997 resultados para LYSOSOMAL STORAGE DISEASE
Resumo:
We investigated the effect of age and sex on the serum activity of hexosaminidase (HEX) and ß-glucuronidase (BGLU) in 275 normal term infants aged 12 h to 12 months. Up to six weeks of life, HEX was significantly higher in boys (P<=0.023). During the age period of 1-26 weeks, BGLU was also higher in boys, but differences were significant only at 2-6 and 7-15 weeks (P<=0.016). The developmental pattern of HEX and BGLU was sex dependent. HEX activity increased in both sexes from 4-7 days of life, reaching a maximum of 1.4-fold the birth value at 2-6 weeks of age in boys (P<0.001) and a maximum of 1.6-fold at 7-15 weeks in girls (P<0.001). HEX activity gradually decreased thereafter, reaching significantly lower levels at 27-53 weeks than during the first three days of life in boys (P = 0.002) and the same level of this age interval in girls. BGLU increased in both sexes from 4-7 days of age, showing a maximum increase at 7-15 weeks (3.3-fold in boys and 2.9-fold in girls, both P<0.001). Then BGLU decreased in boys to a value similar to that observed at 4-7 days of age. In girls, BGLU remained elevated until the end of the first year of life. These results indicate a variation of HEX and BGLU activities during the first year of life and a sex influence on their developmental pattern. This observation should be considered in the diagnosis of GM2 gangliosidosis and mucopolysaccharidosis type VII.
Resumo:
Introducción: La Enfermedad de Fabry (EF), es una enfermedad multisistémica de almacenamiento lisosomal ligada al cromosoma X que afecta principalmente a hombres, pero también puede causar significativa morbilidad en las mujeres heterocigotas (1–5). La deficiencia de la enzyma α-galactosidaseA (α-Gal A,) provoca acumulación de glicosfingolipidos que afectan diferentes tipos celulares entre ellos el endotelio vascular en vasos de pequeño calibre, células epiteliales y Músculo liso en el sistema cardiovascular (cardiomiocitos), sistema nervioso y células epiteliales tubulares del riñón (6,7). Complicaciones como la falla renal es la causa de muerte más frecuente en la EF (7,8). La incidencia se ha calculado en 1 de cada 117.000 nacidos vivos. (9). Objetivos: Determinar la prevalencia de la Enfermedad de Fabry en pacientes con Insuficiencia renal terminal que se encuentren en lista de trasplante y Post-trasplante Renal en Fundación Cardioinfantil Bogotá. Materiales y Métodos: Se realizó un estudio observacional en donde se evaluó la prevalencia de la EF en todos los sujetos mayores de 18 años que se encuentren en lista de trasplante y post-trasplante renal. Resultados: La prevalencia de Enfermedad de Fabry en 98 pacientes con enfermedad renal crónica fue de 7.1% para la muestra general y 12.9% para la muestra con etiología idiopática Conclusiones: La Enfermedad de Fabry es una importante casusa de Enfermedad Renal Crónica Terminal principalmente en el grupo de etiología idiopática. Palabras Clave: Enfermedad de Fabry (FA)
Resumo:
Morbus Hunter, eine lysosomale Speicherkrankheit, ist eine seltene, progrediente, x-chromosomal vererbte Stoffwechselkrankheit, die durch ein Defizit an Iduronat-2-sulfatase (IDS) hervorgerufen wird. Als Folge daraus erfolgt kein Abbau von Heparan- und Dermatansulfat und die Glykosaminoglykane reichern sich in de Lysosomen der Zelle an. M. Hunter ist eine Multisystemerkrankung und weist ein breites klinisches Spektrum mit interindividuell unterschiedlichem Krankheitsbeginn, Ausprägungen und Progression der Symptome auf. Seit 2007 besteht die Therapieoption einer Enzymersatztherapie (ERT) mit Elaprase®. Einige Patienten entwickeln Antikörper gegen das substituierte Enzym, welche partiell neutralisierende Eigenschaften besitzen. Ziel dieser Untersuchung war es zu klären, ob die Neutralisationskapazität der gebildeten Antikörper mittels einer Bestimmung im Mischserum festgestellt werden kann und ob persistierende Antikörper mit Neutralisationskapazität zu einer Einschränkung der Wirksamkeit der Enzymersatztherapie führen. Es sollte weiterhin untersucht werden, ob sich mittels Messung der neuronenspezifischen Enolase (NSE) und S-100 Rückschlüsse auf eine neuropathische Beteiligung ziehen lassen, da bis jetzt noch keine klinische oder biochemische Messmethode existiert, die für M. Hunter-Patienten eine verlässliche Vorhersage für eine neuropathische Beteiligung bietet. 