Gaucher disease is the prototypical lysosomal storage disease.It results from the accumulation of undegrad-ed glucosylceramide in the reticuloendothelial system of the bone marrow,spleen and liver due to deficiency of...Gaucher disease is the prototypical lysosomal storage disease.It results from the accumulation of undegrad-ed glucosylceramide in the reticuloendothelial system of the bone marrow,spleen and liver due to deficiency of the enzyme glucocerebrosidase.This leads to he-matologic,visceral and skeletal maifestions.Build up of glucosylceramide in the liver and spleen results in hepatosplenomegaly.The normal bone marrow is re-placed by the accumulating substrate leading to many of the hematologic signs including anemia.The visceral and skeletal manifestations can be visualized with vari-ous imaging modalities including radiography,com-puted tomography,magnetic resonance imaging(MRI)and radionuclide scanning.Prior to the development of enzyme replacement therapy,treatment was only sup-portive.However,once intravenous enzyme replace-ment therapy became available in the 1990s it quickly became the standard of care.Enzyme replacement therapy leads to improvement in all manifestations.Thevisceral and hematologic manifestations respond more quickly usually within a few months or years.The skel-etal manifestations take much longer,usually several years,to show improvement.In recent years newer treatment strategies,such as substrate reduction thera-py,have been under investigation.Imaging plays a key role in both initial diagnosis and routine monitoring of patient on treatment particularly volumetric MRI of the liver and spleen and MRI of the femora for evaluating bone marrow disease burden.展开更多
BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutati...BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD.CASE SUMMARY Here,we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen,thrombocytopenia,and bone pain,diagnosed by enzymatic and genetic testing.Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C(p.L483P)and exon 7 c.928A>G(p.S310G)of GBA1.The latter was first reported in patients with GD.Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site.The p.S310G mutation in domain 1 may decrease stability between theα2 andα3 helices of GBA1.The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminalβ-sheet.The patient was treated with imiglucerase replacement therapy,and her condition was stable.CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function.This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.展开更多
BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of gl...BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD. CASES SUMMARY Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient). CONCLUSION The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.展开更多
文摘Gaucher disease is the prototypical lysosomal storage disease.It results from the accumulation of undegrad-ed glucosylceramide in the reticuloendothelial system of the bone marrow,spleen and liver due to deficiency of the enzyme glucocerebrosidase.This leads to he-matologic,visceral and skeletal maifestions.Build up of glucosylceramide in the liver and spleen results in hepatosplenomegaly.The normal bone marrow is re-placed by the accumulating substrate leading to many of the hematologic signs including anemia.The visceral and skeletal manifestations can be visualized with vari-ous imaging modalities including radiography,com-puted tomography,magnetic resonance imaging(MRI)and radionuclide scanning.Prior to the development of enzyme replacement therapy,treatment was only sup-portive.However,once intravenous enzyme replace-ment therapy became available in the 1990s it quickly became the standard of care.Enzyme replacement therapy leads to improvement in all manifestations.Thevisceral and hematologic manifestations respond more quickly usually within a few months or years.The skel-etal manifestations take much longer,usually several years,to show improvement.In recent years newer treatment strategies,such as substrate reduction thera-py,have been under investigation.Imaging plays a key role in both initial diagnosis and routine monitoring of patient on treatment particularly volumetric MRI of the liver and spleen and MRI of the femora for evaluating bone marrow disease burden.
基金Supported by Shanxi Key Research and Development Project,No.201903D321133Shanxi Bethune Hospital’s Talent Introduction Scientific Research Start-up Fund Project,No.2021RC038 and 2021RC017。
文摘BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD.CASE SUMMARY Here,we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen,thrombocytopenia,and bone pain,diagnosed by enzymatic and genetic testing.Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C(p.L483P)and exon 7 c.928A>G(p.S310G)of GBA1.The latter was first reported in patients with GD.Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site.The p.S310G mutation in domain 1 may decrease stability between theα2 andα3 helices of GBA1.The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminalβ-sheet.The patient was treated with imiglucerase replacement therapy,and her condition was stable.CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function.This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.
文摘BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD. CASES SUMMARY Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient). CONCLUSION The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.
