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1.
J Clin Neuromuscul Dis ; 19(1): 19-26, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28827485

RESUMO

OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.


Assuntos
Força Muscular/genética , Debilidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Miosite de Corpos de Inclusão/congênito , Adolescente , Adulto , Idoso , Feminino , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Atividade Motora/genética , Miosite de Corpos de Inclusão/complicações , Miosite de Corpos de Inclusão/genética , Ácido N-Acetilneuramínico/genética , Adulto Jovem
2.
Am J Hematol ; 92(9): 929-939, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28569047

RESUMO

This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.


Assuntos
Terapia de Reposição de Enzimas , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Esplenectomia
3.
Mol Genet Metab ; 120(1-2): 47-56, 2017 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28040394

RESUMO

In Gaucher disease (GD), deficiency of lysosomal acid ß-glucosidase results in a broad phenotypic spectrum that is classified into three types based on the absence (type 1 [GD1]) or presence and severity of primary central nervous system involvement (type 2 [GD2], the fulminant neuronopathic form, and type 3 [GD3], the milder chronic neuronopathic form). Enzyme replacement therapy (ERT) with imiglucerase ameliorates and prevents hematological and visceral manifestations in GD1, but data in GD3 are limited to small, single-center series. The effects of imiglucerase ERT on hematological, visceral and growth outcomes (note: ERT is not expected to directly impact neurologic outcomes) were evaluated during the first 5years of treatment in 253 children and adolescents (<18years of age) with GD3 enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The vast majority of GBA mutations in this diverse global population consisted of only 2 mutations: L444P (77%) and D409H (7%). At baseline, GD3 patients exhibited early onset of severe hematological and visceral disease and growth failure. During the first year of imiglucerase treatment, hemoglobin levels and platelet counts increased and liver and spleen volumes decreased, leading to marked decreases in the number of patients with moderate or severe anemia, thrombocytopenia, and hepatosplenomegaly. These improvements were maintained through Year 5. There was also acceleration in linear growth as evidenced by increasing height Z-scores. Despite devastating disease at baseline, the probability of surviving for at least 5years after starting imiglucerase was 92%. In this large, multinational cohort of pediatric GD3 patients, imiglucerase ERT provided a life-saving and life-prolonging benefit for patients with GD3, suggesting that, with proper treatment, many such severely affected patients can lead productive lives and contribute to society.


Assuntos
Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/genética , Mutação , Adolescente , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Doença de Gaucher/classificação , Doença de Gaucher/genética , Glucosilceramidase/uso terapêutico , Humanos , Masculino , Sistema de Registros , Análise de Sobrevida , Resultado do Tratamento
4.
Mol Genet Metab ; 120(1-2): 1-7, 2017 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27866832

RESUMO

To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady's research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady's efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady's pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases.


Assuntos
Terapia de Reposição de Enzimas/história , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Terapia de Reposição de Enzimas/métodos , Doença de Gaucher/tratamento farmacológico , História do Século XX , História do Século XXI , Humanos , Pesquisadores
5.
J Neurol ; 263(2): 257-262, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26566914

RESUMO

Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middle-aged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (≤165 cm for males; ≤155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A>G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A>G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.


Assuntos
DNA Mitocondrial/genética , Síndrome MELAS/epidemiologia , Síndrome MELAS/genética , Acidente Vascular Cerebral/genética , Adulto , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Adulto Jovem
6.
Radiology ; 277(2): 546-54, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26035587

