RESUMO
Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme ß-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.
Assuntos
Encéfalo/fisiopatologia , Modelos Animais de Doenças , Ovinos , Doença de Tay-Sachs/fisiopatologia , Doença de Tay-Sachs/veterinária , Animais , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Doença de Tay-Sachs/genéticaRESUMO
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 JovemRESUMO
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 , EsplenectomiaRESUMO
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 TratamentoRESUMO
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 , PesquisadoresRESUMO
BACKGROUND AND PURPOSE: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO. METHODS: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns. RESULTS: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern. CONCLUSIONS: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.
Assuntos
Doença de Fabry/diagnóstico por imagem , Forame Oval Patente/diagnóstico por imagem , Ataque Isquêmico Transitório/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Adolescente , Adulto , Doença de Fabry/epidemiologia , Feminino , Forame Oval Patente/epidemiologia , Humanos , Ataque Isquêmico Transitório/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Adulto JovemRESUMO
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 JovemRESUMO
BACKGROUND AND PURPOSE: Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke. METHODS: We used data from the Stroke in Fabry Patients study, a large prospective, hospital-based, screening study for Fabry disease in young patients (aged <55 years) with stroke in whom cardiovascular risk factors and family history of stroke were obtained and detailed stroke subtyping was performed. RESULTS: A family history of stroke was present in 1578 of 4232 transient ischemic attack and ischemic stroke patients (37.3%). Female patients more often had a history of stroke in the maternal lineage (P=0.027) than in the paternal lineage. There was no association with stroke subtype according to Trial of Org 10172 in Acute Stroke Treatment nor with the presence of white matter disease on brain imaging. Patients with dissection less frequently reported a family history of stroke (30.4% versus 36.3%; P=0.018). Patients with a parental history of stroke more commonly had siblings with stroke (3.6% versus 2.6%; P=0.047). CONCLUSIONS: Although present in about a third of patients, a family history of stroke is not specifically related to stroke pathogenic subtypes in patients with young stroke. Young women with stroke more often report stroke in the maternal lineage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.
Assuntos
Doença de Fabry/diagnóstico , Doença de Fabry/genética , Família , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/genética , Estudos de Coortes , Doença de Fabry/epidemiologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologiaRESUMO
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 , UltrassonografiaRESUMO
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 Fina , 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 , Imageamento por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Bainha de Mielina/metabolismo , Retina/patologia , Transfecção , Estados Unidos , beta-Galactosidase/genéticaRESUMO
BACKGROUND: Translating knowledge derived from medical research into the clinical setting is dependent on the representativeness of included patients. Therefore we compared baseline data of patients included in a recent large study addressing young stroke in comparison to a large representative stroke registry. METHODS: We analysed baseline data of 5023 patients (age 18-55 years) with an acute cerebrovascular event included in the sifap1 (Stroke in Young Fabry Patients) study. For comparison 17007 stroke patients (age 18-55 years) documented (2004-2010) in a statutory stroke registry of the Institute of Quality Assurance Hesse of the Federal State of Hesse (GQH), Germany. RESULTS: Among 17007 juvenile (18-55 years) patients identified in the GQH registry 15997 had an ischaemic stroke or TIA (91%) or an intracranial haemorrhage (9%). In sifap1 5023 subjects were included. Sex distribution was comparable (men: 59% sifap1 versus 60.5% GQH) whereas age differed between the groups: median age was 46 years in sifap1 versus 49 years in GQH. Slightly higher percentages for diabetes mellitus and hypertension in the GQH registry were noted. There were no differences in stroke severity as assessed by NIHSS (median 3) and mRS (median 2). In patients with ischaemic stroke or TIA (n = 4467 sifap1; n = 14522 GQH) higher rates of strokes due to small artery occlusion and atherosclerosis occurred in older age groups; cardioembolism and strokes of other determined cause occurred more frequently in younger patients. CONCLUSIONS: The comparison of baseline characteristics between the sifap1 study and the GQH registry revealed differences mainly determined by age.
