Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.
BACKGROUND: Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected ≤ 40 years (HUA ≤ 40) and > 40 years, gout patients with disease onset ≤ 40 years (Gout ≤ 40) and > 40 years, and normouricemic healthy controls (HC). METHODS: Plasma samples were collected from 94 asymptomatic HUA (77% HUA ≤ 40) subjects, 196 gout patients (59% Gout ≤ 40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied. RESULTS: Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA ≤ 40 and Gout ≤ 40 without ULT. Multivariate statistics differentiated HUA ≤ 40 and Gout ≤ 40 groups from HC with an overall accuracy of > 95%. CONCLUSION: Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA ≤ 40 and Gout ≤ 40 patients, together with a correction of this imbalance with ULT.
- MeSH
- antiuratika terapeutické užití MeSH
- dna (nemoc) * diagnóza farmakoterapie MeSH
- hyperurikemie * diagnóza farmakoterapie MeSH
- kyselina močová MeSH
- lidé MeSH
- lipidomika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Sulfur amino acids are essential nutrients needed for proteosynthesis and production of compounds that are necessary for methylations and redox reactions. Homocysteine is an intermediate in the intracellular methionine turnover and may serve as a universal marker of sulfur metabolism. Each year about 65,000-74,000 total homocysteine analyses are performed in the Czech Republic and about 1% are grossly abnormal. These abnormalities may be caused by unrecognized B-vitamin deficiencies, severe genetic defects and other culprits. This project is focused on systematic analysis of the causes of intermediate hyperhomocysteinemia and of hypohomocysteinemia in the Czech population as a basis for personalized management. The project aims are as follows: as/to identify subject with severely abnormal total homocysteine concentrations in collaborating departments, b/to examine etiology by a combination of targeted vitamin analysis, analysis of sulfur compounds and next generation sequencing, and c/to develop national recommendations on total homocysteine testing and patient care.
Aminokyseliny obsahující síru jsou esenciálními složkami potravy a slouží k syntéze bílkovin a dalších sloučenin nezbytných pro methylační a redoxní reakce. Homocystein je meziproduktem při intracelulárních přeměnách methioninu a je považován za univerzální marker metabolismu sirných látek. V České republice se každoročně provede 65 000-74 000 vyšetření celkového homocysteinu a přibližně 1% výsledků má výrazně abnormální hodnoty. Tyto abnormality mohou být způsobené nerozpoznanými deficity vitaminů skupiny B, závažnými genetickými nemocemi a dalšími příčinami. Předmětem tohoto projektu je systematická analýza příčin výrazné hyperhomocysteinemie a hypohomocysteinemie v české populaci jako podklad pro personalizovanou péči. Řešení projektu má následující cíle: a/identifikovat osoby s výrazně abnormálními koncentracemi celkového homocysteinu ve spolupracujících pracovištích; b/vyšetřit příčinu kombinací cílené analýzy vitaminů a sirných sloučenin a dále metodami sekvenování nové generace a c/vypracovat národní doporučení pro vyšetřování celkového homocysteinu a následnou péči.
- Klíčová slova
- genetika, genetics, sekvenování nové generace (NGS), foláty, homocystein, homocystinurie, vitamin B12, homocystinuria, Metabolomika, Metabolomics, vitamín B12, Hyperhomocysteinemie, Hypohomocysteinemie, Homocysteine, Hyperhomocysteinemia, Hypohomocysteinemia, Folates, Next-Generation Sequencing (NGS),
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
PURPOSE: Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD. METHODS: We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies. RESULTS: We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts. CONCLUSION: Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.
