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1.
Br J Ophthalmol ; 103(3): 315-326, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30612093

RESUMO

Gaucher disease (GD) results from a deficiency of glucocerebrosidase activity and the subsequent accumulation of the enzyme's metabolites, principally glucosylsphingosine and glucosylceramide. There are three principal forms: Type I, which is the most common, is usually considered non-neuronopathic. Type II, III and IIIc manifest earlier and have neurological sequelae due to markedly reduced enzyme activity. Gaucher's can be associated with ophthalmological sequelae but these have not been systematically reviewed. We therefore performed a comprehensive literature review of all such ophthalmic abnormalities associated with the different types of Gaucher disease. We systematically searched the literature (1950 - present) for functional and structural ocular abnormalities arising in patients with Gaucher disease and found that all subtypes can be associated with ophthalmic abnormalities; these range from recently described intraocular lesions to disease involving the adnexae, peripheral nerves and brain. In summary, Gaucher can affect most parts of the eye. Rarely is it sight-threatening; some but not all manifestations are amenable to treatment, including with enzyme replacement and substrate reduction therapy. Retinal involvement is rare but patients with ocular manifestations should be monitored and treated early to reduce the risk of progression and further complications. As Gaucher disease is also associated with Parkinsons disease and may also confer an increased risk of malignancy (particularly haematological forms and melanoma), any ocular abnormalities should be fully investigated to exclude these potential underlying conditions.


Assuntos
Oftalmopatias/diagnóstico , Doença de Gaucher/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Oftalmopatias/classificação , Oftalmopatias/etiologia , Doença de Gaucher/classificação , Doença de Gaucher/etiologia , Glucosilceramidas/sangue , Humanos , Doenças por Armazenamento dos Lisossomos/classificação , Doenças por Armazenamento dos Lisossomos/etiologia , Fenótipo , Psicosina/análogos & derivados , Psicosina/sangue
2.
Blood Cells Mol Dis ; 68: 60-65, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28457694

RESUMO

Gaucher disease is mainly caused by the deficiency of lysosomal acid ß-glucosidase. Gaucher disease caused by the deficiency of saposin C is rare. Here we report a patient mainly presenting with hepatosplenomegaly, thrombocytopenia and anemia. EEG examination revealed increased theta waves. Gaucher cells identified in his bone marrow and the highly elevated plasma chitotriosidase activity and glucosylsphingosine supported a diagnosis of Gaucher disease. However, the leukocyte ß-glucosidase activity was in a normal range. Sanger sequencing revealed a novel maternal exonic mutation c.1133C>G (p.Pro378Arg) in exon 10 of the PSAP gene, which codes the Sap C domain of PSAP protein. To search for other underlying mutations in this patient, whole genome sequencing was applied and revealed a deletion involving exon 2 to 7 of PSAP gene. The deletion appears as a de novo event on paternal chromosome. We concluded that biallelic mutations of PSAP gene were the cause of this patient's Gaucher disease. Our finding expands the mutation spectrum of Gaucher disease with saposin C deficiency.


Assuntos
Doença de Gaucher/etiologia , Doença de Gaucher/genética , Mutação Puntual , Saposinas/deficiência , Sequência de Bases , Criança , Éxons , Deleção de Genes , Humanos , Masculino , Mutação de Sentido Incorreto , Saposinas/genética , Deleção de Sequência
3.
Blood Rev ; 30(6): 431-437, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27265538

RESUMO

Gaucher disease (GD) is characterized by large amounts of lipid-storing macrophages and is associated with accumulation of iron. High levels of ferritin are a hallmark of the disease. The precise mechanism underlying the changes in iron metabolism has not been elucidated. A systematic search was conducted to summarize available evidence from the literature on iron metabolism in GD and its potential pathophysiological implications. We conclude that in GD, a chronic low grade inflammation state can lead to high ferritin levels and increased hepcidin transcription with subsequent trapping of ferritin in macrophages. Extensive GD manifestations with severe anemia or extreme splenomegaly can lead to a situation of iron-overload resembling hemochromatosis. We hypothesize that specifically this latter situation carries a risk for the occurrence of associated conditions such as the increased cancer risk, metabolic syndrome and neurodegeneration.