30 Patienten wurden in die retrospektive/prospektive Kohortenstudie eingeschlossen. Bei der Bestimmung der IDS-Aktivität im Mischserum mit einem gesunden Menschen zeigten fünf der Patienten (17%) in zwölf Mischseren eine um ≥ 40% reduzierte Aktivität. Zwei (7%) der 30 untersuchten Patienten wurden mit dieser Methode als positiv für persistierende neutralisierende Antikörper identifiziert. Zum gleichen Ergebnis bezüglich der persistierenden neutralisierenden Antikörper führten die Anti-Elaprase®-Immunglobulin-Bestimmungen unter Berücksichtigung des Bestimmungszeitpunkts, die bei Shire Pharmaceuticals durchgeführt wurden. Die Untersuchungsergebnisse lassen den Schluss zu, dass die gebildeten Antikörper auch intraindividuell unterschiedlich sind. Zudem interagieren sie mit den verschiedensten Epitopen des Enzyms der ERT und besitzen nicht alle neutralisierende Eigenschaften. Aufgrund der heterogenen Zusammensetzung folgt die Hemmung der Enzymaktivität vermutlich keiner eindeutigen Kinetik. Anti-Elaprase®-Immunglobulin G spielt für die Neutralisationskapazität jedoch eine wichtige Rolle. Die Auswertung und Beurteilung der Einschränkung der Wirksamkeit der Therapie hervorgerufen durch die Antikörper mit Neutralisationskapazität gestaltete sich kompliziert. Im Ergebnis zeigte sich, dass sich die beiden Patienten mit persistierenden neutralisierenden Antikörpern in der Entwicklung der klinischen Parameter interindividuell stark unterschieden. Um einen Zusammenhang zwischen klinischem Verlauf und Antikörperbildung gegen die ERT zu finden, müssen in einem größeren Patientenkollektiv mehr Patienten mit persistierenden neutralisierenden Antikörpern identifiziert werden und der Einfluss der Antikörper untersucht werden. Die Untersuchung der NSE und S-100 ergab, dass weder die Konzentration der NSE noch der S-100 Rückschlüsse auf die neuropathische Beteiligung des Patienten zulässt.
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Fucosidosis is a rare lysosomal storage disease. A 14-year-old girl is presented, with recurrent infections, progressive dystonic movement disorder and mental retardation with onset in early childhood. The clinical picture was also marked by mild morphologic features, but absent dysostosis multiplex and organomegaly. MRI images at 6.5 years of age were reminiscent of pallidal iron deposition ("eye-of-the-tiger" sign) seen in neurodegeneration with brain iron accumulation (NBIA) disorders. Progressively spreading angiokeratoma corporis diffusum led to the correct diagnosis. This case extends the scope of clinical and neuroradiological manifestations of fucosidosis.
Resumo:
The G M1-gangliosidosis is an autosomal recessive lysosomal storage disease caused by structural defects of the beta-galactosidase gene (GLB1) which lead to a severe phenotypical impairment in homozygous individuals, whereas heterozygous carriers remain clinically normal. Currently employed DNA parentage tests include the analysis of microsatellites, which also have a diagnostic predictive value. The aim of this study was to provide a reliable tool for genotyping the canine GLB1 which can be effectively integrated in parentage testing investigations. For this purpose the association between the GLB1 gene and the AHT K253 microsatellite was analyzed in 30 Alaskan huskies (11 GLB1+/+, 17 GLB1+/- and 2 GLB1-/- dogs). The 143 bp AHT K253 microsatellite allele was identified only in GLB1+/- and GLB1-/- animals and was in strong linkage disequilibrium with the causative mutation for G M1-gangliosidosis, a 19 bp duplication within exon 15 of the GLB1 gene. The results of the present study revealed a 100% concordance between the previous established genotypes and those obtained after the analysis of the AHT K253 microsatellite. Thus, the genotype of the AHT K253 microsatellite, which is routinely determined during dog parentage testing, has a high predictive value for the G M1-gangliosidosis carrier status.
