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1.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922740

RESUMO

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat.


Assuntos
Arritmias Cardíacas/terapia , Terapia de Reposição de Enzimas , Doença de Fabry/terapia , alfa-Galactosidase/administração & dosagem , alfa-Galactosidase/metabolismo , Animais , Arritmias Cardíacas/enzimologia , Arritmias Cardíacas/etiologia , Doença de Fabry/complicações , Doença de Fabry/enzimologia , Humanos
2.
Int J Mol Sci ; 22(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379210

RESUMO

Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that "in vitro" amenability may not always reflect "in vivo" amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Terapia de Reposição de Enzimas , Doença de Fabry/terapia , Isoenzimas/uso terapêutico , Proteínas Recombinantes/uso terapêutico , alfa-Galactosidase/uso terapêutico , 1-Desoxinojirimicina/uso terapêutico , Humanos
3.
J Parkinsons Dis ; 10(1): 141-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31594250

RESUMO

BACKGROUND: Sporadic Parkinson's disease (PD) patients have lower α-galactosidase A (α-GAL A) enzymatic activity and Fabry disease (FD) patients potentially carry an increased risk of PD. OBJECTIVE: Determination of PD prevalence in FD and clinical, biochemical and vascular neuroimaging description of FD pedigrees with concomitant PD. METHODS: Clinical screening for PD in 229 FD patients belonging to 31 families, harbouring GLA gene mutation p.F113L, and subsequent pedigree analysis. Gender-stratified comparison of FD+/PD+ patients with their family members with FD but without PD (FD+/PD-) regarding Mainz scores, plasma & leukocytes α-GAL A enzymatic activity, urinary Gb3 and plasma Lyso-Gb3, vascular brain neuroimaging. RESULTS: Prevalence of PD in FD was 1.3% (3/229) (3% in patients aged ≥50 years). Three FD patients, one female (73 years old) (P1) and two males (60 and 65 years old) (P2 and P3), three different pedigrees, presented akinetic-rigid PD, with weak response to levodopa (16% - 36%), and dopaminergic deficiency on 18F-DOPA PET. No pathogenic mutations were found in a PD gene panel. FD+/PD+ patients had worse clinical severity of FD (above upper 75% IQR in Mainz scores), and cortico-subcortical white matter/small vessel lesions. P3 patient was under enzyme therapy, started 1 year before PD diagnosis. P2-P3 patients had higher leucocyte α-GAL A activity (2,2-3 vs.1,0 (median)(nmol/h/mg)). CONCLUSION: We have shown a high prevalence of PD in a late-onset phenotype of FD, presenting high cerebrovascular burden and weak response to levodopa. Further studies will untangle how much of this PD phenotype is due to Gb3 deposition versus cerebrovascular lesions in the nigro-striatal network.


Assuntos
Encéfalo/diagnóstico por imagem , Doença de Fabry , Glicolipídeos/metabolismo , Leucócitos/enzimologia , Doença de Parkinson , Esfingolipídeos/metabolismo , alfa-Galactosidase/metabolismo , Adulto , Idoso , Estudos de Coortes , Comorbidade , Doença de Fabry/diagnóstico por imagem , Doença de Fabry/enzimologia , Doença de Fabry/epidemiologia , Doença de Fabry/fisiopatologia , Feminino , Glicolipídeos/sangue , Glicolipídeos/urina , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/enzimologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Linhagem , Fenótipo , Prevalência , Esfingolipídeos/sangue , Esfingolipídeos/urina , alfa-Galactosidase/sangue , alfa-Galactosidase/genética
4.
Clin Interv Aging ; 12: 1843-1857, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158667

RESUMO

Imbalance and tripping over obstacles as a result of altered gait in older adults, especially in patients with Parkinson's disease (PD), are one of the most common causes of falls. During obstacle crossing, patients with PD modify their behavior in order to decrease the mechanical demands and enhance dynamic stability. Various descriptions of dynamic traits of gait that have been collected over longer periods, probably better synthesize the underlying structure and pattern of fluctuations in gait and can be more sensitive markers of aging or early neurological dysfunction and increased risk of falls. This confirmation challenges the clinimetric of different protocols and paradigms used for gait analysis up till now, in particular when analyzing obstacle crossing. The authors here present a critical review of current knowledge concerning the interplay between the cognition and gait in aging and PD, emphasizing the differences in gait behavior and adaptability while walking over different and challenging obstacle paradigms, and the implications of obstacle negotiation as a predictor of falls. Some evidence concerning the effectiveness of future rehabilitation protocols on reviving obstacle crossing behavior by trial and error relearning, taking advantage of dual-task paradigms, physical exercise, and virtual reality have been put forward in this article.


