RESUMEN
BACKGROUND AND PURPOSE: Individuals with GBA (glucocerebrosidase) mutations are at increased risk of Parkinson's disease (PD). It is still debated, however, whether this increased risk results from impaired glucocerebrosidase activity leading to substrate accumulation. Comparing the presence of prodromal PD marker in GBA mutation carriers and patients with Gaucher disease (GD) (in which substrate accumulation is extensive) can assist in clarifying this issue. METHODS: In this cross-sectional study, we compared the hyperechogenic area of the substantia nigra, a prodromal PD marker, in large cohorts of GBA mutation carriers (n = 71) and patients with GD (n = 145). Our control populations were healthy, non-carriers (n = 49) and patients with GBA -related PD (n = 11). Substrate accumulation was assessed from dry blood spot levels of glucosylsphingosine. RESULTS: Our findings indicate no contribution of substrate accumulation, as the area of hyperechogenicity is similarly enlarged relative to healthy controls in both GBA mutation carriers and patients with GD. Moreover, this similarity between GBA carriers and patients with GD persists when comparing only carriers of the N370S (c.1226A>G) mutation (n = 38) with untreated patients with GD who were homozygotes for the same mutation (n = 47). In addition, measurements of hyperechogenic area did not correlate with levels of glucosylsphingosine in the untreated patients with GD. CONCLUSION: The presence of a marker of prodromal PD (substantia nigra hyperechogenicity) is independent of substrate accumulation in a population with mutated GBA . Although further longitudinal studies are needed to determine the precise predictive value of this marker for GBA -related PD, our findings raise doubts regarding the contribution of substance reduction strategies to PD prevention.
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Enfermedad de Gaucher/diagnóstico por imagen , Glucosilceramidasa/genética , Enfermedad de Parkinson/diagnóstico por imagen , Sustancia Negra/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Estudios Transversales , Femenino , Enfermedad de Gaucher/genética , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/genética , Síntomas Prodrómicos , Psicosina/análogos & derivados , UltrasonografíaRESUMEN
The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. For insight into how GD management varies among countries, we analyzed treatment patterns in GOS. As of October 30, 2015, data on GD-specific treatment (enzyme replacement therapy, substrate reduction therapy, or chemical chaperone therapy) received at any time were available for 647 patients. At analysis, velaglucerase alfa (316/573, 55.1%) and imiglucerase (184/573, 32.1%) were the treatments most widely used. Of the 647 treated patients, 446 (68.9%) had been treated for >5years and 368 (56.9%) had received only one GD-specific drug therapy. There were 377 patients who received velaglucerase alfa. Velaglucerase alfa was most widely used at 60U/kg every other week (134/492 dose entries, 27.2%), but there were differences in dosing between the three highest-enrolling countries (defined as >100 GOS patients enrolled in each), with most patients in Israel receiving <20U/kg, most patients in the United Kingdom receiving 20 to <40U/kg, and most in the United States receiving 60U/kg. This analysis provides a foundation upon which to examine real-life outcomes data from different treatment regimens globally.
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Terapia de Reemplazo Enzimático/métodos , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Esquema de Medicación , Femenino , Enfermedad de Gaucher/epidemiología , Glucosilceramidasa/administración & dosificación , Humanos , Masculino , Resultado del TratamientoRESUMEN
Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.
