Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha... more Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha galactosidase A. Enzyme replacement therapy (ERT) is commercially available and has been demonstrated to improve cardiac and renal outcomes. Predictive scores, such as the Fabry International Prognostic Index (FIPI), have been developed to stratify disease severity; however, these have not been validated to predict outcomes in patients receiving ERT. We show that the FIPI score at baseline can predict outcomes in a group of patients on long-term ERT.
Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficie... more Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficient β-glucocerebrosidase activity and accumulation of its substrate glucosylceramide. Bone disease is present in around 84% of GD patients, ranging from bone loss including osteopenia and osteonecrosis to abnormal bone remodelling in the form of Erlenmeyer flask formation. The range of severity and variety of types of bone disease found in GD patients indicate the involvement of several mechanisms. Here we investigate the effects of exogenous sphingolipids on osteoclasts, osteoblasts, plasma cells and mesenchymal stem cells (MSC) and the interactions between these cell types. Osteoclasts were differentiated from the peripheral blood of Gaucher patients and control subjects. Osteoblasts were differentiated from mesenchymal stem cells isolated from bone marrow aspirates of Gaucher patients and control subjects. The human osteoblast cell line SaOS-2 was also investigated. Osteoclasts, osteob...
Gaucher disease (GD) is a rare autosomal recessive disorder caused by deficient activity of β-glu... more Gaucher disease (GD) is a rare autosomal recessive disorder caused by deficient activity of β-glucocerebrosidase resulting in the accumulation of glucosylceramide. Bone disease is a common feature with radiological evidence in up to 93% of patients. Severity of bone involvement ranges from osteoporosis to pathological fractures. The progressive course of type 1 GD is largely mitigated by treatment with enzyme replacement therapy (ERT) or substrate reduction. A number of studies have shown some patients suffer bone events while receiving ERT. Studies of biochemical markers of bone turnover have generated varied results and as a consequence are not generally used to assess bone disease in GD. In vitro osteoclast generation from peripheral blood samples of 74 Gaucher patients followed over a period of up to 10 years was correlated with bone events, reports of bone pain, anaemia, spleen status, bone mineral density, chitotriosidase activity, treatment with Gaucher specific therapies, bi...
... Atul Mehta Royal Free Hospital and University College Medical School, Pond Street, NW3 2QG, L... more ... Atul Mehta Royal Free Hospital and University College Medical School, Pond Street, NW3 2QG, London, UK Tel.: +44 207 830 2814 Fax: +44 207 830 2313 [email protected] ... Page 2. Expert Rev. Endocrinol. Metab. 5(5), (2010) 642 Mehta Drug Profile ...
Sequence analysis of the 3&am... more Sequence analysis of the 3' end of the 16S rRNA gene of mitochondrial DNA (mtDNA) revealed a single base change G----A, at position 3010. This mutation was first identified in a patient who had recovered from chloramphenicol-induced aplastic anaemia (CAP-induced AA). A link between this mutation and CAP-induced AA was ruled out by investigating three other similar patients, none of whom had the mutation. This mutation lies within or near the chloramphenicol binding site in a part of the 16S rRNA gene which shows high evolutionary conservation and where polymorphisms have not been previously reported. Hybridization tests with appropriate oligonucleotide probes in 114 individuals reveal that this mutation has a polymorphic frequency of about 14% in Europeans.
Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of a-ga... more Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of a-galactosidase A. Storage of globotriaosylceramide ultimately results in multiorgan pathology, including cerebrovascular, cardiovascular and renal disease. Vascular involvement is evident throughout the body but the mechanisms by which storage on a cellular level leads to endorgan pathology are unknown. Here the evidence for abnormal blood flow, vessel architecture and endothelial function will be reviewed and possible models of vascular pathology discussed. The effects of reversal of storage within vessels by enzyme replacement therapy (ERT) and the possibilities for intervention with additional agents will be considered. Conclusion: The pathology of Fabry disease has an important vascular component, although the underlying pathophysiology is unclear. Preliminary evidence suggests that ERT may have beneficial effects on the vascular component of this multisystem disease.