Assuntos
Ferritinas/metabolismo , Doença de Gaucher/etiologia , Doença de Gaucher/metabolismo , Ferro/metabolismo , Ferritinas/sangue , Doença de Gaucher/complicações , Doença de Gaucher/terapia , Hepcidinas/sangue , Hepcidinas/metabolismo , Humanos , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/terapia , Síndrome Metabólica/etiologia , Síndrome Metabólica/terapia , Neoplasias/etiologia , Doenças Neurodegenerativas/etiologia
4.
Yi Chuan ; 37(6): 510-6, 2015 06.
Artigo em Chinês | MEDLINE | ID: mdl-26351046

RESUMO

Gaucher's disease (GD) also named glucocerebroside lipidosis, is the most common kind of 1ysosomal storage disorder. It results from an autosomal recessive deficiency of the lysosomal enzyme acid ß-glucosidase/ ß-glucocerebrosidase (GBA), which is responsible for hydrolysis of glucocerebroside/glucosylceramide (GlcCer) into glucose and ceramide. Absent or reduced enzymatic activity of GBA leads to multisystemic accumulation of GlcCer in mononuclear phagocyte system and various tissues, such as brain, liver, spleen and so on, causing brain injury, liver splenomegaly, bone damage, the reduction of blood cells and individual growth retardation. GD type I could be treated by enzyme replacement therapy (ERT), but GD types II and III have not effective treatment. In this review, we summarize the recent progress on pathogenic mechanism and therapies in GD.


Assuntos
Doença de Gaucher/etiologia , Doença de Gaucher/terapia , Animais , Terapia de Reposição de Enzimas , Terapia Genética , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Mutação
5.
J Neurol Sci ; 356(1-2): 129-36, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26104567

RESUMO

Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57Bl/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP(+) (1-methyl-4-phenylpyridinium) or alpha-synuclein (α-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP-induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both α-Syn and MPP(+) induced toxicity in vitro. However, only CBE-induced enhancement of MPP(+) toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat. Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity.


Assuntos
Doença de Gaucher/etiologia , Doenças Mitocondriais/etiologia , Transtornos Parkinsonianos/complicações , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/prevenção & controle , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Antígenos de Histocompatibilidade/metabolismo , Inositol/análogos & derivados , Inositol/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Pediatr Endocrinol Rev ; 12 Suppl 1: 72-81, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25345088

RESUMO

Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options.


Assuntos
Doença de Gaucher/diagnóstico , Doença de Gaucher/etiologia , Doença de Gaucher/genética , Glucosilceramidase/genética , Humanos
7.
Crit Rev Oncog ; 18(3): 163-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23510062

RESUMO

Gaucher disease (GD) is an inherited error of metabolism due to a deficiency of glucocerebrosidase. This leads to excessive storage of glucocerebroside in the liver, spleen, bone, and bone marrow. Patients develop anemia, thrombocytopenia, hepatosplenomegaly, bone infarcts, aseptic necrosis of bone, and osteoporosis. There are three types of GD; types 2 and 3 have neurological involvement. With the advent of enzyme replacement therapy and substrate reduction therapy, the natural history of the disease has been has significantly changed, with a marked decrease in morbidity, especially for type 1 patients. This article reviews a broad spectrum of information regarding Gaucher disease, from the history of the disease to newer therapies still in the investigational stage.


Assuntos
Doença de Gaucher , Doença de Gaucher/diagnóstico , Doença de Gaucher/epidemiologia , Doença de Gaucher/etiologia , Doença de Gaucher/história , Doença de Gaucher/terapia , História do Século XIX , História do Século XX , História do Século XXI , Humanos
8.
Crit Rev Oncog ; 18(3): 235-46, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23510066

RESUMO

Clinical observations spanning almost half a century have demonstrated a consistent association of type 1 Gaucher disease (GD1) and cancers. However, the cellular and molecular bases of the association are not understood. Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency of acid ß-glucosidase that underlies the accumulation of glucosylceramide in lysosomes of mononuclear phagocytes and immune dysregulation. The overall cancer risk is markedly increased in GD, and the determinants of malignancy in a subset of patients with GD1 are not known. The association of GD and cancer is most striking for hematological malignancies, with the risk for multiple myeloma estimated at almost 37-fold compared to the general population; some studies have also suggested increased cancer risk for non-hematological malignancies. There is no association of overall severity of GD to risk of cancer, although there is an increased prevalence of splenectomy among patients exhibiting the GD/cancer phenotype. Moreover, there appears to be an increased incidence of multiple consecutive cancers in individual patients. Several factors could contribute to cancer development in GD, including polarization of macrophages to the alternatively activated phenotype, chronic inflammation, chronic B-cell stimulation, splenectomy, hyperferritinemia, lysosomal dysfunction, and endoplasmic reticulum stress. Recent studies have highlighted T-cell dysfunction and modifier genes contributing to an increased cancer risk in GD. Macrophage-targeted enzyme replacement therapy (ERT) reverses systemic features of GD1; while cancer risk appears to be reduced in the era of ERT, it is not known whether this is a direct effect of therapy. Delineation of the mechanisms underlying the increased cancer risk in GD will provide additional novel insights into the role of lipids and macrophages in cancer pathogenesis and, moreover, have the potential to reveal novel therapeutic targets.


