidum, surrounded by low signals in the remaining part of the pallidum and accompanied by similar lesions in substantia nigra is typical for panthotenate kinase deficiency - a rare neurodegenerative disorder of central nervous system. (author)

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

Science.gov (United States)

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

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment.

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Bruno Scarpellini

Full Text Available We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR, before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment.Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD] was detected.Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment.

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Scarpellini, Bruno; Zanoni, Michelle; Sucupira, Maria Cecilia Araripe; Truong, Hong-Ha M; Janini, Luiz Mario Ramos; Segurado, Ismael Dale Cotrin; Diaz, Ricardo Sobhie

2016-01-01

We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected. Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

Reference values of amino acids, acylcarnitines and succinylacetone by tandem mass spectrometry for use in newborn screening in southwest Colombia.

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Céspedes, Nora; Valencia, Angela; Echeverry, Carlos Alberto; Arce-Plata, Maria Isabel; Colón, Cristóbal; Castiñeiras, Daisy E; Hurtado, Paula Margarita; Cocho, Jose Angel; Herrera, Sócrates; Arévalo-Herrera, Myriam

2017-09-30

Inborn errors of metabolism (IEM) represent an important public health problem due to current diagnosis and treatment limitations, poor life quality of affected patients, and consequent untimely child death. In contrast to classical methods, tandem mass spectrometry (MS/MS) has allowed simultaneous evaluation of multiple metabolites associated with IEM offering higher sensitivity, low false positive rates and high throughput. Determine concentration levels for amino acids and acylcarnitines in blood of newborns from Colombia, to establish reference values for further use in diagnosis of IEM. Implementation of a method to determine amino acids, acylcarnitines and succinylacetone in newborn dried blood spots using MS/MS, and its application in a cross-sectional study conducted in 891 healthy neonates from Cali and Quibdo cities is described. fifty-seven analytes that allow the diagnosis of more than 40 different pathologies were tested. The method showed to be linear, precise and accurate. Healthy neonates 1-18 days of age were included, 523 from Cali and 368 from Quibdo; 52% male and 48% female. Age-related differences on the concentration levels of amino acids and acylcarnitines were observed whereas no significant differences by gender were found. The study has contributed to reveal the usual concentration levels of amino acids, acylcarnitines and succinylacetone that could be used as reference for the establishment of a newborn metabolic screening program in Colombia.

Genetic Causes of Putative Autosomal Recessive Intellectual Disability Cases in Hamedan Province

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Milad Bastami

2012-04-01

Full Text Available Objective: The aim of this study was to investigate the genetic causes of autosomal recessive intellectual disabilities (AR-ID in Hamadan province of Iran. Materials & Methods: In this descriptive-analytical cross-sectional study, 25 families with more than one affected with putative autosomal recessive intellectual disability were chosen with collaboration of Welfare Organization of Hamadan province. Families were included a total of 60 patients (39 male and 21 female whose intellectual disability had been confirmed by Raven IQ test. Each family was asked for clinical examination and getting consent form. Blood sample was collected from each family. One proband from each family was tested for CGG repeat expansion in FMR1 gene, chromosomal abnormalities and inborn errors of metabolism. We also performed homozygosity mapping based on STR markers for seven known MCPH loci in families with primary microcephaly and AR-ID. Results: Five families had full mutation of Fragile X syndrome. No chromosomal abnormalities were identified. Metabolic screening revealed one family with Medium Chain Acyl CoA Dehydrogenase deficiency. None of three families with primary microcephaly and AR-ID showed linkage to any of known seven MCPH loci. Conclusion: The main causes of ID in Hamadan province were Fragile X syndrome and Autosomal Recessive Primary Microcephaly with the frequencies of 20% and 12%, respectively.

Early diagnosis of adenylosuccinate lyase deficiency using a high-throughput screening method and a trial of oral S-adenosyl-l-methionine as a treatment method.

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van Werkhoven, Michiel A; Duley, John A; McGown, Ivan; Munce, Teresa; Freeman, Jeremy L; Pitt, James J

2013-11-01

The aim of this study was to develop a high-throughput urine screening technique for adenylosuccinate lyase (ADSL) deficiency and to evaluate S-adenosyl-l-methionine (SAMe) as a potential treatment for this disorder. Testing for succinyladenosine (S-Ado), a marker of ADSL deficiency, was incorporated into a screening panel for urine biomarkers for inborn errors of metabolism using electrospray tandem mass spectrometry. Liquid chromatography-mass spectrometry and high-performance liquid chromatography were used to confirm and monitor the response of metabolites to oral SAMe treatment. Increased levels of S-Ado were detected in a 3-month-old male infant with hypotonia and seizures. ADSL gene sequencing revealed a previously described c.-49T>C mutation and a novel c.889_891dupAAT mutation, which was likely to disrupt enzyme function. After 9 months of SAMe treatment, there was no clear response evidenced in urine metabolite levels or clinical parameters. These results demonstrate proof of the principle for the high-throughput urine screening technique, allowing earlier diagnosis of patients with ADSL deficiency. However, early treatment with SAMe does not appear to be effective in ADSL deficiency. It is suggested that although SAMe treatment may ameliorate purine nucleotide deficiency, it cannot correct metabolic syndromes in which a toxic nucleotide is present, in this case presumed to be succinylaminoimidazole carboxamide ribotide. © 2013 Mac Keith Press.

Serum Biotin Levels in Women Complaining of Hair Loss.

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Trüeb, Ralph M

2016-01-01

Biotin is a coenzyme for carboxylase enzymes that assist various metabolic reactions involved in fatty acid synthesis, branched-chain amino acid catabolism, and gluconeogenesis important for maintenance of healthy skin and hair. Due to its availability, affordability, and effective marketing for this purpose, biotin is a popular nutritional supplement for treatment of hair loss. However, there are little data on the frequency of biotin deficiency in patients complaining of hair loss and on the value of oral biotin for treatment of hair loss that is not due to an inborn error of biotin metabolism or deficiency. The aim of this study was to determine the frequency and significance of biotin deficiency in women complaining of hair loss. Biotin deficiency was found in 38% of women complaining of hair loss. Of those showing diffuse telogen effluvium in trichograms (24%), 35% had evidence of associated seborrheic-like dermatitis. About 11% of patients with biotin deficiency had a positive personal history for risk factors for biotin deficiency. The custom of treating women complaining of hair loss in an indiscriminate manner with oral biotin supplementation is to be rejected, unless biotin deficiency and its significance for the complaint of hair loss in an individual has been demonstrated on the basis of a careful patient history, clinical examination, determination of serum biotin levels, and exclusion of alternative factors responsible for hair loss.

Lesch-Nyhan variant syndrome: variable presentation in 3 affected family members.

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Sarafoglou, Kyriakie; Grosse-Redlinger, Krista; Boys, Christopher J; Charnas, Laurence; Otten, Noelle; Broock, Robyn; Nyhan, William L

2010-06-01

Lesch-Nyhan disease is an inborn error of purine metabolism that results from deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). The heterogeneity of clinical phenotypes seen in HPRT deficiency corresponds to an inverse relationship between HPRT enzyme activity and clinical severity. With rare exception, each mutation produces a stereotypical pattern of clinical disease; onset of neurologic symptoms occurs during infancy and is thought to be nonprogressive. To document a family in which a single HPRT gene mutation has led to 3 different clinical and enzymatic phenotypes. Case report. Settings A university-based outpatient metabolic clinic and a biochemical genetics laboratory. Patients Three males (2 infants and their grandfather) from the same family with Lesch-Nyhan variant, including one of the oldest patients with Lesch-Nyhan variant at diagnosis (65 years). Clinical and biochemical observations. Sequencing of 5 family members revealed a novel mutation c.550G>T in exon 7 of the HPRT gene. The considerably variable clinical phenotype corresponded with the variable enzymatic activity in the 3 males, with the grandfather being the most severely affected. The different phenotypes encountered in the enzymatic analysis of cultured fibroblasts from a single mutation in the same family is unprecedented. The significant decrease in the grandfather's HPRT enzymatic activity compared with that of his grandchildren could be a function of the Hayflick Limit Theory of cell senescence.