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Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/terapia , Calidad de Vida , Consenso , Manejo de la Enfermedad , Europa (Continente)/epidemiología , Enfermedad de Gaucher/epidemiología , Enfermedad de Gaucher/psicología , HumanosRESUMEN
Anthropometric adjustments of bone measurements are necessary in Prader-Willi syndrome patients to correctly assess the bone status of these patients. This enables physicians to get a more accurate diagnosis of normal versus abnormal bone, allow for early and effective intervention, and achieve better therapeutic results. INTRODUCTION: Bone mineral density (BMD) is decreased in patients with Prader-Willi syndrome (PWS). Because of largely abnormal body height and weight, traditional BMD Z-scores may not provide accurate information in this patient group. The goal of the study was to assess a cohort of individuals with PWS and characterize the development of low bone density based on two adjustment models applied to a dataset of BMD and bone mineral content (BMC) from dual-energy X-ray absorptiometry (DXA) measurements. METHODS: Fifty-four individuals, aged 5-20 years with genetically confirmed PWS, underwent DXA scans of spine and hip. Thirty-one of them also underwent total body scans. Standard Z-scores were calculated for BMD and BMC of spine and total hip based on race, sex, and age for all patients, as well as of whole body and whole-body less head for those patients with total-body scans. Additional Z-scores were generated based on anthropometric adjustments using weight, height, and percentage body fat and a second model using only weight and height in addition to race, sex, and age. RESULTS: As many PWS patients have abnormal anthropometrics, addition of explanatory variables weight, height, and fat resulted in different bone classifications for many patients. Thus, 25-70 % of overweight patients, previously diagnosed as normal, were subsequently diagnosed as below normal, and 40-60 % of patients with below-normal body height changed from below normal to normal depending on bone parameter. CONCLUSIONS: This is the first study to include anthropometric adjustments into the interpretation of BMD and BMC in children and adolescents with PWS. This enables physicians to get a more accurate diagnosis of normal versus abnormal BMD and BMC and allows for early and effective intervention.
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Antropometría , Densidad Ósea , Síndrome de Prader-Willi/diagnóstico , Absorciometría de Fotón , Adolescente , Estatura , Peso Corporal , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Valores de Referencia , Adulto JovenRESUMEN
Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.
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Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Tejido Adiposo/metabolismo , Adulto , Anciano , Anticuerpos/inmunología , Anticuerpos Neutralizantes/inmunología , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Terapia de Reemplazo Enzimático/efectos adversos , Femenino , Glucosilceramidasa/administración & dosificación , Glucosilceramidasa/inmunología , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
The risk of bleeding during dental procedures may be increased in patients with Gaucher disease. We aimed to evaluate potential coagulation and platelet function abnormalities and targeted therapy accordingly. Patients with type 1 Gaucher disease who were treated at the Oral and Maxilo-Facial surgery clinic at Sheba Medical Center between 2003 and 2010 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, dental therapy and outcome. Bleeding was defined as excessive bleeding during or immediately following procedure. Coagulation studies and platelet function tests including aggregometry were performed on all patients. Dental procedures (n = 14, including eight teeth extractions, two crown lengthening procedures, one cyst enucleation and three deep dental scaling) of seven patients were studied. Mean platelet count prior to procedure was 73 K ± 14.8 mm(3). Patients bleeding risk score was calculated according to previous history of bleeding tendency, degree of thrombocytopenia, presence of comorbid coagulopathy and the type of dental procedure. Two patients with highest risk score received prophylactic platelet transfusions, three patients (medium-risk) received DDAVP preprocedure and all received systemic tranexamic acid, which was the only systemic therapy for low-risk patients. Meticulous surgical local haemostasis was applied. No excessive intra-operative or postoperative bleeding occurred. Patients with Gaucher disease who have thrombocytopenia and abnormal platelet function tests may be safely treated if meticulous haemostasis is applied along with systemic therapy as required. Platelet transfusions are not mandatory and should be applied considering the procedure-related risk and the patient's calculated haematological risk for bleeding.
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Atención Odontológica/efectos adversos , Enfermedad de Gaucher/complicaciones , Hemorragia Bucal/etiología , Procedimientos Quirúrgicos Orales/efectos adversos , Trombocitopenia/etiología , Adulto , Antifibrinolíticos/uso terapéutico , Estudios de Cohortes , Desamino Arginina Vasopresina/uso terapéutico , Femenino , Hemostáticos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Hemorragia Bucal/prevención & control , Pruebas de Función Plaquetaria , Hemorragia Posoperatoria/etiología , Valor Predictivo de las Pruebas , Factores de Riesgo , Extracción Dental/efectos adversos , Adulto JovenRESUMEN
Gaucher disease is a systemic lysosomal storage disorder with a high prevalence among Ashkenazi Jews. It is caused by an inherited deficiency of the lysosomal enzyme glucocerebrosidase. Common signs and symptoms include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal involvement. Oral and dental manifestations are less commonly seen. These manifestations are often asymptomatic, although they may be detected by routine dental x-rays. There are several case reports and a few larger series published describing patients with Gaucher disease who have mandibulo-maxillofacial involvement. This review aims to examine the oral manifestations observed in Gaucher disease and to suggest practical guidelines for dealing with these often worrisome signs. Among the critical issues are the benign nature of Gaucher cell infiltration of the mandible and the critical importance of being prepared for postprocedure bleeding and/or infections. Therefore, it is essential that dental practitioners be aware of the possible oral and dental complications of Gaucher disease, as well as the available treatment modalities.
