147 results on '"Walter JH"'
Search Results
2. Impact of age at onset and newborn screening on outcome in organic acidurias
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Heringer, J, Valayannopoulos, V, Lund, AM, Wijburg, FA, Freisinger, P, Baric, I, Baumgartner, MR, Burgard, P, Burlina, AB, Chapman, K A, Saladelafont, ECI, Karall, D, Muhlhausen, C, Riches, V, Schiff, M, Sykut-Cegielska, J, Walter, JH, Zeman, J, Williams, Monique, Chabrol, B, Kolker, S, Pediatrics, Paediatric Metabolic Diseases, Reproduction and Genetics, Neurogenetics, and Clinical sciences more...
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0301 basic medicine ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Methylmalonic acid ,Late onset ,Glutaric aciduria type 1 ,030105 genetics & heredity ,Asymptomatic ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Neonatal Screening ,Metabolic Diseases ,Intellectual Disability ,Genetics ,Journal Article ,Medicine ,Humans ,Young adult ,Age of Onset ,Child ,Amino Acid Metabolism, Inborn Errors ,Genetics (clinical) ,Newborn screening ,Glutaryl-CoA Dehydrogenase ,business.industry ,Brain Diseases, Metabolic ,Infant, Newborn ,Brain Diseases, Metabolic, Inborn ,Infant ,food and beverages ,Odds ratio ,Middle Aged ,medicine.disease ,Vitamin B 12 ,chemistry ,Child, Preschool ,Female ,Amino Acid Transport Disorders, Inborn ,Age of onset ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Methylmalonic Acid - Abstract
BACKGROUND AND AIM: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. METHODS: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). RESULTS: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p more...
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- 2016
Catalog
3. Pyruvate dehydrogenase E3 binding protein (protein X) deficiency
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Brown, RM, primary, Head, RA, additional, Morris, AAM, additional, Raiman, JAJ, additional, Walter, JH, additional, Whitehouse, WP, additional, and Brown, GK, additional
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- 2006
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4. Pyruvate dehydrogenase deficiency presenting as dystonia in childhood
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Head, RA, primary, de Goede, CGEL, additional, Newton, RWN, additional, Walter, JH, additional, McShane, MA, additional, Brown, RM, additional, and Brown, GK, additional
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- 2004
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5. Feeding infants with undiluted goat's milk can mimic tyrosinaemia type 1
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Hendriksz, CJ, primary and Walter, JH, additional
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- 2004
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6. Development of Nanobodies Against Hemorrhagic and Myotoxic Components of Bothrops atrox Snake Venom
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Henri Bailon Calderon, Verónica Olga Yaniro Coronel, Omar Alberto Cáceres Rey, Elizabeth Gaby Colque Alave, Walter Jhon Leiva Duran, Carlos Padilla Rojas, Harrison Montejo Arevalo, David García Neyra, Marco Galarza Pérez, César Bonilla, Benigno Tintaya, Giulia Ricciardi, Natalia Smiejkowska, Ema Romão, Cécile Vincke, Juan Lévano, Mary Celys, Bruno Lomonte, and Serge Muyldermans more...
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nanobodies ,snake ,venom ,myotoxic ,hemorrhagic ,neutralization ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Snake envenoming is a globally neglected public health problem. Antivenoms produced using animal hyperimmune plasma remain the standard therapy for snakebites. Although effective against systemic effects, conventional antivenoms have limited efficacy against local tissue damage. In addition, potential hypersensitivity reactions, high costs for animal maintenance, and difficulties in obtaining batch-to-batch homogeneity are some of the factors that have motivated the search for innovative and improved therapeutic products against such envenoming. In this study, we have developed a set of nanobodies (recombinant single-domain antigen-binding fragments from camelid heavy chain-only antibodies) against Bothrops atrox snake venom hemorrhagic and myotoxic components. An immune library was constructed after immunizing a Lama glama with whole venom of B. atrox, from which nanobodies were selected by phage display using partially purified hemorrhagic and myotoxic proteins. Biopanning selections retrieved 18 and eight different nanobodies against the hemorrhagic and the myotoxic proteins, respectively. In vivo assays in mice showed that five nanobodies inhibited the hemorrhagic activity of the proteins; three neutralized the hemorrhagic activity of whole B. atrox venom, while four nanobodies inhibited the myotoxic protein. A mixture of the anti-hemorrhagic and anti-myotoxic nanobodies neutralized the local tissue hemorrhage and myonecrosis induced by the whole venom, although the nanobody mixture failed to prevent the venom lethality. Nevertheless, our results demonstrate the efficacy and usefulness of these nanobodies to neutralize important pathologies of the venom, highlighting their potential as innovative therapeutic agents against envenoming by B. atrox, a viperid species causing many casualties in South America. more...
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- 2020
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7. Pediatric aneurysmal bone cyst of the distal tibia
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Goss, LR, primary and Walter, JH, primary
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- 1997
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8. Two “new” treatable inherited biosynthetic disorders
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Walter, JH, primary
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- 1996
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9. Pigmented villonodular synovitis. Pedal manifestations
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Walter, JH, primary, Galitz, J, primary, and Robertson, DW, primary
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- 1994
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10. Myxoid chondrosarcoma-induced pathologic fracture
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Walter, JH, primary, Peacock, D, primary, and Powell, A, primary
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- 1994
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11. External fixation in hallux abducto valgus surgery
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Walter Jh and Duke Hf
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medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,General Medicine ,biology.organism_classification ,Metatarsus ,Orthopedic Fixation Devices ,Osteotomy ,Surgery ,Radiography ,Valgus ,External fixation ,medicine ,Humans ,Hallux Valgus ,business - Published
- 1982
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12. External fixation in the treatment of metatarsal nonunions
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Walter Jh and Pressman Mm
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Adult ,Orthodontics ,External fixation ,Postoperative Complications ,business.industry ,medicine.medical_treatment ,Humans ,Medicine ,Female ,General Medicine ,business ,Metatarsus ,Orthopedic Fixation Devices - Published
- 1981
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13. External fixation in hallux abducto valgus surgery
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Duke, HF, primary and Walter, JH, primary
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- 1982
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14. Digital blood perfusion following injections of plain lidocaine and lidocaine with epinephrine
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Scarlet, JJ, primary, Walter, JH, primary, and Bachmann, RJ, primary
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- 1978
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15. Osteogenesis imperfecta
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Caputo, PJ, primary and Walter, JH, primary
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- 1983
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16. Randomised controlled trial of L-carnitine as a nutritional supplement in preterm infants.
