Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
J Inherit Metab Dis ; 45(6): 1106-1117, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36093991

RESUMO

Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.


Assuntos
Galactosemias , Feminino , Humanos , Recém-Nascido , Alelos , Galactose , Galactosemias/genética , Galactosemias/diagnóstico , Homozigoto , UTP-Hexose-1-Fosfato Uridililtransferase/genética
2.
J Inherit Metab Dis ; 43(6): 1199-1204, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32748411

RESUMO

Galactosemia is a rare, treatable hereditary disorder of carbohydrate metabolism. We investigated the etiology of decreased GALT enzyme activity in a cohort of newborns referred by the Florida Newborn Screening Program with no detectable GALT variants in diagnostic molecular tests. Six affected individuals from four families with Guatemalan heritage were included. GALT enzyme activity ranged from 20% to 34% of normal. Clinical findings were unremarkable except for speech delay in two children. Via genome sequencing followed by Sanger confirmation we showed that all affected individuals were homozygous for a deep intronic GALT variant, c.1059+390A>G, which segregated as an autosomal recessive trait in all families. The intronic variant disrupts splicing and leads to a premature termination and is associated with a single haplotype flanking GALT, suggesting a founder effect. In conclusion, we present a deep intronic GALT variant leading to a biochemical variant form of galactosemia. This variant remains undiagnosed until it is specifically targeted in molecular testing.


Assuntos
Galactosemias/diagnóstico , Homozigoto , Mutação , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Pré-Escolar , Saúde da Família , Feminino , Galactosemias/sangue , Galactosemias/genética , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , UTP-Hexose-1-Fosfato Uridililtransferase/deficiência
3.
J Neuropsychiatry Clin Neurosci ; 32(1): 67-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31564234

RESUMO

OBJECTIVE: The purpose of this study was to determine whether patients with functional movement disorders (FMDs) differ in their internal versus external locus of control (LOC) and whether LOC in these patients affected disease severity, quality of life, and functional impairment compared with control subjects with degenerative (Parkinson's disease) and nondegenerative (focal dystonia) neurological conditions. METHODS: A total of 156 patients with FMD (N=45), Parkinson's disease (N=64), and focal dystonia (N=47) were recruited between June 2015 and August 2017. The authors administered the general Levenson Multidimensional LOC (LOC-G) and health-specific Multidimensional Health LOC (LOC-H) scales. An internal LOC was represented similarly in both scales: the external LOC included "chance" and "powerful others" in the LOC-G measure and chance, "other people," and "doctors" in the LOC-H measure. Quality of life, functional impairment, and FMD severity were assessed. One-way analysis of variance and adjusted logistic regressions were used, as well as ordinary least-squares between and within groups, respectively. RESULTS: Patients with FMD had lower external chance LOC-G scores compared with patients in the Parkinson's disease group (odds ratio=0.90, p=0.03) and higher internal (odds ratio=1.22, p=0.01) and lower external (odds ratio=0.77, p=0.02) doctors LOC-H scores compared with patients in the focal dystonia group. External powerful others LOC-G score was associated with functional impairment (regression coefficient=-0.04, p=0.02). There were no effects of LOC on quality of life or disease severity. CONCLUSIONS: Patients with FMD exhibited high "within our control" internal general and health-specific frame of reference. LOC had no influence on quality of life or disease severity in this patient population.


Assuntos
Transtorno Conversivo/psicologia , Distúrbios Distônicos/psicologia , Controle Interno-Externo , Transtornos dos Movimentos/psicologia , Doença de Parkinson/psicologia , Transtornos Psicofisiológicos/psicologia , Adulto , Idoso , Transtorno Conversivo/fisiopatologia , Estudos Transversais , Distúrbios Distônicos/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/fisiopatologia , Doença de Parkinson/fisiopatologia , Transtornos Psicofisiológicos/fisiopatologia , Qualidade de Vida , Índice de Gravidade de Doença
5.
Mol Genet Genomics ; 283(6): 575-89, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20437057