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

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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.

Xenotransplantation of neonatal porcine liver cells.

Science.gov (United States)

Garkavenko, O; Emerich, D F; Muzina, M; Muzina, Z; Vasconcellos, A V; Ferguson, A B; Cooper, I J; Elliott, R B

2005-01-01

Xenotransplantation of porcine liver cell types may provide a means of overcoming the shortage of suitable donor tissues to treat hepatic diseases characterized by inherited inborn errors of metabolism or protein production. Here we report the successful isolation, culture, and xenotransplantation of liver cells harvested from 7- to 10-day-old piglets. Liver cells were isolated and cultured immediately after harvesting. Cell viability was excellent (>90%) over the duration of the in vitro studies (3 weeks) and the cultured cells continued to significantly proliferate. These cells also retained their normal secretory and metabolic capabilities as determined by continued release of albumin, factor 8, and indocyanin green (ICG) uptake. After 3 weeks in culture, porcine liver cells were loaded into immunoisolatory macro devices (Theracyte devices) and placed into the intraperitoneal cavity of immunocompetant CD1 mice. Eight weeks later, the devices were retrieved and the cells analyzed for posttransplant determinations of survival and function. Post mortem analysis confirmed that the cell-loaded devices were biocompatible, and were well-tolerated without inducing any notable inflammatory reaction in the tissues immediately surrounding the encapsulated cells. Finally, the encapsulated liver cells remained viable and functional as determined by histologic analyses and ICG uptake/release. The successful harvesting, culturing, and xenotransplantation of functional neonatal pig liver cells support the continued development of this approach for treating a range of currently undertreated or intractable hepatic diseases.

The role of brain magnetic resonance imaging in the diagnosis of pantothenate kinase deficiency (previously Hallervorden-Spatz disease): case report

International Nuclear Information System (INIS)

Gizewska, M.; Bieleninik, A.; Adamczyk, T.; Walczak, M.; Cyrylowski, L.; Abramczyk, G.; Nowacki, P.

2005-01-01

Panthotenate kinase deficiency is a rare metabolic disorder from the group of neuroaxonal dystrophy. It is characterized by symptoms of extrapiramidal system impairment, general dystonia, progressive gait disturbances, limbs rigidity, dyskinesias, choreoatetotic movements, dysarthria and progressive dementia. On the brain MRI, T2 - weighted images demonstrate typical, symmetrical '' eye of the tiger '' sign with hyperintensive signals from the central parts of the pallidum, surrounded by low signals in the pallidum and accompanied by hypointensity in substantia nigra resulting from iron deposition. We present a case of 13.5 year old boy with gait disturbances, increase muscles tone, dysartria, aggressive behavior and learning difficulties progressing from the early childhood. In the differential diagnosis a number of inborn errors of metabolism was excluded. Finding on the brain MRI in T2- weighted images typical picture of '' eye of the tiger '' led to a diagnosis of panthotenate kinase deficiency. In subsequent years of observation, despite attempts of baclofen and calcium panthotenate treatment, progression of pyramidal-extrapyramidal syndrome is observed. In children with symptoms of progressive extrapyramidal tract impairment, a sign of '' eye of the tiger '' with hyperintensive signals from the central parts of the pallidum, surrounded by low signals in the remaining part of the pallidum and accompanied by similar lesions in substantia nigra is typical for panthotenate kinase deficiency - a rare neurodegenerative disorder of central nervous system. (author)

Avaliação antropométrica de pacientes com suspeita de erros inatos do metabolismo Anthropometric evaluation of patients with suspected innate errors of metabolism

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Francilia de Kássia Brito-Silva

2012-09-01

Full Text Available OBJETIVOS: avaliar antropometricamente os pacientes com suspeita de erros inatos do metabolismo (EIM e descrever a prevalência de distúrbios nutricionais (desnutrição, sobrepeso e obesidade. MÉTODOS: foram avaliados 55 pacientes de 0 a 10 anos, de acordo com os índices antropométricos (A/I, P/I E P/A e IMC/I, no laboratório de erros inatos do metabolismo (LEIM da Universidade Federal do Pará, através de balança e antropômetro. Os dados foram coletados a partir da ficha de atendimento do LEIM. Para o diagnóstico nutricional foram utilizados os programas Anthro e Anthro Plus e o programa SPSS para a análise estatística. RESULTADOS: os pacientes atendidos pertenciam, na maioria, a faixa etária de sete meses a nove anos. Os principais sintomas foram atraso no desenvolvimento neuropsicomotor e infecções frequentes. Quanto ao estado nutricional, foi observado déficit de 23,7% no indicador de peso para idade, déficit de 50,9% no indicador de altura para idade, excesso de peso e obesidade de 15,4% para peso para altura, e 25,1% para índice de massa corporal para idade. CONCLUSÕES: os pacientes apresentaram estado nutricional inadequados, o qual na ausência de diagnóstico de EIM, os fatores envolvidos devem ser mais bem averiguados.OBJECTIVES: to provide an anthropometric evaluation of patients suspected of having innate errors of metabolism (IEMs and report the prevalence of nutritional disorders (malnutrition, overweight and obesity. METHODS: fifty-five patients aged between 0 and 10 years were evaluated for anthropometric indices (H/A, W/A and W/H and BMI/A, in the innate errors of metabolism laboratory (LEIM of the Federal University of Pará, using scales and an anthropometer. The data were collected using an LEIM form. Nutritional diagnosis was carried out using the Anthro and Anthro Plus programs and the SPSS statistics package. RESULTS: the patients attended were mostly aged between seven months and nine years. The main

Laboratory errors and patient safety.

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Miligy, Dawlat A

2015-01-01

Laboratory data are extensively used in medical practice; consequently, laboratory errors have a tremendous impact on patient safety. Therefore, programs designed to identify and reduce laboratory errors, as well as, setting specific strategies are required to minimize these errors and improve patient safety. The purpose of this paper is to identify part of the commonly encountered laboratory errors throughout our practice in laboratory work, their hazards on patient health care and some measures and recommendations to minimize or to eliminate these errors. Recording the encountered laboratory errors during May 2008 and their statistical evaluation (using simple percent distribution) have been done in the department of laboratory of one of the private hospitals in Egypt. Errors have been classified according to the laboratory phases and according to their implication on patient health. Data obtained out of 1,600 testing procedure revealed that the total number of encountered errors is 14 tests (0.87 percent of total testing procedures). Most of the encountered errors lay in the pre- and post-analytic phases of testing cycle (representing 35.7 and 50 percent, respectively, of total errors). While the number of test errors encountered in the analytic phase represented only 14.3 percent of total errors. About 85.7 percent of total errors were of non-significant implication on patients health being detected before test reports have been submitted to the patients. On the other hand, the number of test errors that have been already submitted to patients and reach the physician represented 14.3 percent of total errors. Only 7.1 percent of the errors could have an impact on patient diagnosis. The findings of this study were concomitant with those published from the USA and other countries. This proves that laboratory problems are universal and need general standardization and bench marking measures. Original being the first data published from Arabic countries that

Prediction of the metabolic cost of walking with and without loads.

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Duggan, A; Haisman, M F

1992-04-01

Measurement of the metabolic cost of walking inconveniences subjects, and requires skilled technical support and expensive equipment. These factors have stimulated interest in predictive equations. The present study assessed existing equations. Under each of 17 combinations of gradient (0-6%) and carried load (4.1-37.4 kg), 7-12 men undertook treadmill walking at 1.67 m/s. Measured oxygen consumption and respiratory exchange ratio were used to calculate metabolic rate (MRobserved). Metabolic rate was also predicted from the equation of Pandolf et al. (1977) (MRpandolf) and, where appropriate, from another five equations relating to walking without loads. MRobserved and MRpandolf did not differ significantly (p greater than 0.05) under any combination of gradient and load. The overall mean MRobserved and MRpandolf of 609 W and 602 W, respectively, also did not differ significantly (p greater than 0.05). These variables were highly correlated (r = 0.94) with a standard deviation about the prediction error of 47 W. For level walking without loads, the mean predictions from the equations of Pandolf et al. (1977) and Cotes and Meade (1960) did not differ significantly (p greater than 0.05) from the mean MRobserved of 428 Watts, but four other equations overestimated by 17-74 W. In conclusion, the Pandolf et al. (1977) equation has given good results across the range of combinations of load and gradient tested, and the errors are considered acceptable for most practical purposes.

Errors in Neonatology

OpenAIRE

Antonio Boldrini; Rosa T. Scaramuzzo; Armando Cuttano

2013-01-01

Introduction: Danger and errors are inherent in human activities. In medical practice errors can lean to adverse events for patients. Mass media echo the whole scenario. Methods: We reviewed recent published papers in PubMed database to focus on the evidence and management of errors in medical practice in general and in Neonatology in particular. We compared the results of the literature with our specific experience in Nina Simulation Centre (Pisa, Italy). Results: In Neonatology the main err...

Errors in abdominal computed tomography

International Nuclear Information System (INIS)

Stephens, S.; Marting, I.; Dixon, A.K.

1989-01-01

Sixty-nine patients are presented in whom a substantial error was made on the initial abdominal computed tomography report. Certain features of these errors have been analysed. In 30 (43.5%) a lesion was simply not recognised (error of observation); in 39 (56.5%) the wrong conclusions were drawn about the nature of normal or abnormal structures (error of interpretation). The 39 errors of interpretation were more complex; in 7 patients an abnormal structure was noted but interpreted as normal, whereas in four a normal structure was thought to represent a lesion. Other interpretive errors included those where the wrong cause for a lesion had been ascribed (24 patients), and those where the abnormality was substantially under-reported (4 patients). Various features of these errors are presented and discussed. Errors were made just as often in relation to small and large lesions. Consultants made as many errors as senior registrar radiologists. It is like that dual reporting is the best method of avoiding such errors and, indeed, this is widely practised in our unit. (Author). 9 refs.; 5 figs.; 1 tab

Scaling prediction errors to reward variability benefits error-driven learning in humans.

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Diederen, Kelly M J; Schultz, Wolfram

2015-09-01

Effective error-driven learning requires individuals to adapt learning to environmental reward variability. The adaptive mechanism may involve decays in learning rate across subsequent trials, as shown previously, and rescaling of reward prediction errors. The present study investigated the influence of prediction error scaling and, in particular, the consequences for learning performance. Participants explicitly predicted reward magnitudes that were drawn from different probability distributions with specific standard deviations. By fitting the data with reinforcement learning models, we found scaling of prediction errors, in addition to the learning rate decay shown previously. Importantly, the prediction error scaling was closely related to learning performance, defined as accuracy in predicting the mean of reward distributions, across individual participants. In addition, participants who scaled prediction errors relative to standard deviation also presented with more similar performance for different standard deviations, indicating that increases in standard deviation did not substantially decrease "adapters'" accuracy in predicting the means of reward distributions. However, exaggerated scaling beyond the standard deviation resulted in impaired performance. Thus efficient adaptation makes learning more robust to changing variability. Copyright © 2015 the American Physiological Society.

Comparing Absolute Error with Squared Error for Evaluating Empirical Models of Continuous Variables: Compositions, Implications, and Consequences

Science.gov (United States)

Gao, J.

2014-12-01

Reducing modeling error is often a major concern of empirical geophysical models. However, modeling errors can be defined in different ways: When the response variable is continuous, the most commonly used metrics are squared (SQ) and absolute (ABS) errors. For most applications, ABS error is the more natural, but SQ error is mathematically more tractable, so is often used as a substitute with little scientific justification. Existing literature has not thoroughly investigated the implications of using SQ error in place of ABS error, especially not geospatially. This study compares the two metrics through the lens of bias-variance decomposition (BVD). BVD breaks down the expected modeling error of each model evaluation point into bias (systematic error), variance (model sensitivity), and noise (observation instability). It offers a way to probe the composition of various error metrics. I analytically derived the BVD of ABS error and compared it with the well-known SQ error BVD, and found that not only the two metrics measure the characteristics of the probability distributions of modeling errors differently, but also the effects of these characteristics on the overall expected error are different. Most notably, under SQ error all bias, variance, and noise increase expected error, while under ABS error certain parts of the error components reduce expected error. Since manipulating these subtractive terms is a legitimate way to reduce expected modeling error, SQ error can never capture the complete story embedded in ABS error. I then empirically compared the two metrics with a supervised remote sensing model for mapping surface imperviousness. Pair-wise spatially-explicit comparison for each error component showed that SQ error overstates all error components in comparison to ABS error, especially variance-related terms. Hence, substituting ABS error with SQ error makes model performance appear worse than it actually is, and the analyst would more likely accept a

Abnormal error monitoring in math-anxious individuals: evidence from error-related brain potentials.

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Macarena Suárez-Pellicioni

Full Text Available This study used event-related brain potentials to investigate whether math anxiety is related to abnormal error monitoring processing. Seventeen high math-anxious (HMA and seventeen low math-anxious (LMA individuals were presented with a numerical and a classical Stroop task. Groups did not differ in terms of trait or state anxiety. We found enhanced error-related negativity (ERN in the HMA group when subjects committed an error on the numerical Stroop task, but not on the classical Stroop task. Groups did not differ in terms of the correct-related negativity component (CRN, the error positivity component (Pe, classical behavioral measures or post-error measures. The amplitude of the ERN was negatively related to participants' math anxiety scores, showing a more negative amplitude as the score increased. Moreover, using standardized low resolution electromagnetic tomography (sLORETA we found greater activation of the insula in errors on a numerical task as compared to errors in a non-numerical task only for the HMA group. The results were interpreted according to the motivational significance theory of the ERN.

Heuristic errors in clinical reasoning.

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Rylander, Melanie; Guerrasio, Jeannette

2016-08-01

Errors in clinical reasoning contribute to patient morbidity and mortality. The purpose of this study was to determine the types of heuristic errors made by third-year medical students and first-year residents. This study surveyed approximately 150 clinical educators inquiring about the types of heuristic errors they observed in third-year medical students and first-year residents. Anchoring and premature closure were the two most common errors observed amongst third-year medical students and first-year residents. There was no difference in the types of errors observed in the two groups. Errors in clinical reasoning contribute to patient morbidity and mortality Clinical educators perceived that both third-year medical students and first-year residents committed similar heuristic errors, implying that additional medical knowledge and clinical experience do not affect the types of heuristic errors made. Further work is needed to help identify methods that can be used to reduce heuristic errors early in a clinician's education. © 2015 John Wiley & Sons Ltd.

Awareness of technology-induced errors and processes for identifying and preventing such errors.

Science.gov (United States)

Bellwood, Paule; Borycki, Elizabeth M; Kushniruk, Andre W

2015-01-01

There is a need to determine if organizations working with health information technology are aware of technology-induced errors and how they are addressing and preventing them. The purpose of this study was to: a) determine the degree of technology-induced error awareness in various Canadian healthcare organizations, and b) identify those processes and procedures that are currently in place to help address, manage, and prevent technology-induced errors. We identified a lack of technology-induced error awareness among participants. Participants identified there was a lack of well-defined procedures in place for reporting technology-induced errors, addressing them when they arise, and preventing them.

Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options.

Science.gov (United States)

Wasim, Muhammad; Awan, Fazli Rabbi; Khan, Haq Nawaz; Tawab, Abdul; Iqbal, Mazhar; Ayesha, Hina

2018-04-01

Inborn errors of metabolism (IEMs) are a group of inherited metabolic disorders which are caused by mutations in the specific genes that lead to impaired proteins or enzymes production. Different metabolic pathways are perturbed due to the deficiency or lack of enzymes. To date, more than 500 IEMs have been reported with most of them being untreatable. However, fortunately 91 such disorders are potentially treatable, if diagnosed at an earlier stage of life. IEMs have been classified into different categories and one class of IEMs, characterized by the physiological disturbances of amino acids is called as aminoacidopathies. Out of 91 treatable IEM, thirteen disorders are amino acid related. Aminoacidopathies can be detected by chromatography and mass spectrometry based analytical techniques (e.g., HPLC, GC-MS, LC-MS/MS) for amino acid level changes, and through genetic assays (e.g., PCR, TaqMan Genotyping, DNA sequencing) at the mutation level in the corresponding genes. Hence, this review is focused to describe thirteen common aminoacidopathies namely: Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Homocystinuria/Methylene Tetrahydrofolate Reductase (MTHFR) deficiency, Tyrosinemia type II, Citrullinemia type I and type II, Argininosuccinic aciduria, Carbamoyl Phosphate Synthetase I (CPS) deficiency, Argininemia (arginase deficiency), Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, N-Acetylglutamate Synthase (NAGS) deficiency, Ornithine Transcarbamylase (OTC) deficiency, and Pyruvate Dehydrogenase (PDH) complex deficiency. Furthermore, the etiology, prevalence and commonly used analytical techniques for screening of aminoacidopathies are briefly described. This information would be helpful to researchers and clinicians especially from developing countries to initiate newborn screening programs for aminoacidopathies.

Acute rhabdomyolysis and inflammation.

Science.gov (United States)

Hamel, Yamina; Mamoune, Asmaa; Mauvais, François-Xavier; Habarou, Florence; Lallement, Laetitia; Romero, Norma Beatriz; Ottolenghi, Chris; de Lonlay, Pascale

2015-07-01

Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which leads to leakage of potentially toxic cellular content into the systemic circulation. Acquired causes by direct injury to the sarcolemma are most frequent. The inherited causes are: i) metabolic with failure of energy production, including mitochondrial fatty acid ß-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, more rarely mitochondrial respiratory chain deficiency, purine defects and peroxysomal α-methyl-acyl-CoA-racemase defect (AMACR), ii) structural causes with muscle dystrophies and myopathies, iii) calcium pump disorder with RYR1 gene mutations, iv) inflammatory causes with myositis. Irrespective of the cause of rhabdomyolysis, the pathology follows a common pathway, either by the direct injury to sarcolemma by increased intracellular calcium concentration (acquired causes) or by the failure of energy production (inherited causes), which leads to fiber necrosis. Rhabdomyolysis are frequently precipitated by febrile illness or exercise. These conditions are associated with two events, elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines. To illustrate these points in the context of energy metabolism, protein thermolability and the potential benefits of arginine therapy, we focus on a rare cause of rhabdomyolysis, aldolase A deficiency. In addition, our studies on lipin-1 (LPIN1) deficiency raise the possibility that several diseases involved in rhabdomyolysis implicate pro-inflammatory cytokines and may even represent primarily pro-inflammatory diseases. Thus, not only thermolability of mutant proteins critical for muscle function, but also pro-inflammatory cytokines per se, may lead to metabolic decompensation and rhabdomyolysis.

Einstein's error

International Nuclear Information System (INIS)

Winterflood, A.H.

1980-01-01

In discussing Einstein's Special Relativity theory it is claimed that it violates the principle of relativity itself and that an anomalous sign in the mathematics is found in the factor which transforms one inertial observer's measurements into those of another inertial observer. The apparent source of this error is discussed. Having corrected the error a new theory, called Observational Kinematics, is introduced to replace Einstein's Special Relativity. (U.K.)

Controlling errors in unidosis carts

Directory of Open Access Journals (Sweden)

Inmaculada Díaz Fernández

2010-01-01

Full Text Available Objective: To identify errors in the unidosis system carts. Method: For two months, the Pharmacy Service controlled medication either returned or missing from the unidosis carts both in the pharmacy and in the wards. Results: Uncorrected unidosis carts show a 0.9% of medication errors (264 versus 0.6% (154 which appeared in unidosis carts previously revised. In carts not revised, the error is 70.83% and mainly caused when setting up unidosis carts. The rest are due to a lack of stock or unavailability (21.6%, errors in the transcription of medical orders (6.81% or that the boxes had not been emptied previously (0.76%. The errors found in the units correspond to errors in the transcription of the treatment (3.46%, non-receipt of the unidosis copy (23.14%, the patient did not take the medication (14.36%or was discharged without medication (12.77%, was not provided by nurses (14.09%, was withdrawn from the stocks of the unit (14.62%, and errors of the pharmacy service (17.56% . Conclusions: It is concluded the need to redress unidosis carts and a computerized prescription system to avoid errors in transcription.Discussion: A high percentage of medication errors is caused by human error. If unidosis carts are overlooked before sent to hospitalization units, the error diminishes to 0.3%.

Errors and violations

International Nuclear Information System (INIS)

Reason, J.

1988-01-01

This paper is in three parts. The first part summarizes the human failures responsible for the Chernobyl disaster and argues that, in considering the human contribution to power plant emergencies, it is necessary to distinguish between: errors and violations; and active and latent failures. The second part presents empirical evidence, drawn from driver behavior, which suggest that errors and violations have different psychological origins. The concluding part outlines a resident pathogen view of accident causation, and seeks to identify the various system pathways along which errors and violations may be propagated

Imagery of Errors in Typing

Science.gov (United States)

Rieger, Martina; Martinez, Fanny; Wenke, Dorit

2011-01-01

Using a typing task we investigated whether insufficient imagination of errors and error corrections is related to duration differences between execution and imagination. In Experiment 1 spontaneous error imagination was investigated, whereas in Experiment 2 participants were specifically instructed to imagine errors. Further, in Experiment 2 we…

Magnetic Nanoparticle Thermometer: An Investigation of Minimum Error Transmission Path and AC Bias Error

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Zhongzhou Du

2015-04-01

Full Text Available The signal transmission module of a magnetic nanoparticle thermometer (MNPT was established in this study to analyze the error sources introduced during the signal flow in the hardware system. The underlying error sources that significantly affected the precision of the MNPT were determined through mathematical modeling and simulation. A transfer module path with the minimum error in the hardware system was then proposed through the analysis of the variations of the system error caused by the significant error sources when the signal flew through the signal transmission module. In addition, a system parameter, named the signal-to-AC bias ratio (i.e., the ratio between the signal and AC bias, was identified as a direct determinant of the precision of the measured temperature. The temperature error was below 0.1 K when the signal-to-AC bias ratio was higher than 80 dB, and other system errors were not considered. The temperature error was below 0.1 K in the experiments with a commercial magnetic fluid (Sample SOR-10, Ocean Nanotechnology, Springdale, AR, USA when the hardware system of the MNPT was designed with the aforementioned method.

Prioritising interventions against medication errors

DEFF Research Database (Denmark)

Lisby, Marianne; Pape-Larsen, Louise; Sørensen, Ann Lykkegaard

errors are therefore needed. Development of definition: A definition of medication errors including an index of error types for each stage in the medication process was developed from existing terminology and through a modified Delphi-process in 2008. The Delphi panel consisted of 25 interdisciplinary......Abstract Authors: Lisby M, Larsen LP, Soerensen AL, Nielsen LP, Mainz J Title: Prioritising interventions against medication errors – the importance of a definition Objective: To develop and test a restricted definition of medication errors across health care settings in Denmark Methods: Medication...... errors constitute a major quality and safety problem in modern healthcare. However, far from all are clinically important. The prevalence of medication errors ranges from 2-75% indicating a global problem in defining and measuring these [1]. New cut-of levels focusing the clinical impact of medication...

Metabolismo do cálcio na fenilcetonúria Calcium metabolism in phenilke

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Fabiana Ferreira Martins

2009-06-01

Full Text Available A Fenilcetonúria é um erro inato do metabolismo do aminoácido fenilalanina. O tratamento é essencialmente dietético e envolve uma restrição severa no consumo de alimentos contendo aminoácido fenilalanina. Embora a alimentação seja complementada com fórmulas a fim de suprir as necessidades de vitaminas, minerais e aminoácidos essenciais, carências nutricionais ainda ocorrem. Isto se deve, principalmente, à restrição de fontes protéicas, que acarreta deficiência na ingestão de diversos nutrientes, dentre eles o cálcio. O cálcio possui importante relação com a formação mineral óssea. Estudos recentes demonstram que portadores de fenilcetonúria apresentam freqüentemente osteopenia e fraturas, sendo a maior incidência em crianças acima de 8 anos de idade. O rápido aumento da estatura, a dieta deficiente em cálcio e níveis de aminoácido fenilalanina elevados têm sido descritos como os principais fatores para a aquisição de massa óssea inadequada. A suplementação de cálcio em crianças saudáveis mostrou um efeito positivo sobre a aquisição de massa óssea na fase da pré-puberdade. Assim, torna-se relevante compreender a necessidade da suplementação de cálcio em pacientes fenilcetonúria, a fim de favorecer o desenvolvimento ósseo esperado.Phenylketonuria is an inborn error of the metabolism of the amino acid phenylalanine. The treatment is essentially dietetic and involves a severe restriction in the consumption of foods containing aminoacid phenylalanine. Although the diet is complemented with supplements in order to meet the vitamin, mineral and essential amino acid requirements, nutritional deficiencies still occur. This is mainly due to restricting the consumption of protein sources, which results in low intake of several nutrients, including calcium. Calcium is strongly related to bone mineral formation. Recent studies have demonstrated that patients with phenylketonuria often present osteopenia and

Learning from Errors

Science.gov (United States)

Metcalfe, Janet

2017-01-01

Although error avoidance during learning appears to be the rule in American classrooms, laboratory studies suggest that it may be a counterproductive strategy, at least for neurologically typical students. Experimental investigations indicate that errorful learning followed by corrective feedback is beneficial to learning. Interestingly, the…

Error-information in tutorial documentation: Supporting users' errors to facilitate initial skill learning

NARCIS (Netherlands)

Lazonder, Adrianus W.; van der Meij, Hans

1995-01-01

Novice users make many errors when they first try to learn how to work with a computer program like a spreadsheet or wordprocessor. No matter how user-friendly the software or the training manual, errors can and will occur. The current view on errors is that they can be helpful or disruptive,

Medication error detection in two major teaching hospitals: What are the types of errors?

Directory of Open Access Journals (Sweden)

Fatemeh Saghafi

2014-01-01

Full Text Available Background: Increasing number of reports on medication errors and relevant subsequent damages, especially in medical centers has become a growing concern for patient safety in recent decades. Patient safety and in particular, medication safety is a major concern and challenge for health care professionals around the world. Our prospective study was designed to detect prescribing, transcribing, dispensing, and administering medication errors in two major university hospitals. Materials and Methods: After choosing 20 similar hospital wards in two large teaching hospitals in the city of Isfahan, Iran, the sequence was randomly selected. Diagrams for drug distribution were drawn by the help of pharmacy directors. Direct observation technique was chosen as the method for detecting the errors. A total of 50 doses were studied in each ward to detect prescribing, transcribing and administering errors in each ward. The dispensing error was studied on 1000 doses dispensed in each hospital pharmacy. Results: A total of 8162 number of doses of medications were studied during the four stages, of which 8000 were complete data to be analyzed. 73% of prescribing orders were incomplete and did not have all six parameters (name, dosage form, dose and measuring unit, administration route, and intervals of administration. We found 15% transcribing errors. One-third of administration of medications on average was erroneous in both hospitals. Dispensing errors ranged between 1.4% and 2.2%. Conclusion: Although prescribing and administrating compromise most of the medication errors, improvements are needed in all four stages with regard to medication errors. Clear guidelines must be written and executed in both hospitals to reduce the incidence of medication errors.

Social aspects of clinical errors.

Science.gov (United States)

Richman, Joel; Mason, Tom; Mason-Whitehead, Elizabeth; McIntosh, Annette; Mercer, Dave

2009-08-01

Clinical errors, whether committed by doctors, nurses or other professions allied to healthcare, remain a sensitive issue requiring open debate and policy formulation in order to reduce them. The literature suggests that the issues underpinning errors made by healthcare professionals involve concerns about patient safety, professional disclosure, apology, litigation, compensation, processes of recording and policy development to enhance quality service. Anecdotally, we are aware of narratives of minor errors, which may well have been covered up and remain officially undisclosed whilst the major errors resulting in damage and death to patients alarm both professionals and public with resultant litigation and compensation. This paper attempts to unravel some of these issues by highlighting the historical nature of clinical errors and drawing parallels to contemporary times by outlining the 'compensation culture'. We then provide an overview of what constitutes a clinical error and review the healthcare professional strategies for managing such errors.

Passive quantum error correction of linear optics networks through error averaging

Science.gov (United States)

Marshman, Ryan J.; Lund, Austin P.; Rohde, Peter P.; Ralph, Timothy C.

2018-02-01

We propose and investigate a method of error detection and noise correction for bosonic linear networks using a method of unitary averaging. The proposed error averaging does not rely on ancillary photons or control and feedforward correction circuits, remaining entirely passive in its operation. We construct a general mathematical framework for this technique and then give a series of proof of principle examples including numerical analysis. Two methods for the construction of averaging are then compared to determine the most effective manner of implementation and probe the related error thresholds. Finally we discuss some of the potential uses of this scheme.

Apologies and Medical Error

Science.gov (United States)

2008-01-01

One way in which physicians can respond to a medical error is to apologize. Apologies—statements that acknowledge an error and its consequences, take responsibility, and communicate regret for having caused harm—can decrease blame, decrease anger, increase trust, and improve relationships. Importantly, apologies also have the potential to decrease the risk of a medical malpractice lawsuit and can help settle claims by patients. Patients indicate they want and expect explanations and apologies after medical errors and physicians indicate they want to apologize. However, in practice, physicians tend to provide minimal information to patients after medical errors and infrequently offer complete apologies. Although fears about potential litigation are the most commonly cited barrier to apologizing after medical error, the link between litigation risk and the practice of disclosure and apology is tenuous. Other barriers might include the culture of medicine and the inherent psychological difficulties in facing one’s mistakes and apologizing for them. Despite these barriers, incorporating apology into conversations between physicians and patients can address the needs of both parties and can play a role in the effective resolution of disputes related to medical error. PMID:18972177

Errors in Neonatology

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Antonio Boldrini

2013-06-01

Full Text Available Introduction: Danger and errors are inherent in human activities. In medical practice errors can lean to adverse events for patients. Mass media echo the whole scenario. Methods: We reviewed recent published papers in PubMed database to focus on the evidence and management of errors in medical practice in general and in Neonatology in particular. We compared the results of the literature with our specific experience in Nina Simulation Centre (Pisa, Italy. Results: In Neonatology the main error domains are: medication and total parenteral nutrition, resuscitation and respiratory care, invasive procedures, nosocomial infections, patient identification, diagnostics. Risk factors include patients’ size, prematurity, vulnerability and underlying disease conditions but also multidisciplinary teams, working conditions providing fatigue, a large variety of treatment and investigative modalities needed. Discussion and Conclusions: In our opinion, it is hardly possible to change the human beings but it is likely possible to change the conditions under they work. Voluntary errors report systems can help in preventing adverse events. Education and re-training by means of simulation can be an effective strategy too. In Pisa (Italy Nina (ceNtro di FormazIone e SimulazioNe NeonAtale is a simulation center that offers the possibility of a continuous retraining for technical and non-technical skills to optimize neonatological care strategies. Furthermore, we have been working on a novel skill trainer for mechanical ventilation (MEchatronic REspiratory System SImulator for Neonatal Applications, MERESSINA. Finally, in our opinion national health policy indirectly influences risk for errors. Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge research

Human errors and mistakes

International Nuclear Information System (INIS)

Wahlstroem, B.

1993-01-01

Human errors have a major contribution to the risks for industrial accidents. Accidents have provided important lesson making it possible to build safer systems. In avoiding human errors it is necessary to adapt the systems to their operators. The complexity of modern industrial systems is however increasing the danger of system accidents. Models of the human operator have been proposed, but the models are not able to give accurate predictions of human performance. Human errors can never be eliminated, but their frequency can be decreased by systematic efforts. The paper gives a brief summary of research in human error and it concludes with suggestions for further work. (orig.)

Error-related potentials during continuous feedback: using EEG to detect errors of different type and severity

Science.gov (United States)

Spüler, Martin; Niethammer, Christian

2015-01-01

When a person recognizes an error during a task, an error-related potential (ErrP) can be measured as response. It has been shown that ErrPs can be automatically detected in tasks with time-discrete feedback, which is widely applied in the field of Brain-Computer Interfaces (BCIs) for error correction or adaptation. However, there are only a few studies that concentrate on ErrPs during continuous feedback. With this study, we wanted to answer three different questions: (i) Can ErrPs be measured in electroencephalography (EEG) recordings during a task with continuous cursor control? (ii) Can ErrPs be classified using machine learning methods and is it possible to discriminate errors of different origins? (iii) Can we use EEG to detect the severity of an error? To answer these questions, we recorded EEG data from 10 subjects during a video game task and investigated two different types of error (execution error, due to inaccurate feedback; outcome error, due to not achieving the goal of an action). We analyzed the recorded data to show that during the same task, different kinds of error produce different ErrP waveforms and have a different spectral response. This allows us to detect and discriminate errors of different origin in an event-locked manner. By utilizing the error-related spectral response, we show that also a continuous, asynchronous detection of errors is possible. Although the detection of error severity based on EEG was one goal of this study, we did not find any significant influence of the severity on the EEG. PMID:25859204

Error-related potentials during continuous feedback: using EEG to detect errors of different type and severity

Directory of Open Access Journals (Sweden)

Martin eSpüler

2015-03-01

Full Text Available When a person recognizes an error during a task, an error-related potential (ErrP can be measured as response. It has been shown that ErrPs can be automatically detected in tasks with time-discrete feedback, which is widely applied in the field of Brain-Computer Interfaces (BCIs for error correction or adaptation. However, there are only a few studies that concentrate on ErrPs during continuous feedback.With this study, we wanted to answer three different questions: (i Can ErrPs be measured in electroencephalography (EEG recordings during a task with continuous cursor control? (ii Can ErrPs be classified using machine learning methods and is it possible to discriminate errors of different origins? (iii Can we use EEG to detect the severity of an error? To answer these questions, we recorded EEG data from 10 subjects during a video game task and investigated two different types of error (execution error, due to inaccurate feedback; outcome error, due to not achieving the goal of an action. We analyzed the recorded data to show that during the same task, different kinds of error produce different ErrP waveforms and have a different spectral response. This allows us to detect and discriminate errors of different origin in an event-locked manner. By utilizing the error-related spectral response, we show that also a continuous, asynchronous detection of errors is possible.Although the detection of error severity based on EEG was one goal of this study, we did not find any significant influence of the severity on the EEG.

Deductive Error Diagnosis and Inductive Error Generalization for Intelligent Tutoring Systems.

Science.gov (United States)

Hoppe, H. Ulrich

1994-01-01

Examines the deductive approach to error diagnosis for intelligent tutoring systems. Topics covered include the principles of the deductive approach to diagnosis; domain-specific heuristics to solve the problem of generalizing error patterns; and deductive diagnosis and the hypertext-based learning environment. (Contains 26 references.) (JLB)

VOLUMETRIC ERROR COMPENSATION IN FIVE-AXIS CNC MACHINING CENTER THROUGH KINEMATICS MODELING OF GEOMETRIC ERROR

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Pooyan Vahidi Pashsaki

2016-06-01

Full Text Available Accuracy of a five-axis CNC machine tool is affected by a vast number of error sources. This paper investigates volumetric error modeling and its compensation to the basis for creation of new tool path for improvement of work pieces accuracy. The volumetric error model of a five-axis machine tool with the configuration RTTTR (tilting head B-axis and rotary table in work piece side A΄ was set up taking into consideration rigid body kinematics and homogeneous transformation matrix, in which 43 error components are included. Volumetric error comprises 43 error components that can separately reduce geometrical and dimensional accuracy of work pieces. The machining accuracy of work piece is guaranteed due to the position of the cutting tool center point (TCP relative to the work piece. The cutting tool is deviated from its ideal position relative to the work piece and machining error is experienced. For compensation process detection of the present tool path and analysis of the RTTTR five-axis CNC machine tools geometrical error, translating current position of component to compensated positions using the Kinematics error model, converting newly created component to new tool paths using the compensation algorithms and finally editing old G-codes using G-code generator algorithm have been employed.

Non-stationary (13)C-metabolic flux ratio analysis.

Science.gov (United States)

Hörl, Manuel; Schnidder, Julian; Sauer, Uwe; Zamboni, Nicola

2013-12-01

(13)C-metabolic flux analysis ((13)C-MFA) has become a key method for metabolic engineering and systems biology. In the most common methodology, fluxes are calculated by global isotopomer balancing and iterative fitting to stationary (13)C-labeling data. This approach requires a closed carbon balance, long-lasting metabolic steady state, and the detection of (13)C-patterns in a large number of metabolites. These restrictions mostly reduced the application of (13)C-MFA to the central carbon metabolism of well-studied model organisms grown in minimal media with a single carbon source. Here we introduce non-stationary (13)C-metabolic flux ratio analysis as a novel method for (13)C-MFA to allow estimating local, relative fluxes from ultra-short (13)C-labeling experiments and without the need for global isotopomer balancing. The approach relies on the acquisition of non-stationary (13)C-labeling data exclusively for metabolites in the proximity of a node of converging fluxes and a local parameter estimation with a system of ordinary differential equations. We developed a generalized workflow that takes into account reaction types and the availability of mass spectrometric data on molecular ions or fragments for data processing, modeling, parameter and error estimation. We demonstrated the approach by analyzing three key nodes of converging fluxes in central metabolism of Bacillus subtilis. We obtained flux estimates that are in agreement with published results obtained from steady state experiments, but reduced the duration of the necessary (13)C-labeling experiment to less than a minute. These results show that our strategy enables to formally estimate relative pathway fluxes on extremely short time scale, neglecting cellular carbon balancing. Hence this approach paves the road to targeted (13)C-MFA in dynamic systems with multiple carbon sources and towards rich media. © 2013 Wiley Periodicals, Inc.

Errorful and errorless learning: The impact of cue-target constraint in learning from errors.

Science.gov (United States)

Bridger, Emma K; Mecklinger, Axel

2014-08-01

The benefits of testing on learning are well described, and attention has recently turned to what happens when errors are elicited during learning: Is testing nonetheless beneficial, or can errors hinder learning? Whilst recent findings have indicated that tests boost learning even if errors are made on every trial, other reports, emphasizing the benefits of errorless learning, have indicated that errors lead to poorer later memory performance. The possibility that this discrepancy is a function of the materials that must be learned-in particular, the relationship between the cues and targets-was addressed here. Cued recall after either a study-only errorless condition or an errorful learning condition was contrasted across cue-target associations, for which the extent to which the target was constrained by the cue was either high or low. Experiment 1 showed that whereas errorful learning led to greater recall for low-constraint stimuli, it led to a significant decrease in recall for high-constraint stimuli. This interaction is thought to reflect the extent to which retrieval is constrained by the cue-target association, as well as by the presence of preexisting semantic associations. The advantage of errorful retrieval for low-constraint stimuli was replicated in Experiment 2, and the interaction with stimulus type was replicated in Experiment 3, even when guesses were randomly designated as being either correct or incorrect. This pattern provides support for inferences derived from reports in which participants made errors on all learning trials, whilst highlighting the impact of material characteristics on the benefits and disadvantages that accrue from errorful learning in episodic memory.

Decoding of DBEC-TBED Reed-Solomon codes. [Double-Byte-Error-Correcting, Triple-Byte-Error-Detecting

Science.gov (United States)

Deng, Robert H.; Costello, Daniel J., Jr.