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Shortland GJ, Walter JH, Stroud C, Fleming PJ, Speidel BD, Marlow N, Shortland, G J, Walter, J H, Stroud, C, Fleming, P J, Speidel, B D, and Marlow, N
- Abstract
Aims: To evaluate the effect of L-carnitine supplementation (25 mg/kg/d) on the growth and incidence of hypoglycaemia in preterm infants.Methods: A double blind, placebo controlled randomised trial, stratified for gestational age, was conducted of 86 preterm infants between 28 and 34 gestational weeks. The median gestational ages in the carnitine group and placebo groups were 30.7 weeks (range 28.0 to 33.6) and 31.4 weeks (range 28.0 to 33.9), respectively. The median birthweights were 1.557 kg (range 0.944 to 2.275) and 1.645 kg (range 0.885 to 2.545), respectively.Results: Mean plasma free carnitine concentrations were below values for normal term infants in both groups on day 1 (carnitine group 44.8 mumol/l, placebo group 25.5 mumol/l) in the placebo group on day 7 (50.7 mumol/l), but in neither group on days 14 and 28. Total, free, and acylcarnitine concentrations were significantly increased in both urine and blood in the L-carnitine group. There was no significant difference between the placebo and carnitine supplemented groups in growth rate, as assessed by weight, length, skinfold thickness and head circumference measurements, or in the incidence of episodes of hypoglycaemia.Conclusion: The addition of carnitine as a nutritional supplement at a dose of 25 mg/kg/day did not improve growth in our group of preterm infants nor protect them from episodes of hypoglycaemia. [ABSTRACT FROM AUTHOR] more...- Published
- 1998
17. Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes.
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Vidali S, Gerlini R, Thompson K, Urquhart JE, Meisterknecht J, Aguilar-Pimentel JA, Amarie OV, Becker L, Breen C, Calzada-Wack J, Chhabra NF, Cho YL, da Silva-Buttkus P, Feichtinger RG, Gampe K, Garrett L, Hoefig KP, Hölter SM, Jameson E, Klein-Rodewald T, Leuchtenberger S, Marschall S, Mayer-Kuckuk P, Miller G, Oestereicher MA, Pfannes K, Rathkolb B, Rozman J, Sanders C, Spielmann N, Stoeger C, Szibor M, Treise I, Walter JH, Wurst W, Mayr JA, Fuchs H, Gärtner U, Wittig I, Taylor RW, Newman WG, Prokisch H, Gailus-Durner V, and Hrabě de Angelis M more...
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- Animals, Electron Transport Complex III, Exons, Homozygote, Humans, Mice, Phenotype, Sequence Deletion, Mitochondrial Diseases genetics
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Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh
-/- ), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh-/- mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL ), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh-/- mouse is a valuable model for future studies of human CIII deficiency., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.) more...- Published
- 2021
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18. Correction to: Impact of age at onset and newborn screening on outcome in organic acidurias.
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Heringer J, Valayannopoulos V, Lund AM, Wijburg FA, Freisinger P, Barić I, Baumgartner MR, Burgard P, Burlina AB, Chapman KA, I Saladelafont EC, Karall D, Mühlhausen C, Riches V, Schiff M, Sykut-Cegielska J, Walter JH, Zeman J, Chabrol B, and Kölker S more...
- Abstract
Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.
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- 2018
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19. Correction to: Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.
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Posset R, Garcia-Cazorla A, Valayannopoulos V, Leão Teles E, Dionisi-Vici C, Brassier A, Burlina AB, Burgard P, Cortès-Saladelafont E, Dobbelaere D, Couce ML, Sykut-Cegielska J, Häberle J, Lund AM, Chakrapani A, Schiff M, Walter JH, Zeman J, Vara R, and Kölker S more...
- Abstract
Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.
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- 2018
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20. Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing.
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Ghosh A, Schlecht H, Heptinstall LE, Bassett JK, Cartwright E, Bhaskar SS, Urquhart J, Broomfield A, Morris AA, Jameson E, Schwahn BC, Walter JH, Douzgou S, Murphy H, Hendriksz C, Sharma R, Wilcox G, Crushell E, Monavari AA, Martin R, Doolan A, Senniappan S, Ramsden SC, Jones SA, and Banka S more...
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- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Metabolism, Inborn Errors genetics, Young Adult, High-Throughput Nucleotide Sequencing methods, Metabolism, Inborn Errors diagnosis
- Abstract
Background: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches., Methods: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs., Results: In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0.0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0.0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that the use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause., Conclusion: NGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis., Competing Interests: Competing interests: Arunabha Ghosh reports travel grants from Shire Plc, Biomarin Pharmaceutical, outside the submitted work. Alexander Broomfield reports consulting fees from Genzyme, Synageva, outside the submitted work. Christian Hendriksz is director of FYMCA Ltd and reports consulting fees and travel grants from Actelion, Alexion, Amicus, Biomarin, Inventiva, Sanofi Genzyme and Shire and research grants from Actelion, Amicus, Biomarin, Sanofi Genzyme and Shire, outside the submitted work. Gisela Wilcox reports travel grants from Biomarin, Genzyme, Shire, Vitaflo and Actelion, outside the submitted work. Simon Jones reports travel grants, research grants and consultancy fees from Genzyme, Shire, Biomarin, Ultragenyx, Alexion, and PTC, outside the submitted work. Helene Schlecht, Lesley Heptinstall, John Bassett, Eleanor Cartwright, Sanjeev Bhaskar, Jill Urquhart, Andrew Morris, Elisabeth Jameson, Bernd Schwahn, John Walter, Sofia Douzgou, Helen Murphy, Reena Sharma, Ellen Crushell, Ardeshir Monavari, Richard Martin, Anne Doolan, Senthil Senniappan, Simon Ramsden and Siddharth Banka have nothing to disclose., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.) more...