RESUMO

Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, whereas only a limited number of bacteria are able to synthesize PC. Intriguingly, many of the bacteria with PC-containing membranes interact with eukaryotic hosts. PC is one of the major membrane lipids in the phytopathogenic bacterium Agrobacterium tumefaciens. The presence of PC is critical for diverse cellular processes like motility, biofilm formation, stress resistance, and virulence. The exact role of PC in these processes is unknown. Here, we examined the global consequences of the complete loss of PC at the proteomic and transcriptomic levels. Both strategies validated the impaired virulence gene induction responsible for the virulence defect of the PC-deficient mutant. In addition, the proteomic approach revealed a limited subset of proteins with altered abundance including the reduced flagellar proteins FlaA and FlaB, which explains the motility defect of the PC mutant. At the whole-genome level, the loss of PC was correlated with altered expression of up to 13% of all genes, most encoding membrane or membrane-associated proteins and proteins with functions in the extracytoplasmic stress response. Our integrated analysis revealed that A. tumefaciens dynamically remodels its membrane protein composition in order to sustain normal growth in the absence of PC.


Assuntos
Agrobacterium tumefaciens/genética , Agrobacterium tumefaciens/metabolismo , Agrobacterium tumefaciens/patogenicidade , Fosfatidilcolinas/metabolismo , Fatores de Virulência/genética , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Genômica , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Organismos Geneticamente Modificados , Proteoma/análise , Proteoma/metabolismo , Proteômica , Fatores de Virulência/deficiência
6.
Mol Genet Metab Rep ; 23: 100571, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32140415

RESUMO

BACKGROUND: Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by mutations in the gene encoding phenylalanine hydroxylase, an enzyme that converts phenylalanine to tyrosine. Untreated, PKU is characterized by a range of neuropsychological and neurocognitive impairments. Due to ubiquitous newborn genetic screening programs, treatment for PKU can be commenced shortly after birth and can prevent many of the severe manifestations of the disease. However, lifelong management is critical for patients with PKU as high levels of phenylalanine are neurotoxic. As for all chronic diseases, long-term management can be challenging and most adult patients with PKU become lost to follow-up (LTFU). A survey of PKU clinics across the United States and a multidisciplinary Expert Meeting were conducted to develop best practices to engage LTFU patients with PKU. RESULTS: We defined LTFU patients with PKU as "patients with no contact with the clinic for at least 2 consecutive years." Combining the results from our survey and our discussion at the Expert Meeting, we have prepared six best practice recommendations to engage LTFU patients with PKU: 1) Ensure patients are aware of the current treatment guidelines for PKU; 2) Communicate to patients any new treatment and diet options as they become available for PKU; 3) Consider the neuropsychological and neurocognitive aspects of PKU; 4) Prioritize motivated LTFU patients; 5) Explore new approaches of outreach to LTFU patients; and 6) Formalize approaches to track and/or identify PKU patients. CONCLUSION: We strongly advocate the importance of engaging LTFU patients with PKU and encourage implementation of our best practice recommendations. Although it takes time and effort to engage LTFU patients, we believe that clinics are capable of supporting this significant patient group.

7.
J Bacteriol ; 190(2): 571-80, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17993534

RESUMO

Phosphatidylcholine (PC) is the major phospholipid in eukaryotic membranes. In contrast, it is found in only a few prokaryotes including members of the family Rhizobiaceae. In these bacteria, PC is required for pathogenic and symbiotic plant-microbe interactions, as shown for Agrobacterium tumefaciens and Bradyrhizobium japonicum. At least two different phospholipid N-methyltransferases (PmtA and PmtX) have been postulated to convert phosphatidylethanolamine (PE) to PC in B. japonicum by three consecutive methylation reactions. However, apart from the known PmtA enzyme, we identified and characterized three additional pmt genes (pmtX1, pmtX3, and pmtX4), which can be functionally expressed in Escherichia coli, showing different substrate specificities. B. japonicum expressed only two of these pmt genes (pmtA and pmtX1) under all conditions tested. PmtA predominantly converts PE to monomethyl PE, whereas PmtX1 carries out both subsequent methylation steps. B. japonicum is the first bacterium known to use two functionally different Pmts. It also expresses a PC synthase, which produces PC via condensation of CDP-diacylglycerol and choline. Our study shows that PC biosynthesis in bacteria can be much more complex than previously anticipated.


