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1.
Osteoporos Int ; 29(9): 2069-2078, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29858631

RESUMEN

Adipose tissue produces different inflammatory cytokines which compromise bone mineral accrual during puberty. Vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), interleukin (IL)-8, and interferon-gamma (IFN-γ) are significantly related to bone mineral accrual during pubertal maturation in boys with different BMI values. INTRODUCTION: This longitudinal study aims to identify the inflammatory markers that most strongly associate with pubertal bone mineral density (BMD) increment in boys with overweight and obesity (OWB). METHODS: Twenty-six OWB and 29 normal-weight boys were followed yearly for 3 years to measure changes in 12 serum inflammatory markers, BMD (by DXA), and apparent volumetric BMD. The OWB group was further divided into two subgroups according to their BMI gain during the 3-year period. Data through time points presented as slopes were used to calculate correlation coefficients to explore the possible relationships between variables of interest. In the whole study group, linear mixed effects (LME) models were also used. RESULTS: Increment in serum VEGF concentration was inversely associated with an increase in total body (TB) BMD (r = - 0.82, P = 0.02) and TB bone mineral content (BMC)/height (r = - 0.82, P = 0.02) in those OWB whose BMI gain was higher during pubertal years. In the whole study group, the LME model confirmed the inverse association between VEGF and TB BMC/height (P < 0.05). EGF was inversely associated with LS BMD and LS BMAD (P < 0.05), whereas there was a positive association between IL-8 and TB BMAD and between IFN-γ and LS BMD (P < 0.05). CONCLUSIONS: Lower increment in BMD in OWB with higher BMI gain is associated with increasing serum VEGF concentration during pubertal maturation. VEGF, EGF, IL-8, and IFN-γ are significantly associated with BMD during pubertal maturation in boys with different BMI values.


Asunto(s)
Mediadores de Inflamación/metabolismo , Sobrepeso/sangre , Pubertad/sangre , Antropometría/métodos , Biomarcadores/sangre , Índice de Masa Corporal , Niño , Citocinas/sangre , Factor de Crecimiento Epidérmico/sangre , Humanos , Estudios Longitudinales , Masculino , Obesidad/sangre , Obesidad/fisiopatología , Sobrepeso/fisiopatología , Pubertad/fisiología , Maduración Sexual/fisiología , Testosterona/sangre , Factor A de Crecimiento Endotelial Vascular/sangre
2.
Blood Cells Mol Dis ; 68: 203-208, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28274788

RESUMEN

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.


Asunto(s)
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 , Humanos
3.
Orphanet J Rare Dis ; 11(1): 65, 2016 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-27189384

RESUMEN

BACKGROUND: As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters. RESULTS: Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male. CONCLUSIONS: Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.


Asunto(s)
Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Adolescente , Niño , Preescolar , Estudios Transversales , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Actividad Motora , Mutación , alfa-Glucosidasas/genética , alfa-Glucosidasas/metabolismo
4.
Blood Cells Mol Dis ; 57: 35-41, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26852653

RESUMEN

OBJECTIVE: This was a retrospective data analysis to evaluate the treatment response to enzyme replacement therapy (ERT) with Velaglucerase alfa using whole-body magnetic resonance imaging (MRI). MATERIALS AND METHODS: A baseline and follow-up MRI were performed on 18 Gaucher Type 1 patients at an interval of 11.6 months. The MRI score systems determined the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), and the Vertebra-Disc-Ratio (VDR). The Severity Score Index Type 1 (GD-DS3) was also assessed. RESULTS: The baseline MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.70; while, the follow-up MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.73. The baseline GD-DS3 median was 2.40 (BMB excl.: 0.50) and the follow-up median was 2.00 (BMB excl.: 0.50). There was weak statistical significance with the Wilcoxon signed-rank test for the DGS (p=0.034) and GD-DS3 (p=0.047) between both MRIs. CONCLUSION: Velaglucerase alfa therapy is a effective long-term treatment for Gaucher Type 1 patients who are newly diagnosed or switching therapies. Measurements with whole-body MRI and an objective scoring system were reliable tools for detecting early stage bone marrow activity. Further research is needed to evaluate the "Booster-Effect" of Velaglucerase alfa therapy in Gaucher skeletal disease.


Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Femenino , Estudios de Seguimiento , Enfermedad de Gaucher/patología , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Imagen de Cuerpo Entero/métodos
5.
JIMD Rep ; 23: 17-26, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25772320

RESUMEN

INTRODUCTION: Niemann-Pick type C disease is a rare disorder caused by impaired intracellular lipid transport due to mutations in either the NPC1 or the NPC2 gene. Ninety-five % of NPC patients show mutations in the NPC1 gene. A much smaller number of patients suffer from NPC2 disease and present respiratory failure as one of the most frequent symptoms. Several plasma oxysterols are highly elevated in NPC1 and can be used as a biomarker in the diagnosis of NPC1. METHODS: Plasma cholestane-3ß,5α,6ß-triol was evaluated as biomarker for NPC2 by GC/MS and LC-MS/MS analysis. The diagnosis was confirmed by Sanger sequencing and filipin staining. RESULTS: We report three NPC2 patients with typical respiratory problems and a detailed description of the nature of the lung disease in one of them. All patients had elevated levels of plasma cholestane-3ß,5α,6ß-triol. In two of these patients, the positive oxysterol result led to a rapid diagnosis of NPC2 by genetic analysis. The phenotype of the third patient has been described previously. In this patient a cholestane-3ß,5α,6ß-triol concentration markedly above the reference range was found. CONCLUSIONS: Measurement of plasma cholestane-3ß,5α,6ß-triol enables to discriminate between controls and NPC1 and NPC2 patients, making it a valuable biomarker for the rapid diagnosis not only for NPC1 but also for NPC2 disease.The measurement of oxysterols should be well kept in mind in the differential diagnosis of lysosomal diseases, as the elevation of oxysterols in plasma may speed up the diagnosis of NPC1 and NPC2.

6.
J Neuromuscul Dis ; 2(s1): S18, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-27858615
7.
Eur J Neurol ; 22(2): 369-76, e27, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25367349

RESUMEN

BACKGROUND AND PURPOSE: Respiratory muscle weakness is the major cause of early death in patients with adult Pompe disease. It first manifests as nocturnal hypercapnia, eventually leading to sleep disruption. Sleep-related symptoms along with motor performance, forced vital capacity (FVC) and respiratory symptoms were investigated in 65 adult patients with Pompe disease. METHODS: Patients answered the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Rotterdam Nine-item Handicap Scale, the SF-36 health-related quality of life questionnaire, and a respiratory symptom questionnaire. In all patients, the 6-min walk test was performed and FVC was obtained. Polysomnography and oxycapnometry results were available in 31 patients. RESULTS: Sixty patients received enzyme replacement therapy, and 32 individuals were on home ventilatory support. Reduced sleep quality was highly prevalent (PSQI > 5; 43.1%) and correlated with both excessive daytime sleepiness (Epworth Sleepiness Scale > 10; 24.6%) and fatigue (Fatigue Severity Scale > 4; 72.3%). The SF-36 health-related quality of life questionnaire was reduced in the physical domains, and was inversely correlated with sleep quality, FVC and motor performance. In 11 out of 17 non-ventilated patients with polysomnography records, sleep-disordered breathing was present, and duration of nocturnal oxygen desaturation (SaO2 < 90%) was significantly correlated to the PSQI global score. CONCLUSIONS: In adult Pompe disease, sleep disturbances are a common cause of excessive daytime sleepiness and fatigue. Sleep-related symptoms may be indicative of respiratory muscle weakness and should give rise to further work-up of sleep-disordered breathing.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Músculos Respiratorios/fisiopatología , Síndromes de la Apnea del Sueño/etiología , Trastornos del Sueño-Vigilia/etiología , Adolescente , Adulto , Anciano , Fatiga/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
8.
Nervenarzt ; 84(12): 1467-72, 2013 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-24264645

RESUMEN

As Pompe disease glycogen storage disease type 2 with a severely reduced life expectancy is now a treatable disorder, accurate diagnostic procedures and evidence-based indications for therapy are mandatory. We screened the literature for consensus reports and published trial data of late-onset Pompe disease. These data were summarized in a Delphi consensus method approach. The clinical suspicion of late-onset Pompe disease should be substantiated by the validated dry blood spot test measurement for acid α-glucosidase activity. Alternatively, enzyme activity analysis in lymphocytes is also feasible. Glucosidase α gene sequencing for verifying the diagnosis is recommended. A muscle biopsy including measurements of acid α-glucosidase activity and glycogen concentration is warranted for differential diagnosis in selected cases. The confirmed diagnosis should lead to a multidisciplinary treatment approach, possibly including enzyme replacement therapy.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Adulto , Factores de Edad , Biopsia , Conducta Cooperativa , Estudios Transversales , Técnica Delphi , Diagnóstico Diferencial , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Adhesión a Directriz , Humanos , Comunicación Interdisciplinaria , Imagen por Resonancia Magnética , Músculo Esquelético/patología , Examen Neurológico , Ensayos Clínicos Controlados Aleatorios como Asunto , alfa-Glucosidasas/uso terapéutico
10.
J Neurol ; 257(1): 91-7, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19649685

RESUMEN

Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.


Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , alfa-Glucosidasas/uso terapéutico , Adulto , Edad de Inicio , Anciano , Creatina Quinasa/metabolismo , Terapia de Reemplazo Enzimático/efectos adversos , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Población Blanca , Adulto Joven , alfa-Glucosidasas/administración & dosificación , alfa-Glucosidasas/efectos adversos
11.
J Inherit Metab Dis ; 32 Suppl 1: S321-5, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19894140

RESUMEN

Hurler-Scheie syndrome is caused by alpha-l-iduronidase deficiency. Enzyme replacement therapy (ERT) can improve physical capacity and reduces organomegaly. However, the effect on bradytrophic connective tissue is limited. As intravenously administered enzyme cannot cross the blood-brain barrier, the therapy of choice for the more severe Hurler syndrome is haematopoietic stem cell transplantation (HCT). In the more attenuated Scheie syndrome, neurological impairment is less severe; therefore, ERT may be appropriate to treat these patients. Information on long-term outcome in Scheie patients undergoing ERT is scarce. We report a 38-year-old female Scheie patient who has been on ERT for 8 years. While non-neurological symptoms improved, she developed paresthesias in her hands and feet and progressive pain in her legs. Somatosensory evoked potentials were abnormal, suggesting dysfunction of the dorsal funiculus and lemniscus medialis. After 6 years of ERT, a spinal MRI showed dural thickening at the upper cervical spine. These soft-tissue deposits are presumably due to the accumulation of mucopolysaccharides. Intramedullary hyperintensities at the level of C1/2 revealed cervical myelopathy. An MRI before the start of ERT had shown milder spinal lesions. Cystic lesions in the white matter of the centrum semiovale due to dilated Virchow-Robin spaces were essentially unchanged compared with the MRI scan before ERT. Decompression of the spinal cord resulted in clinical improvement. In an adult patient with Scheie syndrome, ERT failed to prevent progression of cervical myelopathy. Clinical significance of cerebral changes is unclear. Whether early HCT or intrathecal ERT could have prevented these lesions remains speculative.


Asunto(s)
Terapia de Reemplazo Enzimático , Iduronidasa/uso terapéutico , Mucopolisacaridosis I/complicaciones , Mucopolisacaridosis I/tratamiento farmacológico , Compresión de la Médula Espinal/etiología , Adulto , Encéfalo/patología , Vértebras Cervicales , Progresión de la Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Mucopolisacaridosis I/fisiopatología , Compresión de la Médula Espinal/patología , Compresión de la Médula Espinal/fisiopatología
12.
J Inherit Metab Dis ; 32(5): 660-664, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19655269

RESUMEN

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.


Asunto(s)
Enfermedad de Gaucher/terapia , Directrices para la Planificación en Salud , Consejo , Terapia de Reemplazo Enzimático/métodos , Enfermedad de Gaucher/clasificación , Enfermedad de Gaucher/diagnóstico , Humanos , Apoyo Social
13.
Mol Genet Metab ; 98(3): 243-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19656703

RESUMEN

Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration. We report findings from a retrospective observational cohort study assessing the effects of miglustat on neurological disease progression in patients treated in the clinical practice setting. Data from all NP-C patients prescribed miglustat at 25 expert centers were evaluated using a disease disability scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation, manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included (mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range) miglustat exposure was 1.46 (0.05-4.51) years. Mean annual progression was +0.11 score units/year from diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to -0.01 score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological disease on miglustat was observed in all age groups, but the magnitude of the effect was greater in patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data support previous clinical trial findings indicating clinically relevant beneficial effects of miglustat on neurological disease progression in patients with NP-C.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Inhibidores Enzimáticos/uso terapéutico , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 1-Desoxinojirimicina/administración & dosificación , 1-Desoxinojirimicina/uso terapéutico , Adolescente , Niño , Estudios de Cohortes , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Masculino , Enfermedad de Niemann-Pick Tipo C/patología , Estudios Retrospectivos , Resultado del Tratamiento
14.
Mol Genet Metab ; 93(3): 275-81, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18078773