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Atención Dental para Enfermos Crónicos , Enfermedad de Gaucher/complicaciones , Enfermedades Mandibulares/etiología , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Atención Dental para Enfermos Crónicos/efectos adversos , Humanos , Enfermedades Mandibulares/patología , Hemorragia Bucal/etiología , Hemorragia Posoperatoria/etiología , Infección de la Herida Quirúrgica , Erupción DentalRESUMEN
INTRODUCTION: Therapeutic goals have been described to monitor achievement, maintenance and continuity of therapeutic response in patients with type 1 Gaucher disease receiving enzyme replacement therapy. AIM: To benchmark the impact of velaglucerase alfa treatment against therapeutic goals for 5 key clinical parameters of type 1 Gaucher disease (anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology). METHODS: In an open-label Phase I/II study, twelve adults with symptomatic type 1 Gaucher disease and intact spleens received velaglucerase alfa for 9 months (60 U/kg infusion every other week [EOW]). Eleven patients completed the study and 10 enrolled in a long-term extension. After 1 year, patients who achieved ≥ 2 hematological or organ goals began step-wise dose reduction from 60 to 45 then 30 U/kg EOW. Data for anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology at baseline and 4 years are available for 8 patients (3 male, 5 female). The proportion of patients at goal for anemia, thrombocytopenia, hepatomegaly and splenomegaly at baseline was compared with the proportion achieving each goal at 4 years. The proportion achieving the skeletal pathology goal was determined on the basis of Z-score improvement from baseline to 4 years. The proportion of patients who achieved all 5 goals at 4 years was compared with the proportion at goal for all 5 parameters at baseline. RESULTS: At baseline, no patient was at goal for all clinical parameters. After 1 year of treatment, all patients maintained goals present at baseline, and all achieved ≥ 2 goals. All 8 patients began step-wise dose reduction from 60 to 30 U/kg EOW between 15 and 18 months. By year 4 of treatment, all patients met goals for all 5 clinical parameters; therefore 100% achievement was seen for each of the 5 long-term, therapeutic goals. DISCUSSION: In this velaglucerase alfa Phase I/II and extension study, clinically meaningful achievement of each long-term, therapeutic goal was observed for each patient, despite dose reduction after 1 year. This is the first report of a cohort where all patients receiving ERT for type 1 Gaucher disease achieved all 5 of these long-term, therapeutic goals within 4 years of starting treatment and after ≥ 2years dose reduction.
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Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Enfermedad de Gaucher/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
A high prevalence of low levels of cobalamin had been found in a survey of multi-ethnic normal individuals in Israel. The purpose of this study was to investigate the incidence of cobalamin deficiency among Israeli couples suffering from infertility. All couples seen at the in vitro fertilization clinic at an urban hospital (Shaare Zedek Medical Center) in Jerusalem for a 6-month period were invited. Mean cobalamin levels were 259.2 pg ml(-1) in males and 275.1 pg ml(-1) in females (normal >200 pg ml(-1)), 35.5% of 172 men and 23.3% of 223 females had cobalamin deficiency (P = 0.01). There were 171 couples with complete demographic questionnaires and cobalamin values for each partner. In 74 couples (43.3%), one partner was cobalamin deficient, with no significant difference between those with unexplained infertility versus those with explained infertility; and in 13 couples, both partners were cobalamin deficient. Thirty-nine per cent of all men with an abnormal semen analysis had cobalamin deficiency, a finding that requires further investigation. This study questions whether higher rates of male infertility in Israel are partially ascribable to cobalamin deficiency. Recommendation for supplementation in both males and females to achieve high-normal levels of cobalamin would be prudent.
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Infertilidad Femenina/sangre , Infertilidad Masculina/etiología , Deficiencia de Vitamina B 12/complicaciones , Vitamina B 12/sangre , Adulto , Femenino , Humanos , Infertilidad Femenina/epidemiología , Infertilidad Masculina/sangre , Infertilidad Masculina/epidemiología , Israel/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Vitamina B 12/uso terapéutico , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/dietoterapiaRESUMEN
Gaucher disease (GD) type 1 is the most frequent autosomal recessive disorder among Ashkenazi Jews, but because the phenotype is tremendously variable, including it in the 'Ashkenazi Panel' of carrier screening is controversial. As part of a nationwide study conducted in Israel to evaluate the outcomes of carrier screening for GD, we studied the experience of 65/82 (79%) of the couples identified as being at risk for an affected child. We found that pre-test information was regarded as insufficient and improved in post-result counseling. About 70% of the subjects interpreted the genetic counseling as directive, mostly toward prenatal diagnosis (PND) but against pregnancy termination of affected fetuses. We evaluated the various motivations that had led couples to utilize PND. Subjects' attitudes toward pregnancy termination correlated with their specific genotypes, with their perception of the severity of GD and with attending additional medical consultation. Of the 30 interviewed participants who were faced with having an affected fetus, 80% came to terms with their decision to utilize PND, but about half of the few who terminated the pregnancy regret their decision. Despite questionable benefits of screening, most of the participants did not regret having been tested and supported the continuation of this program. We offer explanations for these findings and suggest extensive genetic and medical counseling for any future carrier screening for low penetrance, treatable disease.
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Composición Familiar , Enfermedad de Gaucher/genética , Pruebas Genéticas/psicología , Pruebas Genéticas/estadística & datos numéricos , Conocimientos, Actitudes y Práctica en Salud , Diagnóstico Prenatal/psicología , Diagnóstico Prenatal/estadística & datos numéricos , Adulto , Femenino , Humanos , Masculino , Medición de RiesgoRESUMEN
OBJECTIVES: To test neurocognitive function in patients with late-onset Tay-Sachs disease (LOTS) using a computerized system to assess whether cognition is a clinically relevant outcome measure of possible therapeutic intervention in LOTS. METHODS: Ten adults with Tay-Sachs disease were administered at least one battery of the Mindstreams Neurotrax system for evaluation of cognitive function. Six sub-scores and a Global Cognitive Score (GCS) were tabulated. A disease specific severity score was also devised with six domains. RESULTS: Despite identical genotypes, all patients but the two oldest had > or = 3/6 sub-scores one standard deviation below normal mean (100); verbal and executive functions were most affected. The severity score measured other functions. CONCLUSIONS: Because of provocative findings on re-testing in patients exposed to miglustat, and despite the very small cohort, cognitive function may be an appropriate and clinically relevant outcome measure for future therapeutic interventions in LOTS.
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Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Técnicas de Diagnóstico Neurológico , Enfermedad de Tay-Sachs/complicaciones , Adulto , Edad de Inicio , Anciano , Algoritmos , Diagnóstico por Computador/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Proyectos de Investigación , Índice de Severidad de la EnfermedadRESUMEN
Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid beta-glucosidase. The most prevalent mutant genotype in type I Gaucher disease, N370S/N370S, is commonly thought to confer a mild phenotype presenting in adulthood. To characterize a subset of more severely affected N370S homozygotes, we assessed the phenotypes at or near the time of diagnosis of all N370S homozygotes with available data enrolled in the International Collaborative Gaucher Group Gaucher Registry. N370S compound heterozygotes were analyzed for comparison, as they are expected to present with a more severe phenotype. Of 798 N370S homozygotes and 1,278 N370S compound heterozygotes identified, 32% (251/788) and 65% (820/1269), respectively, were diagnosed before age 20 years. At diagnosis, N370S homozygotes as compared to N370S compound heterozygotes had the following clinical characteristics: irreversible skeletal lesions 17% (34/198) for N370S homozygotes versus 26% (76/290) for N370S compound heterozygotes; anaemia 18% (59/327) versus 29% (145/494); thrombocytopenia 52% (170/327) versus 62% (281/453); hepatomegaly 44% (83/190) versus 72% (141/195); splenomegaly 73% (142/194) versus 91% (178/195); and osteopenia or osteoporosis 48.6% (34/70) versus 51% (25/49). Some N370S homozygotes exhibited more severe clinical manifestations: 9% (29/327) had severe thrombocytopenia; 3% (5/190) had severe hepatomegaly; 11% (22/194) had severe splenomegaly; 7% (18/255) reported bone crises; 11% (8/70) had osteoporosis. In conclusion, N370S homozygosity does not consistently confer a mild, adult-onset phenotype. Gaucher disease patients with the N370S/N370S genotype exhibit a high degree of phenotypic heterogeneity and some may be at risk for early disease onset and severe clinical manifestations.