RESUMO

PURPOSE: To determine whether quantitative differences in shear-wave velocity (SWV) exist between normal skeletal muscle and those affected by GNE-related myopathy and to examine the effects of muscle anisotropy, depth, and axial preload on SWV in a healthy control group. MATERIALS AND METHODS: This study was approved by the institutional review board and compliant with HIPAA. Informed consent was obtained from all study volunteers. Eight patients (four women and four men aged 30-50 years) with genetically and biopsy-proved GNE-related myopathy and five healthy volunteers (three women and two men aged 27-33 years) underwent SWV imaging with use of a 9-MHz linear transducer. The gastrocnemius muscles were evaluated in the patients with GNE-related myopathy, and the gastrocnemius, vastus lateralis, and rectus femoris muscles were evaluated in the healthy cohort. The effect of muscle anisotropy, axial preload, and sample volume depth were examined in the healthy cohort. The effect of anisotropy at a fixed depth and preload were examined in the patients with GNE-related myopathy. RESULTS: Irrespective of the muscle, the mean SWV was significantly higher with the transverse orientation than with the longitudinal orientation (P < .001). In the healthy cohort, the mean SWV for superficial measurements was significantly lower than that for deep measurements (P < .02). The mean SWV with preload was significantly higher with compression (P < .001) for the rectus femoris only. The mean SWV was significantly lower in patients with GNE-related myopathy than in control subjects (P < .02). CONCLUSION: SWV parametric imaging may provide a useful quantitative adjunct in the assessment of disease activity in patients with GNE-related myopathy. There is diminished SWV and muscle anisotropy in GNE-related myopathy.


Assuntos
Miopatias Distais/diagnóstico por imagem , Miopatias Distais/genética , Complexos Multienzimáticos/genética , Músculo Esquelético/diagnóstico por imagem , Adulto , Miopatias Distais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Mutação/genética , Projetos Piloto , Estudos Prospectivos , Ultrassonografia
7.
Mol Genet Metab ; 111(4): 513-21, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24581871

RESUMO

G(M1)-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal ß-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from G(M1)-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a G(M1)-mouse. The bears presented at ages 10-14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T(2)-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid ß-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with G(M1)-ganglioside predominating. G(A1) content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the G(M1)-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the G(M1) mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with G(M1)-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population.


Assuntos
Gangliosidose GM1/genética , Gangliosidose GM1/patologia , Ursidae/genética , Animais , Sequência de Bases , Cerebelo/patologia , Cerebelo/ultraestrutura , Cromatografia em Camada Delgada , Análise Mutacional de DNA , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Feminino , Fibroblastos/enzimologia , Fibroblastos/patologia , Gangliosídeos/metabolismo , Gangliosidose GM1/enzimologia , Regulação da Expressão Gênica , Genoma/genética , Humanos , Cartilagem Hialina/patologia , Cartilagem Hialina/ultraestrutura , Hidrolases/metabolismo , Túbulos Renais/patologia , Túbulos Renais/ultraestrutura , Imagem por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Bainha de Mielina/metabolismo , Retina/patologia , Transfecção , Estados Unidos , beta-Galactosidase/genética
8.
PLoS One ; 8(8): e71894, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24015197

RESUMO

OBJECTIVE: Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings. METHODS: Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease. RESULTS: Four patients were identified as having a "possible" history of MS, and 7 patients as "definite" cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load. CONCLUSION: There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.


Assuntos
Erros de Diagnóstico , Doença de Fabry/diagnóstico , Esclerose Múltipla/diagnóstico , Adulto , Idoso , Encéfalo/patologia , Análise Mutacional de DNA , Diagnóstico Tardio , Diagnóstico Diferencial , Doença de Fabry/líquido cefalorraquidiano , Doença de Fabry/genética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Esclerose Múltipla/líquido cefalorraquidiano , alfa-Galactosidase/genética
9.
Mol Genet Metab ; 108(1): 65-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23158871

RESUMO

A 12 year-old female presented with a seven-year history of progressive muscle weakness, atrophy, tremor and fasciculations. Cognition was normal. Rectal biopsy revealed intracellular storage material and biochemical testing indicated low hexosaminidase activity consistent with juvenile-onset G(M2)-gangliosidosis. Genetic evaluation revealed compound heterozygosity with two novel mutations in the hexosaminidase ß-subunit (c.512-3 C>A and c.1613+15_1613+18dup). Protein analysis was consistent with biochemical findings and indicated only a small portion of ß-subunits were properly processed. These results provide additional insight into juvenile-onset G(M2)-gangliosidoses and further expand the number of ß-hexosaminidase mutations associated with motor neuron disease.


Assuntos
Doença dos Neurônios Motores/genética , Mutação , beta-N-Acetil-Hexosaminidases/genética , Idade de Início , Criança , Feminino , Humanos , Doença dos Neurônios Motores/psicologia
10.
Sci Transl Med ; 4(165): 165ra163, 2012 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-23253610

RESUMO

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.


