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1.
Nanotoxicology ; : 1-17, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34752713

RESUMO

This article presents an automated image-processing workflow for quantitative assessment of SPION accumulation in tissue sections stained with Prussian blue for iron detection. We utilized supervised machine learning with manually labeled features used for training the classifier. Performance of the classifier was validated by 10-fold cross-validation of obtained data and by measuring Dice and Jaccard Similarity Coefficients between manually segmented image and automated segmentation. The proposed approach provides time and cost-effective solution for quantitative imaging analysis of SPION in tissue with a precision similar to that obtained via thresholding method for stain quantification. Furthermore, we exploited the classifiers to generate segmented 3D volumes from histological slides. This enabled visualization of particles which were obscured in original 3D histology stacks. Our approach offers a powerful tool for preclinical assessment of the precise tissue-specific SPION biodistribution, which could affect both their toxicity and their efficacy as nanocarriers for medicines.

2.
Adv Healthc Mater ; : e2101544, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34706167

RESUMO

Prostate cancer (PCa), one of the leading causes of cancer-related deaths, currently lacks effective treatment for advanced-stage disease. Paclitaxel (PTX) is a highly active chemotherapeutic drug and the first-line treatment for PCa; however, conventional PTX formulation causes severe hypersensitivity reactions and limits PTX use at high concentrations. In the pursuit of high molecular weight, biodegradable, and pH-responsive polymeric carriers, one conjugates PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over 2 weeks in a pH-responsive manner while also obtaining a degree of epimerization of PTX to 7-epi-PTX. Serum proteins stabilize tert-Ser-PTX, with enhanced stability in human serum versus PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrate IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrate that tert-Ser-PTX significantly reduces the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibits primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as confirmed by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice carrying orthotopic LNCaP tumors. Overall, the results suggest the application of tert-Ser-PTX as a robust antitumor/antimetastatic treatment for PCa.

3.
Children (Basel) ; 8(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34682117

RESUMO

BACKGROUND: Growth failure is commonly reported in children with PMM2-CDG. The aim of the study was to delineate the longitudinal anthropometric phenotype of patients with PMM2-CDG and attempt to find some correlations between the genotype and anthropometric phenotype. MATERIALS AND METHODS: Retrospective chart review of PMM2-CDG patients' medical records was performed regarding the anthropometric measurements (head circumference, body length/height, body weight, body mass index) and PMM2 variants. RESULTS: A negative tendency of growth evolution was observed. Patients found to be heterozygous for R141H grew slower than other patients. Body weight was correlated with body height. A negative tendency of the growth rate of head circumference was observed. Patients found to be heterozygous for R141H experienced slower growth than other patients. CONCLUSIONS: Long-term observational studies are essential to characterize the anthropometric phenotype. The body growth failure, as well as head circumference growth failure, were more severe in patients found to be heterozygous for R141H.

4.
Acta Biochim Pol ; 68(4): 791-793, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34486878

RESUMO

BACKGROUND: Several transferrin gene polymorphisms are known to result in a shifted IEF pattern. The aim of this study was to characterize the transferrin gene polymorphisms observed in patients from one referral center. MATERIALS AND METHODS: Patients with solely increased pentasialo-Tf were selected. The whole exome sequencing was done from probands (patients) and from DNA available from their parents. RESULTS: Two various polymorphisms in the transferrin gene: c.2012G>A, p.Gly671Glu and c.1027C>T, p.Arg343Trp, were found. CONCLUSIONS: Two transferrin gene polymorphisms: c.2012G>A, p.(Gly671Glu) and c.1027C>T, p.(Arg343Trp) solely correspond to an elevated pentasialo-Tf.

5.
Front Pediatr ; 9: 696918, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34291020

RESUMO

Background: Congenital disorders of glycosylation (CDG) and NGLY1-CDDG (NGLY1-congenital disorder of deglycosylation) usually represent multisystem (especially neurovisceral) diseases with liver involvement reported in some of them. The aim of the study was to characterize the liver phenotype in CDG and NGLY1-CDDG patients hospitalized in our Institute, and to find the most specific features of liver disease among them. Material and Methods: The study involved 39 patients (from 35 families) with CDG, and two patients (from two families) with NGLY1-CDDG, confirmed molecularly, for whom detailed characteristics of liver involvement were available. They were enrolled based on the retrospective analysis of their medical records. Results: At the time of the first consultation, 13/32 patients were diagnosed with hepatomegaly; none of them with splenomegaly. As many as 23/32 persons had elevated serum transaminases, including 16 (70%) who had mildly elevated levels. During the long-term follow-up (available for 19 patients), serum transaminases normalized in 15/19 (79%) of them, including a spontaneous normalization in 12/15 (80%) of them. The GGT activity was observed to be normal in all study cases. Protein C, protein S and antithrombin activities in plasma were observed in 16 patients, and they were decreased in all of them. Conclusions: It is necessary to conduct a long-term follow-up of liver disease in CDG to obtain comprehensive data.

6.
Mol Genet Metab Rep ; 27: 100726, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33643843

RESUMO

Introduction: The incidence and prevalence of congenital disorders of glycosylation (CDG) have not been well established. The aim of the study was to evaluate the prevalence, incidence and genotypes of CDG patients diagnosed during the last 23 years in Poland (1997 - 30th October 2020). Material and methods: The diagnosis was based on serum Tf IEF which is performed at The Children's Memorial Health Institute (CMHI) in Warsaw. Based on demographic data, the prevalence of CDG among the Polish population in 2020 as well as the birth prevalence of CDG from 1990 to 2020 were estimated. Results: 39 patients (from 35 families) with molecularly confirmed CDG were diagnosed, including 17 (44%) patients (from 16 families) with PMM2-CDG. The c.422G > A, p.Arg141His and c.691G > A, p.Val231Met pathogenic missense variants were the most common identified PMM2 variants. Eleven other patients were diagnosed with CDG based on serum Tf IEF analysis only; the molecular analysis is pending. Ten CDG patients died, including 6 with PMM2-CDG, 1 with PGM1-CDG and 1 with DPAGT1-CDG. The prevalence of CDG in the Polish population was estimated at approximately 1 per million while that of PMM2 at 0.4 per million. The annual incidence of CDG was estimated at 0.013 per 100,000 people in 2020. Conclusions: A low frequence of CDG in our study could be underestimated.

7.
Pediatr Neonatol ; 62(3): 278-283, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33663989

RESUMO

BACKGROUND: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and their attachment to proteins and lipids. Histologically, liver steatosis, fibrosis and cirrhosis have been reported in CDG. The aim of the study was to characterize the histopathological and ultrastructural liver changes in CDG patients hospitalized in our Institute, and to find the most characteristic features, as articles concerning the liver microscopic features in CDG are sparse. METHODS: Out of 32 CDG patients diagnosed and followed-up in our Institute, the liver biopsy was performed in 4 of them, including 2 with MPI-CDG, 1 with SRD5A3-CDG, and 1 with PGM1-CDG, as a part of diagnostic process. In one patient, diagnosed post mortem with PMM2-CDG, the histopathological study comprised liver autopsy samples. RESULTS: The most common histopathological liver finding was the presence of steatosis (4/5) of varying severity, the mixed macro- and microvesicular type as well as the foamy degeneration of hepatocytes. In two patients, liver steatosis was associated with fibrosis, stage 4 (cirrhosis) and 2 according to Batts and Ludwig classification, respectively. In two patients, besides steatosis, mild inflammatory infiltrates composed of lymphoid cells in portal tracts were observed. No correlation between the patient's age and histopathological features was observed. CONCLUSIONS: The histopathological changes in the liver of CDG patients are miscellaneous; thus, based on the microscopic examination only, we can not identify (even suspect) the exact CDG. The most common histopathologic finding in our cohort of CDG patients was the presence of liver steatosis (of various severity) and foamy degeneration of hepatocytes.


Assuntos
Defeitos Congênitos da Glicosilação , Estudos de Coortes , Humanos , Cirrose Hepática
8.
Acta Biochim Pol ; 68(1): 139-142, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667052

RESUMO

Congenital disorders of glycosylation (CDG) are a growing, heterogeneous group of genetic disorders caused by a defect in the glycoprotein synthesis. The first and still widely used method for routine CDG screening was isoelectric focusing (IEF) of serum transferrin. Dried blood spot (DBS) testing is commonly used in newborn screening procedures to detect inborn errors of metabolism. The aim of this study was to demonstrate the reliability of the IEF method in DBS testing. Dried blood spot testing can help in the postmortem diagnosis of CDG disorders when other material is unavailable. The patterns and concentrations of transferrin isoforms in serum and DBS are comparable, and slight differences do not affect interpretation of results.


Assuntos
Defeitos Congênitos da Glicosilação/sangue , Defeitos Congênitos da Glicosilação/diagnóstico , Teste em Amostras de Sangue Seco/métodos , Programas de Rastreamento/métodos , Transferrina/análise , Estudos de Casos e Controles , Humanos , Focalização Isoelétrica/métodos , Isoformas de Proteínas/análise , Reprodutibilidade dos Testes
9.
Orphanet J Rare Dis ; 16(1): 17, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407696

RESUMO

BACKGROUND: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical, and molecular findings of CDG patients, and to present the long-term follow-up. MATERIAL AND METHODS: A single-center study (1995-2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation was performed. RESULTS: Among 32 patients included into the study, there were 12 PMM2-CDG, 3 ALG13-CDG, 3 ALG1-CDG, 1 ALG3-CDG, 3 MPI-CDG, 1 PGM1-CDG, 4 SRD5A3-CDG, 1 DPAGT1-CDG, 3 ATP6AP1-CDG, 1 ATP6V0A2-CDG. The phenotypic and genotypic spectrum during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between asialo-Tf and tetrasialo-Tf, as well as between disialo-Tf and tetrasialo-Tf. Within CDG type I, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG was assessed and we found that % of asialo-Tf, monosialo-Tf, and disialo-Tf was significantly lowered, whereas tetrasialo-Tf and pentasialo-Tf rose, coming closer or falling into the reference range. CONCLUSIONS: The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM1-CDG patient, improved patients' clinical picture and Tf isoform profiles.


Assuntos
Defeitos Congênitos da Glicosilação , ATPases Vacuolares Próton-Translocadoras , Defeitos Congênitos da Glicosilação/genética , Seguimentos , Genótipo , Glicosilação , Humanos , Manosiltransferases , Fenótipo
10.
Postepy Biochem ; 66(3): 213-228, 2020 09 30.
Artigo em Polonês | MEDLINE | ID: mdl-33315314

RESUMO

Congenital disorders of glycosylation (CDG) are a group of genetic disorders caused by abnormal N- and O-glycosylation pathway of proteins and lipids. The glycosylation process plays an important role in the proper functioning of the body and its disorder leads to serious clinical defects. The clinical picture is extremely heterogeneous, including symptoms involving many organs or systems with predominantly neurological manifestation.A broad clinical phenotype poses a challenge in CDG diagnosis. A large group among CDG are defects associated with protein N-hypoglycosylation. A simple test its diagnosis is isoelectrofocusing (IEF) of serum transferrin which is still the "gold standard" in the diagnostics. Normal isoform transferrin profile does not rule out all glycosylation defects. Molecular diagnostics play an important role and the dissemination of next generation sequencing (NGS) has allowed new disorders to be identified.


Assuntos
Defeitos Congênitos da Glicosilação , Defeitos Congênitos da Glicosilação/diagnóstico , Glicosilação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Patologia Molecular , Isoformas de Proteínas , Transferrina/metabolismo
11.
Diagnostics (Basel) ; 10(10)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977617

RESUMO

Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children's Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients' medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1-Q2) was 2.5 years (1.5-9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0-20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one-severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients.