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Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/genética , Homocigoto , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Sistema de RegistrosRESUMEN
The molecular diagnosis of Gaucher disease has been difficult due to the existence of several different point mutations in the glucocerebrosidase gene and due to the presence of a tightly linked, highly homologous pseudogene. We now report the occurrence of a "Lepore-like" glucocerebrosidase fusion gene in which the 5' end is the functional gene and the 3' end is the pseudogene. This further complicates the molecular diagnosis of Gaucher disease but sheds light on the molecular anatomy of the glucocerebrosidase gene complex and on the pathogenesis of this important storage disease.
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Enfermedad de Gaucher/genética , Genes , Glucosidasas/genética , Glucosilceramidasa/genética , Seudogenes , Adulto , Southern Blotting , Células Cultivadas , Clonación Molecular , ADN/genética , Femenino , Fibroblastos/enzimología , Enfermedad de Gaucher/enzimología , Enfermedad de Gaucher/fisiopatología , Biblioteca de Genes , Humanos , Mutación , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , Piel/enzimologíaRESUMEN
BACKGROUND: Despite interest in causes of dementia in older persons, particularly in post-menopausal women, it is unclear whether hormone replacement therapy (HRT) is a risk factor. AIM: To assess cognitive function in post-menopausal women with high educational status receiving HRT, compared to non-users. DESIGN: Cognitive functioning was assessed with in women aged 55-60 years with at least university-level education, using the Mindstreams system, a computerized cognitive battery with multiple domains. RESULTS: Of 165 women meeting the inclusion/exclusion criteria, 82 women (49.7%) declined participation. Of the remaining 83, 40 (48.2%) had never received HRT; the remainder was divided into women receiving 5-9 years HRT (n = 29)versus those with >or=10 years HRT (n = 11). There were no statistically significant differences between HRT users and non-users in global scores or sub-domains of cognitive functioning, and no difference between those women receiving HRT for 5-9 years vs. >or=10 years. DISCUSSIONS: Long-term HRT does not appear to impair cognitive functioning in highly-educated women. Recommendations regarding post-menopausal HRT should be made on an individual basis.
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Cognición/efectos de los fármacos , Terapia de Reemplazo de Estrógeno , Desempeño Psicomotor , Cognición/fisiología , Escolaridad , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Patients with symptomatic Gaucher's disease sometimes have non-specific symptoms (such as general malaise with widespread musculoskeletal pains) that respond poorly to enzyme replacement treatment. These may indicate fibromyalgia syndrome; if so, other therapeutic options might be more appropriate. AIM: To identify patients with Gaucher's disease for whom fibromyalgia-specific therapy may be therapeutic. DESIGN: Questionnaire-based survey. METHODS: Adult patients (n = 109) with non-neuronopathic Gaucher's disease and adult healthy controls (n = 108) completed health-related questionnaires including the Fibromyalgia Impact Questionnaire, and underwent testing with a dolorimeter to ascertain sensitivity at 22 tender points. RESULTS: Six patients, but no controls, met the criteria for fibromyalgia. Patients with fibromyalgia had a significantly greater incidence of co-morbidities (p = 0.014) relative to other patients with Gaucher's disease; four suffered from bone involvement and were receiving enzyme therapy, but two were untreated. DISCUSSION: The presence of fibromyalgia-specific trigger points may result from multiple aetiologies, or may be an independently-sorting predisposition. Our findings cannot distinguish between these possibilities, but if fibromyalgia were the cause, enzyme replacement therapy would be expensive and inappropriate.
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Fibromialgia/complicaciones , Enfermedad de Gaucher/complicaciones , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Fibromialgia/diagnóstico , Humanos , Lactante , Masculino , Persona de Mediana EdadRESUMEN
Transilial bone biopsy confirmed heparin-induced osteopenia in a 23-year-old postpartum patient. Histomorphometric measurements during the reversible stage of bone disease that followed discontinuation of the heparin sodium therapy revealed signs of recovery; these were superimposed on a loose trabecular structure typical of osteoporosis. The histomorphometric evidence of recovery correlated well with signs of clinical improvement. In the majority of patients, heparin therapy during pregnancy is innocuous; however, discontinuation of treatment is recommended at the earliest signs of osteoporosis.
