Fabry Disease (FD) is a rare lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) enzyme deficiency, resulting in glycosphingolipid accumulation. Its clinical spectrum ranges from severe classical...Fabry Disease (FD) is a rare lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) enzyme deficiency, resulting in glycosphingolipid accumulation. Its clinical spectrum ranges from severe classical to milder nonclassical or late-onset phenotypes. Renal involvement, termed Fabry Nephropathy (FN), can vary from mild proteinuria to kidney failure. FN diagnosis, especially in nonclassical cases with a genetic Variant of Unknown Significance (VUS) in the GLA gene, poses challenges. Measurement of plasma lyso-Gb3 levels is gaining importance in FN diagnosis, while renal biopsy with electron microscopy remains the gold standard in equivocal cases. Treatment options include Enzyme Replacement Therapy (ERT) and chaperone therapy, demanding careful candidate selection due to high treatment costs. Research has predominantly focused on classical FD, revealing modest treatment benefits. However, evidence for treating patients, especially females, with milder nonclassical or late-onset phenotypes is scarce, emphasizing the necessity for placebo-controlled clinical trials in these subgroups. Meanwhile, participation in global FD registries can improve our understanding of disease management. Case Presentation: A woman in her late sixties presented with moderate chronic kidney disease, mild proteinuria, and microscopic hematuria. Her family history included a prevalence of renal, cardiac and cerebrovascular diseases. Kidney biopsy revealed characteristic myelin figures and zebra bodies in podocytes, strongly suggestive of FN. Genetic analysis identified a VUS in the GLA gene (c.655A > C, p.Ile219Leu), introducing diagnostic uncertainty. Further investigations revealed severe cardiac involvement. Considering the recurring difficulty presented by the finding of a VUS in the GLA gene during FN assessments, along with the uncertainty regarding the need for treatment in nonclassical or late-onset FD phenotypes, especially in women, this case becomes a central focus for a thorough review of the literature. This rev展开更多
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 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
This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in child...This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.展开更多
Splenomegaly, sometimes of massive extent, occurs in a large number of hereditary diseases, some relatively prevalent and others, rare to ultra-rare. Because physicians are often unfamiliar with the less common disord...Splenomegaly, sometimes of massive extent, occurs in a large number of hereditary diseases, some relatively prevalent and others, rare to ultra-rare. Because physicians are often unfamiliar with the less common disorders, patients may suffer because of diagnostic delay or diagnostic error and may undergo invasive, non-innocuous procedures such as splenectomy that are potentially avoidable were the correct diagnosis suspected. In this review article, we discuss the definition and clinical ramifications of “massive” splenomegaly and describe several rare genetic disorders that are sometimes associated with marked splenic enlargement as well as four additional hereditary “splenomegalic” lysosomal storage diseases (cholesterol esterase storage disease, Niemann-Pick C disease, acid sphingomyelinase deficiency disease, Gaucher disease) in which approved or promising experimental treatments should generally obviate the need for palliative splenectomy. We also summarize current concepts about the appropriate use of splenectomy in patients with β-thalassemia, hereditary spherocytosis and Gaucher disease and discuss surgical alternatives to classical total splenectomy for these disorders.展开更多
BACKGROUND Fabry disease(FD)is a rare X-linked lysosomal storage disease caused by a deficiency of the enzymeα-galactosidase A.CASE SUMMARY Herein,we analyzed a four-generation Chinese family.The proband is a 57-year...BACKGROUND Fabry disease(FD)is a rare X-linked lysosomal storage disease caused by a deficiency of the enzymeα-galactosidase A.CASE SUMMARY Herein,we analyzed a four-generation Chinese family.The proband is a 57-yearold woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago.Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm,left ventricular end-diastolic diameter of 63.1 mm,and moderate-to-severe mitral regurgitation.Cardiac magnetic resonance indicated an enlarged left heart and right atrium,decreased left ventricular systolic and diastolic function,a left ventricular ejection fraction of 20%,and thickening of the left ventricular septum.In March 2019,gene and enzyme activity tests confirmed the diagnosis of FD.Her son was diagnosed with FD after gene and enzyme activity assay,and was prescribed agalsidase-βfor enzyme replacement therapy in July 2020.Two sisters of the proband were also diagnosed with FD by genetic testing.Both of them had a history of atrial fibrillation.CONCLUSION A novel mutation was identified in a Chinese family with FD,in which the male patient had a low level of enzyme activity,early-onset,and severe organ involvement.Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.展开更多