Assuntos
Doença de Canavan/terapia , Terapia Genética , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Doença de Canavan/metabolismo , Criança , Pré-Escolar , Humanos , Lactente , Estudos Prospectivos
11.
J Hypertens ; 29(12): 2387-94, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21970939

RESUMO

OBJECTIVE: In untreated Fabry patients without overt autonomic dysfunction and normal baroreflex sensitivity (BRS) at rest, BRS is impaired during orthostatic, sympathetic challenge but normalizes after enzyme-replacement therapy (ERT) (Hilz et al., J Hypertens 2010; 28:1438-1448). This study evaluated BRS during parasympathetic challenge with six cycles per minute metronomic deep breathing (MDB) in Fabry patients before and after ERT. METHODS: In 22 Fabry patients (28 ±â€Š8 years), we monitored RR-intervals (RRIs), SBP, and respiratory frequency during spontaneous breathing (spont_breath) and MDB, before and after 18 (11 patients) or 23 months (11 patients) of biweekly ERT (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) RRI fluctuations, parasympathetic high-frequency (0.15-0.5 Hz) RRI fluctuations, sympathetically mediated low-frequency powers of SBP and high-frequency powers of SBP. We calculated BRS (ms/mmHg) during spont_breath and MDB as low-frequency-high-frequency alpha index (coherence >0.5). We compared parameters during spont_breath and MDB within and between patients before and after ERT and 15 age-matched (27 ±â€Š5 years) healthy men (RANOVA and posthoc analysis; significance: P < 0.05). RESULTS: During spont_breath and MDB, parameters were similar between groups. Within the three groups, RRIs were lower, whereas RRI low-frequency powers and SBP low-frequency powers were higher during MDB than during spont_breath. BRS was similar during MBD and spont_breath in untreated patients (P > 0.05), but increased significantly with MDB in patients after ERT (P = 0.048) and in controls (P = 0.035). CONCLUSION: In untreated Fabry patients, MDB uncovers impaired BRS. After 18 or 23 months of ERT, MDB-induced BRS increase is similar in Fabry patients and controls, demonstrating that ERT not only restores sympathetic but also parasympathetic baroreflex activation.


Assuntos
Barorreflexo/fisiologia , Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Doença de Fabry/fisiopatologia , Respiração , Mecânica Respiratória/fisiologia , alfa-Galactosidase/uso terapêutico , Adulto , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doença de Fabry/enzimologia , Humanos , Isoenzimas/uso terapêutico , Masculino , Sistema Nervoso Parassimpático , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/fisiopatologia , Proteínas Recombinantes , Mecânica Respiratória/efeitos dos fármacos , alfa-Galactosidase/sangue
12.
Mol Genet Metab ; 104(1-2): 35-8, 2011 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21831682

RESUMO

A large number of mutations, and several polymorphisms, have been characterized in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase, the activity of which is impaired in Gaucher disease. In this communication we summarize published and new data concerning biochemical characterization of the E326K amino acid change (1093G>A in the GBA1 cDNA) in tissue culture and its association with Parkinson disease, suggesting it is a disease causing mutation and not merely a polymorphism in the GBA gene.


Assuntos
Substituição de Aminoácidos/genética , Glucosilceramidase/genética , Mutação/genética , Heterozigoto , Humanos , Doença de Parkinson/genética , Técnicas de Cultura de Tecidos
13.
Mol Genet Metab ; 102(1): 6-12, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20926324

RESUMO

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or ß subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy.


Assuntos
Gangliosidoses GM2/tratamento farmacológico , Pirimetamina/uso terapêutico , Adulto , Ensaios Enzimáticos , Feminino , Glucosilceramidase/sangue , Hexosaminidase A/sangue , Hexosaminidase B/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pirimetamina/efeitos adversos , Pirimetamina/sangue , Adulto Jovem , beta-Galactosidase/sangue
14.
Sensors (Basel) ; 11(1): 138-61, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22346571

RESUMO

Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox(®)), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT's selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE(®) biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE(®) laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin and reperfusion effects actually while enoxaparin is inhibiting blood clots to alleviate AIS symptomatology. This research is directly correlated with the medical and clinical needs of stroke victims. The data are clinically relevant, not only to movement dysfunction but also to the depressive mood that stroke patients often endure. These are the first studies to image brain neurotransmitters while any stroke medications, such as anti-platelet/anti-thrombotic and/or anti-glycoprotein are working in organ systems to alleviate the debilitating consequences of brain trauma and stroke/brain attacks.


Assuntos
Anticoagulantes/uso terapêutico , Técnicas Biossensoriais , Lesões Encefálicas/metabolismo , Dopamina/metabolismo , Enoxaparina/uso terapêutico , Serotonina/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Velocidade do Fluxo Sanguíneo , Lesões Encefálicas/patologia , Técnicas Eletroquímicas , Fluxometria por Laser-Doppler , Masculino , Neurônios Motores/metabolismo , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia
15.
Mol Genet Metab ; 101(4): 357-63, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20817517

RESUMO

Autopsy studies of four Jacob sheep dying within their first 6-8 months of a progressive neurodegenerative disorder suggested the presence of a neuronal storage disease. Lysosomal enzyme studies of brain and liver from an affected animal revealed diminished activity of hexosaminidase A (Hex A) measured with an artificial substrate specific for this component of ß-hexosaminidase. Absence of Hex A activity was confirmed by cellulose acetate electrophoresis. Brain lipid analyses demonstrated the presence of increased concentrations of G(M2)-ganglioside and asialo-G(M2)-ganglioside. The hexa cDNA of Jacob sheep was cloned and sequenced revealing an identical number of nucleotides and exons as in human HexA and 86% homology in nucleotide sequence. A missense mutation was found in the hexa cDNA of the affected sheep caused by a single nucleotide change at the end of exon 11 resulting in skipping of exon 11. Transfection of normal sheep hexa cDNA into COS1 cells and human Hex A-deficient cells led to expression of Hex S but no increase in Hex A indicating absence of cross-species dimerization of sheep Hex α-subunit with human Hex ß-subunits. Using restriction site analysis, the heterozygote frequency of this mutation in Jacob sheep was determined in three geographically separate flocks to average 14%. This large naturally occurring animal model of Tay-Sachs disease is the first to offer promise as a means for trials of gene therapy applicable to human infants.


Assuntos
Hexosaminidase A/genética , Hexosaminidase A/metabolismo , Doenças dos Ovinos/genética , Doença de Tay-Sachs/veterinária , Animais , Sequência de Bases , Química Encefálica , Células COS , Cercopithecus aethiops , Clonagem Molecular , DNA Complementar/genética , Modelos Animais de Doenças , Feminino , Gangliosídeo G(M2)/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos , Masculino , Dados de Sequência Molecular , Ácido N-Acetilneuramínico/metabolismo , Mutação Puntual , Homologia de Sequência do Ácido Nucleico , Ovinos , Doenças dos Ovinos/enzimologia , Doença de Tay-Sachs/enzimologia , Doença de Tay-Sachs/genética , Transfecção , beta-N-Acetil-Hexosaminidases/genética , beta-N-Acetil-Hexosaminidases/metabolismo
16.
J Hypertens ; 28(7): 1438-48, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20125036

RESUMO

OBJECTIVE: Fabry patients have autonomic dysfunction but usually do not present clinically overt signs of orthostatic dysregulation. This study evaluated orthostatic regulation and baroreflex sensitivity (BRS) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy (ERT). METHODS: In 22 Fabry patients (aged 28W8 years), we assessed electrocardiographic RR intervals (RRIs), SBP, DBP and respiratory frequency, in supine and standing position, before and after 18 (11 patients) or 23 months (11 patients) of biweekly alpha-galactosidase A infusions (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetically mediated low-frequency (0.04-0.15 Hz) and parasympathetically mediated high-frequency (0.15-0.5 Hz) RRI fluctuations, and sympathetic low-frequency powers of blood pressure fluctuations. We normalized RRI powers by relating low-frequency and high-frequency powers to total powers (low-frequency + high-frequency powers), assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance. As a measure of BRS, we used the alpha-index, obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP (coherence>0.5). We compared parameters in supine and standing position of untreated and treated patients with those of 15 healthy age-matched (27+/-5 years) men (repeated-measure analysis of variance, significance at P<0.05). RESULTS: Supine biosignals were similar in all groups. Upon standing, RRIs were lower in controls and patients after ERT than in patients before ERT (P<0.05); normalized RRI high-frequency powers as well as BRS decreased, whereas DBP, low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only (P<0.05). CONCLUSION: Reduced increase in heart rate, blood pressure and sympathetic activation, and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon standing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function, which, in turn, is an established parameter of improved disease prognosis.


