OBJECTIVES: The newborn screening (NBS) program in the Republic of Serbia has several decades of tradition, but it has not included any organic acidemias (OA). Therefore, this study aimed to establish the cut-offs of the corresponding NBS markers in the population of healthy newborns. METHODS: In dried blood samples (DBS) collected from 1,771 healthy newborns, we analyzed levels of propionylcarnitine (C3), isovalerylcarnitine (C5), and glutarylcarnitine (C5DC) using tandem mass spectrometry. Further we calculated the following ratios: C3/acetylcarnitine (C3/C2), C3/palmitoylcarnitine (C3/C16), C5/ free carnitine (C0), C5/C2, C5/C3, C5DC/octanoylcarnitine (C8), and C5DC/C0. RESULTS: The cut-offs for methylmalonic acidemia (MMA) or propionic acidemia (PA) were C3>5.73 μmol/L, C3/C2>0.23, and C3/C16>2.36. Based on the study findings, the screening results indicative for isovaleric acidemia (IVA) would include C5>0.372 μmol/L, C5/C0>0.020, C5/C2>0.019, and C5/C3>0.31. Finally, C5DC>0.303 μmol/L, C5DC/C8>7.1, and C5DC/C0>0.019 would justify further testing for glutaric acidemia type I (GA1). The cut-offs were satisfactorily validated via the comparison with worldwide estimates and data for several Caucasian populations. CONCLUSIONS: The levels of the OA biomarkers in the Serbian population of healthy newborns have a distribution pattern similar to the other world populations. Therefore, the proposed cut-offs represent a reliable starting point for the future development of the OA NBS.

• MeSH
• biologické markery MeSH
• glutaryl-CoA-dehydrogenasa nedostatek   MeSH
• isovaleryl-CoA-dehydrogenasa MeSH
• lidé MeSH
• metabolické nemoci mozku MeSH
• novorozenec MeSH
• propionová acidemie * diagnóza   MeSH
• vrozené poruchy metabolismu aminokyselin MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Srbsko MeSH

Urea, as an end product of protein metabolism and an abundant polar compound, significantly complicates the metabolomic analysis of urine by GC-MS. We developed a sample preparation method removing urea from urine samples prior the GC-MS analysis. The method based on urease immobilized on magnetic microparticles was compared with the others that are conventionally used (liquid-liquid extraction, free urease protocol), and samples without any treatment. To study the impact of sample preparation approaches on the quality of analytical data, we employed comprehensive metabolomic analysis (using both GC-MS and LC-MS/MS platforms) of standard material based on human urine. Multivariate statistical analysis has shown that immobilized urease treatment provides similar results to a free urease approach. However, significant alterations in the profiles of metabolites were observed in the samples without any treatment and after the extraction. Compared to other approaches that were tested, the immobilization of urease on microparticles reduces both the number of artifacts and the variability of the metabolites (average CV of extraction 19.7%, no treatment 11.4%, free urease 5.0%, and immobilized urease 2.5%). The method that was developed was applied in a GC-MS metabolomic experiment of glutaric aciduria type I, where both known diagnostically important biomarkers and unknowns, as the most discriminating compounds, were found.

• MeSH
• analýza hlavních komponent MeSH
• chromatografie kapalinová metody   MeSH
• enzymy imobilizované moč   MeSH
• glutaryl-CoA-dehydrogenasa nedostatek   metabolismus   MeSH
• lidé MeSH
• magnetické jevy * MeSH
• metabolické nemoci mozku metabolismus   MeSH
• metabolom MeSH
• metabolomika metody   MeSH
• metody pro přípravu analytických vzorků * MeSH
• močovina metabolismus   MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí metody   MeSH
• reprodukovatelnost výsledků MeSH
• studie proveditelnosti MeSH
• tandemová hmotnostní spektrometrie MeSH
• ureasa moč   MeSH
• vrozené poruchy metabolismu aminokyselin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• dítě MeSH
• dospělí MeSH
• glutaryl-CoA-dehydrogenasa nedostatek   metabolismus   MeSH
• kojenec MeSH
• kyselina methylmalonová metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mentální retardace metabolismus   patologie   MeSH
• metabolické nemoci mozku vrozené metabolismus   patologie   MeSH
• metabolické nemoci mozku metabolismus   patologie   MeSH
• metabolické nemoci metabolismus   patologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• novorozenecký screening metody   MeSH
• předškolní dítě MeSH
• věk při počátku nemoci MeSH
• vitamin B 12 metabolismus   MeSH
• vrozené poruchy metabolismu aminokyselin metabolismus   patologie   MeSH
• vrozené poruchy transportu aminokyselin metabolismus   patologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• acidóza genetika   vrozené   MeSH
• glutaryl-CoA-dehydrogenasa metabolismus   nedostatek   MeSH
• lidé MeSH
• metabolické nemoci mozku MeSH
• nízkoproteinová dieta metody   MeSH
• novorozenecký screening MeSH
• předškolní dítě MeSH
• prognóza MeSH
• psychomotorické poruchy genetika   klasifikace   MeSH
• vrozené poruchy metabolismu aminokyselin * diagnostické zobrazování   dietoterapie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

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.

• MeSH
• argininjantarová acidurie diagnóza   MeSH
• chronické selhání ledvin komplikace   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• glutaryl-CoA-dehydrogenasa nedostatek   MeSH
• játra metabolismus   MeSH
• Kaplanův-Meierův odhad MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolické nemoci mozku diagnóza   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc z nedostatku ornithinkarbamoyltransferázy diagnóza   MeSH
• novorozenec MeSH
• novorozenecký screening MeSH
• předškolní dítě MeSH
• propionová acidemie diagnóza   MeSH
• registrace MeSH
• senioři MeSH
• vrozené poruchy cyklu močoviny diagnóza   MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

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.

• MeSH
• dítě MeSH
• dospělí MeSH
• glutaryl-CoA-dehydrogenasa nedostatek   MeSH
• hyperamonemie diagnóza   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mentální retardace MeSH
• metabolické nemoci mozku diagnóza   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc z nedostatku ornithinkarbamoyltransferázy diagnóza   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• registrace MeSH
• senioři MeSH
• vrozené poruchy cyklu močoviny diagnóza   MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   MeSH
• zvracení MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH