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GBA1 is one of the common risk genes of Parkinson′s disease (PD), which encodes glucocerebrosidase. It is difficult to distinguish PD patients with heterozygous variants of GBA1 ( GBA1-PD) from idiopathic Parkinson′s disease patients, but GBA1-PD tends to progress faster, be more severe, and be more likely to be associated with cognitive impairment and other non-motor symptoms. The pathological mechanism of the increased risk of PD in GBA1 heterozygous variant carriers may be related to autophagy-lysosome dysfunction and mitochondrial dysfunction. Targeted therapy for GBA1 is expected to become a new direction of precision therapy for PD. In this article, the epidemiology and clinical features of GBA1-PD, the possible pathogenesis of GBA1 variation, and the therapeutic strategies for GBA1-PD were elaborated.
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Abstract Gaucher disease (GD) is one of the most common lysosomal disorders, occurring in approximately 1 in 40,000 live births worldwide. Since 2014 enzyme replacement therapy (ERT) with taliglucerase alfa has been the treatment of choice for adult patients with GD in Brazil. The aim of this study was to evaluate the long-term efficacy and safety of taliglucerase alfa in a cohort of Brazilian patients treated at a referral center for inborn errors of metabolism. All patients who received at least one infusion of the enzyme at the study center were considered eligible to participate. Patients were followed for adverse reactions and events throughout the study period. Platelets, hemoglobin, chitotriosidase activity, bone marrow burden (BMB) score, bone mineral density, and the severity score index (SSI) were analyzed. For patients who were switched to taliglucerase alfa from imiglucerase, the same variables were compared before and after the switch. At 9-year follow-up, all parameters of interest had remained stable or improved. The overall rate of adverse events was lower than in other studies that evaluated long-term ERT with taliglucerase, and no serious adverse events were considered related to treatment. Based on our findings, ERT with taliglucerase alfa is an effective and safe approach for treatment of patients with GD.
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Abstract Introduction Gaucher's disease (GD) is an autosomal-recessive lysosomal storage disorder that results from hereditary deficiency of the acid glucocerebrosidase enzyme, encoded by the GBA gene necessary for the degradation of glucosylceramide. Objective molecularly characterize the variants found in the GBA gene present in patients from the Southwest of Colombia with GD. Material and methods 19 patients were included in the study, clinically and enzymatically diagnosed with GD. A molecular analysis of the GBA gene was performed and the variants were subsequently searched in different population and clinical databases. A bioinformatic analysis was performed. Results The variants in the GBA gene reported were classified into: 14/19 homozygous patients, 4/19 compound heterozygote and 1/19 heterozygous. The presence of 7 variants coding for 8 different genotypes was reported. Also the known mutations like Asn409Ser, p.Leu483Pro, p.Lys237Glu, p.Glu427Lys, and p.Arg535His were identified in these patients. The most frequent genotype was p. Asn409Ser / Asn409Ser (36%). All the variants presented a pathogenic clinical significance. Conclusion The given study will make it possible to understand the susceptibility to GD in the population. This can help maintain the health quotient of the population through premarital counseling and therefore minimize the burden of disease among the population.
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Abstract Introduction: Gaucher disease (GD) is one of the common lysosomal storage disorder (LSD) with an estimated frequency of one in 40,000 newborns globally. GD is an autosomal recessive condition, which results from mutations in the GBA1 gene, causing partial or complete deficiency of β-glucocerebrosidase enzyme activity, which leads to the widespread accumulation of the substrate glucosylceramide. Aims: This report presents different challenges of clinical management and communication between medical specialties to reach diagnose of any rare disease in Mozambique, a low-income country, which health system has limited infrastructure, trained personnel, and budget for diagnosis and to provide treatment for rare genetic disorders such as GD. Case Presentation: The patient was a 15-year old black female patient of Mozambican nationality born from non-consanguineous parents. Three of the four patient's siblings were healthy; one sister had died of a disease with a similar clinical features. Our patient presented with abdominal distention and hepatosplenomegaly. Blood tests revealed pancytopenia and a high level of ferritin. Liver biopsy and histologic examination revealed infiltration of the splenic parenchyma and portal area of the liver as well as enlarged histiocytic cells with granular cytoplasm. Magnetic resonance imaging showed liver enlargement, changes in the femoral heads without osteonecrosis, a pathological fracture of the third thoracic vertebrae (T3), with absence of brain and spinal cord neurological abnormalities. The biochemical investigation disclosed low levels of β-glucocerebrosidase (0.223 nmol/h/ml; normal: above 0.98) and increased levels of lyso-Gb1 (0.43 µg/ml; normal: up to 0.003). Genotyping of the GBA1 gene indicated the presence of the pathogenic variant p.Arg87Trp (R48W) in homozygosis. Discussion and Conclusion: To the best of our knowledge, this report describes the first case of GD type 1 confirmed via biochemical and molecular genetic testing in Mozambique. As awareness of the GD and rare genetic diseases among Mozambican health professionals is very limited, and resources for diagnosis are scarce in the national health system, it is possible that other cases remain undiagnosed in this low-income country.