Assuntos
Bradyrhizobium/enzimologia , Metiltransferases/genética , Metiltransferases/metabolismo , Bradyrhizobium/genética , Clonagem Molecular , DNA Bacteriano/química , DNA Bacteriano/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Deleção de Genes , Expressão Gênica , Dados de Sequência Molecular , Mutagênese Insercional , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Análise de Sequência de DNA , Especificidade por Substrato
8.
Expert Rev Neurother ; 18(11): 825-845, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30269610

RESUMO

INTRODUCTION: The increasing development and availability of portable and wearable technologies is rapidly expanding the field of technology-based objective measures (TOMs) in neurological disorders, including Parkinson disease (PD). Substantial challenges remain in the recognition of disease phenomena relevant to patients and clinicians, as well as in the identification of the most appropriate devices to carry out these measurements. Areas covered: The authors systematically reviewed PubMed for studies employing technology as outcome measures in the assessment of PD-associated motor and nonmotor abnormalities. Expert commentary: TOMs minimize intra- and inter-rater variability in clinical assessments of motor and nonmotor phenomena in PD, improving the accuracy of clinical endpoints. Critical unmet needs for the integration of TOMs into clinical and research practice are the identification and validation of relevant endpoints for individual patients, the capture of motor and nonmotor activities from an ecologically valid environment, the integration of various sensor data into an open-access, common-language platforms, and the definition of a regulatory pathway for approval of TOMs. The current lack of multidomain, multisensor, smart technologies to measure in real time a wide scope of relevant changes remain a significant limitation for the integration of technology into the assessment of PD motor and nonmotor functional disability.

9.
Eur J Cell Biol ; 89(12): 888-94, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20656373

RESUMO

Phosphatidylcholine (PC), a typical eukaryotic membrane phospholipid, is present in only about 10% of all bacterial species, in particular in bacteria interacting with eukaryotes. A number of studies revealed that PC plays a fundamental role in symbiotic and pathogenic microbe-host interactions. Agrobacterium tumefaciens mutants lacking PC are unable to elicit plant tumors. The human pathogens Brucella abortus and Legionella pneumophila require PC for full virulence. The plant symbionts Bradyrhizobium japonicum and Sinorhizobium meliloti depend on wild-type levels of PC to establish an efficient root nodule symbiosis. Two pathways for PC biosynthesis are known in bacteria, the methylation pathway and the phosphatidylcholine synthase (Pcs) pathway. The methylation pathway involves a three-step methylation of phosphatidylethanolamine by at least one phospholipid N-methyltransferase to yield phosphatidylcholine. In the Pcs pathway, choline is condensed directly with CDP-diacylglycerol to form PC. This review focuses on the biosynthetic pathways and the significance of PC in bacteria with an emphasis on plant-microbe interactions.


Assuntos
Bactérias/metabolismo , Células Eucarióticas/microbiologia , Fosfatidilcolinas/biossíntese , Fosfatidilcolinas/metabolismo , Animais , Bactérias/crescimento & desenvolvimento , Bactérias/patogenicidade , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Transdução de Sinais/fisiologia
10.
Mol Genet Genomics ; 280(1): 59-72, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18446372

RESUMO

Phosphatidylcholine (PC) is the major phospholipid in eukaryotic membranes. In contrast, it is found in only a limited number of bacteria including members of the Rhizobiales. Here, PC is required for pathogenic and symbiotic plant-microbe interactions, as shown for Agrobacterium tumefaciens and Bradyrhizobium japonicum, respectively. Two different phospholipid N-methyltransferases, PmtA and PmtX1, convert phosphatidylethanolamine (PE) to PC by three consecutive methylation reactions in B. japonicum. PmtA mainly catalyzes the first methylation reaction converting PE to monomethyl PE, which then serves as substrate for PmtX1 performing the last two methylation reactions. Disruption of the pmtA gene results in a significantly reduced PC content causing a defect in symbiosis with the soybean host. A genome-wide survey for differentially expressed genes in the pmtA mutant with a custom-made Affymetrix gene chip revealed that PC reduction affects transcription of a strictly confined set of genes. Among the 11 up regulated genes were pmtX3 and pmtX4, which code for isoenzymes of PmtA. The expression of two typical two-component systems, a MarR-like regulator and two proteins of a RND-type (resistance nodulation cell division) efflux system were differentially expressed in the pmtA mutant. Our data suggests that a decrease in the PC content of B. japonicum membranes induces a rather specific transcriptional response involving three different transcriptional regulators all involved in the regulatory fine-tuning of a RND-type transport system.