1987-01-01

A problem in designing semiconductor memories is to provide some measure of error control without requiring excessive coding overhead or decoding time. In LSI and VLSI technology, memories are often organized on a multiple bit (or byte) per chip basis. For example, some 256 K bit DRAM's are organized in 32 K x 8 bit-bytes. Byte-oriented codes such as Reed-Solomon (RS) codes can provide efficient low overhead error control for such memories. However, the standard iterative algorithm for decoding RS codes is too slow for these applications. The paper presents a special decoding technique for double-byte-error-correcting, triple-byte-error-detecting RS codes which is capable of high-speed operation. This technique is designed to find the error locations and the error values directly from the syndrome without having to use the iterative algorithm to find the error locator polynomial.

High cortisol awakening response is associated with impaired error monitoring and decreased post-error adjustment.

Science.gov (United States)

Zhang, Liang; Duan, Hongxia; Qin, Shaozheng; Yuan, Yiran; Buchanan, Tony W; Zhang, Kan; Wu, Jianhui

2015-01-01

The cortisol awakening response (CAR), a rapid increase in cortisol levels following morning awakening, is an important aspect of hypothalamic-pituitary-adrenocortical axis activity. Alterations in the CAR have been linked to a variety of mental disorders and cognitive function. However, little is known regarding the relationship between the CAR and error processing, a phenomenon that is vital for cognitive control and behavioral adaptation. Using high-temporal resolution measures of event-related potentials (ERPs) combined with behavioral assessment of error processing, we investigated whether and how the CAR is associated with two key components of error processing: error detection and subsequent behavioral adjustment. Sixty university students performed a Go/No-go task while their ERPs were recorded. Saliva samples were collected at 0, 15, 30 and 60 min after awakening on the two consecutive days following ERP data collection. The results showed that a higher CAR was associated with slowed latency of the error-related negativity (ERN) and a higher post-error miss rate. The CAR was not associated with other behavioral measures such as the false alarm rate and the post-correct miss rate. These findings suggest that high CAR is a biological factor linked to impairments of multiple steps of error processing in healthy populations, specifically, the automatic detection of error and post-error behavioral adjustment. A common underlying neural mechanism of physiological and cognitive control may be crucial for engaging in both CAR and error processing.

Learning from Errors

Directory of Open Access Journals (Sweden)

MA. Lendita Kryeziu

2015-06-01

Full Text Available “Errare humanum est”, a well known and widespread Latin proverb which states that: to err is human, and that people make mistakes all the time. However, what counts is that people must learn from mistakes. On these grounds Steve Jobs stated: “Sometimes when you innovate, you make mistakes. It is best to admit them quickly, and get on with improving your other innovations.” Similarly, in learning new language, learners make mistakes, thus it is important to accept them, learn from them, discover the reason why they make them, improve and move on. The significance of studying errors is described by Corder as: “There have always been two justifications proposed for the study of learners' errors: the pedagogical justification, namely that a good understanding of the nature of error is necessary before a systematic means of eradicating them could be found, and the theoretical justification, which claims that a study of learners' errors is part of the systematic study of the learners' language which is itself necessary to an understanding of the process of second language acquisition” (Corder, 1982; 1. Thus the importance and the aim of this paper is analyzing errors in the process of second language acquisition and the way we teachers can benefit from mistakes to help students improve themselves while giving the proper feedback.

[3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome].

Science.gov (United States)

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.

Severe hypertriglyceridemia-related acute pancreatitis.

Science.gov (United States)

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.

The Bloodgen Project of the European Union, 2003-2009.

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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

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.

Diagnosis of Smith-Lemli-Opitz syndrome by ultraviolet spectrophotometry

Directory of Open Access Journals (Sweden)

F.B. Scalco

2003-10-01

Full Text Available Smith-Lemli-Opitz syndrome (SLOS is an autosomal recessive disorder due to an inborn error of cholesterol metabolism, characterized by congenital malformations, dysmorphism of multiple organs, mental retardation and delayed neuropsychomotor development resulting from cholesterol biosynthesis deficiency. A defect in 3ß-hydroxysteroid-delta7-reductase (delta7-sterol-reductase, responsible for the conversion of 7-dehydrocholesterol (7-DHC to cholesterol, causes an increase in 7-DHC and frequently reduces plasma cholesterol levels. The clinical diagnosis of SLOS cannot always be conclusive because of the remarkable variability of clinical expression of the disorder. Thus, confirmation by the measurement of plasma 7-DHC levels is needed. In the present study, we used a simple, fast, and selective method based on ultraviolet spectrophotometry to measure 7-DHC in order to diagnose SLOS. 7-DHC was extracted serially from 200 µl plasma with ethanol and n-hexane and the absorbance at 234 and 282 nm was determined. The method was applied to negative control plasma samples from 23 normal individuals and from 6 cases of suspected SLOS. The method was adequate and reliable and 2 SLOS cases were diagnosed.

Histopathological effects on the eye development during perinatal growth of albino rats maternally treated with experimental phenylketonuria during pregnancy

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Hany A. Hefty

2016-04-01

Full Text Available Phenylketonuria (PKU is a genetic disorder that is characterized by an inability of the body to utilize the essential amino acid, phenylalanine. The disease results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine to tyrosine. Although, this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known about the mechanisms involved in the pathology of PKU during neonatal brain development. Elevated concentrations of plasma phenylalanine were induced in pregnant rats by oral administration of 50mg/100g body weight alpha-methylphenylalanine plus phenylalanine supplementation at a dosage of 60mg/100g body weight two times daily after 6th day of onset of gestation till 14 & 16 days prenatal as well as at parturition. Treatment with alpha-methylphenylalanine resulted in significant reduction of retinal cell layers of prenatal fetuses and delivered newborns.   Histological abnormalities were detected manifested by either hyaline degeneration of lens structure or inducing lens cataract as well as comparative atrophy of retina associated with the development of malignant polypoid mass in the ganglionic cell layers in contact with the lens.

A fatal case of hypernatraemic dehydration in a neonate.

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Staub, Eveline; Wilkins, Barry

2012-09-01

Problems with lactation can result in hypernatraemic dehydration in the neonate, with potentially severe adverse consequences. This is illustrated in this fatal case of a 10 day old neonate who presented with excessive hypernatraemic dehydration due to insufficient breast milk intake, resulting in cerebral sinus vein thrombosis with cerebral haemorrhage and infarction. Differential diagnosis included excessive sodium intake (through inappropriately mixed formula or house remedies or through hyperaldosteronism) and high water deficit (renal or gastrointestinal losses, nephrogenic or central diabetes insipidus), all of which were ruled out by specific investigations or history. No evidence was found for inborn error of metabolism. The dehydration in this baby, however, was accentuated by trans-epidermal water loss due to an ichthyosiform skin condition. This first ever reported Australian fatality from neonatal hypernatraemic dehydration supports the concern of health care professionals over rising incidences of this entity in exclusively breastfed infants, and should encourage endorsement of improved monitoring of weight loss in newborns and breastfeeding support for their mothers. © 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

First report of HGD mutations in a Chinese with alkaptonuria.

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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.

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

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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.

High Phenobarbital Clearance During Continuous Renal Replacement Therapy

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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

Fatal Hyperammonemic Brain Injury from Valproic Acid Exposure

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Danny Bega

2012-12-01

Full Text Available Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. Case: A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 µmol/l. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate. Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure.

Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.

Science.gov (United States)

Brunetti, Dario; Dusi, Sabrina; Morbin, Michela; Uggetti, Andrea; Moda, Fabio; D'Amato, Ilaria; Giordano, Carla; d'Amati, Giulia; Cozzi, Anna; Levi, Sonia; Hayflick, Susan; Tiranti, Valeria

2012-12-15

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration.

Disease: H00363 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available nantly with Candida albicans. Invasive candidiasis is a major cause of morbidity and mortality in the intens...or persistent infections are observed (chronic mucocutaneous candidiasis disease). Infectious disease IL17RA...gal resistance in invasive candidiasis. ... JOURNAL ... Eur J Med Res 16:187-95 (2011) DOI:10.1186/2047-783X-16-... JL ... TITLE ... Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. ... JOURNAL ... Science 332:65-8 (2011) DOI:10.1126/science.1200439 ...