Assuntos
Pesquisa Biomédica/métodos , Vigilância da População/métodos , Acidente Vascular Cerebral/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologiaRESUMO
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 , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Esclerose Múltipla/líquido cefalorraquidiano , alfa-Galactosidase/genéticaRESUMO
Headache as symptom of stroke is linked to gender, history of migraine, younger age, cerebellar stroke, and low blood pressure. These associations have been controversial, large scale studies are missing. We used the stroke in young fabry patients study to examine the association of demographic, clinical and imaging factors with the occurrence of headache in 4,431 young ischaemic stroke patients (18-55 years; mean: 44.7 years) with an ischemic cerebrovascular event (CVE) (ischemic stroke-IS 75.9%, TIA 24.1%). Headache in males occurred more frequently in bilateral localisation (right/left/bilateral: 27.5, 24.6, 39.2%, p < 0.01), but not in females (40.3, 34.7, 39.6%). Headache occurrence was more often associated in both genders with IS or TIA in the posterior cerebral territory (male: 33.2%, p < 0.05; female: 51.0%, p < 0.01) and vertebrobasilar arteries (male: 44.8%, p < 0.001; female: 51.2%, p < 0.001). The larger the size of the most prominent lesion the more likely patients were complaining headache during the IS (≤1 cm vs. >half lobe: 19.5 vs. 28.4% in male, p < 0.001; 28.9 vs. 39.1% in female, p < 0.01). Binary logistic regression analyses revealed lower age (p < 0.001), female sex (p < 0.001), larger size of the largest lesion (p < 0.001), and localization in the vertebrobasilar territory (p < 0.001) as predictors for headache during CVE. Headache at stroke onset is more common during IS in females, younger patients, with greater size of the acute lesion, and affected in posterior cerebral artery or vertebrobasilar system. Headache is a leading symptom in specific combination of stroke factors. These factors should be taken into account when patients report headache during IS or TIA.
Assuntos
Cefaleia/epidemiologia , Cefaleia/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. METHODS: Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. RESULTS: Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). CONCLUSIONS: Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov.Unique identifier: NCT00414583.
Assuntos
Doença de Fabry/diagnóstico , Doença de Fabry/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Doença Aguda , Adolescente , Adulto , Fatores Etários , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/genética , Estudos de Coortes , Europa (Continente)/epidemiologia , Doença de Fabry/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/genética , Adulto JovemRESUMO
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/psicologiaRESUMO
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 ProspectivosRESUMO
Alexander disease (AxD) is a usually fatal astrogliopathy primarily caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. We describe three patients with unique characteristics, and whose mutations have implications for AxD diagnosis and studies of intermediate filaments. Patient 1 is the first reported case with a noncoding mutation. The patient has a splice site change producing an in-frame deletion of exon 4 in about 10% of the transcripts. Patient 2 has an insertion and deletion at the extreme end of the coding region, resulting in a short frameshift. In addition, the mutation was found in buccal DNA but not in blood DNA, making this patient the first reported chimera. Patient 3 has a single-base deletion near the C-terminal end of the protein, producing a short frameshift. These findings recommend inclusion of intronic splice site regions in genetic testing for AxD, indicate that alteration of only a small fraction of GFAP can produce disease, and provide caution against tagging intermediate filaments at their C-terminal end for cell biological investigations.
Assuntos
Doença de Alexander/genética , Mutação da Fase de Leitura/genética , Proteína Glial Fibrilar Ácida/genética , Splicing de RNA/genética , Adulto , Astrócitos/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , MutaçãoRESUMO
Cerebral micro- and macro-vasculopathy have been described in Fabry disease (FD). Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. We measured the hippocampus volumes in a group of clinically affected patients with FD and correlated the findings with the cognitive performance of the patients. Hippocampal volumes were determined manually on T1-weighted MR-images of 25 FD patients (age 36.5 ± 11.0 years) and 20 age-matched controls. Additionally, individual white matter (WM) and gray matter (GM) volumes were measured using brain segmentation analyses. After controlling for age, white matter lesion (WML) volume, and WM/GM-volumes hippocampal volumes were significantly decreased in FD. These findings were substantially more pronounced in a subgroup of men with FD. WM and WM/GM volumes, and memory function did not significantly differ between patients and controls. In patients with FD hippocampal volumes were neither significantly correlated to WML volume nor to WM or WM/GM volumes. Hippocampus atrophy was not driven by the WML or other brain tissue atrophy and seems to correlate with the neuronal involvement in FD. In this young to middle-aged Fabry cohort the hippocampus degeneration was functionally compensated without memory impairment. Longitudinal studies are needed to determine whether this degenerative component in FD will progress and, in concert with the individual WML-load, predict subsequent cognitive decline.