Assuntos
Bradyrhizobium/genética , Bradyrhizobium/metabolismo , Perfilação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilcolinas/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla/genética , Regulação Bacteriana da Expressão Gênica , Concentração de Íons de Hidrogênio , Metiltransferases/genética , Metiltransferases/metabolismo , Modelos Biológicos , Organismos Geneticamente Modificados , Oxirredução , Fosfatos/farmacologia , Glycine max/metabolismo , Glycine max/microbiologia
11.
Mol Microbiol ; 62(3): 906-15, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17010159

RESUMO

Phosphatidylcholine (PC, lecithin) has long been considered a solely eukaryotic membrane lipid. Only a minority of all bacteria is able to synthesize PC. The plant-transforming bacterium Agrobacterium tumefaciens encodes two potential PC forming enzymes, a phospholipid N-methyltransferase (PmtA) and a PC synthase (Pcs). We show that PC biosynthesis and tumour formation on Kalanchoë plants was impaired in the double mutant. The virulence defect was due to a complete lack of the type IV secretion machinery in the Agrobacterium PC mutant. Our results strongly suggest that PC in bacterial membranes is an important determinant for the establishment of host-microbe interactions.


Assuntos
Agrobacterium tumefaciens/patogenicidade , Membrana Celular/metabolismo , Fosfatidilcolinas/metabolismo , Agrobacterium tumefaciens/genética , Regulação Bacteriana da Expressão Gênica , Mutação , Óperon , Fosfatidiletanolamina N-Metiltransferase/genética , Fosfatidiletanolamina N-Metiltransferase/metabolismo , Tumores de Planta/microbiologia , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Virulência
12.
Microbiology (Reading) ; 151(Pt 5): 1313-1323, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15870442

RESUMO

Pseudomonas aeruginosa is an opportunistic pathogen which causes a variety of diseases, including respiratory tract infections in patients suffering from cystic fibrosis. Therapeutic treatment of P. aeruginosa infections is still very difficult because the bacteria exhibit high intrinsic resistance against a variety of different antibiotics and, in addition, form stable biofilms, e.g. in the human lung. Several virulence factors are produced by P. aeruginosa, among them the two lectins LecA and LecB, which exert different cytotoxic effects on respiratory epithelial cells and presumably facilitate bacterial adhesion to the airway mucosa. Here, the physiology has been studied of the lectin LecB, which binds specifically to L-fucose. A LecB-deficient P. aeruginosa mutant was shown to be impaired in biofilm formation when compared with the wild-type strain, suggesting an important role for LecB in this process. This result prompted an investigation of the subcellular localization of LecB by cell fractionation and subsequent immunoblotting. The results show that LecB is abundantly present in the bacterial outer-membrane fraction. It is further demonstrated that LecB could be released specifically by treatment of the outer-membrane fraction with p-nitrophenyl alpha-L-fucose, whereas treatment with D-galactose had no effect. In contrast, a LecB protein carrying the mutation D104A, which results in a defective sugar-binding site, was no longer detectable in the membrane fraction, suggesting that LecB binds to specific carbohydrate ligands located at the bacterial cell surface. Staining of biofilm cells using fluorescently labelled LecB confirmed the presence of these ligands.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Biofilmes/crescimento & desenvolvimento , Lectinas/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Membrana Celular/metabolismo , Fucose/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Lectinas/química , Lectinas/genética , Ligantes , Mutação , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Frações Subcelulares/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA