Molecular Characterization of the GBA Gene in Patients from Southwest of Colombia with Gaucher Disease

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.

Analysis of GBA gene mutation in three families with Gaucher disease / 临床儿科杂志

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.

Platelet transfusion refractoriness caused by GBA gene mutation in one patient with Gaucher disease / 临床检验杂志

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.

Clinical features and GBA gene mutation in two siblings with typeⅢ Gaucher disease / 临床儿科杂志

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.

Clinical and genetic characteristics of Gaucher disease according to phenotypic subgroups / 소아과

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.

Clinical and genetic characteristics of Gaucher disease according to phenotypic subgroups / 소아과

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.