Time filter

Source Type

Thessaloníki, Greece

Klar A.,Bikur Cholim General Hospital | Klar A.,Pediatrics Gastroenterology Unit | Navon-Elkan P.,Bikur Cholim General Hospital | Navon-Elkan P.,Shaare Zedek Medical Center | And 8 more authors.
European Journal of Pediatrics | Year: 2010

Three siblings with recalcitrant leg ulceration, splenomegaly, photosensitive rash, and autoantibodies were suspected of having prolidase deficiency. Urine was checked for iminodipeptiduria, fibroblasts were cultured and analyzed for prolidase activity, and DNA was extracted for identifying the causative mutation. Glycyl proline was found as the dominant dipeptide in the urine. The activity of proline dipeptidase in fibroblasts was 2.5% of control fibroblasts. Sequence analysis of the PEPD gene revealed a homozygous nonsense C→G transition at nucleotide 768. In conclusion, prolidase deficiency was diagnosed in siblings with skin ulceration autoantibodies and a lupus-like disease. A novel nonsense mutation was found, associated with the severe outcome of our patients. © 2009 Springer-Verlag. Source

Cluse Z.N.,Metabolic Laboratory | Fudge A.N.,Metabolic Laboratory | Whiting M.J.,Metabolic Laboratory | Mcwhinney B.,HPLC LC MS MS Chromatography Section | And 2 more authors.
Annals of Clinical Biochemistry | Year: 2012

Background: We evaluated the recently released chemiluminescence assay for 25-hydroxy vitamin D (25-OHD) on the Immunodiagnostic Systems iSYS (IDS-iSYS) automated analyser. Methods: The IDS-iSYS comparison was performed using patient samples previously measured for 25-OHD by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (n =119) and an IDS enzyme immunoassy (IDS-EIA) method (n =64). Limit of detection and limit of quantification were determined from a precision profile. Imprecision was assessed using quality control material and pooled serum. External QAP material (Vitamin D External Quality Assessment Scheme, UK) was analysed to establish inaccuracy. Linearity was assessed by two dilution studies. Cross-reactivity was determined by three serial dilution studies of patient samples with known 25-OHD2 concentrations. Results: The IDS-iSYS correlated well with both established methods (iSYS =1.03LC-MS/MS 2 6.53, R2 =0.82 and iSYS =1.07IDS-EIA 2 1.61, R2 =0.86). Imprecision of the iSYS assay for IDS control material was 13.4% at 32 nmol/L, 10% at 78 nmol/L, 9.4% at 161 nmol/L, and for the pooled material 9.3% at 72 nmol/L and 5.6% at 158 nmol/L. The evaluation found the assay to be highly accurate (IDS-iSYS =0.93ALTM {thorn} 3.79, R2 =0.94) and linear (obs1 =0.93exp1 2 5.05, R2 =0.99 (P =0.256); and obs2 =0.97exp2 + 6.07, R2 =0.97 (P =0.654); ALTM, all-laboratory trimmed mean). Cross-reactivity studies demonstrated no significant difference to the calculated total 25-OHD as measured by LC-MS/MS. Conclusions: Even though the imprecision of the iSYS was found to be greater than that of the LC-MS/MS and EIA methods, the performance characteristics of the IDS-iSYS 25-OHD assay are suitable for routine diagnostic purposes on a high throughput automated analyser. Source

Kolker S.,University of Heidelberg | Cazorla A.G.,Servicio de Neurologia and CIBERER | Valayannopoulos V.,Institut Universitaire de France | Lund A.M.,Copenhagen University | And 47 more authors.
Journal of Inherited Metabolic Disease | Year: 2015

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. © 2015, SSIEM. Source

Posset R.,University of Heidelberg | Garcia-Cazorla A.,Hospital San Joan de Deu | Valayannopoulos V.,Assistance Publique Hopitaux de Paris | Teles E.L.,Hospital de S. Joao | And 33 more authors.
Journal of Inherited Metabolic Disease | Year: 2016

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. © 2016 SSIEM Source

Navarro-Sastre A.,Institute Investigacion Biomedica Pi Sunyer | Navarro-Sastre A.,Research Center Biomedica En Red Of Enfermedades Raras | Tort F.,Institute Investigacion Biomedica Pi Sunyer | Tort F.,Research Center Biomedica En Red Of Enfermedades Raras | And 25 more authors.
American Journal of Human Genetics | Year: 2011

We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months. Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low. Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G>T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545+5G>A) mutation. The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases. Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished. In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation. Similar biochemical effects were observed in Saccharomyces cerevisiae upon deletion of NFU1, resulting in lower lipoylation and SDH activity. Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins. © 2011 The American Society of Human Genetics. Source

Discover hidden collaborations