Assuntos
Envelhecimento/fisiologia , Cognição/fisiologia , Marcha/fisiologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/reabilitação , Fenômenos Biomecânicos , Humanos , Caminhada
5.
Clin Neurol Neurosurg ; 126: 47-54, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25203713

RESUMO

Parkinsonian features have been described in patients with POLG1 mutations. Notwithstanding, the clinical expression has been revealed heterogeneous and the response to dopaminergic treatment has been document in few cases. We aim to describe the longitudinal clinical features and the treatment response of three unrelated patients with neurodegenerative parkinsonism, preceded by PEO and SANDO syndromes, who harbor POLG1 mutations, including two novel mutations. It was documented a sustained response to levodopa, at 3 and 8 years of follow-up of parkinsonian syndrome, and reduced striatal dopamine uptake. We review the genotypic and phenotypic spectrum of POLG1-related parkinsonism. Our observations stimulate the debate around the role of mitochondrial DNA defects in the pathogenesis of neurodegenerative parkinsonism.


Assuntos
Antiparkinsonianos/farmacologia , DNA Polimerase Dirigida por DNA/genética , Levodopa/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Idoso , Antiparkinsonianos/administração & dosagem , DNA Polimerase gama , DNA Mitocondrial/genética , Feminino , Genótipo , Humanos , Levodopa/administração & dosagem , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento
6.
Acta Med Port ; 24 Suppl 4: 761-8, 2011 Dec.
Artigo em Português | MEDLINE | ID: mdl-22863482

RESUMO

In current medical practice, the diagnosis of Parkinson's disease remains essentially clinical. This practice determines that the diagnosis of Parkinson's disease is done in an already advanced neuropathological stage of the disease. The aim of this study is to review the validity of cerebrospinal fluid protein biological markers in the early diagnosis of Parkinson's disease. The a-synuclein and DJ-1 proteins, due to their role in the hereditary Parkinson's disease, have been the most widely studied cerebrospinal biomarkers. Nevertheless, they have had divergent results mostly owing to different processing, identification and control of laboratory techniques. The new proteomic techniques, directed to the detection of multiple undifferentiated proteins in cerebrospinal fluid (eg. ceruloplasmin, chromogranin B, apoH), are promising. The early diagnosis of Parkinson's disease is imperious as it is a progressive neurodegenerative disorder that causes extensive morbidity. Most of current scientific research in Parkinson's disease is focused on the discovery of neuroprotective drugs. Thus, the definition of biomarkers for the early diagnosis of Parkinson's disease is highly relevant.


Assuntos
Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Precoce , Humanos
7.
J Neurol ; 256(10): 1655-62, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19471849

RESUMO

Impairment of Parkinson's disease (PD) axial motor signs (AMS) has been described as a risk factor for dementia. Executive dysfunction is an important feature in recently proposed clinical diagnostic criteria for PD dementia. To clarify the relationship between AMS progression and executive cognitive performance, we conducted a 6-year prospective study in PD patients without AMS impairment at baseline. A hospital-based cohort of PD patients (n = 24) without dementia, in the initial motor stage (Hoehn-Yahr < or = 2), and matched controls (n = 20) were followed prospectively over a 6-year period. Neuropsychological tests were performed in both groups, and motor function (including AMS: speech, gait, postural instability) was evaluated in the PD group. The PD group had a significantly higher decline in neuropsychological test scores than did the controls. Most of the neuropsychological and motor decline occurred in the last 4 years. In UPDRS III, progression of AMS and especially speech were the most important motor variables related to dementia. There was a correlation between speech impairment progression and declines in MMSE (r = -0.598, p = 0.002), Clock Drawing (r = -0.671, p < 0.001), Semantic Verbal Fluency (r = -0.435, p = 0.034), Alternating Sequences (r = 0.497, p = 0.014), and Raven's Coloured Progressive Matrices (r = -0.735, p < 0.001). PD patients with higher speech impairment progression showed more rapid declines in some neuropsychological tests. Further studies are needed to clarify the different roles of speech, gait and postural instability on the initial phases of cognitive dysfunction.


Assuntos
Demência/epidemiologia , Discinesias/epidemiologia , Doença de Parkinson/epidemiologia , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Índice de Gravidade de Doença , Distúrbios da Fala/epidemiologia
8.
Neuromuscul Disord ; 16(8): 507-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16919951
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