Putting into practice error management theory: Unlearning and learning to manage action errors in construction.

Science.gov (United States)

Love, Peter E D; Smith, Jim; Teo, Pauline

2018-05-01

Error management theory is drawn upon to examine how a project-based organization, which took the form of a program alliance, was able to change its established error prevention mindset to one that enacted a learning mindfulness that provided an avenue to curtail its action errors. The program alliance was required to unlearn its existing routines and beliefs to accommodate the practices required to embrace error management. As a result of establishing an error management culture the program alliance was able to create a collective mindfulness that nurtured learning and supported innovation. The findings provide a much-needed context to demonstrate the relevance of error management theory to effectively address rework and safety problems in construction projects. The robust theoretical underpinning that is grounded in practice and presented in this paper provides a mechanism to engender learning from errors, which can be utilized by construction organizations to improve the productivity and performance of their projects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Rounding errors in weighing

International Nuclear Information System (INIS)

Jeach, J.L.

1976-01-01

When rounding error is large relative to weighing error, it cannot be ignored when estimating scale precision and bias from calibration data. Further, if the data grouping is coarse, rounding error is correlated with weighing error and may also have a mean quite different from zero. These facts are taken into account in a moment estimation method. A copy of the program listing for the MERDA program that provides moment estimates is available from the author. Experience suggests that if the data fall into four or more cells or groups, it is not necessary to apply the moment estimation method. Rather, the estimate given by equation (3) is valid in this instance. 5 tables

Error-finding and error-correcting methods for the start-up of the SLC

International Nuclear Information System (INIS)

Lee, M.J.; Clearwater, S.H.; Kleban, S.D.; Selig, L.J.

1987-02-01

During the commissioning of an accelerator, storage ring, or beam transfer line, one of the important tasks of an accelertor physicist is to check the first-order optics of the beam line and to look for errors in the system. Conceptually, it is important to distinguish between techniques for finding the machine errors that are the cause of the problem and techniques for correcting the beam errors that are the result of the machine errors. In this paper we will limit our presentation to certain applications of these two methods for finding or correcting beam-focus errors and beam-kick errors that affect the profile and trajectory of the beam respectively. Many of these methods have been used successfully in the commissioning of SLC systems. In order not to waste expensive beam time we have developed and used a beam-line simulator to test the ideas that have not been tested experimentally. To save valuable physicist's time we have further automated the beam-kick error-finding procedures by adopting methods from the field of artificial intelligence to develop a prototype expert system. Our experience with this prototype has demonstrated the usefulness of expert systems in solving accelerator control problems. The expert system is able to find the same solutions as an expert physicist but in a more systematic fashion. The methods used in these procedures and some of the recent applications will be described in this paper

Barriers to medical error reporting

Directory of Open Access Journals (Sweden)

Jalal Poorolajal

2015-01-01

Full Text Available Background: This study was conducted to explore the prevalence of medical error underreporting and associated barriers. Methods: This cross-sectional study was performed from September to December 2012. Five hospitals, affiliated with Hamadan University of Medical Sciences, in Hamedan,Iran were investigated. A self-administered questionnaire was used for data collection. Participants consisted of physicians, nurses, midwives, residents, interns, and staffs of radiology and laboratory departments. Results: Overall, 50.26% of subjects had committed but not reported medical errors. The main reasons mentioned for underreporting were lack of effective medical error reporting system (60.0%, lack of proper reporting form (51.8%, lack of peer supporting a person who has committed an error (56.0%, and lack of personal attention to the importance of medical errors (62.9%. The rate of committing medical errors was higher in men (71.4%, age of 50-40 years (67.6%, less-experienced personnel (58.7%, educational level of MSc (87.5%, and staff of radiology department (88.9%. Conclusions: This study outlined the main barriers to reporting medical errors and associated factors that may be helpful for healthcare organizations in improving medical error reporting as an essential component for patient safety enhancement.

Reward positivity: Reward prediction error or salience prediction error?

Science.gov (United States)

Heydari, Sepideh; Holroyd, Clay B

2016-08-01

The reward positivity is a component of the human ERP elicited by feedback stimuli in trial-and-error learning and guessing tasks. A prominent theory holds that the reward positivity reflects a reward prediction error signal that is sensitive to outcome valence, being larger for unexpected positive events relative to unexpected negative events (Holroyd & Coles, 2002). Although the theory has found substantial empirical support, most of these studies have utilized either monetary or performance feedback to test the hypothesis. However, in apparent contradiction to the theory, a recent study found that unexpected physical punishments also elicit the reward positivity (Talmi, Atkinson, & El-Deredy, 2013). The authors of this report argued that the reward positivity reflects a salience prediction error rather than a reward prediction error. To investigate this finding further, in the present study participants navigated a virtual T maze and received feedback on each trial under two conditions. In a reward condition, the feedback indicated that they would either receive a monetary reward or not and in a punishment condition the feedback indicated that they would receive a small shock or not. We found that the feedback stimuli elicited a typical reward positivity in the reward condition and an apparently delayed reward positivity in the punishment condition. Importantly, this signal was more positive to the stimuli that predicted the omission of a possible punishment relative to stimuli that predicted a forthcoming punishment, which is inconsistent with the salience hypothesis. © 2016 Society for Psychophysiological Research.

Learning from errors in super-resolution.

Science.gov (United States)

Tang, Yi; Yuan, Yuan

2014-11-01

A novel framework of learning-based super-resolution is proposed by employing the process of learning from the estimation errors. The estimation errors generated by different learning-based super-resolution algorithms are statistically shown to be sparse and uncertain. The sparsity of the estimation errors means most of estimation errors are small enough. The uncertainty of the estimation errors means the location of the pixel with larger estimation error is random. Noticing the prior information about the estimation errors, a nonlinear boosting process of learning from these estimation errors is introduced into the general framework of the learning-based super-resolution. Within the novel framework of super-resolution, a low-rank decomposition technique is used to share the information of different super-resolution estimations and to remove the sparse estimation errors from different learning algorithms or training samples. The experimental results show the effectiveness and the efficiency of the proposed framework in enhancing the performance of different learning-based algorithms.

Error management process for power stations

International Nuclear Information System (INIS)

Hirotsu, Yuko; Takeda, Daisuke; Fujimoto, Junzo; Nagasaka, Akihiko

2016-01-01

The purpose of this study is to establish 'error management process for power stations' for systematizing activities for human error prevention and for festering continuous improvement of these activities. The following are proposed by deriving concepts concerning error management process from existing knowledge and realizing them through application and evaluation of their effectiveness at a power station: an entire picture of error management process that facilitate four functions requisite for maraging human error prevention effectively (1. systematizing human error prevention tools, 2. identifying problems based on incident reports and taking corrective actions, 3. identifying good practices and potential problems for taking proactive measures, 4. prioritizeng human error prevention tools based on identified problems); detail steps for each activity (i.e. developing an annual plan for human error prevention, reporting and analyzing incidents and near misses) based on a model of human error causation; procedures and example of items for identifying gaps between current and desired levels of executions and outputs of each activity; stages for introducing and establishing the above proposed error management process into a power station. By giving shape to above proposals at a power station, systematization and continuous improvement of activities for human error prevention in line with the actual situation of the power station can be expected. (author)

Error detecting capabilities of the shortened Hamming codes adopted for error detection in IEEE Standard 802.3

Science.gov (United States)

Fujiwara, Toru; Kasami, Tadao; Lin, Shu

1989-09-01

The error-detecting capabilities of the shortened Hamming codes adopted for error detection in IEEE Standard 802.3 are investigated. These codes are also used for error detection in the data link layer of the Ethernet, a local area network. The weight distributions for various code lengths are calculated to obtain the probability of undetectable error and that of detectable error for a binary symmetric channel with bit-error rate between 0.00001 and 1/2.

From mind to mouth: event related potentials of sentence production in classic galactosemia.