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Objective To explore the significance of GBA gene mutation and gene detection in diagnosis of Gaucher disease. Method The clinical data and genetic testing results of 3 probands from 3 unrelated Gaucher families and their family members were analyzed. Results A compound heterozygous mutation of c.907C>A and c.1448T>C was found in the proband of the first family, which was inherited from parents respectively. Another complex heterozygous mutation of c.1174delC and c.1226A>G was found in the proband of second family, which was inherited from parents respectively, and the variant c.1174delC was a new mutation, which has not been reported in the literature according to the search by HGMD. The homozygous nucleotide variation of c.1342G>C and heterozygous nucleotide variation of c.1263_1317del was found in the proband of the third family and the c.1263_1317del heterozygous mutation was inherited from father. Conclusion The mutation of GBA gene was the cause of Gaucher disease in these 3 families and Gaucher disease can be diagnosed by molecular genetics in clinic.
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Objective To analyze the mutation characteristics of GBA gene in one patient with Gaucher disease and platelet transfusion refractoriness.Methods A female patient with anemia and thrombocytopenia showed platelet transfusion refractoriness,and then the proband and her family were performed bone marrow smear,β-glucocerebrosidase activity in leukocytes (dried blood spot assay),Bultrasonography and gene sequencing examination and pedigree investigation.Results Pedigree investigation showed that the heterozygous mutation of GBA gene existed in the father,mother,son,daughter and sister of the proband.Bone marrow cytomorphologic examination showed that Gaucher cells accounted for 6.0% in the female patient.The β-glucocerebrosidase activity in leukocytes was 3.78 nmol/(h · mg Pro).B-ultrasonography showed slightly splenomegaly.Gene sequencing found that the homozygous mutation of GBA gene,c.484A > G,existed in the female patient.Conclusion The patients with Gaucher disease may appear platelet transfusion refractoriness due to hypersplenism.The mutation of GBA gene is the main pathogenic factor of the family with Gaucher disease.
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Objectives: To study disease severity and response to enzyme replacement therapy in Gaucher disease. Methods: Updated data was captured from records of 37 patients (35 reported previously) with confirmed diagnosis of Gaucher disease from January 1995 through December 2011 (31, 83.8 %) and prospectively from January 2012 through June 2013 (6, 16.2 %). Severity of manifestations was determined by Gaucher disease Severity Score Index. Response to enzyme replacement therapy was assessed in terms of attainment of therapeutic goals. Results: Moderate to severe manifestations (domain score of > 2) were observed in treated patients at baseline (83%, 58%, 66% and 25% for anemia, thrombocytopenia, hepatomegaly and leucopenia, respectively and 100% for splenomegaly and elevated plasma chitotriosidase). None of the 11 patients treated with synthetic enzyme (average annual dose 23 to 53 units/kg) attained all therapeutic goals in the recommended time frame, particularly the visceral, skeletal and growth domains. Conclusions: Early onset of moderate to severe disease in Indian patients mandates early therapy with optimum doses to ensure attainment of all recommended therapeutic goals.
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Objective To report clinical manifestations, electroencephalogram (EEG), and the genotypes of two siblings with type Ⅲ Gaucher disease.Methods Two patients with different features were siblings. Their clinical data, signs, peripheral leukocytes acid β-glucosidase activity, andGBA gene were analyzed.Results (1) The proband was a boy. He visited us at the age of nine years old because of hepatosplenomegaly, thrombocytopenia and growth retardation without any neurologic symp-toms. He had normal intelligence but abnormal EEG ifndings. The activity of acid β-glucosidase in his leucocytes decreased to 1.5 nmol h-1·mg-1 Pr (normal range 6.0-16.7 nmol h-1·mg-1 Pr), supporting the diagnosis of type Ⅲ Gaucher disease. (2) The elder sister of the proband was 12 years old. She had tonic-clonic seizure and myoclonus seizure from the age of seven years old. Mild hepatomegaly, abnormal EEG, poor effect for antiepileptics, and progressive deterioration of psychomotor abilities were found. Her blood leucocytes acid β-glucosidase activity decreased to 1.8 nmol h-1·mg-1 Pr (normal range 6.0-16.7 nmol h-1·mg-1 Pr). Two heterozygous missense mutations, c.680A>G, (p.N188S) and c.1342G>C (p.D409H) were detected from the two siblings, respec-tively.Conclusions Patients with type Ⅲ Gaucher disease usually have the onset in childhood with typical features of Gaucher disease without neurologic involvement. Abnormal EEG may be helpful to the differential diagnosis of type I or type Ⅲ. On the other hand, neurologic manifestations could be presented as the ifrst symptom in some patients without viscera enlargement. The patients of type Ⅲ Gaucher disease with the same genotype could have different phenotypes, even between the siblings.