文摘Fabry Disease (FD) is a rare lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) enzyme deficiency, resulting in glycosphingolipid accumulation. Its clinical spectrum ranges from severe classical to milder nonclassical or late-onset phenotypes. Renal involvement, termed Fabry Nephropathy (FN), can vary from mild proteinuria to kidney failure. FN diagnosis, especially in nonclassical cases with a genetic Variant of Unknown Significance (VUS) in the GLA gene, poses challenges. Measurement of plasma lyso-Gb3 levels is gaining importance in FN diagnosis, while renal biopsy with electron microscopy remains the gold standard in equivocal cases. Treatment options include Enzyme Replacement Therapy (ERT) and chaperone therapy, demanding careful candidate selection due to high treatment costs. Research has predominantly focused on classical FD, revealing modest treatment benefits. However, evidence for treating patients, especially females, with milder nonclassical or late-onset phenotypes is scarce, emphasizing the necessity for placebo-controlled clinical trials in these subgroups. Meanwhile, participation in global FD registries can improve our understanding of disease management. Case Presentation: A woman in her late sixties presented with moderate chronic kidney disease, mild proteinuria, and microscopic hematuria. Her family history included a prevalence of renal, cardiac and cerebrovascular diseases. Kidney biopsy revealed characteristic myelin figures and zebra bodies in podocytes, strongly suggestive of FN. Genetic analysis identified a VUS in the GLA gene (c.655A > C, p.Ile219Leu), introducing diagnostic uncertainty. Further investigations revealed severe cardiac involvement. Considering the recurring difficulty presented by the finding of a VUS in the GLA gene during FN assessments, along with the uncertainty regarding the need for treatment in nonclassical or late-onset FD phenotypes, especially in women, this case becomes a central focus for a thorough review of the literature. This rev
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.
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.
基金supported by the following funding sources:National Institutes of Health,F31-NS078911,https://www.nih.gov(NSH)New York State Department of Health,NYS-DOH-C026877,http://www.stemcell.ny.gov(NSH)+4 种基金New York State Department of Health,NYS-DOH-C029557,http://www.stemcell.ny.gov(MN)New York State Department of Health,NYS-DOH-C026877,http://www.stemcell.ny.gov(CJF)Hunter’s Hope,http://www.huntershope.org/site/Page Server(MN)Children’s Neurobiological Solutions Foundation,http://pediatricbrainfoundation.org(MN)the Legacy of Angels,http://tloaf.org(MN)
文摘This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.
文摘Splenomegaly, sometimes of massive extent, occurs in a large number of hereditary diseases, some relatively prevalent and others, rare to ultra-rare. Because physicians are often unfamiliar with the less common disorders, patients may suffer because of diagnostic delay or diagnostic error and may undergo invasive, non-innocuous procedures such as splenectomy that are potentially avoidable were the correct diagnosis suspected. In this review article, we discuss the definition and clinical ramifications of “massive” splenomegaly and describe several rare genetic disorders that are sometimes associated with marked splenic enlargement as well as four additional hereditary “splenomegalic” lysosomal storage diseases (cholesterol esterase storage disease, Niemann-Pick C disease, acid sphingomyelinase deficiency disease, Gaucher disease) in which approved or promising experimental treatments should generally obviate the need for palliative splenectomy. We also summarize current concepts about the appropriate use of splenectomy in patients with β-thalassemia, hereditary spherocytosis and Gaucher disease and discuss surgical alternatives to classical total splenectomy for these disorders.
基金Supported by Key Research and Development Program of Zhejiang Province,No.2019C03022.
文摘BACKGROUND Fabry disease(FD)is a rare X-linked lysosomal storage disease caused by a deficiency of the enzymeα-galactosidase A.CASE SUMMARY Herein,we analyzed a four-generation Chinese family.The proband is a 57-yearold woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago.Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm,left ventricular end-diastolic diameter of 63.1 mm,and moderate-to-severe mitral regurgitation.Cardiac magnetic resonance indicated an enlarged left heart and right atrium,decreased left ventricular systolic and diastolic function,a left ventricular ejection fraction of 20%,and thickening of the left ventricular septum.In March 2019,gene and enzyme activity tests confirmed the diagnosis of FD.Her son was diagnosed with FD after gene and enzyme activity assay,and was prescribed agalsidase-βfor enzyme replacement therapy in July 2020.Two sisters of the proband were also diagnosed with FD by genetic testing.Both of them had a history of atrial fibrillation.CONCLUSION A novel mutation was identified in a Chinese family with FD,in which the male patient had a low level of enzyme activity,early-onset,and severe organ involvement.Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.