12.
Acta Biochim Pol ; 67(2): 225-228, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32436673

RESUMO

Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The paper presents a case of Polish NICCD patient presenting with low birth weight, failure to thrive, prolonged cholestatic jaundice with coagulopathy and hypoalbuminemia with normal results of MS/MS newborn screening but with high blood citrulline level observed at 3 months of age. Unreported findings included N-hypoglycosylation and increased serum very-long-chain fatty acids (VLCFA), probably secondary to liver impairment. Final diagnosis was established based on whole-exome sequencing (WES) analysis.


Assuntos
Transtornos da Coagulação Sanguínea/complicações , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/etiologia , Citrulinemia/complicações , Citrulinemia/diagnóstico , Hipoalbuminemia/complicações , Icterícia Obstrutiva/diagnóstico , Icterícia Obstrutiva/etiologia , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/tratamento farmacológico , Citrulina/sangue , Citrulinemia/sangue , Citrulinemia/tratamento farmacológico , Diagnóstico Precoce , Seguimentos , Humanos , Hipoalbuminemia/sangue , Hipoalbuminemia/tratamento farmacológico , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Icterícia Obstrutiva/sangue , Icterícia Obstrutiva/tratamento farmacológico , Masculino , Triagem Neonatal , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico , Vitaminas/uso terapêutico , Sequenciamento Completo do Exoma
13.
Breast Cancer Res Treat ; 181(3): 571-580, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378053

RESUMO

PURPOSE: The association between pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC) for breast cancer and Circulating Tumour Cells (CTCs) is not clear. The aim of this study was to assess whether CTC enumeration could be used to predict pathological response to NAC in breast cancer as measured by the Miller-Payne grading system. METHODS: Twenty-six patients were recruited, and blood samples were taken pre- and post-NAC. CTCs were isolated using the ScreenCell device and stained using a modified Giemsa stain. CTCs were enumerated by 2 pathologists and classified as single CTCs, doublets, clusters/microemboli and correlated with the pathological response as measured by the Miller-Payne grading system. χ2 or ANOVA was performed in SPSS 24.0 statistics software for associations. RESULTS: 89% of patients had invasive ductal carcinoma (IDC) and 11% invasive lobular carcinoma (ILC). At baseline 85% of patients had CTCs present, median 7 (0-161) CTCs per 3 ml of whole blood. Post-chemotherapy, 58% had an increase in CTCs. This did not correlate with the Miller-Payne grade of response. No significant association was identified between the number of CTCs and clinical characteristics; however, we did observe a correlation between pre-treatment CTC counts and body mass index, p < 0.05. CONCLUSIONS: Patients with a complete response to NAC still had CTCs present, suggesting enumeration is not sufficient to aid surgery stratification. Additional characterisation and larger studies are needed to further characterise CTCs isolated pre- and post-chemotherapy. Long-term follow-up of these patients will determine the significance of CTCs in NAC breast cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Terapia Neoadjuvante/mortalidade , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Células Neoplásicas Circulantes/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida
14.
JIMD Rep ; 53(1): 80-82, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32395412

RESUMO

In 2016, 11 male patients were reported with immunodeficiency and hepatic, gastric and (in some) neurological disease due to X-linked ATP6AP1 deficiency (ATP6AP1-CDG). In 2018, three other patients were reported with additional features: connective tissue abnormalities, sensorineural hearing loss, hyperopia, glomerular and tubular dysfunction, exocrine pancreatic insufficiency and altered amino acid and lipid metabolism. We here present a follow-up of three reported siblings showing progression of deafness to total hearing loss, progressive loss of hair up to alopecia, chestnut skin and, at last follow-up, in some of them proteinuria. Three female carriers showed a normal serum transferrin isoelectrofocusing but in two of them there was a persistent proteinuria.