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Heparina/efectos adversos , Osteoporosis/inducido químicamente , Adulto , Femenino , Heparina/uso terapéutico , Humanos , Osteoporosis/patología , Embarazo , Complicaciones del Embarazo/patologíaRESUMEN
A 24-year-old man had repeated episodes of meningococcal meningitis. Selective deficiency of the eighth component of complement (C8) was demonstrated in the patient, his twin brother, and in one of five siblings. As the parents were first cousins of normal phenotype, this pattern is suggestive of an autosomal recessive heredity. The present report brings the total number of patients given the diagnosis of C8 deficiency to 14, and calls attention to the existence of this condition in Jews of Sephardic (Mediterranean) origin.
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Complemento C8/deficiencia , Judíos , Meningitis Meningocócica/inmunología , Adulto , Complemento C8/genética , Humanos , Masculino , Linaje , RecurrenciaRESUMEN
BACKGROUND: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. METHODS: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. RESULTS: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.
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Enfermedad de Gaucher/epidemiología , Sistema de Registros/estadística & datos numéricos , Adolescente , Adulto , Anciano , Alelos , Niño , Preescolar , Comparación Transcultural , Estudios Transversales , Femenino , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/genética , Frecuencia de los Genes/genética , Humanos , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Estados Unidos/epidemiologíaRESUMEN
We have reviewed our experiences with the clinical, laboratory, radiologic, and genetic features of 53 patients with Gaucher disease. Most were evaluated during early adult life, with a mean age of 33 years. Our patients were evaluated in a referral center, and therefore the data need to be interpreted with caution when applied to the general patient population, which includes a greater proportion of very mild cases. Thirty-nine patients were Ashkenazi Jews, 13 were non-Jewish and 1 was half-Jewish. The most common presenting symptom was bleeding related to splenomegaly and thrombocytopenia. The chronic symptoms, evaluated an average of 20 years after the diagnosis had been established, were mainly skeletal. Splenectomy had been performed in 43% of our patients and there was no evidence that this procedure accelerated the progression of liver and bone involvement. DNA from the patients was examined for 20 different mutations. The association between the 1226G/1226G genotype and a milder clinical course, and between the 1226G/84GG and 1226/1448C genotypes with more severe clinical manifestations, was confirmed. Repeated follow-up examinations in 29 patients revealed that in the majority of the patients, progression of the disease occurs during childhood, adolescence, or early adulthood with a marked tendency for stabilization thereafter. This observation suggests that Gaucher disease in most of the patients is not a relentless progressive disorder but a rather stable disorder during adulthood. The indications for the newly introduced intravenous enzyme replacement therapy as well as of future experimental treatments should be examined in the light of the natural history of the disease.
Asunto(s)
Enfermedad de Gaucher , Adolescente , Adulto , Anciano , Enfermedades Óseas Metabólicas/etiología , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/diagnóstico por imagen , Enfermedad de Gaucher/genética , Genotipo , Humanos , Lactante , Hepatopatías/etiología , Enfermedades Pulmonares/etiología , Masculino , Persona de Mediana Edad , Radiografía , Índice de Severidad de la Enfermedad , EsplenectomíaRESUMEN
The causes of megaloblastic anemia were studied in a survey of patients admitted to six Israeli hospitals over a period of 15 yr. Among the 203 patients identified, 69% had pernicious anemia, 12% had gastrointestinal disease, 9% had primary nutritional deficiency of whom only 1% were associated with pregnancy, and 7% had selective vitamin B12 malabsorption with albuminuria. Comparison with previously published surveys showed, that in contrast with earlier studies where primary nutritional deficiency was the cause of megaloblastic anemia in about 70% of cases and pernicious anemia in only 20%, in more recent studies the proportion of cases with primary nutritional anemia in general and those associated with pregnancy in particular was much lower. This is most probably the result of improved standards of living and a national program of preventive folate supplementation at maternity clinics. A potential hazard of such preventive programs is the aggravation of neurological complications in patients with undiagnosed vitamin B12 deficiency. Early recognition of pernicious anemia and other forms of selective B12 malabsorption is a new challenge created by the changing pattern of megaloblastic anemias.