Persistent tryptase elevation in a patient with Gaucher disease.
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ABSTRACT:
SUBMITTER: Schussler E
PROVIDER: S-EPMC8145058 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC6519056 | biostudies-literature
Project description:Gaucher disease (GD) is a recessive metabolic disorder caused by a deficiency of the GBA gene-encoded enzyme β-glucocerebrosidase. We characterized a cohort of 36 Albanian GD patients, 31 with GD type 1 and 5 affected by GD types 2, 3, and an intermediate GD phenotype between type 2 and type 3. Of the 12 different GBA alleles that we detected, the most frequently observed was p.Asn409Ser, followed by p.[Asp448His;His294Gln]. The prevalence of the p.Leu483Pro allele was approximately 10-fold lower than reported in other populations. We identified a novel pathogenic missense variant (c.1129G>A; p.Ala377Thr). All five of our non-type 1 patients had genotypes consisting of the p.[Asp448His;His294Gln] allele in combination with another severe GBA allele. The median Lyso-Gb1 level of treated patients carrying the p.[Asp448His;His294Gln] and no p.Asn409Ser allele was significantly higher than that of treated individuals homozygous or compound heterozygous for the p.Asn409Ser allele. In conclusion, the most important distinguishing features of the Albanian GD patient population are the underrepresentation of the p.Leu483Pro allele and an unusually high number of p.[Asp448His;His294Gln] alleles originating from a common Balkan founder event. The presence of at least one p.Asn409Ser allele is associated with mild disease and low Lyso-Gb1 biomarker levels, while compound heterozygosity involving p.[Asp448His;His294Gln] and no p.Asn409Ser entails severe phenotypes and high Lyso-Gb1 levels.
| S-EPMC7802630 | biostudies-literature
Project description:The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.
| S-EPMC5814927 | biostudies-literature
Project description:Patients with Gaucher disease (GD), a rare autosomal recessive glycosphingolipid storage disease, commonly present to hematologists with unexplained splenomegaly, thrombocytopenia, anemia, and bone symptoms. Patients with GD may develop other manifestations, such as autoimmune thrombocytopenia, monoclonal gammopathy, multiple myeloma, or, even more rarely, other hematological malignancies; sometimes they are first diagnosed during an assessment of those disorders. Although the diagnosis and management of patients with GD have significantly evolved over the last 30 years, some patients remain poor responders to GD-specific therapy, needing novel and investigational therapies. Ideally, patients with GD, like patients with other rare diseases, should be managed by a multidisciplinary team expert with the diverse clinical manifestations and potential GD-related or -unrelated comorbidities. The hematology community should be knowledgeable regarding the presentation and the variety of hematologic complications and comorbidities associated with Gaucher disease.
| S-EPMC7727517 | biostudies-literature
Project description:Biallelic mutations in GBA1 cause the lysosomal storage disorder Gaucher disease, and carriers of GBA1 variants have an increased risk of Parkinson's disease (PD). It is still unknown whether GBA1 variants are also associated with other movement disorders. We present the case of a woman with type 1 Gaucher disease who developed acute dystonia and parkinsonism at 35 years of age during a recombinant enzyme infusion treatment. She developed severe dystonia in all extremities and a bilateral pill-rolling tremor that did not respond to levodopa treatment. Despite the abrupt onset of symptoms, neither Sanger nor whole genome sequencing revealed pathogenic variants in ATP1A3 associated with rapid-onset dystonia-parkinsonism (RDP). Further examination showed hyposmia and presynaptic dopaminergic deficits in [18F]-DOPA PET, which are commonly seen in PD but not in RDP. This case extends the spectrum of movement disorders reported in patients with GBA1 mutations, suggesting an intertwined phenotype.
| S-EPMC10548083 | biostudies-literature
Project description:Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities. In conclusion, gpNMB acts as a marker for glucosylceramide-laden macrophages in man and mouse and gpNMB should be considered as candidate biomarker for Gaucher disease in treatment monitoring.
| S-EPMC5011488 | biostudies-literature
Project description:BackgroundGaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities.AimThe Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing.MethodsAn anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori.ResultsFor type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis.ConclusionThe signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.
| S-EPMC6852187 | biostudies-literature
Project description:Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme β-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved potency, efficacy and reduced estrogenic/antiestrogenic activity compared to the original hits. Here we present the design, synthesis and structure activity relationships that led to the lead molecule Compound 31.
| S-EPMC7569734 | biostudies-literature
Project description:BackgroundThe variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease.Case presentationWe report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment.ConclusionsThis case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.
| S-EPMC5248516 | biostudies-literature
Project description:BackgroundGaucher disease (GD) is an inborn error of metabolism caused by mutations in the gene (GBA) coding for glucocerebrosidase (GCase), inherited in an autosomal recessive pattern. GD patients have up to 9% risk of developing PD.Case presentationWe report two patients with GD that developed PD at different disease stages.ConclusionWe reviewed the literature on the coexistence of PD and GD and speculate that the severity of symptoms may be related to the type of GBA mutation inherited.
| S-EPMC5440911 | biostudies-literature