SUMMARY Lysosomal storage diseases are a group of genetic disorders that result from the defect in lysosomal function. Signs and symptoms are variable, it is difficult to diagnose this group of disease merely by the c...SUMMARY Lysosomal storage diseases are a group of genetic disorders that result from the defect in lysosomal function. Signs and symptoms are variable, it is difficult to diagnose this group of disease merely by the clinical manifestation. The diagnosis usually is made by measuring the activity of the corresponding enzyme. Gene mutational analysis is useful for the diagnosis of some of the lysosome storage diseases. The treatment has focused on the replacement of the defective enzyme responsible for the disease and the hematopoietic stem cell transplantation. Both of them have achieved exciting outcomes in some of the diseases.展开更多
Infantile (INCL, NCL1) and late-infantile (LINCL, NCL2) neuronal ceroid lipofuscinoses have been found to result from genetic deficiency of genes CLN 1 and CLN 2, respectively. The application of molecular analyses ca...Infantile (INCL, NCL1) and late-infantile (LINCL, NCL2) neuronal ceroid lipofuscinoses have been found to result from genetic deficiency of genes CLN 1 and CLN 2, respectively. The application of molecular analyses can facilitate prenatal diagnosis for families affected by NCL1 or NCL2, in which the familial mutation(s) have been identified. Molecular testing with allele-specific primer extension and DNA sequencing was performed in nine pregnancies, four from two NCL1 families and five from five NCL2 families. Lysosomal enzyme activity assays were carried out as well.Four fetuses from three pregnancies in NCL1 families were found to be carriers for a mutation 451C-T in the CLN 1 gene and one was normal. Prenatal testing of three NCL2 families who carried mutation R208X in the CLN 2 gene showed that all fetuses were carriers. In NCL2 families who carried either mutation IVS5-1C or/and IVS5-1A two normal pregnancies were detected. Our studies indicate that DNA testing, which may provide definitive prenatal diagnosis for NCL, may be used in combination with lysosomal enzyme activity analyses.展开更多
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 review aims to propose a practical algorithm that integrates clinical, biochemical, and genetic markers for FN screening and diagnosis. Additionally, it explores treatment benefits in nonclassical or late-onset FD phenotypes, with a focus on female patients.展开更多
文摘SUMMARY Lysosomal storage diseases are a group of genetic disorders that result from the defect in lysosomal function. Signs and symptoms are variable, it is difficult to diagnose this group of disease merely by the clinical manifestation. The diagnosis usually is made by measuring the activity of the corresponding enzyme. Gene mutational analysis is useful for the diagnosis of some of the lysosome storage diseases. The treatment has focused on the replacement of the defective enzyme responsible for the disease and the hematopoietic stem cell transplantation. Both of them have achieved exciting outcomes in some of the diseases.
文摘Infantile (INCL, NCL1) and late-infantile (LINCL, NCL2) neuronal ceroid lipofuscinoses have been found to result from genetic deficiency of genes CLN 1 and CLN 2, respectively. The application of molecular analyses can facilitate prenatal diagnosis for families affected by NCL1 or NCL2, in which the familial mutation(s) have been identified. Molecular testing with allele-specific primer extension and DNA sequencing was performed in nine pregnancies, four from two NCL1 families and five from five NCL2 families. Lysosomal enzyme activity assays were carried out as well.Four fetuses from three pregnancies in NCL1 families were found to be carriers for a mutation 451C-T in the CLN 1 gene and one was normal. Prenatal testing of three NCL2 families who carried mutation R208X in the CLN 2 gene showed that all fetuses were carriers. In NCL2 families who carried either mutation IVS5-1C or/and IVS5-1A two normal pregnancies were detected. Our studies indicate that DNA testing, which may provide definitive prenatal diagnosis for NCL, may be used in combination with lysosomal enzyme activity analyses.
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 review aims to propose a practical algorithm that integrates clinical, biochemical, and genetic markers for FN screening and diagnosis. Additionally, it explores treatment benefits in nonclassical or late-onset FD phenotypes, with a focus on female patients.
基金武汉市科技创新平台-儿童神经疾病临床医学研究中心资助项目(2014-160)Wuhan Science and Technology Innovation Platform-Children Nerve Disease Clinical Medical Research Center Funded Projects(2014-160)