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- 2017
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21. The complete European guidelines on phenylketonuria: diagnosis and treatment.
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van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, and van Spronsen FJ more...
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- Europe, Humans, Phenylketonurias diagnosis, Phenylketonurias therapy, Practice Guidelines as Topic
- Abstract
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future. more...
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- 2017
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22. Key European guidelines for the diagnosis and management of patients with phenylketonuria.
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van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefz FK, van Rijn M, Walter JH, and MacDonald A more...
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- Biopterins administration & dosage, Biopterins analogs & derivatives, Delphi Technique, Disease Management, Europe, Humans, Phenylalanine blood, Phenylketonurias blood, Phenylketonurias diagnosis, Phenylketonurias diet therapy
- Abstract
We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 μmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 μmol/L and 600 μmol/L, and lifelong treatment is recommended if the concentration is more than 600 μmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 μmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 μmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 μmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.) more...
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- 2017
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23. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.
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Posset R, Garcia-Cazorla A, Valayannopoulos V, Teles EL, Dionisi-Vici C, Brassier A, Burlina AB, Burgard P, Cortès-Saladelafont E, Dobbelaere D, Couce ML, Sykut-Cegielska J, Häberle J, Lund AM, Chakrapani A, Schiff M, Walter JH, Zeman J, Vara R, and Kölker S more...
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- Adolescent, Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors metabolism, Argininosuccinate Synthase metabolism, Child, Citrullinemia diagnosis, Citrullinemia metabolism, Female, Humans, Hyperammonemia diagnosis, Hyperammonemia metabolism, Infant, Newborn, Late Onset Disorders diagnosis, Late Onset Disorders metabolism, Male, Neonatal Screening methods, Prospective Studies, Urea metabolism, Ammonium Compounds metabolism, Nervous System Diseases diagnosis, Nervous System Diseases metabolism, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn metabolism
- Abstract
Background: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation., Aims: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome., Methods: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry., Results: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome., Conclusions: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment. more...
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- 2016
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24. Impact of age at onset and newborn screening on outcome in organic acidurias.
- Author
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Heringer J, Valayannopoulos V, Lund AM, Wijburg FA, Freisinger P, Barić I, Baumgartner MR, Burgard P, Burlina AB, Chapman KA, I Saladelafont EC, Karall D, Mühlhausen C, Riches V, Schiff M, Sykut-Cegielska J, Walter JH, Zeman J, Chabrol B, and Kölker S more...
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- Adolescent, Adult, Age of Onset, Amino Acid Metabolism, Inborn Errors metabolism, Amino Acid Transport Disorders, Inborn metabolism, Brain Diseases, Metabolic metabolism, Brain Diseases, Metabolic, Inborn metabolism, Child, Child, Preschool, Female, Glutaryl-CoA Dehydrogenase metabolism, Humans, Infant, Infant, Newborn, Intellectual Disability metabolism, Intellectual Disability pathology, Male, Metabolic Diseases metabolism, Methylmalonic Acid metabolism, Middle Aged, Neonatal Screening methods, Vitamin B 12 metabolism, Young Adult, Amino Acid Metabolism, Inborn Errors pathology, Amino Acid Transport Disorders, Inborn pathology, Brain Diseases, Metabolic pathology, Brain Diseases, Metabolic, Inborn pathology, Glutaryl-CoA Dehydrogenase deficiency, Metabolic Diseases pathology
- Abstract
Background and Aim: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation., Methods: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO)., Results: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl(-)) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl(-): 10 % versus 39 %, p = 0.002; GA1: 26 % versus 73 %, p < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl(-) to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used., Conclusions: NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl(-). Huge diversity of therapeutic interventions hampers our understanding of optimal treatment. more...
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- 2016
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25. Erratum to: Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency.
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Knowles L, Morris AA, and Walter JH
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- 2016
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26. Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency.
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Knowles L, Morris AA, and Walter JH
- Abstract
S-adenosyl methionine, which is formed from methionine, is an essential methyl donor within the central nervous system. Methionine is formed by the enzyme methionine synthase for which 5-methyltetrahydrofolate (5-MTHF) and homocysteine are substrates. Patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency cannot make 5-MTHF and have extremely low levels in the CSF. As a consequence, methylation reactions in the CNS are compromised, and this is likely to play an important role in the neurological abnormalities that occur in MTHFR deficiency. Although treatment with oral betaine can remethylate homocysteine to methionine in the liver, betaine crosses the blood-brain barrier poorly, and CSF levels of methionine remain low. We report three patients with severe MTHFR deficiency (enzyme activity ≤1% of controls) who had undetectable levels of CSF 5-MTHF at diagnosis and while on treatment with either folic acid or calcium folinate. Only treatment with oral 5-MTHF given as calcium mefolinate at doses of 15-60 mg/kg/day resulted in an increase in CSF 5-MTHF. more...
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- 2016
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27. Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation.
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Kölker S, Cazorla AG, Valayannopoulos V, Lund AM, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Augoustides-Savvopoulou P, Aksglaede L, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Chabrol B, Chakrapani A, Chapman K, I Saladelafont EC, Couce ML, de Meirleir L, Dobbelaere D, Dvorakova V, Furlan F, Gleich F, Gradowska W, Grünewald S, Jalan A, Häberle J, Haege G, Lachmann R, Laemmle A, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, de Baulny HO, Ortez C, Peña-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Staufner C, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, and Burgard P more...
- Published
- 2015
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28. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation.
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Kölker S, Garcia-Cazorla A, Valayannopoulos V, Lund AM, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Augoustides-Savvopoulou P, Aksglaede L, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Chabrol B, Chakrapani A, Chapman K, I Saladelafont EC, Couce ML, de Meirleir L, Dobbelaere D, Dvorakova V, Furlan F, Gleich F, Gradowska W, Grünewald S, Jalan A, Häberle J, Haege G, Lachmann R, Laemmle A, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, de Baulny HO, Ortez C, Peña-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Staufner C, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, and Burgard P more...
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- Adolescent, Adult, Aged, Child, Child, Preschool, Europe, Female, Humans, Infant, Infant, Newborn, Intellectual Disability, Male, Middle Aged, Registries, Vomiting, Young Adult, Amino Acid Metabolism, Inborn Errors diagnosis, Brain Diseases, Metabolic diagnosis, Glutaryl-CoA Dehydrogenase deficiency, Hyperammonemia diagnosis, Ornithine Carbamoyltransferase Deficiency Disease diagnosis, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Background: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific., Aims/methods: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry., Results: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only)., Conclusions: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis. more...
- Published
- 2015
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29. Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype.
- Author
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Kölker S, Valayannopoulos V, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Boy SP, Rasmussen MB, Burgard P, Chabrol B, Chakrapani A, Chapman K, Cortès I Saladelafont E, Couce ML, de Meirleir L, Dobbelaere D, Furlan F, Gleich F, González MJ, Gradowska W, Grünewald S, Honzik T, Hörster F, Ioannou H, Jalan A, Häberle J, Haege G, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, Murphy E, de Baulny HO, Ortez C, Pedrón CC, Pintos-Morell G, Pena-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Lund AM, and Cazorla AG more...
- Published
- 2015
- Full Text
- View/download PDF
30. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype.
- Author
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Kölker S, Valayannopoulos V, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Boy SP, Rasmussen MB, Burgard P, Chabrol B, Chakrapani A, Chapman K, Cortès I Saladelafont E, Couce ML, de Meirleir L, Dobbelaere D, Furlan F, Gleich F, González MJ, Gradowska W, Grünewald S, Honzik T, Hörster F, Ioannou H, Jalan A, Häberle J, Haege G, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, Murphy E, de Baulny HO, Ortez C, Pedrón CC, Pintos-Morell G, Pena-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Lund AM, and Garcia-Cazorla A more...
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Europe, Female, Humans, Infant, Infant, Newborn, Kaplan-Meier Estimate, Kidney Failure, Chronic complications, Liver metabolism, Male, Middle Aged, Neonatal Screening, Phenotype, Registries, Young Adult, Amino Acid Metabolism, Inborn Errors diagnosis, Argininosuccinic Aciduria diagnosis, Brain Diseases, Metabolic diagnosis, Glutaryl-CoA Dehydrogenase deficiency, Ornithine Carbamoyltransferase Deficiency Disease diagnosis, Propionic Acidemia diagnosis, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Background: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood., Aims: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages., Results: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population., Conclusions: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases. more...
- Published
- 2015
- Full Text
- View/download PDF
31. Newborn screening for homocystinuria.
- Author
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Walter JH, Jahnke N, and Remmington T
- Subjects
- Early Diagnosis, Humans, Infant, Newborn, Neonatal Screening, Cystathionine beta-Synthase deficiency, Homocystinuria diagnosis
- Abstract
Background: Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. This is an update of a previously published review., Objectives: To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 08 June 2015., Selection Criteria: Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population., Data Collection and Analysis: No studies were identified for inclusion in the review., Main Results: No studies were identified for inclusion in the review., Authors' Conclusions: We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken. more...
- Published
- 2015
- Full Text
- View/download PDF
32. Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin.
- Author
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Breen C, White FJ, Scott CA, Heptinstall L, Walter JH, Jones SA, and Morris AA
- Subjects
- Female, Humans, Infant, Newborn, Treatment Outcome, Pyruvate Carboxylase Deficiency Disease drug therapy, Triglycerides therapeutic use
- Abstract
Unlabelled: Pyruvate carboxylase (PC) deficiency (OMIM 266150) is an autosomal recessive disorder that usually presents with lactic acidaemia and severe neurological dysfunction, leading to death in infancy. Because the enzyme is involved in gluconeogenesis and anaplerosis of the Krebs cycle, therapeutic strategies have included avoiding fasting and attempts to correct the defect of anaplerosis. Triheptanoin is a triglyceride of C7 fatty acids. The oxidation of odd chain fatty acids leads to the production not only of acetyl-CoA but also of propionyl-CoA, which is an anaplerotic substrate for the Krebs cycle. One infant with PC deficiency has previously been treated with triheptanoin as well as citrate and 2-chloropropionate. We report two further patients with PC deficiency, who were treated with triheptanoin, continuously from 11 and 21 days of age. They were also given citrate, aspartate and dichloroacetate. Triheptanoin did not lead to any clinical or biochemical improvement. The plasma and CSF lactate concentrations remained high with episodes of severe ketoacidosis and lactic acidosis. Both patients had severe hearing loss, roving eye movements, seizures and very limited neurodevelopmental progress; they died at the ages of 7 and 8 months., Conclusion: Though triheptanoin did not alter the clinical course in our patients, it was well tolerated. It remains possible that less severely affected patients might benefit from this form of therapy. more...
- Published
- 2014
- Full Text
- View/download PDF
33. Newborn screening for homocystinuria.
- Author
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Walter JH, Jahnke N, and Remmington T
- Subjects
- Early Diagnosis, Humans, Infant, Newborn, Neonatal Screening, Cystathionine beta-Synthase deficiency, Homocystinuria diagnosis
- Abstract
Background: Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications., Objectives: To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 15 May 2013., Selection Criteria: Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population., Data Collection and Analysis: No studies were identified for inclusion in the review., Main Results: No studies were identified for inclusion in the review., Authors' Conclusions: We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken. more...
