Gene/Protein Disease Symptom Drug Enzyme Compound
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Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by defects in the activity of the lysosomal enzyme, glucocerebrosidase, resulting in intracellular accumulation of glucosylceramide (GlcCer). Neuronopathic forms, which comprise only a small percent of GD patients, are characterized by neurological impairment and neuronal cell death. Little is known about the pathways leading from GlcCer accumulation to neuronal death or dysfunction but defective calcium homeostasis appears to be one of the pathways involved. Recently, endoplasmic reticulum stress together with activation of the unfolded protein response (UPR) has been suggested to play a key role in cell death in neuronopathic forms of GD, and moreover, the UPR was proposed to be a common mediator of apoptosis in LSDs (Wei et al. (2008) Hum. Mol. Genet. 17, 469-477). We now systematically examine whether the UPR is activated in neuronal forms of GD using a selection of neuronal disease models and a combination of western blotting and semi-quantitative and quantitative real-time polymerase chain reaction. We do not find any changes in either protein or mRNA levels of a number of typical UPR markers including BiP, CHOP, XBP1, Herp and GRP58, in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. We conclude that the proposition that the UPR is a common mediator for apoptosis in all neurodegenerative LSDs needs to be re-evaluated.
Hum Mol Genet 2009 Apr 15
PMID:No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease. 1919 29

Imiglucerase (Cerezyme) has been the standard of care for treatment of Gaucher disease, a lysosomal storage disorder resulting from deficiency of glucocerebrosidase, since its approval in 1994. Infusions are typically given once every 2 weeks. However, many patients have expressed a desire for less frequent infusions as a matter of convenience. This clinical study assessed the safety and efficacy of intravenous imiglucerase infused once every 4 weeks (Q4) compared to once every 2 weeks (Q2) at the same total monthly dose in adult patients with clinically stable Gaucher disease type 1 (GD1). This was a 24-month, open-label, randomized, Phase 4, dose-frequency study conducted in 25 centers worldwide. Patients receiving imiglucerase were randomized to receive their monthly dose biweekly (n=33) or every 4 weeks (n=62). Changes from baseline in hemoglobin, platelets, liver and spleen volumes, bone crisis, and bone disease comprised a predefined composite endpoint; achievement or maintenance of established Gaucher disease therapeutic goals comprised a secondary endpoint. Sixty-three percent of Q4- and 81% of Q2-treated patients met the composite endpoint at Month 24; 89% of Q4- and 100% of Q2-treated patients met the therapeutic goals-based endpoint. The frequency of related adverse events was comparable between treatment groups. This study suggests that with comprehensive monitoring, a Q4 imiglucerase infusion regimen may be a safe and effective treatment option for the majority of clinically stable adult patients with GD1 but may not be appropriate for all GD1 patients. Continued monitoring in patients treated with Q4 dosing is required to assess long-term effectiveness.
Mol Genet Metab 2009 Apr
PMID:A randomized trial comparing the efficacy and safety of imiglucerase (Cerezyme) infusions every 4 weeks versus every 2 weeks in the maintenance therapy of adult patients with Gaucher disease type 1. 2058 May 83

Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. Point mutations, duplications and triplications in the alpha-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the beta-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.
Hum Mol Genet 2009 Apr 15
PMID:Parkinson's disease: from monogenic forms to genetic susceptibility factors. 1929 1

A number of studies have shown altered cytokine levels in serum from Gaucher disease patients, including changes in levels of the anti-inflammatory cytokine, interleukin-10 (IL-10). However, the source of IL-10, or the mechanisms leading to changes in IL-10 serum levels are not known. We now show that mouse macrophages treated with an active site-directed inhibitor of glucocerebrosidase, or macrophages from a mouse model of Gaucher disease, the L444P mouse, release significantly less IL-10 than their untreated counterparts, but that TNFalpha release is unaffected. These changes are due to reduced transcription of IL-10 mRNA in macrophages. The reduction in IL-10 secretion observed in animal models of Gaucher disease macrophages may be of relevance to explain the increase in inflammation that is often observed in Gaucher disease.
Blood Cells Mol Dis
PMID:Impaired IL-10 transcription and release in animal models of Gaucher disease macrophages. 1938 Feb 42

The identification of hot spots, i.e., binding regions that contribute substantially to the free energy of ligand binding, is a critical step for structure-based drug design. Here we present the application of two fragment-based methods to the detection of hot spots for DJ-1 and glucocerebrosidase (GCase), targets for the development of therapeutics for Parkinson's and Gaucher's diseases, respectively. While the structures of these two proteins are known, binding information is lacking. In this study we employ the experimental multiple solvent crystal structures (MSCS) method and computational fragment mapping (FTMap) to identify regions suitable for the development of pharmacological chaperones for DJ-1 and GCase. Comparison of data derived via MSCS and FTMap also shows that FTMap, a computational method for the identification of fragment binding hot spots, is an accurate and robust alternative to the performance of expensive and difficult crystallographic experiments.
J Comput Aided Mol Des 2009 Aug
PMID:Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase. 1952 72