RESUMEN

Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It presents at any age, with variable rates of progression ranging from a rapidly progressive course, often fatal by one-year of age, to a more slowly, but nevertheless relentlessly progressive course, resulting in significant morbidity and premature mortality. In infants, early initiation of enzyme replacement therapy is needed to gain the maximum therapeutic benefit, underscoring the need for early diagnosis. Several new methods for measuring GAA activity have been developed. The Pompe Disease Diagnostic Working Group met to review data generated using the new methods, and to establish a consensus regarding the application of the methods for the laboratory diagnosis of Pompe disease. Skin fibroblasts and muscle biopsy have traditionally been the samples of choice for measuring GAA activity. However, new methods using blood samples are rapidly becoming adopted because of their speed and convenience. Measuring GAA activity in blood samples should be performed under acidic conditions (pH 3.8-4.0), using up to 2 mM of the synthetic substrate 4-methylumbelliferyl-alpha-D-glucoside or glycogen (50 mg/mL), in the presence of acarbose (3-9 microM) to inhibit the isoenzyme maltase-glucoamylase. The activity of a reference enzyme should also be measured to confirm the quality of the sample. A second test should be done to support the diagnosis of Pompe disease until a program for external quality assurance and proficiency testing of the enzymatic diagnosis in blood is established.


Asunto(s)
Glucano 1,4-alfa-Glucosidasa/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Técnicas de Laboratorio Clínico , Humanos , Lactante
15.
J Inherit Metab Dis ; 30(6): 935-42, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17994286

RESUMEN

The European Task Force for Neuronopathic Gaucher Disease (NGD) met in 2006 to review its 2001 guidelines. Fifty-five patients from five European countries were reviewed; 29 were male and 26 female. The majority of the patients were homozygous for the L444P mutation. All had been on enzyme replacement therapy (ERT). However, there was considerable variation in the dose of ERT, as well as an uneven distribution of risk factors. Thus, the oldest patients were on the lowest doses, and several had had a total splenectomy, while the youngest patients had a high proportion of compound heterozygosity and were on the highest doses, and very few had had a splenectomy. This heterogeneity rendered analysis very difficult. However, some observations were possible. The older patients appeared to remain relatively stable despite a low dose of ERT. In the younger patients, there was no clear effect of high-dose ERT. However, the period of follow-up was too short in many patients to draw valid conclusions. These data will be used to draw up revised guidelines.


Asunto(s)
Terapia Enzimática , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Glucosilceramidasa/genética , Heterocigoto , Homocigoto , Humanos , Pruebas de Inteligencia , Masculino , Enfermedades del Sistema Nervioso/patología , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
16.
J Inherit Metab Dis ; 30(4): 614, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17694354

RESUMEN

Anderson-Fabry disease is an X-linked disorder that is caused by deficiency of the lysosomal enzyme alpha-galactosidase A. Symptoms include chronic progressive painful small-fibre neuropathy, cornea verticillata, renal failure and heart disease. Interestingly, female heterozygous patients may also show severe symptoms. After clinical suspicion, usually the determination of alpha-galactosidase activity in leukocytes is requested first. Alternatively, an enzymatic assay using dried blood specimens has been described. Dried blood samples require less material and are substantially more stable (several months at room temperature) than whole-blood specimens. To validate the new method and to asses its usefulness for diagnosis of female patients, enzyme activities of alpha-galactosidase, beta-galactosidase and beta-glucuronidase from 78 known Fabry patients were compared (29 males, 47 females) between both materials. In summary, the determination of alpha-galactosidase activity using dried blood and leukocytes as well as the ratio of alpha-galactosidase to beta-glucuronidase in dried blood can improve the diagnostic specificity in cases of female patients who are difficult to identify when only leukocyte enzyme activities are considered.


Asunto(s)
Enzimas/análisis , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Leucocitos/enzimología , Análisis Químico de la Sangre/métodos , Recolección de Muestras de Sangre , Femenino , Glucuronidasa/sangre , Humanos , Masculino , Reproducibilidad de los Resultados , Factores Sexuales , alfa-Galactosidasa/sangre , beta-Galactosidasa/sangre
17.
J Inherit Metab Dis ; 28(5): 733-41, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16151905

RESUMEN

6-Hexadecanoylamino-4-methylumbelliferylphosphorylcholine (HMUPC) was shown to be a specific substrate for the determination of acid (lysosomal) sphingomyelinase (ASM; gene SMPD1). Fibroblasts (n = 27) and leukocytes (n = 8) from both the A and B types of Niemann-Pick disease showed < 6% and < 10% of mean normal ASM activity, respectively. Niemann-Pick A or B patients bearing the Q292K mutation had apparently normal ASM activity with our new artificial substrate. These patients with false-normal sphingomyelinase activity, however, could readily be detected by determining the extent of inhibition of enzymatic hydrolysis of the artificial substrate HMU-PC by an unlabelled natural substrate, in particular lysosphingomyelin. This approach is generally applicable. Our novel assay for ASM combines the ease of a rapid and robust enzyme assay using a fluorogenic substrate with the specificity of an ASM assay using a natural substrate. Such assays are obviously more convenient to the diagnostic laboratory, since radiolabelled substrates are not required.