Assuntos
Doença de Gaucher/complicações , Neoplasias/etiologia , Animais , Doença de Gaucher/etiologia , Humanos
9.
Clin Adv Hematol Oncol ; 10(6 Suppl 8): 1-16, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22895100

RESUMO

Gaucher disease is an inherited lysosomal storage disorder caused by mutations in the gene that encodes the lysosomal enzyme glucocerebrosidase. Inadequate enzymatic activity causes cells to become engorged due to an accumulation of glycolipids. Engorged cells then accumulate in various organs, resulting in a range of signs and symptoms. Gaucher disease occurs worldwide but is more common among individuals of Ashkenazi Jewish descent. Approximately 90% of patients with Gaucher disease have non-neuronopathic (type 1) disease, which is characterized by hematologic sequelae, potentially disabling skeletal complications, and late-onset neurologic complications. The other 2 subtypes of Gaucher disease cause neuronopathic disease, with early involvement of the central nervous system. Type 2 Gaucher disease results in death in infancy, while type 3 disease causes variable neurologic manifestations ranging from minimal ocular effects to seizures, ataxia, and cognitive regression. Because of its relative rarity, Gaucher disease often remains misdiagnosed or undiagnosed for some time. However, early diagnosis and appropriate treatment are essential for reducing the risk of complications, improving quality of life, and avoiding inappropriate procedures. Given the prevalence of hematologic manifestations associated with this condition, patients with undiagnosed Gaucher disease may seek treatment from hematologists or oncologists. Therefore, hematology and oncology clinicians need to be aware of the potential for Gaucher disease and consider it in their differential diagnosis.


Assuntos
Doença de Gaucher/diagnóstico , Doença de Gaucher/etiologia , Humanos , Prognóstico
10.
Mov Disord ; 26(9): 1593-604, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21618611

RESUMO

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as α-synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms.


Assuntos
Doença de Gaucher/epidemiologia , Doença de Gaucher/genética , Glucosilceramidase/genética , Doenças por Armazenamento dos Lisossomos/genética , Doença de Parkinson/genética , Doença de Gaucher/etiologia , Glucosilceramidase/deficiência , Humanos , Doenças por Armazenamento dos Lisossomos/epidemiologia
12.
Anal Biochem ; 381(2): 276-8, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18619939

RESUMO

The low levels of human lysosomal glucocerebrosidase activity expressed in transiently transfected Chinese hamster ovary (CHO) cells were investigated. Reverse transcription PCR (RT-PCR) demonstrated that a significant portion of the transcribed RNA was misspliced owing to the presence of a cryptic splice site in the complementary DNA (cDNA). Missplicing results in the deletion of 179 bp of coding sequence and a premature stop codon. A repaired cDNA was constructed abolishing the splice site without changing the amino acid sequence. The level of glucocerebrosidase expression was increased sixfold. These data demonstrate that for maximum expression of any cDNA construct, the transcription products should be examined.


Assuntos
Processamento Alternativo , Glucosilceramidase/genética , Sítios de Splice de RNA , Sequência de Aminoácidos , Animais , Sequência de Bases , Células CHO , Cricetinae , Cricetulus , Análise Mutacional de DNA , DNA Complementar , Doença de Gaucher/etiologia , Doença de Gaucher/genética , Glucosilceramidase/isolamento & purificação , Glucosilceramidase/metabolismo , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
World J Gastroenterol ; 14(25): 3968-73, 2008 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-18609679