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GM(1)-gangliosidosis is a lysosomal storage disease that is inherited as an autosomal recessive disorder, predominantly caused by structural defects in the beta-galactosidase gene (GLB1). The molecular cause of GM(1)-gangliosidosis in Alaskan huskies was investigated and a novel 19-bp duplication in exon 15 of the GLB1 gene was identified. The duplication comprised positions +1688-+1706 of the GLB1 cDNA. It partially disrupted a potential exon splicing enhancer (ESE), leading to exon skipping in a fraction of the transcripts. Thus, the mutation caused the expression of two different mRNAs from the mutant allele. One transcript contained the complete exon 15 with the 19-bp duplication, while the other transcript lacked exon 15. In the transcript containing exon 15 with the 19-bp duplication a premature termination codon (PTC) appeared, but due to its localization in the last exon of canine GLB1, nonsense-mediated RNA decay (NMD) did not occur. As a consequence of these molecular events two different truncated GLB1 proteins are predicted to be expressed from the mutant GLB1 allele. In heterozygous carrier animals the wild-type allele produces sufficient amounts of the active enzyme to prevent clinical signs of disease. In affected homozygous dogs no functional GLB1 is synthesized and G(M1)-gangliosidosis occurs.
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Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase B (ASB), which is involved in degradation of dermatan sulfate and chondroitin 4-sulfate. A MPS VI mouse model was generated by targeted disruption of the ASB gene. Homozygous mutant animals exhibit ASB enzyme deficiency and elevated urinary secretion of dermatan sulfate. They develop progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age facial dysmorphia becomes overt, long bones are shortened, and pelvic and costal abnormalities are observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals are seen. All major parenchymal organs show storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice are fertile and mortality is not elevated up to 15 months of age. This mouse model will be a valuable tool for studying pathogenesis of MPS VI and may help to evaluate therapeutical approaches for lysosomal storage diseases.
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We have studied the use of adenovirus-mediated gene transfer to reverse the pathologic changes of lysosomal storage disease caused by beta-glucuronidase deficiency in the eyes of mice with mucopolysaccharidosis VII. A recombinant adenovirus carrying the human beta-glucuronidase cDNA coding region under the control of a non-tissue-specific promoter was injected intravitreally or subretinally into the eyes of mice with mucopolysaccharidosis VII. At 1-3 weeks after injection, the treated and control eyes were examined histochemically for beta-glucuronidase expression and histologically for phenotypic correction of the lysosomal storage defect. Enzymatic expression was detected 1-3 weeks after injection. Storage vacuoles in the retinal pigment epithelium (RPE) were still present 1 week after gene transfer but were reduced to undetectable levels by 3 weeks in both intravitreally and subretinally injected eyes. There was minimal evidence of ocular pathology associated with the viral injection. These data indicate that adenovirus-mediated gene transfer to the eye may provide for adjunctive therapy for lysosomal storage diseases affecting the RPE in conjunction with enzyme replacement and/or gene therapies for correction of systemic disease manifestations. The data also support the view that recombinant adenovirus may be useful as a gene therapy vector for retinal degenerations that result from a primary genetic defect in the RPE cells.
Resumo:
Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3; also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified α-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered α-gal A, (ii) to assess the pharmacokinetics of i.v.-administered α-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. α-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified α-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of α-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of α-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.
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Mucolipidosis, type IV (ML-IV) is an autosomal recessive storage disease that is characterized by lysosomal accumulation of sphingolipids, phospholipids, and acid mucopolysaccharides. Unlike most other storage diseases, the lysosomal hydrolases participating in the catabolism of the stored molecules appear to be normal. In the present study, we examined the hypothesis that the ML-IV phenotype might arise from abnormal transport along the lysosomal pathway. By using various markers for endocytosis, we found that plasma membrane internalization and recycling were nearly identical in ML-IV and normal fibroblasts. A fluorescent analog of lactosylceramide (LacCer) was used to study plasma membrane lipid internalization and subsequent transport. Lipid internalization at 19°C was similar in both cell types; however, 40–60 min after raising the temperature to 37°C, the fluorescent lipid accumulated in the lysosomes of ML-IV cells but was mainly concentrated at the Golgi complex of normal fibroblasts. Biochemical studies demonstrated that at these time points, hydrolysis of the lipid analog was minimal (∼7%) in both cell types. A fluorescence ratio imaging assay was developed to monitor accumulation of fluorescent LacCer in the lysosomes and showed that the apparent concentration of the lipid increased more rapidly and to a greater extent in ML-IV cells than in normal fibroblasts. By 60 min, LacCer apparently decreased in the lysosomes of normal fibroblasts but not in ML-IV cells, suggesting that lipid efflux from the lysosomes was also impaired. These results demonstrate that there is a defect in ML-IV fibroblasts that affects membrane sorting and/or late steps of endocytosis.
