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Santiago de Compostela, Spain

Bueno M.A.,Dietetics and Nutrition Unit | Lage S.,Cruces Hospital | Delgado C.,Dietetics and Nutrition Unit | Andrade F.,Cruces Hospital | And 4 more authors.
Metabolism: Clinical and Experimental | Year: 2012

Objective: To evaluate the protocol we propose for detecting BH 4-responsive patients and the possibility of delimiting more precisely the population to be tested. Methods: We recruited 102 phenylketonuric patients on a phenylalanine (Phe)-restricted diet. The initial stage of the protocol was a 24-h BH4 loading test involving Phe loading and subsequent ingestion of the cofactor, a 50% fall in blood Phe levels being considered a positive response. The non-responders at this stage then completed a one-week therapeutic test combining BH4 administration and daily protein intake meeting recommended dietary allowances, to assess whether the 24-h test had detected all responders. Results: The 24-h test detected almost all BH4 responders (30.3% of the 99 patients included in the analysis), with just two patients (2.0%) subsequently responding positively to the therapeutic test. The 24-h test did not give any false positive results. Conclusions: The 24-h BH4 loading test is clinically useful for screening phenylketonuric patients. Specifically, 95% of patients with Phe levels < 700 μmol/L, and none with Phe levels > 1500 μmol/L were BH4-responsive. Given these results, we conclude that patients with Phe levels < 700 μmol/L or > 1500 μmol/L probably do not need to be tested, prioritising the identification of BH4-responsiveness among individuals with intermediate Phe concentrations, between the aforementioned values. Additionally, our results suggest that the therapeutic test only needs to be performed in cases where the reduction in blood Phe levels after cofactor administration is within the range 40%-50%. © 2012 Elsevier Inc.

Ventura F.V.,Research Institute for Medicines and Pharmaceutical science | Ventura F.V.,University of Lisbon | Leandro P.,Research Institute for Medicines and Pharmaceutical science | Leandro P.,University of Lisbon | And 17 more authors.
Clinical Genetics | Year: 2014

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the commonest genetic defect of mitochondrial fatty acid β-oxidation. About 60% of MCADD patients are homozygous for the c.985A>G (p.Lys329Glu) mutation in the ACADM gene (G985 allele). Herein, we present the first report on the molecular and biochemical spectrum of Portuguese MCADD population. From the 109 patients studied, 83 were diagnosed after inclusion of MCADD in the national newborn screening, 8 following the onset of symptoms and 18 through segregation studies. Gypsy ancestry was identified in 85/109 patients. The G985 allele was found in homozygosity in 102/109 patients, in compound heterozygosity in 6/109 and was absent in one patient. Segregation studies in the Gypsy families showed that 93/123 relatives were carriers of the G985 allele, suggesting its high prevalence in this ethnic group. Additionally, three new substitutions-c.218A>G (p.Tyr73Cys), c.503A>T (p.Asp168Val) and c.1205G>T (p.Gly402Val)-were identified. Despite the particularity of the MCADD population investigated, the G985 allele was found in linkage disequilibrium with H1(112) haplotype. Furthermore, two novel haplotypes, H5(212) and H6(122) were revealed. © 2013 John Wiley & Sons A/S.

Laszlo A.,University of Szeged | Elpeleg O.N.,Metabolic Disorders Unit | Horvath K.,Semmelweis University | Jakobs C.,Metabolic | And 8 more authors.
Ideggyogyaszati Szemle | Year: 2010

The authors summarize the pathomechanism of the myelination process, the clinical, radiological and the genetical aspects of the leukodystrophies, as in 18q deletion syndrome, adrenoleukodysrtophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher leukodystrophy, Alexander disease and olivo-ponto- cerebellar atrophy (OPCA).

Desbats M.A.,University of Padua | Vetro A.,Biotechnology Research Laboratory | Limongelli I.,University of Pavia | Lunardi G.,University of Padua | And 14 more authors.
European Journal of Human Genetics | Year: 2015

Coenzyme Q 10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q 10. Coenzyme Q 10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q 10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ 10 supplementation, we decided to treat with CoQ 10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis. © 2015 Macmillan Publishers Limited All rights reserved.

Caciotti A.,Paediatric Neurology Unit and Laboratories | Tonin R.,Paediatric Neurology Unit and Laboratories | Tonin R.,University of Florence | Rigoldi M.,Rare Metabolic Diseases Unit | And 29 more authors.
Human Mutation | Year: 2015

Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression. © 2014 WILEY PERIODICALS, INC.

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