RESUMO

Gaucher disease (GD) is an autosomal recessive disease which if undiagnosed or diagnosed late results in devastating complications. Because of the heterozygous nature of GD, there is a wide spectrum of clinical presentation. Clinicians should be aware of this rare but potentially treatable disease in patients who present with unexplained organomegaly, anemia, massive splenomegaly, ascites and even cirrhosis of unknown origin. The treatment options for adult type GD include enzyme replacement treatment (ERT) and substrate reduction treatment (SRT) depending on the status of the patient. Future treatment options are gene therapy and "smart molecules" which provide specific cure and additional treatment options. In this review, we present the key issues about GD and new developments that gastroenterologists should be aware of.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Doença de Gaucher/etiologia , Doença de Gaucher/terapia , Glucosilceramidase/uso terapêutico , Gastroenteropatias/etiologia , Gastroenteropatias/terapia , Doença de Gaucher/complicações , Doença de Gaucher/enzimologia , Doença de Gaucher/patologia , Terapia Genética/métodos , Glucosilceramidase/deficiência , Inibidores de Glicosídeo Hidrolases , Humanos , Resultado do Tratamento , alfa-Glucosidases/metabolismo
15.
Proc Natl Acad Sci U S A ; 104(32): 13192-7, 2007 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-17670938

RESUMO

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due to misfolding, raising the possibility of small-molecule chaperone correction of the defect. Screening large compound libraries by quantitative high-throughput screening (qHTS) provides comprehensive information on the potency, efficacy, and structure-activity relationships (SAR) of active compounds directly from the primary screen, facilitating identification of leads for medicinal chemistry optimization. We used qHTS to rapidly identify three structural series of potent, selective, nonsugar glucocerebrosidase inhibitors. The three structural classes had excellent potencies and efficacies and, importantly, high selectivity against closely related hydrolases. Preliminary SAR data were used to select compounds with high activity in both enzyme and cell-based assays. Compounds from two of these structural series increased N370S mutant glucocerebrosidase activity by 40-90% in patient cell lines and enhanced lysosomal colocalization, indicating chaperone activity. These small molecules have potential as leads for chaperone therapy for Gaucher disease, and this paradigm promises to accelerate the development of leads for other rare genetic disorders.


Assuntos
Inibidores Enzimáticos/química , Doença de Gaucher/enzimologia , Glucosilceramidase/antagonistas & inibidores , Chaperonas Moleculares/fisiologia , Células Cultivadas , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/etiologia , Humanos , Lisossomos/enzimologia , Relação Estrutura-Atividade
16.
Mol Genet Metab ; 90(2): 148-56, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17079175

RESUMO

Gaucher disease is a disorder of sphingolipid metabolism resulting from an inherited deficiency of the lysosomal hydrolase glucocerebrosidase. Affected individuals present with a spectrum of clinical symptoms ranging from hepatosplenomegaly, haematological abnormalities, and bone pain in type 1 disease, to severe neurodegeneration and premature death in types 2 and 3 disease. Although the basic biochemical defect is well characterized, there remains a poor understanding of the underlying pathophysiology of disease. In vitro studies suggest that macrophage glucocerebroside storage leads to tissue dysfunction through complex mechanisms involving altered intracellular calcium homeostasis and apoptosis. In order to study the pathogenic roles of these complex interactions, a viable animal model for Gaucher disease is needed. The complexity of this single gene disorder has been emphasized by the varied results of previous murine Gaucher models, ranging from perinatal lethality to phenotypically and biochemically asymptomatic animals. Recognizing the need to modulate the biochemical phenotype in mice to produce a relevant model, we have created a murine strain with key exons of the glucocerebrosidase gene flanked by loxP sites. We show that expression of Cre-recombinase in cells of hematopoietic and endothelial origin results in deficiency of glucocerebrosidase in the liver, spleen, bone marrow, and peripheral white cells. Glucocerebroside storage in this model leads to progressive splenomegaly with Gaucher cell infiltration and modest storage in the liver by 26 weeks of age. These results indicate the utility of this loxP GBA targeted murine strain for understanding the complex pathophysiology of Gaucher disease.