Resumo:
Background. Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of -Galactosidase A (-Gal A). Fabry nephropathy typically progresses throughout the fifth decade to end-stage renal disease (ESRD), requiring hemodialysis and/or kidney transplantation. Objective. To estimate the prevalence of FD among ESRD males on hemodialysis treatment in Rio Grande do Sul, the southernmost state of Brazil. Methods. Screening for -Gal A activity was performed by a dried blood spot (normal reference value: 1.5 nmoles/hour/mL). Positive screening results were confirmed by plasma -Gal A activity assay (reference value: 3.3 nmoles/hour/mL). Results. Five hundred fifty-eight male patients on hemodialysis were evaluated. Of these, only two had low -Gal A activity and were diagnosed with Fabry disease (0.36%). One of these, age 42, had left ventricular hypertrophy and renal manifestations of Fabry disease without the classic symptoms. The other, age 46, had the classical manifestations of angiokeratomas, acroparesthesias, hypohidrosis, and ocular opacities. Conclusions. Although the prevalence of Fabry disease was very low in our study (0.36%), routine screening of male hemodialysis patients would enable earlier identification of many other affected relatives in their families who might benefit from specific clinical treatment.
Resumo:
Introduction and Aims: Fabry disease is an X-linked lysosomal storage disorder caused by absence or deficient activity of the lysosomal enzyme alpha-galactosidase A. Renal manifestations occur early in life in a significant proportion of children, in many women and in almost all men with Fabry disease. These manifestations ultimately progress to end-stage renal disease in nearly all males and in some female patients. Data on kidney transplantation in patients with Fabry disease who are receiving enzyme replacement therapy (ERT), however, are scarce. Methods: We examined the clinical characteristics of kidney transplant recipients (KTRs) in the Fabry Outcome Survey (FOS) - a European database of patients with Fabry disease that was established to monitor the safety and outcome of ERT. Results: Of the 752 patients enrolled in FOS up to October 2005, 34 (4.5%) were reported to be KTRs. The mean age of these 32 male and 2 female patients was 45 ± 9 years, the median time since the transplant was 9 years, the median estimated glomerular filtration rate (eGFR) was 46 mL/min/1.73 m2 and the median level of proteinuria was 180 mg/24 hours. ERT was well tolerated, with mild infusion-related reactions reported in only one patient. Amongst these patients, 53% were reported to have hypertension, 71% left ventricular hypertrophy, 27% cardiac valve disease and 27% arrhythmia. A total of 23 (68%) of the patients (1 female, 22 males) were receiving ERT with agalsidase alfa (Replagal; Shire Human Genetic Therapies, UK), with a median duration of treatment of 2.5 years. There were no differences in age or time since transplantation between treated and untreated patients. The median eGFRs were 46 and 49 mL/min/1.73 m2 and the median levels of proteinuria were 200 and 160 mg/24 hours, respectively. Conclusions: KTRs represent a significant minority of individuals enrolled in a large international registry of patients with Fabry disease (FOS). Approximately two-thirds of KTRs with Fabry disease enrolled in FOS receive ERT with agalsidase alfa, which is well tolerated. Comparison of treated and untreated patients has the potential to examine effects of ERT on the progression of renal and cardiovascular disease.
Resumo:
BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by a reduced activity of the lysosomal enzyme alpha-galactosidase A. The disorder ultimately leads to organ damage (including renal failure) in males and females. However, heterozygous females usually present a milder phenotype with a later onset and a slower progression. METHODS: A combined enzymatic and genetic strategy was used, measuring the activity of alpha-galactosidase A and genotyping the alpha-galactosidase A gene (GLA) in dried blood samples (DBS) of 911 patients undergoing haemodialysis in centers across Spain. RESULTS: GLA alterations were found in seven unrelated patients (4 males and 3 females). Two novel mutations (p.Gly346AlafsX347 and p.Val199GlyfsX203) were identified as well as a previously described mutation, R118C. The R118C mutation was present in 60% of unrelated patients with GLA causal mutations. The D313Y alteration, considered by some authors as a pseudo-deficiency allele, was also found in two out of seven patients. CONCLUSIONS: Excluding the controversial D313Y alteration, FD presents a frequency of one in 182 individuals (0.55%) within this population of males and females undergoing haemodialysis. Moreover, our findings suggest that a number of patients with unexplained and atypical symptoms of renal disease may have FD. Screening programmes for FD in populations of individuals presenting severe kidney dysfunction, cardiac alterations or cerebrovascular disease may lead to the diagnosis of FD in those patients, the study of their families and eventually the implementation of a specific therapy.