- Published
- 2013
- Full Text
- View/download PDF
34. The Proline/Citrulline Ratio as a Biomarker for OAT Deficiency in Early Infancy.
- Author
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de Sain-van der Velden MG, Rinaldo P, Elvers B, Henderson M, Walter JH, Prinsen BH, Verhoeven-Duif NM, de Koning TJ, and van Hasselt P
- Abstract
Deficiency of ornithine-δ-aminotransferase (OAT) in humans results in gyrate atrophy. Early diagnosis may allow initiation of treatment before irreversible damage has occurred. However, diagnosis is commonly delayed well into adulthood because of the nonspecific character of initial symptoms. Here, we report findings in a neonate who was evaluated because of a positive family history of OAT deficiency. The reversed enzymatic flux in early infancy resulted in borderline low ornithine concentration - evoking urea cycle disturbances - and increased proline. In addition, plasma citrulline was low. Consequently, the proline/citrulline ratio in plasma was increased compared to controls. To find out whether amino acid profiling in neonatal dried blood spots is suitable to detect OAT deficiency, we evaluated the original newborn dried blood spots of two affected patients and compared it with a database of >450,000 newborns tested in Minnesota since 2004. Proline concentrations (777 and 1,381 μmol/L) were above the 99 percentile (776 μmol/L) of the general population, and citrulline concentrations (4.5 and 4.9 μmol/L) only just above the 1 percentile (4.37 μmol/L). The proline/citrulline ratio was 172.9 and 281.8, respectively. This ratio was calculated retrospectively in the normal population, and the 99 percentile was 97.6. Applying this ratio for NBS could lead to early and specific detection of neonatal OAT deficiency, with no additional expense to newborn screening laboratories quantifying amino acids. Given that early diagnosis of OAT disease can lead to earlier treatment and prevent visual impairment, further studies are indicated to evaluate whether newborn screening for OAT deficiency is warranted. more...
- Published
- 2012
- Full Text
- View/download PDF
35. Newborn screening for homocystinuria.
- Author
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Walter JH, Jahnke N, and Remmington T
- Subjects
- Humans, Infant, Newborn, Cystathionine beta-Synthase deficiency, Homocystinuria diagnosis, Neonatal Screening
- Abstract
Background: Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications., Objectives: To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis., Search Strategy: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 27 June 2011., Selection Criteria: Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population., Data Collection and Analysis: No studies were identified for inclusion in the review., Main Results: No studies were identified for inclusion in the review., Authors' Conclusions: We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken. more...
- Published
- 2011
- Full Text
- View/download PDF
36. MR spectroscopy-based brain metabolite profiling in propionic acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation.
- Author
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Davison JE, Davies NP, Wilson M, Sun Y, Chakrapani A, McKiernan PJ, Walter JH, Gissen P, and Peet AC
- Subjects
- Adolescent, Child, Child, Preschool, Encephalitis metabolism, Female, Humans, Infant, Male, Propionic Acidemia complications, Basal Ganglia metabolism, Encephalitis etiology, Liver Transplantation, Magnetic Resonance Spectroscopy methods, Propionic Acidemia metabolism
- Abstract
Background: Propionic acidaemia (PA) results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS) to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes., Methods: Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging., Results: MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group., Conclusions: The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue. Thus there is a need for improved brain protective strategies during acute metabolic decompensations. MRS provides a non-invasive tool for which could be employed to evaluate novel treatments aimed at restoring basal ganglia homeostasis. The results from the liver transplantation sub-group supports the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute decompensations which are associated with the risk of brain infarction. more...
- Published
- 2011
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37. Vitamin B12 deficiency and phenylketonuria.
- Author
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Walter JH
- Subjects
- Humans, Nervous System Diseases complications, Nitrous Oxide metabolism, Phenylketonurias blood, Vitamin B 12 blood, Vitamin B 12 Deficiency blood, Vitamin B 12 Deficiency prevention & control, Phenylketonurias complications, Vitamin B 12 Deficiency complications
- Abstract
The literature regarding the vitamin B(12) status of patients with phenylketonuria was reviewed. Adequate amounts of B(12) are provided in products used in dietary treatment; however, a number of case reports and cohort studies document deficiency in those who have discontinued taking amino acid, mineral and vitamin supplements but who continue to eat only very limited amounts of natural protein. Symptoms and signs of B(12) deficiency are variable but severe deficiency may cause serious neurological disease. Nitrous oxide anaesthesia is a particular risk. It is recommended that plasma total homocysteine and plasma or urinary methylmalonate should be routinely measured, as they are more sensitive markers of deficiency than serum B(12) concentrations. Functional B(12) deficiency can occur in the presence of a normal B(12) concentration., (Copyright © 2011 Elsevier Inc. All rights reserved.) more...
- Published
- 2011
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38. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters.
- Author
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Hörster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, Das AM, De Klerk JBC, Dionisi-Vici C, Geb S, Gökcay G, Guffon N, Maier EM, Morava E, Walter JH, Schwahn B, Wijburg FA, Lindner M, Grünewald S, Baumgartner MR, and Kölker S more...
- Subjects
- Adolescent, Adult, Age of Onset, Amino Acid Metabolism, Inborn Errors epidemiology, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors mortality, Child, Child, Preschool, Cobamides deficiency, Cohort Studies, Female, Humans, Infant, Infant, Newborn, Male, Methylmalonyl-CoA Mutase genetics, Outcome Assessment, Health Care, Prognosis, Survival Analysis, Young Adult, Amino Acid Metabolism, Inborn Errors diagnosis, Biomarkers analysis, Methylmalonyl-CoA Mutase deficiency
- Abstract
Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients. more...