15.
Nanomaterials (Basel) ; 10(3)2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32213961

RESUMO

Magnetic hyperthermia involves the use of iron oxide nanoparticles to generate heat in tumours following stimulation with alternating magnetic fields. In recent times, this treatment has undergone numerous clinical trials in various solid malignancies and subsequently achieved clinical approval to treat glioblastoma and prostate cancer in 2011 and 2018, respectively. However, despite recent clinical advances, many questions remain with regard to the underlying mechanisms involved in this therapy. One such query is whether intracellular or extracellular nanoparticles are necessary for treatment efficacy. Herein, we compare the effects of intracellular and extracellular magnetic hyperthermia in BxPC-3 cells to determine the differences in efficacy between both. Extracellular magnetic hyperthermia at temperatures between 40-42.5 °C could induce significant levels of necrosis in these cells, whereas intracellular magnetic hyperthermia resulted in no change in viability. This led to a discussion on the overall relevance of intracellular nanoparticles to the efficacy of magnetic hyperthermia therapy.

16.
JIMD Rep ; 51(1): 82-88, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32071843

RESUMO

Objectives: Together with the lysosomal storage diseases, NGLY1 deficiency is a congenital disorder of deglycosylation (NGLY1-CDDG). Since the first report in 2012, 26 patients have been described. All but one were diagnosed by exome or genome sequencing; the remaining one was identified by finding an increased concentration of an urinary marker.The aim of this study was to describe the clinical, biochemical, and molecular features of the first Polish patient diagnosed with NGLY1-CDDG, to provide an overview of the literature and to propose a diagnostic algorithm. Results: A Polish patient presented with global developmental delay, hyperkinetic movement disorder, stagnation of head growth, hypolacrimia, elevated serum transaminases, and hypolipidemia in infancy. Whole exome sequencing revealed two heterozygous nonsense variants in the NGLY1 gene (a novel and an unreported). Literature review revealed global developmental disability in all reported patients, and hyperkinetic movements as well as alacrima/hypolacrima in nearly all. Conclusions: NGLY1-CDDG should be considered in patients with developmental disability associated with a hyperkinetic movement disorder and alacrimia/hypolacrima. Absence of the latter two symptoms does not rule out this diagnosis.

17.
Mol Genet Metab Rep ; 22: 100559, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31921599

RESUMO

Introduction: Methylmalonic Aciduria (MMA) is a heterogeneous group of rare diseases leading to accumulation of methylmalonic acid in body fluids. One of the causes of the disease is the methylmalonic aciduria, cblA type (cblA - type MMA), conditioned by a mutation in the MMAA gene, which is essential for the proper functioning of a cofactor of the methylmalonyl-CoA mutase. The symptoms of the disease, depending on the cause, may manifest themselves at different ages. Most patients are sensitive to high doses of hydroxycobalamin, which is associated with better prognosis. Material and method: The purpose of the study was to retrospectively analyze the clinical picture and effects of treatment of patients with methylmalonic aciduria related to mutation in the MMAA gene. Results: Five patients with diagnosed cblA - type MMA were presented. At the time of diagnosis the median of age was 18.8 months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development. Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients. All of them were sensitive to the treatment with vitamin B12. The median of therapy duration and observation is 12.2 years. During the treatment, good metabolic control was achieved in all patients, but their cognitive development is delayed. Three patients have renal failure and pharmacologically treated arterial hypertension. Conclusions: Patients with a mutation in the MMAA gene are sensitive to treatment with hydroxocobalamine, but the inclusion of appropriate treatment does not protect against neurodevelopmental disorders and chronic kidney disease.