- MeSH
- alely MeSH
- lidé MeSH
- peroxizomy genetika metabolismus MeSH
- proteiny genetika MeSH
- transport proteinů fyziologie MeSH
- Zellwegerův syndrom * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod: Mukopolysacharidóza I. typu (MPS I) patří do skupiny lysosomálních střádavých onemocnění, jejichž příčinou je dědičná porucha enzymu katalyzujícího odbourávání glykosaminoglykanů, které se hromadí v tkáních. Onemocnění se projevuje různou tíží a variabilitou klinických příznaků, jež v čase progredují. Vzhledem k existenci cílené léčby, tj. enzymové substituční terapie a transplantace hematopoetických kmenových buněk, zabraňující rozvoji příznaků nebo významně zpomalující průběh onemocnění, je klíčové co nejčasnější diagnostikování nemoci. Metoda: Prezentujeme kazuistiku dívky s MPS I (fenotypem m. Hurler-Scheie) bez typických „hrubých rysů“ v obličeji, ale s dalším charakteristickým příznakem kontraktur obrazu „drápovitých rukou“, které se rozvinuly již na začátku druhého roku života a vyžadovaly operační řešení. Dále byla přítomná splenomegalie a nově rozvinutá pupeční kýla. Výsledky: Diagnóza byla stanovena až ve věku čtyř let na základě kombinace biochemických a enzymologických vyšetření s následnou konfirmací na molekulárněgenetické úrovni průkazem patogenních mutací v genu IDUA. Byla ihned zahájena enzymová substituční terapie laronidázou a pro riziko další progrese a rozvoje neurologické symptomatologie byla následně indikována k transplantaci hematopoetických kmenových buněk. Závěr: U pacienta s MPS I se vždy nemusí prezentovat charakteristická kraniofaciální dysmorfie, ale jsou popisovány další symptomy, organomegalie, syndrom karpálního tunelu a/nebo kontraktury na rukou. Vzhledem k dostupnosti laboratorní diagnostiky a cílené léčby je pro pacienty klíčové zkrácení doby mezi prvními příznaky onemocnění a diagnózou na minimum, protože s každou prodlevou se stav nenávratně horší a léčba dosahuje uspokojivých výsledků, pouze pokud je zahájena včas.
Introduction: Mucopolysaccharidosis type I (MPS I) belongs to the group of lysosomal storage diseases, the cause of which is an inherited disorder of an enzyme catalyzing catabolism of glycosaminoglycans, which accumulate in tissues. The disease manifests with varying severity and variability of clinical symptoms, that progress over time. Given the existence of targeted therapies, i.e. enzyme replacement therapy and hematopoietic stem cell transplantation, that prevent the development of the symptoms or significantly slow the progression of the disease, early diagnosis is crucial. Method: We present a case study of a girl, who suffers from MPS I (m. Hurler-Scheie phenotype), without the typical coarse facial features, but has another characteristic symptom and thus hand contractures forming a „claw hand“, which developed at the beginning of the second year of life and required a surgical management. In addition, splenomegaly and a newly developed umbilical hernia were present. Results: The diagnosis was established at the age of 4 years on the basis of a combination of biochemical and enzymological examinations, which were followed by confirmation at the molecular genetic level by detection of 2 pathogenic mutations of the IDUA gene. Enzyme replacement therapy with laronidase was initiated immediately. For a risk of further progression and development of neurological symptoms the hematopoietic stem cell transplantation was subsequently indicated. Conclusion: A patient with MPS I may not always present with the chracteristic craniofacial dysmorphia, but other symptoms such as organomegaly, carpal tunnel syndrom and/or hand contractures have been described. Given the availability of laboratory diagnostics and targeted treatment, it is crucial for the patients to minimalize the time between the first signs of the disease and the diagnosis, because with each delay the patient’s health condition irreversibly worsens, and the therapy achieves satisfactory results only if initiated in time. Key words: lysosomal storage disorders, mucopolysaccharidosis type I (MPS I), m. Hurler-Scheie, glycosaminoglycans, enzyme replacement therapy
- MeSH
- enzymová substituční terapie metody MeSH
- lidé MeSH
- lyzozomální nemoci z ukládání diagnóza patologie terapie MeSH
- mukopolysacharidóza I * diagnóza patologie terapie MeSH
- předškolní dítě MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Niemann‐Pickova choroba typu B (NPB) představuje vzácnou dědičnou metabolickou chorobu, která má velmi široké spektrum příznaků s různým věkem nástupu a tíží. Přesná diagnostika je založena na enzymologickém a současně genetickém vyšetření. V současné době je již dostupná specifická léčba pomocí enzymové substituční terapie olipudázou alfa. V tomto článku prezentujeme dospělého pacienta s náhodným nálezem splenomegalie, u kterého byla následně potvrzena diagnóza NPB.
Niemann-Pick disease type B (NPB) is a rare inherited metabolic disease that has a very wide spectrum of symptoms with different ages of onset and severity. Accurate diagnosis is based on an enzymological and genetic examination. Currently, a specific treatment using enzyme replacement therapy with olipudase alfa is already available. In this article, we present an adult patient with a random finding of splenomegaly, in whom the diagnosis of NPB was subsequently confirmed.
The present study aimed to elucidate the effect of sulforaphane (a natural isothiocyanate) on oxidative stress and mitochondrial dysfunction during and at selected periods following status epilepticus (SE) induced in immature 12-day-old rats by Li-pilocarpine. Dihydroethidium was employed for the detection of superoxide anions, immunoblot analyses for 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) levels and respiratory chain complex I activity for evaluation of mitochondrial function. Sulforaphane was given i.p. in two doses (5 mg/kg each), at PD 10 and PD 11, respectively. The findings of the present study indicate that both the acute phase of SE and the early period of epileptogenesis (1 week and 3 weeks following SE induction) are associated with oxidative stress (documented by the enhanced superoxide anion production and the increased levels of 3-NT and 4-HNE) and the persisting deficiency of complex I activity. Pretreatment with sulforaphane either completely prevented or significantly reduced markers of both oxidative stress and mitochondrial dysfunction. Since sulforaphane had no direct anti-seizure effect, the findings suggest that the ability of sulforaphane to activate Nrf2 is most likely responsible for the observed protective effect. Nrf2-ARE signaling pathway can be considered a promising target for novel therapies of epilepsy, particularly when new compounds, possessing inhibitory activity against protein-protein interaction between Nrf2 and its repressor protein Keap1, with less "off-target" effects and, importantly, with an optimal permeability and bioavailability properties, become available commercially.
- MeSH
- faktor 2 související s NF-E2 * metabolismus MeSH
- isothiokyanatany farmakologie MeSH
- KEAP-1 metabolismus MeSH
- krysa rodu rattus MeSH
- mitochondrie metabolismus MeSH
- oxidační stres MeSH
- status epilepticus * metabolismus MeSH
- sulfoxidy metabolismus farmakologie MeSH
- superoxidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cíl studie: Zhodnocení výsledků transplantace kmenových buněk krvetvorby (HSCT, hematopoietic stem cell transplantation) u dětí s dědičnými metabolickými poruchami (DMP) a maligní infantilní osteopetrózou (MIOP) v České republice od začátku transplantačního programu v roce 1989 do současnosti. Metody: V období 1/1993 až 12/2021 bylo ve FN v Motole provedeno celkem 31 alogenních HSCT u 22 pacientů s DMP a 5 pacientů s MIOP. Dárcem kmenových buněk byl HLA identický sourozenec (MSD, matched sibling donor), nepříbuzný dárce (MUD, matched unrelated donor) nebo haploidentický rodinný dárce (MMFD, mismatched family donor). Zdrojem kmenových buněk byla kostní dřeň (KD), periferní kmenové buňky (PBSC, peripheral blood stem cells) nebo pupečníková krev (UCB, umbilical cord blood). Předtransplantační přípravný režim byl použit v souladu s doporučením IEWP-EBMT (Evropská pracovní skupina pro transplantace vrozených onemocnění). Výsledky: 1. alogenní HSCT podstoupilo 22 pacientů s DMP a 5 pacientů s MIOP. Medián věku v době HSCT byl 19,5 měsíce. Primární přihojení štěpu po 1. transplantaci bylo dokumentováno u 24 z 27 pacientů (89 %). U 3 pacientů byla z důvodu nepřihojení či odhojení štěpu nutná retransplantace. Akutní reakce štěpu proti hostiteli (GVHD) byla dokumentována u 11 pacientů (41 %), těžkou formu gr. III vyvinul pouze 1 pacient, chronickou GVHD 1 pacient. Zemřelo celkem 6 pacientů, 3 na komplikace spojené s transplantací, 2 na progresi základního onemocnění, 1 pacient po úspěšné transplantaci na komplikace neurochirurgického výkonu. Celkové přežití je 78 %, 21 z 27 pacientů žije s mediánem doby sledování 169 měsíců po transplantaci (12–347 měsíců), 20 pacientů se zlepšením/stabilizací projevů onemocnění. Závěry: HSCT je v současné době standardní léčebnou metodou u vybraných DMP a MIOP. Naděje na úspěch transplantace vysoce převyšuje její rizika, zásadní je časně stanovená diagnóza a indikace k HSCT. Léčba pacientů vyžaduje komplexní přístup a spolupráci lékařů transplantačního a metabolického centra a dalších specialistů.
Objective: Evaluation of the results of hematopoietic stem cell transplantation (HSCT) in children with inborn errors of metabolism (IEM) and malignant infantile osteopetrosis (MIOP) in the Czech Republic from the beginning of the transplant programme in 1989 to the present. Methods: In the period 1/1993 to 12/2021 a total of 31 allogeneic HSCTs were performed at the University Hospital Motol in 22 patients with IEM and 5 patients with MIOP. Patients were transplanted from HLA identical sibling (MSD), matched unrelated donor (MUD) or mismatched family donor (MMFD). The source of stem cells was bone marrow (BM), peripheral blood stem cells (PBSC) or umbilical cord blood (UCB). The conditioning regimen was used in accordance with the IEWP-EBMT (Inborn Errors Working party – European Bone Marrow Transplant). Results: 22 patients with IEM and 5 patients with MIOP underwent the first allogeneic HSCT at the median age of 19,5 months. Engraftment after the first transplant was documented in 24 of 27 patients (89 %). Three patients underwent retransplantation for primary or secondary graft failure. Acute graft-versus-host disease (GVHD) was documented in 11 patients (41 %), severe form of aGVHD gr. III in 1 patient and chronic GVHD in 1 patient, respectively. A total of 6 patients died, 3 patients due to transplant-related mortality, 2 patients from disease progression, respectively and 1 patient died after a successful transplant due to complications of neurosurgery. The overall survival is 78 %, 21 of 27 patients are alive with a median follow-up of 169 months after transplantation (12-347 months), 20 of them with improvement or stabilization of the disease. Conclusions: HSCT is currently the standard therapy for selected IEM and MIOP. This procedure has become much safer during recent decades, timely diagnosis and indication for HSCT are essential. The treatment requires multidisciplinary management and continuous collaboration with other specialists.
Regulation of H2S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H2S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H2S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H2S synthesis from accumulating homocysteine, which suggests a control of H2S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H2S homeostasis.
- MeSH
- cystein MeSH
- homeostáza MeSH
- homocystein MeSH
- lidé MeSH
- síra MeSH
- sulfan * metabolismus MeSH
- sulfidy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.
- MeSH
- homocystein MeSH
- homocystinurie * diagnóza farmakoterapie MeSH
- kohortové studie MeSH
- lidé MeSH
- methylentetrahydrofolátreduktasa (NADPH2) nedostatek genetika MeSH
- novorozenec MeSH
- psychotické poruchy MeSH
- retrospektivní studie MeSH
- svalová spasticita diagnóza MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
