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Le Touquet – Paris-Plage, France

Haberle J.,University of Zurich | Boddaert N.,Radiologie Hopital Necker | Burlina A.,University of Padua | Chakrapani A.,SteelHouse | And 11 more authors.
Orphanet Journal of Rare Diseases | Year: 2012

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (∼50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients. © 2012 Häberle et al. Source

Sloan J.L.,U.S. National Institutes of Health | Johnston J.J.,U.S. National Institutes of Health | Manoli I.,U.S. National Institutes of Health | Chandler R.J.,U.S. National Institutes of Health | And 22 more authors.
Nature Genetics | Year: 2011

We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in 1/41,000 control individuals, predicting a CMAMMA population incidence of 1/41:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders. © 2011 Nature America, Inc. All rights reserved. Source

Gataullina S.,Necker Enfants Malades Hospital | Lonlay P.D.,University of Paris Descartes | Dellatolas G.,University of Paris Descartes | Valayannapoulos V.,Reference Center for Inherited Metabolic Disorders | And 6 more authors.
Developmental Medicine and Child Neurology | Year: 2013

Aim Having previously shown that comorbidity is a major determinant of neurological sequelae in hypoglycaemia, our aim was to describe the neuroimaging patterns of brain damage in different hypoglycaemic situations and to elucidate the factors that determine lesion topography. Method We reviewed 50 patients (31 females, 19 males) with symptomatic hypoglycaemia (<2.8mmol/L) occurring between 1day and 5years of age (median 4d) who had undergone magnetic resonance imaging (MRI; at least axial T2-weighted, sagittal T1-weighted, and coronal fluid-attenuated inversion recovery [FLAIR]-weighted imaging). MRI was performed during the follow-up examination at least 1month after the occurrence of symptomatic hypoglycaemia, i.e. between 1month and 5years of age (median 3mo). Hypoglycaemia resulted from three inborn errors of metabolism: congenital hyperinsulinism (33 patients), fatty acid β-oxidation disorders (13 patients), or glycogen storage disease type I (four patients). We selected the patients with clear MRI abnormalities and analysed their topography according to aetiology and age at occurrence of the lesion. Results The topography of the brain lesions depended on age: from the neonatal period to 6months of age, lesions predominantly involved the posterior white matter; between 6 and 22months the basal ganglia, and after 22months the parietotemporal cortex (p=0.04). Interpretation The relationship between brain lesions and age could reflect the maturation sequence of the brain. © 2012 Mac Keith Press. Source

Muenzer J.,University of North Carolina at Chapel Hill | Beck M.,University Hospital Freiburg | Giugliani R.,Federal University of Rio Grande do Sul | Suzuki Y.,Gifu University | And 4 more authors.
Genetics in Medicine | Year: 2011

Purpose: To use the Hunter Outcome Survey, an international database, to assess the safety and effectiveness of enzyme replacement therapy with idursulfase in patients with Hunter syndrome who started treatment before 6 years of age. Methods: The study population included all patients enrolled in the Hunter Outcome Survey who started idursulfase infusions (0.5 mg/kg every other week) before 6 years of age and who had at least one follow-up examination recorded. Results: The study population included 124 patients, younger than 6 years, who had a mean age at start of idursulfase of 3.6 ± 1.6 years (mean ± SD). The mean duration of treatment was 22.9 ± 14.6 months. A total of 69 infusion-related reactions occurred in 33 (26.6%) patients, including three serious infusion-related reactions occurring in a single patient. After at least 6 months of idursulfase, urine glycosaminoglycan levels decreased from 592 ± 188 to 218 ± 115 μg/mg creatinine (P < 0.0001, n = 34). Liver size, estimated by palpation, was also significantly decreased (P = 0.005, n = 23). Similar safety and effectiveness results were seen in patients who were aged 6 years or older when initiating idursulfase. CONCLUSION:: No new safety concerns were identified in patients younger than 6 years, and clinical benefit was suggested by the reduction in liver size. © 2011 Lippincott Williams & Wilkins. Source

De Ru M.H.,University of Amsterdam | Boelens J.J.,University Utrecht | Das A.M.,Hannover Medical School | Jones S.A.,University of Manchester | And 12 more authors.
Orphanet Journal of Rare Diseases | Year: 2011

Background: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies. Methods. A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus. Results: Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT. Conclusions: This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases. © 2011 de Ru et al; licensee BioMed Central Ltd. Source

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