Patients with Gaucher disease (GD) are divided into three types based on the presence and rate of progression of the neurologic manifestations. While type 1 GD has a strong predilection in the Jewish Ashkenazi population, both other types lack such a propensity. We report the occurrence of type 2 GD (GD2) in four pregnancies in two Jewish families in Israel (in one case the mother was not Ashkenazi but was from a Sfaradi Jewish family) and also review seven additional cases of GD2 in Ashkenazi Jewish families reported in the literature. Phenotypically, GD2 in Ashkenazi Jews does not differ significantly from this form in other ethnic groups. Genotypic analysis of probands from the two Israeli families demonstrates that each carried two heterozygous glucocerebrosidase mutations. We could find no explanation why GD2 is so rare in the Jewish Ashkenazi population but we could hypothesize that homozygosity for certain Ashkenazi alleles might be lethal, leading to a lower than expected frequency of GD2 and noted that no cases of homozygous L444P has ever been described in Ashkenazi Jews.
Blood Cells Mol Dis
PMID:Type 2 Gaucher disease occurs in Ashkenazi Jews but is surprisingly rare. 1973 74

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously - usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase - and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.
Blood Cells Mol Dis 2010 Jan 15
PMID:Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease. 1980 96

In Gaucher disease (GD), the inherited deficiency of glucocerebrosidase results in the accumulation of glucocerebroside within lysosomes. Although almost 300 mutations in the glucocerebrosidase gene (GBA) have been identified, the ability to predict phenotype from genotype is quite limited. In this study, we sought to examine potential GBA transcriptional regulatory elements for variants that contribute to phenotypic diversity. Specifically, we generated the genomic sequence for the orthologous genomic region ( approximately 39.4kb) encompassing GBA in eight non-human mammals. Computational comparisons of the resulting sequences, using human sequence as the reference, allowed the identification of multi-species conserved sequences (MCSs). Further analyses predicted the presence of two putative clusters of transcriptional regulatory elements upstream and downstream of GBA, containing five and three transcription factor-binding sites (TFBSs), respectively. A firefly luciferase (Fluc) reporter construct containing sequence flanking the GBA gene was used to test the functional consequences of altering these conserved sequences. The predicted TFBSs were individually altered by targeted mutagenesis, resulting in enhanced Fluc expression for one site and decreased expression for seven others sites. Gel-shift assays confirmed the loss of nuclear-protein binding for several of the mutated constructs. These identified conserved non-coding sequences flanking GBA could play a role in the transcriptional regulation of the gene contributing to the complexity underlying the phenotypic diversity seen in GD.
Mol Genet Metab 2010 Mar
PMID:In silico and functional studies of the regulation of the glucocerebrosidase gene. 2000 4

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase. GD is classically divided into three major phenotypes. The most prevailing form is type 1, which presents with variable hepatosplenomegaly, cytopenia, and/or bone disease. In adult patients with mild manifestations, progress of disease might be slow or even absent. As a consequence, treatment with intravenous enzyme replacement or substrate reduction is not always necessary. In the Netherlands, the follow-up of GD patients is centralized, which allows detailed investigation of untreated patients. A retrospective study was conducted in 18 type 1 GD patients, (2 teenagers: 15 and 16 years of age at first visit) who were not treated for at least one year. The chitotriosidase activity, platelet count, hemoglobin level, lumbar bone marrow fat content measured with quantitative chemical shift imaging (QCSI), liver ratio (ml/kg body weight), and spleen volume were recorded. Criteria were developed to score regression, stability or progression of disease. During a mean follow up of 4.5 years (range 1.1-12.2) seven patients (39%) showed spontaneous regression of GD. Eight patients (44%) were stable. Two patients had progressive disease, solely based upon a sustained increase in chitotriosidase activity. A pediatric patient had an increase in splenomegaly but an improvement in bone marrow fat fraction, probably due to aging. Nine patients fulfilled the local criteria to start treatment at first visit, of whom six started treatment within 1.1 to 6.8 years. The other three refused therapy, but nevertheless showed stability or even regression of the disease during a follow up of 4.6, 9.5 and 11.4 years respectively. None of the parameters was predictive of progression or regression of disease. In conclusion, GD in adults can, in some cases, regress spontaneously. No parameters for accurately predicting future disease course exist.
Blood Cells Mol Dis 2010 Mar 15
PMID:Spontaneous regression of disease manifestations can occur in type 1 Gaucher disease; results of a retrospective cohort study. 2007 83

The Pronto Gaucher kits and Pronto Gaucher RecTL Amplification Mix, marketed to identify mutations in the gene for glucocerebrosidase, are widely used for the diagnosis of Gaucher disease. Subjects genotyped using this kit have been reported with an allele including both the common N370S mutation and RecTL, a previously described Gaucher mutation arising from recombination between the glucocerebrosidase gene and pseudogene. Using direct sequencing and real-time PCR, we show that the RecTL, N370S allele is a false positive result, demonstrating possible pitfalls of diagnostic kits.
Mol Genet Metab 2010 May
PMID:False-positive results using a Gaucher diagnostic kit--RecTL and N370S. 2029 60


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