18.
Front Pediatr ; 8: 613224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33520896

RESUMO

Background: Isoelectric focusing (IEF) of serum transferrin (Tf) is still the method of choice for diagnosis of congenital disorders of glycosylation (CDG). An abnormal glycosylation is also a known phenomenon in adult liver disease patients. The aim of this study was to characterize glycosylation disturbances in pediatric patients with primary liver disease. However, there are no reports of this phenomenon in children. Materials and Methods: Between 1995 and 2019, circa 2,000 serum Tf isoform analyses have been performed in children with primary liver diseases; some of them underwent subsequent analyses. We enrolled in this study 19 patients who developed an acute liver injury (ALI)/failure (ALF) or exhibited a chronic liver disease (CLD) and were evaluated and listed for liver transplantation (LTx) or had just undergone this procedure, and secondary abnormal serum Tf isoform profile. Results: Among 12 patients with ALI/ALF, 10 had an increased percentage of asialo-, monosialo-, and disialo-Tf isoforms. All patients with CLD had an increased percentage of asialo- and monosialo-Tf isoform. Two patients diagnosed with recurrent ALF had very specific serum Tf profile with a huge increase in the asialo- and monosialo-Tf isoform. On follow-up analyses (available in some patients), serum Tf IEF profile normalized in parallel to normalization of liver function tests, spontaneously or during treatment, including glucocorticosteroids in AIH, LTx in CLD. Conclusions: All pediatric patients with primary liver disease had increased asialo-Tf as well as monosialo-Tf isoforms. None of them had elevated percentage of trisialo-Tf isoform.

19.
Metab Brain Dis ; 34(2): 641-649, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30570710

RESUMO

Glutaric aciduria type 1 is a neurometabolic disorder, caused by riboflavin-dependent glutaryl-CoA dehydrogenase deficiency. As its consequence, accumulation of the putatively neurotoxic metabolites (glutaric and 3-hydroxyglutaric acids) in body tissues, but especially within the brain, is observed. Estimated incidence of the disease is 1 in 110,000 newborns, The prevalence however may be higher, depending on a specific ethnic group, and result in phenotypic variation as well. In this paper we present clinical data of 13 patients of Polish nationality. They all present a mild phenotype and clinical course of glutaric aciduria type 1. Based on their clinical data, presented herein, we like to pay attention to the phenotypic and neuroimaging features important for the diagnosis of mild form of this disease. Moreover, we present novel molecular data, which may correlate with such a manifestation.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Encéfalo/diagnóstico por imagem , Glutaril-CoA Desidrogenase/deficiência , Neuroimagem , Fenótipo , Encéfalo/metabolismo , Feminino , Glutaratos/metabolismo , Humanos , Recém-Nascido , Masculino , Polônia
20.
J Inherit Metab Dis ; 34(1): 185-95, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21103935

RESUMO

UNLABELLED: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder with especially high mortality and uncertain long-term outcome. The aim of the study was to analyze the influence of diagnostic approach on survival in 59 affected children. Referral to a metabolic center was replaced over time by urine/blood testing in centralized metabolic laboratory (selective screening) and by pilot tandem mass spectrometry newborn screening (NBS). Molecular analysis revealed the prevalent mutation in the HADHA gene in all 58 examined cases. Twenty patients died. The number of detections and number of deaths were respectively 9 and 4 (44%) in the patients recognized by differential diagnosis, 28 and 9 (32%) - by selective screening, and 11 and 1 (9%) - by NBS. In 80% of cases the death occurred before or within 3 weeks from the identification. Urgent and active metabolic service remarkably influenced the surviving. The current age of 39 survivors is 0.5 to 23 yrs (mean 7.2 yrs). The disease frequency estimated on the patients number was 1: 115 450, whereas in the pilot NBS - 1: 109 750 (658 492 neonates tested). Interestingly, the phenylalanine level in asymptomatic neonates frequently exceeded the cut-off values. CONCLUSIONS: 1) Urgent metabolic intervention decreases mortality of LCHAD-deficient patients, but the prognosis is still uncertain. 2) Emergent metabolic reporting and service are crucial also for the survival of neonates detected by NBS. 3) The nationwide selective screening appeared efficient in LCHADD detection in the country. 4) Transient mild hyperphenylalaninaemia may occur in LCHAD-deficient newborns.


Assuntos
Serviço Hospitalar de Emergência , Triagem Neonatal/métodos , Exame Físico/métodos , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/urina , Adolescente , Carnitina/análogos & derivados , Carnitina/análise , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA/métodos , Dessecação , Serviço Hospitalar de Emergência/organização & administração , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/organização & administração , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/urina , Triagem Neonatal/organização & administração , Projetos Piloto , Polimorfismo de Fragmento de Restrição , Sobrevida , Fatores de Tempo , Urinálise/métodos
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