Assuntos
Barorreflexo/efeitos dos fármacos , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Terapia de Reposição de Enzimas/métodos , Doença de Fabry/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Intolerância Ortostática/complicações , alfa-Galactosidase/uso terapêutico , Adulto , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia , Humanos , Masculino , Proteínas Recombinantes/uso terapêutico , Decúbito Dorsal/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos
17.
Genet Med ; 11(6): 425-33, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19346952

RESUMO

PURPOSE: To evaluate the safety and efficacy of miglustat in patients with GM2 gangliosidosis. METHODS: A randomized, multicenter, open-label, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or "no miglustat treatment." This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. RESULTS: Thirty patients (67% male, age range 18-56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to "no miglustat treatment." Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. CONCLUSION: Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Tay-Sachs/tratamento farmacológico , 1-Desoxinojirimicina/efeitos adversos , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Adulto , Idade de Início , Diarreia/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Fadiga/induzido quimicamente , Feminino , Inibidores de Glicosídeo Hidrolases , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Tay-Sachs/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos , Adulto Jovem
18.
Pediatr Neurol ; 40(4): 245-52; discussion 253-5, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19302934

RESUMO

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.


Assuntos
Leucodistrofia de Células Globoides/diagnóstico , Triagem Neonatal/organização & administração , Triagem Neonatal/normas , Análise Mutacional de DNA , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Potenciais Evocados Visuais/fisiologia , Seguimentos , Galactosilceramidase/análise , Galactosilceramidase/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Recém-Nascido , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Imagem por Ressonância Magnética , Modelos Organizacionais , Condução Nervosa/fisiologia , Exame Neurológico , New York , Encaminhamento e Consulta , Medição de Risco , Resultado do Tratamento
20.
Headache ; 49(4): 590-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19245392

RESUMO

OBJECTIVE: Characterize the phenomenon of acute confusional migraine (ACM) among Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and emphasize the possibility of CADASIL in adults with ACM. BACKGROUND: ACM, well described in children, has rarely been reported in adults. Although 30-60% of CADASIL patients have migraine, acute confusional state during migraine has not been described. We describe 7 patients with ACM that complicated up to 50% of the migraine episodes. DESIGN/METHODS: Detailed neurologic evaluation was performed in 20 CADASIL patients; International Classification of Headache Disorders 2nd edition criteria were used to diagnose migraine. RESULTS: The mean age was 51 years. Fourteen patients reported headache and 11 met the criteria for migraine (mean age of onset 25). Seven patients experienced concomitant confusion, within 3 years of migraine onset. Confusion occurred either abruptly or insidiously, at the onset of aura or headache, lasting for 2-48 hours, and ending abruptly. These episodes were stereotypic, characterized by disorientation with agitation, and retrograde amnesia for the episodes. Patients reported disorientation to time and place, inability to recognize friends and relatives, difficulty with finding directions home, fear of getting lost, inability to analyze traffic lights or tell time. Patients reliably predicted the episodes and felt the need to seek a safe place for protection. Severity of the episodes progressed, but a striking improvement occurred after the first stroke. CONCLUSION: ACM may be a presenting feature and important clue, enabling CADASIL to be recognized up to a decade or earlier than at present. Therefore, a brain MRI and/or testing for Notch3 mutations should be considered in adult patients with ACM.


Assuntos
CADASIL/complicações , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/diagnóstico , Adulto , Idoso , Epilepsia/complicações , Epilepsia/diagnóstico , Feminino , Cefaleia/complicações , Cefaleia/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico
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