- Published
- 2009
- Full Text
- View/download PDF
39. A star is born. An in-house media training program produces stellar results.
- Author
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Walter JH
- Subjects
- Program Evaluation, Health Personnel education, Inservice Training, Mass Media
- Published
- 2009
40. Genes, patients, families, doctors-mutation analysis in clinical practice.
- Author
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Walter JH
- Subjects
- Brain Diseases, Metabolic, Inborn diagnosis, Brain Diseases, Metabolic, Inborn genetics, Child, Family, Female, Health Knowledge, Attitudes, Practice, Humans, Infant, Infant, Newborn, Male, Patients, Pedigree, Physicians, Prenatal Diagnosis psychology, DNA Mutational Analysis methods, DNA Mutational Analysis psychology, Genes physiology, Physician-Patient Relations, Professional Practice, Professional-Family Relations
- Abstract
Developments in mutation analysis have led to significant benefits for patients with inherited metabolic disorders and their families. This is particularly the case where new methodologies have prevented the need for invasive tissue biopsies or have allowed carrier detection or first trimester prenatal testing to be undertaken. Whereas in the past it may have only been possible to identify specific 'common' mutations, the availability of techniques, such as automated sequencing, and novel technologies including mutation scanning techniques, multiplex ligation dependent probe amplification, and array technologies, have vastly improved the diagnostic efficiency of molecular testing. more...
- Published
- 2009
- Full Text
- View/download PDF
41. Tolerance to fast: rational and practical evaluation in children with hypoketonaemia.
- Author
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Walter JH
- Subjects
- Acyl-CoA Dehydrogenase deficiency, Acyl-CoA Dehydrogenase genetics, Acyl-CoA Dehydrogenase metabolism, Acyl-CoA Dehydrogenase, Long-Chain genetics, Acyl-CoA Dehydrogenase, Long-Chain metabolism, Child, Dietary Fats metabolism, Fatty Acids metabolism, Humans, Lipid Metabolism, Inborn Errors metabolism, Lipid Metabolism, Inborn Errors therapy, Oxidation-Reduction, Fasting physiology, Ketone Bodies metabolism, Lipid Metabolism, Inborn Errors physiopathology
- Abstract
Prolonged fasting in children with disorder of fat oxidation or ketone body synthesis can lead not only to hypoglycaemia but also to the accumulation of toxic metabolites. The length of time such patients can be safely fasted is important information for caregivers. Most children with MCAD deficiency when well can tolerate 'normal' periods without food, but in more severe disorders such as LCHAD deficiency even these may be associated with acute or chronic damage. Guidelines have been published for safe fasting periods in MCAD but not in other conditions. In the absence of such recommendations, a rational approach must be based on an understanding of the normal physiology of fasting in children of different ages and the pathophysiology associated with the child's particular disorder. Intercurrent infections pose a particular risk and may significantly reduce fasting tolerance. more...
- Published
- 2009
- Full Text
- View/download PDF
42. Bloodspot acylcarnitine and amino acid analysis in cord blood samples: efficacy and reference data from a large cohort study.
- Author
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Walter JH, Patterson A, Till J, Besley GT, Fleming G, and Henderson MJ
- Subjects
- Amino Acids analysis, Blood Chemical Analysis methods, Blood Specimen Collection standards, Carnitine analysis, Carnitine blood, Cohort Studies, Efficiency, False Negative Reactions, Fetal Diseases blood, Fetal Diseases diagnosis, Humans, Infant, Newborn, Metabolic Diseases blood, Metabolic Diseases diagnosis, Mothers, Neonatal Screening methods, Neonatal Screening standards, Reference Values, Time Factors, Amino Acids blood, Blood Chemical Analysis standards, Blood Specimen Collection methods, Carnitine analogs & derivatives, Fetal Blood chemistry
- Abstract
Background: In order to test the feasibility of cord blood screening for inherited metabolic disease, a two-year cohort study of births in six obstetric units from five towns in the north of England was undertaken. These towns have a high prevalence of consanguineous marriages, largely among the immigrant Asian community. The purpose of the study was to determine whether early detection of metabolic disease was possible and whether early intervention would improve prognosis., Methods: Following parental consent, cord blood samples were collected at birth and analysed for acylcarnitine and amino acid profiles by tandem mass spectrometry in one of two laboratories. One laboratory used butylated derivatives, the other used underivatized samples. The same laboratories performed routine blood spot neonatal screening at 5-7 days of age on these babies. Patients with positive results were investigated and treated by a metabolic paediatrician as soon as possible., Results: 24,983 births were examined. 12,952 samples were analysed as butyl derivatives, 12,031 samples were analysed underivatized. The following disorders were detected: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (1 case), 3-methylcrotonyl-CoA carboxylase (MCC) deficiency (2 cases), maternal carnitine transporter defect (2 cases), maternal MCC (1 case). The following disorders were diagnosed subsequently but were not detected by the cord blood screening: phenylketonuria (PKU) (1 case), maple syrup urine disease (MSUD) (2 cases), argininosuccinic aciduria (1 case), methylmalonic acidaemia (MMA) (1 case), glutaric aciduria type 2 (1 case), MCAD deficiency (2 cases), 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (1 case). Comprehensive reference data for all analytes by both methods were obtained., Conclusions: Cord blood testing is of limited value in detecting inherited metabolic disease. The metabolites associated with most disorders examined were not elevated in cord blood. Some maternal disorders, carnitine transporter defect and 3-methlycrotonyl-CoA carboxylase deficiency, are detected. These remain of uncertain clinical significance. Comprehensive reference data have been obtained that will facilitate future interpretation of studies in cord blood. more...
- Published
- 2009
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43. Costeff optic atrophy syndrome: new clinical case and novel molecular findings.