Asunto(s)
Análisis Químico de la Sangre/métodos , Química Clínica/métodos , Fluorometría/métodos , Enfermedades de Niemann-Pick/diagnóstico , Esfingomielina Fosfodiesterasa/química , Ceramidas/química , Pruebas Enzimáticas Clínicas , Diagnóstico Diferencial , Relación Dosis-Respuesta a Droga , Fibroblastos/enzimología , Fibroblastos/metabolismo , Regulación Enzimológica de la Expresión Génica , Hexosaminidasas/química , Humanos , Hidrólisis , Leucocitos/enzimología , Leucocitos/metabolismo , Mutación , Enfermedades de Niemann-Pick/enzimología , Éteres Fosfolípidos/química , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Unión Proteica , Reproducibilidad de los Resultados , Piel/metabolismo , Esfingomielinas/química , Esfingosina/análogos & derivados , Esfingosina/química , Especificidad por Sustrato , Factores de Tiempo
18.
J Inherit Metab Dis ; 28(5): 803-5, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16151917

RESUMEN

Female heterozygous patients with Fabry disease are difficult to identify because of the relatively high residual activity of alpha-galactosidase. We systematically evaluated the activities of various lysosomal enzymes in dried blood samples from Fabry patients and found that the beta-glucuronidase activity was frequently elevated. The ratio of alpha-galactosidase to beta-glucuronidase proved to be a helpful tool for the diagnosis of female Fabry disease patients.


Asunto(s)
Sangre , Terapia Enzimática , Enfermedad de Fabry/diagnóstico , Glucuronidasa/sangre , alfa-Galactosidasa/sangre , Femenino , Heterocigoto , Humanos , Lisosomas/metabolismo , Masculino , Mutación , Valores de Referencia , Manejo de Especímenes
19.
Clin Genet ; 65(4): 299-307, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15025723

RESUMEN

Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system--the Mainz Severity Score Index (MSSI)--to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT-related treatment effects.


Asunto(s)
Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/tratamiento farmacológico , Isoenzimas/uso terapéutico , Índice de Severidad de la Enfermedad , alfa-Galactosidasa/uso terapéutico , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , Manejo de la Enfermedad , Monitoreo de Drogas , Femenino , Heterocigoto , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas Recombinantes , Factores Sexuales , Resultado del Tratamiento
20.
Neuropediatrics ; 34(6): 301-6, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14681755

RESUMEN

This study describes a diagnostic pitfall in the laboratory diagnosis of patients with sphingomyelinase deficiency (SMD; Niemann-Pick disease types A and B; NPA and NPB), in cases where sphingomyelinase activity was not determined with sphingomyelin as the natural enzymic substrate. Four of 24 SMD patients studied had falsely normal or enhanced activity, when a so-called artificial sphingomyelinase substrate, 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine (HNP), was used, whereas SMD was clear with the sphingomyelin substrate. Those four patients had the Q292 K mutation of the acid sphingomyelinase gene (SMPD1) on at least one allele. Three of the four patients (no data available from one) experienced only late-infantile or juvenile, though distinct, neurological involvement, where learning disabilities, hypo- or areflexia or mild ataxia were initial signs. The laboratory pitfall with HNP substrate, which is used in many laboratories, raises the risk that some SMD patients are overlooked, and it prevents the consideration of a late-manifesting neurological course in some patients as well as the planning of enzyme substitution therapy in non-neurological SMD (NPB) patients. Since classical NPB is very rare, it is suggested that SMD patients with late- or mild-manifesting neurological symptoms should better be assigned to additional SMD subgroups than grouped with NPB.


Asunto(s)
Pruebas Enzimáticas Clínicas , Errores Diagnósticos , Mutación , Enfermedades de Niemann-Pick/diagnóstico , Enfermedades de Niemann-Pick/genética , Fosforilcolina/análogos & derivados , Esfingomielina Fosfodiesterasa/deficiencia , Adolescente , Adulto , Anciano , Niño , Preescolar , Humanos , Lactante , Persona de Mediana Edad , Fosforilcolina/metabolismo , Esfingomielina Fosfodiesterasa/genética , Esfingomielinas/metabolismo
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