Assuntos
Doença de Gaucher/etiologia , Glucosilceramidase/genética , Animais , Modelos Animais de Doenças , Doença de Gaucher/patologia , Glucosilceramidase/metabolismo , Glucosilceramidas/metabolismo , Sistema Hematopoético/patologia , Humanos , Integrases/genética , Fígado/enzimologia , Fígado/patologia , Camundongos , Camundongos Knockout , Camundongos Mutantes , Dados de Sequência Molecular , Recombinases/genética , Baço/anormalidades , Baço/enzimologia , Baço/patologia
17.
Neuropediatrics ; 37(3): 163-5, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16967369

RESUMO

Gaucher disease, a rare lysosomal storage disease caused by deficiency of glucocerebrosidase, may present with gastrointestinal bleeding. We report about an 11-month-old boy suffering from acute neuronopathic Gaucher disease who died after massive gastrointestinal bleeding. A gastric ulcer was found as the sole bleeding source. The gastric mucosa showed marked infiltration with Gaucher cells, in particular around the ulcer. Alterations of the gastrointestinal mucosa offer a new explanation for gastrointestinal bleedings in this disease.


Assuntos
Gastroenteropatias/complicações , Doença de Gaucher/etiologia , Hemorragia/complicações , Evolução Fatal , Gastroenteropatias/patologia , Humanos , Lactente , Masculino , Mudanças Depois da Morte
18.
Mol Genet Metab ; 83(1-2): 6-15, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15464415

RESUMO

Gaucher disease, the recessively inherited deficiency of the enzyme glucocerebrosidase and the most common sphingolipidosis, has both non-neurological and neuronopathic forms and a continuum of diverse clinical manifestations. Studies of genotype-phenotype correlations reveal significant genotypic heterogeneity among clinically similar patients, and vastly different phenotypes among patients with the same mutations. The region surrounding the glucocerebrosidase gene (GBA) on chromosome 1q is particularly gene-rich, with a highly homologous pseudogene sequence 16 kb downstream. Recombination events within the GBA locus contribute to the etiology of some mutations in Gaucher disease. Studies of patients with Gaucher disease and atypical manifestations, including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin, seek to define other genetic or environmental factors contributing to the phenotypes. Recent reports demonstrating an association between Gaucher disease and parkinsonism provide an example of heterozygosity for a Mendelian disorder acting as a risk factor for a complex disease. There are rare patients with Gaucher disease and differing genotypes who develop early onset, treatment-refractory parkinsonism. Neuropathology in a group of these patients showed alpha-synuclein-reactive Lewy bodies in brain regions specifically associated with Gaucher disease. Family studies of these probands suggested that the incidence of parkinsonism might be more frequent in obligate heterozygotes. In a complementary finding, the examination of GBA in autopsy samples from individuals with sporadic Parkinson disease identified alterations in the GBA sequence in 14% of the cohort. These studies provide evidence that altered glucocerebrosidase may contribute to a vulnerability to parkinsonism. Moreover, this research demonstrates how insights from rare, single gene disorders like Gaucher disease can provide a window into the etiology of more common, multifactorial genetic diseases.


Assuntos
Doença de Gaucher/etiologia , Glucosilceramidase/genética , Doença de Parkinson/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Doença de Gaucher/genética , Predisposição Genética para Doença , Glucosilceramidase/metabolismo , Heterozigoto , Humanos , Camundongos , Mutação , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Fenótipo
19.
Neth J Med ; 61(1): 3-8, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12688562

RESUMO

Gaucher disease type I is the most common lysosomal storage disorder, with a prevalence of 1:50,000 in most countries. It is caused by an autosomally recessive inherited deficiency of the lysosomal enzyme glucocerebrosidase, leading to the accumulation of glucocerebroside in the macrophages. The lipid-laden macrophages are called Gaucher cells and can be found in the liver, spleen and bone marrow. Gaucher disease type I should be considered in any patient with an unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. The diagnosis is made by showing decreased glucocerebrosidase activity in peripheral blood leucocytes or by demonstrating previously defined DNA mutations. Detailed knowledge about the molecular defect has provided a rationale for therapeutic interventions and attempts have been made to correct the defect at gene level, protein level and by manipulation of metabolism. Clinical trials of gene therapy have been conducted but so far have not resulted in successful intervention. For moderate to severely affected patients, intravenous enzyme supplementation therapy is the treatment of choice, resulting in substantial clinical improvement in the majority of patients. For individuals with mild Gaucher disease, an oral substrate inhibitor can also be considered if intravenous treatment is a less attractive option.


Assuntos
Doença de Gaucher/etiologia , Doença de Gaucher/terapia , Doença de Gaucher/diagnóstico , Humanos
20.
Am J Nurs ; 103(12): 50-60; quiz 61, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14702566
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