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PURPOSE: Gaucher disease is caused by a beta-glucocerebrosidase (GBA) deficiency. The aim of this study is to investigate the clinical and genetic characteristics according to subtypes of Gaucher disease in the Korean population. METHODS: Clinical findings at diagnosis, GBA mutations, and clinical courses were reviewed in 20 patients diagnosed with Gaucher disease. RESULTS: Eleven patients were diagnosed with non-neuronopathic type, 2 with acute neuronopathic type, and 7 with chronic neuronopathic type. Most patients presented with hepatosplenomegaly, thrombocytopenia, and short stature. In the neuronopathic group, variable neurological features, such as seizure, tremor, gaze palsy, and hypotonia, were noted at age 8.7+/-4.3 years. B cell lymphoma, protein-losing enteropathy, and hydrops fetalis were the atypical manifestations. Biomarkers, including chitotriosidase, acid phosphatase, and angiotensin-converting enzyme, increased at the initial evaluation and subsequently decreased with enzyme replacement treatment (ERT). The clinical findings, including hepatosplenomegaly, thrombocytopenia, and skeletal findings, improved following ERT, except for the neurological manifestations. L444P was the most common mutation in our cohort. One novel mutation, R277C, was found. CONCLUSION: Although the clinical outcome for Gaucher disease improved remarkably following ERT, the outcome differed according to subtype. Considering the high proportion of the neuronopathic form in the Korean population, new therapeutic strategies targeting the central nervous system are needed, with the development of a new scoring system and biomarkers representing clinical courses in a more comprehensive manner.
الموضوعات
Humans , Acid Phosphatase , Biomarkers , Central Nervous System , Cohort Studies , Gaucher Disease , Glucosylceramidase , Hexosaminidases , Hydrops Fetalis , Lymphoma, B-Cell , Muscle Hypotonia , Neurologic Manifestations , Paralysis , Protein-Losing Enteropathies , Seizures , Thrombocytopenia , Tremorالملخص
PURPOSE: Gaucher disease is caused by a beta-glucocerebrosidase (GBA) deficiency. The aim of this study is to investigate the clinical and genetic characteristics according to subtypes of Gaucher disease in the Korean population. METHODS: Clinical findings at diagnosis, GBA mutations, and clinical courses were reviewed in 20 patients diagnosed with Gaucher disease. RESULTS: Eleven patients were diagnosed with non-neuronopathic type, 2 with acute neuronopathic type, and 7 with chronic neuronopathic type. Most patients presented with hepatosplenomegaly, thrombocytopenia, and short stature. In the neuronopathic group, variable neurological features, such as seizure, tremor, gaze palsy, and hypotonia, were noted at age 8.7+/-4.3 years. B cell lymphoma, protein-losing enteropathy, and hydrops fetalis were the atypical manifestations. Biomarkers, including chitotriosidase, acid phosphatase, and angiotensin-converting enzyme, increased at the initial evaluation and subsequently decreased with enzyme replacement treatment (ERT). The clinical findings, including hepatosplenomegaly, thrombocytopenia, and skeletal findings, improved following ERT, except for the neurological manifestations. L444P was the most common mutation in our cohort. One novel mutation, R277C, was found. CONCLUSION: Although the clinical outcome for Gaucher disease improved remarkably following ERT, the outcome differed according to subtype. Considering the high proportion of the neuronopathic form in the Korean population, new therapeutic strategies targeting the central nervous system are needed, with the development of a new scoring system and biomarkers representing clinical courses in a more comprehensive manner.
الموضوعات
Humans , Acid Phosphatase , Biomarkers , Central Nervous System , Cohort Studies , Gaucher Disease , Glucosylceramidase , Hexosaminidases , Hydrops Fetalis , Lymphoma, B-Cell , Muscle Hypotonia , Neurologic Manifestations , Paralysis , Protein-Losing Enteropathies , Seizures , Thrombocytopenia , Tremorالملخص
The present study was performed to evaluate the effect of tetracycline-HCl on the change of implant surface microstructure according to application time. Implant with pure titanium machined surface, GBA surface and RBM surface were utilized. Implant surface was rubbed with 50mg/ml tetracycline-HCl solution for 1/2min. 1min. 1 1/2min. 2min. and 2 1/2min. respectively in the test group. Then, specimens were processed for scanning electron microscopic observation. The results of this study were as follow. 1. Both test and control group showed a few shallow grooves and ridges in pure titanium machined surface implants. There were not significant differences between two group. 2. In GBA surfaces, control group exhibit many porous depression, and each depression were divided by strict border. Experimental group applied with tetracycline-HCl for 2min. were similar with control group. But when applied for 2 1/2min. surface alteration and border breakdown started, resulting enlargement of the porous depression. 3. In RBM surface, control group exhibit rough, uneven surface with crater-like depression can be found. The surface alteration started when tetracycline-HCl was applied for 30sec. resulting breakdown of the crater-like depression. Depression became larger as applying time increased.