- Author
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Ho G, Walter JH, and Christodoulou J
- Subjects
- Adolescent, Adolescent Development, Biomarkers urine, Chorea complications, Chorea genetics, Chorea urine, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Glutarates urine, Heterozygote, Homozygote, Humans, Metabolism, Inborn Errors complications, Metabolism, Inborn Errors genetics, Metabolism, Inborn Errors urine, Optic Atrophy complications, Optic Atrophy genetics, Optic Atrophy urine, Pedigree, Phenotype, Spastic Paraplegia, Hereditary complications, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary urine, Chorea diagnosis, Codon, Nonsense, Metabolism, Inborn Errors diagnosis, Optic Atrophy diagnosis, Proteins genetics, Spastic Paraplegia, Hereditary diagnosis
- Abstract
3-Methylglutaconic aciduria (MGA) encompasses a heterogeneous group of disorders, often coinciding with elevated levels of urinary 3-methylglutaric acid. Type I MGA is a disorder of leucine metabolism, while the biological basis for the MGA is unclear for the other types (MGA types II-V). MGA type III (Costeff optic atrophy syndrome, autosomal recessive optic atrophy-3 or optic atrophy plus syndrome, OMIM 258501) is distinguished by early bilateral optic atrophy, later-onset spasticity, extrapyramidal dysfunction, ataxia, and occasional cognitive deficits. It is caused by homozygous mutations in the optic atrophy 3 gene (OPA3). We present a case of a patient with MGA who has infantile-onset optic atrophy, ataxia, extrapyramidal movements and spasticity, but with normal intellect. Sequencing of the patient's DNA revealed a homozygous nonsense mutation c.415C>T (p.Q139X) in exon 2 of transcript 2 of the OPA3 gene, as well as a common silent polymorphism c.231T>C in the same exon. This is the first nonsense mutation found in OPA3. The molecular findings in OPA3 are also reviewed, including mutations in OPA3 that result in autosomal dominant optic atrophy and cataract (ADOAC). The recessive mode of inheritance of MGA type III as a result of the p.Q139X mutation is supported by the carrier status of the unaffected father. more...
- Published
- 2008
- Full Text
- View/download PDF
44. Amnionless (AMN) mutations in Imerslund-Gräsbeck syndrome may be associated with disturbed vitamin B12 transport into the CNS.
- Author
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Luder AS, Tanner SM, de la Chapelle A, and Walter JH
- Abstract
Familial selective vitamin B12 (cobalamin, Cbl) malabsorption (Imerslund-Gräsbeck syndrome, IGS, OMIM 261100) is a group of autosomal recessive disorders characterized by selective malabsorption of Cbl from the terminal ileum in the presence of normal histology. Mutations in the amnionless (AMN) and cubilin (CUBN) genes are known to be causes of IGS. Their gene products combine to form a receptor complex (cubam), which is instrumental in the binding and transport of Cbl in the gut. As opposed to Cbl transport in the terminal ileum, normal transport of Cbl into the CNS is poorly understood and little is known regarding its molecular basis. Studies in adults with neuropsychiatric disease have suggested the presence of an active transport mechanism into the central nervous system constituting a blood-brain barrier (BBB) for Cbl. A child with IGS, compound heterozygous for a missense and a nonsense mutation in the amnionless (AMN) protein gene, was noted to have a high daily cobalamin (Cbl) requirement for neuropsychiatric, but not for systemic metabolic and haematological, remission. Measurements of CSF Cbl revealed evidence that the transport of Cbl into the central nervous system was impaired, and a standard Schilling test was consistent with a dose response of cobalamin transport across the terminal ileum. Amnionless protein is known to be expressed in the fetal and postnatal central nervous system, and is known to be involved in Cbl transport in other tissues such as kidney as well as the gut. It is possible that an active Cbl transport mechanism at the BBB exists, and that the amnionless (AMN) protein may be part of this mechanism, as it is in cobalamin transport in the terminal ileum. more...
- Published
- 2008
- Full Text
- View/download PDF
45. N-carbamylglutamate for neonatal hyperammonaemia in propionic acidaemia.
- Author
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Jones S, Reed CA, Vijay S, Walter JH, and Morris AA
- Subjects
- Biomarkers blood, Female, Humans, Hyperammonemia blood, Hyperammonemia etiology, Infant, Newborn, Intubation, Gastrointestinal, Male, Propionic Acidemia blood, Propionic Acidemia therapy, Time Factors, Treatment Outcome, Ammonia blood, Glutamates administration & dosage, Hyperammonemia drug therapy, Propionic Acidemia complications
- Abstract
Hyperammonaemia is common in neonates with branched-chain organic acidaemias, primarily due to the inhibition of N-acetylglutamate (NAG) synthetase; NAG is an activator for carbamylphosphate synthetase I, the first enzyme of the urea cycle. N-Carbamylglutamate, a NAG analogue, has been reported to correct hyperammonaemia in neonates with organic acidaemias. It is, however, uncertain how the ammonia concentrations in these neonates would have progressed without the drug. We report a neonate with propionic acidaemia, whose plasma ammonia concentration responded dramatically to N-carbamylglutamate, having previously been over 950 μmol/L for 33 h. Our patient presented with poor feeding, hypoglycaemia, acidosis and hyperammonaemia (1044 μmol/L at 65 h of age). The patient was treated with intravenous glucose (12 mg/kg per min), insulin, sodium benzoate, sodium phenylbutyrate, carnitine and continuous veno-venous haemofiltration (CVVH). In spite of these measures, the plasma ammonia concentration remained above 950 μmol/L. After 30 h of CVVH, N-carbamylglutamate (250 mg/kg) was given through a nasogastric tube. Over the following 4 h, the plasma ammonia fell from 1410 μmol/L to 267 μmol/L. Despite stopping CVVH, the ammonia level dropped to 137 μmol/L over the next 2 h and it continued to fall while the intravenous drug doses were reduced. The patient was readmitted, aged 4 weeks, with hyperammonaemia (347 μmol/L) and again this responded to N-carbamylglutamate. In contrast, we report a previous patient with propionic acidaemia who showed no response to a lower dose of N-carbamylglutamate (25 mg/kg). more...
- Published
- 2008
- Full Text
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46. Somatic mosaicism for a PDHA1 mutation in a female with pyruvate dehydrogenase deficiency.
- Author
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Ridout CK, Brown RM, Walter JH, and Brown GK
- Subjects
- Amino Acid Sequence, Base Sequence, Cells, Cultured, DNA Mutational Analysis, Female, Humans, Molecular Sequence Data, Mutation, Mosaicism, Pyruvate Dehydrogenase (Lipoamide) genetics, Pyruvate Dehydrogenase Complex Deficiency Disease genetics
- Abstract
Somatic mosaicism for a mutation in the X-linked PDHA1 gene was found in a girl who presented with manifestations of pyruvate dehydrogenase deficiency. Mutation in the PDHA1 gene was suggested by a mosaic pattern of E1alpha subunit immunostaining; however, initial screening of cDNA and the exons and intron-exon boundaries yielded only normal sequence, apart from a heterozygous 4 bp insertion in intron 10. This was considered to be a polymorphism as it is also present in her unaffected mother who has normal enzyme activity and uniform E1alpha immunostaining in fibroblasts. Detailed genetic analysis, which included isolation of cloned fibroblasts expressing the mutant X chromosome, resulted in the identification of a base substitution in the acceptor splice site of intron 9 which leads to activation of a cryptic upstream splice site. The proportion of cells expressing the mutation was then determined by direct analysis of the X-inactivation pattern. Genetic diagnosis in this unique case of PDHA1 somatic mosaicism was complicated by the absence of an abnormal transcript in primary fibroblasts, the presence of three different alleles and an X-inactivation pattern favouring expression of the normal, paternal, X chromosome. Although the mutation was only present in a proportion of cells, and only expressed in a subset of these due to random X-inactivation, the resulting enzyme defect was sufficient to be clinically apparent. more...
- Published
- 2008
- Full Text
- View/download PDF
47. Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres.
- Author
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Zwickler T, Lindner M, Aydin HI, Baumgartner MR, Bodamer OA, Burlina AB, Das AM, DeKlerk JB, Gökcay G, Grünewald S, Guffon N, Maier EM, Morava E, Geb S, Schwahn B, Walter JH, Wendel U, Wijburg FA, Müller E, Kölker S, and Hörster F more...
- Subjects
- Adolescent, Adult, Amino Acid Metabolism, Inborn Errors drug therapy, Child, Child, Preschool, Humans, Hydroxocobalamin therapeutic use, Infant, Infant, Newborn, Vitamin B 12 therapeutic use, Amino Acid Metabolism, Inborn Errors diagnosis, Methylmalonic Acid urine
- Abstract
The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability. more...
- Published
- 2008
- Full Text
- View/download PDF
48. Carnitine transporter defect: diagnosis in asymptomatic adult women following analysis of acylcarnitines in their newborn infants.
- Author
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Vijay S, Patterson A, Olpin S, Henderson MJ, Clark S, Day C, Savill G, and Walter JH
- Subjects
- Adult, Carnitine blood, Consanguinity, Female, Fetal Blood metabolism, Humans, Infant, Newborn, Male, Mass Spectrometry, Mothers, Organic Cation Transport Proteins physiology, Oxygen metabolism, Solute Carrier Family 22 Member 5, Carnitine analogs & derivatives, Carnitine metabolism, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Organic Cation Transport Proteins genetics
- Abstract
Carnitine transporter defect (CTD) is an autosomal recessive disorder characterized by episodes of non-ketotic hypoglycaemia, hyperammonaemia and liver disease, or by the development of cardiomyopathy, both of which occur in infancy and childhood. Blood carnitine concentrations are extremely low. The diagnosis can be confirmed by finding abnormal fat oxidation and carnitine uptake in skin fibroblasts. The condition has not previously been thought to present later in life or to be benign. We report the identification of four women discovered to have CTD as a consequence of finding low carnitine concentrations in the cord blood or newborn samples from their infants. All four mothers had been asymptomatic and none had a cardiomyopathy. more...
- Published
- 2006
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49. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.
- Author
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Kölker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM, Ribes A, Kalkanoglu HS, Lund AM, Merinero B, Wajner M, Troncoso M, Williams M, Walter JH, Campistol J, Martí-Herrero M, Caswill M, Burlina AB, Lagler F, Maier EM, Schwahn B, Tokatli A, Dursun A, Coskun T, Chalmers RA, Koeller DM, Zschocke J, Christensen E, Burgard P, and Hoffmann GF more...
- Subjects
- Adult, Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors diet therapy, Amino Acid Metabolism, Inborn Errors enzymology, Amino Acid Metabolism, Inborn Errors genetics, Child, Female, Genotype, Glutaryl-CoA Dehydrogenase deficiency, Humans, Infant, Newborn, Male, Neonatal Screening, Phenotype, Survival Rate, Treatment Outcome, Amino Acid Metabolism, Inborn Errors physiopathology, Glutaryl-CoA Dehydrogenase genetics
- Abstract
Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n = 218) or presymptomatically by neonatal screening (n = 23), high-risk screening (n = 24), or macrocephaly (n = 14). Most symptomatic patients (n = 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening. more...
- Published
- 2006
- Full Text
- View/download PDF
50. Clinical approach to treatable inborn metabolic diseases: an introduction.
- Author
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Saudubray JM, Sedel F, and Walter JH
- Subjects
- Humans, Infant, Newborn, Metabolic Networks and Pathways genetics, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Neonatal Screening, Metabolism, Inborn Errors classification, Metabolism, Inborn Errors therapy
- Abstract
In view of the major improvements in treatment, it has become increasingly important that in order for first-line physicians not to miss a treatable disorder they should be able initiate a simple method of clinical screening, particularly in the emergency room. We present a simplified classification of treatable inborn errors of metabolism in three groups. Group 1 includes inborn errors of intermediary metabolism that give rise to an acute or chronic intoxication. It encompasses aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias. Clinical expression can be acute or systemic or can involve a specific organ, and can strike in the neonatal period or later and intermittently from infancy to late adulthood. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins. Group 2 includes inborn errors of intermediary metabolism that affect the cytoplasmic and mitochondrial energetic processes. Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable. Group 3 involves cellular organelles and includes lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Among these, some lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies. Physicians can be faced with the possibility of a treatable inborn error in an emergency, either in the neonatal period or late in infancy to adulthood, or as chronic and progressive symptoms--general (failure to thrive), neurological, or specific for various organs or systems. These symptoms are summarized in four tables. In addition, an extensive list of medications used in the treatment of inborn errors is presented. more...
- Published
- 2006
- Full Text
- View/download PDF
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