Aim: Mutations of the gene (GLA) encoding a-galactosidase A are implicated in Fabry disease, a pr... more Aim: Mutations of the gene (GLA) encoding a-galactosidase A are implicated in Fabry disease, a progressive, X-chromosomal inherited lysosomal storage disorder. FOS-the Fabry Outcome Survey-was established as a long-term surveillance study to describe the natural course of Fabry disease and its response to enzyme replacement therapy in a large cohort of European patients. Clinical phenotype, age of onset and course of Fabry disease are very variable, even within the same family, which makes it difficult to define a genotype-phenotype relationship by analysing individual patients. The FOS database contains detailed medical information on a large cohort of patients and thus has the potential to provide important information to address this question. Methods: At the time of analysis, information on 545 patients belonging to 157 families from nine European countries had been entered into the FOS database. A GLA mutation has been reported in 365 individuals (65% and 68% of all males and females, respectively) in FOS. These data were used to analyse the relationship between genotype and phenotype in Fabry disease. Results: A highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index in male patients with GLA missense mutations (p50.001) as well as in those carrying other types of mutations (p50.001). A positive correlation was also found between the age at entry into FOS and the number of affected organs in male patients with missense mutations, irrespective of whether the change in the amino acid side chain predicted in the a-galactosidase A protein was classified as a conservative or non-conservative change. Conclusion: The data presented here suggest that there is a correlation between genotype and clinical severity.
Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-g... more Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS-the Fabry Outcome Survey-and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy. Conclusion: Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.
We report an unusual dermatological reaction to bortezomib in a 61-year-old man with AL amyloidos... more We report an unusual dermatological reaction to bortezomib in a 61-year-old man with AL amyloidosis. Systemic AL amyloidosis is a rare complication of monoclonal gammopathy or myeloma in which abnormally unstable free light chains cause fibrillary deposits in organs leading to multisystem disease. The treatment of AL amyloidosis is directed at the underlying plasma cell dyscrasia and most regimes have been adapted from myeloma, but drug toxicity is more common in AL amyloidosis because of the more extensive nature of the disease. We report a patient who developed asymptomatic purple discolouration of the veins of his left arm several days after receiving the infusion in his left hand, although the infusion itself had been uncomplicated with no extravasation. The discolouration resolved completely within 2 weeks; there was recurrence on a subsequent dose of bortezomib but this also subsided spontaneously. This reaction may have been transient phlebitis or a local vasogenic reaction; its transient nature and the lack of systemic features suggest it is a benign phenomenon. There appears to be no indication for discontinuation of bortezomib treatment or dose alteration in such cases.
Background: Most male and about 20% of female Fabry patients eventually develop end stage renal d... more Background: Most male and about 20% of female Fabry patients eventually develop end stage renal disease (ESRD). However, pathophysiology of FN is not well-understood. SFR studies can lead to the discovery of FN progression predictors. Aim: To study FN natural history and renal function and structure in 50-60 Fabry patients with a broad range of age from childhood to adulthood before starting enzyme replacement therapy. Preliminary data: We have so far studies renal biopsies from 20 (male/female = 2/ 1) Fabry patients, age 4-44 years; Glomerular structural parameters, including volume fraction of globotriaosylceramide (GL3) inclusions in podocytes [Vv(Inc/PC)], Abstracts/Molecular Genetics and Metabolism 99 (2010) S8-S41 S27
Finding a clone in the bone marrow of a patient with a hematologic disorder is important to confi... more Finding a clone in the bone marrow of a patient with a hematologic disorder is important to confirm the neoplastic nature of the disease and may be indicative of prognosis. Since cytogenetic analysis detects only ectively dividing clones, the presence of a single abnormal cell among 20 cells analyzed raises doubts about its clonal nature. Fluorescence in situ hybridization (FISH) enables rapid detection of certain chromosomal abnormalities in metaphase and interphase cells, thus enabling detection of minor or inactive clones. Seven patients with hematologic malignancy each having random cell(s) were investigated thus: at diagnosis, with MDS and a cell with + 8 (two cases) or + 9 (one case) and with AML and a cell with +4 (one case), +7 lone case), or two cells with + 9, +22/+ 10, + 1Z + 17 (one case). One patient with ALL in remission had one cell with trisomy 4. One patient, a male aged 66 years with refractory anemia with ringed sideroblasts, was found to have a minor trisomy 8 clone in his diagnostic marrow. A follow-up marrow 42 months later showed no trisomy 8 cell among 62 metaphases analyzed, and the percentage of trisomic cells using FISH on interphase cells was within the control range. This patient has survived for more than 42 months requiring no treatment. Single-cell abnormalities in the other six cases proved to be random events. Thus it appears that single-cell abnormalities may not be clonal or at most indicate the presence of a minor clone well below the level of cytogenetic detection. The prognostic significance of s~!ch minor clones is at present unclear.
Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency o... more Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the lysosomal enzyme alpha galactosidase A. Clinical features include neuropathic pain, rash, proteinuria renal failure, stroke and cardiomyopathy accompanied by a reduced life expectancy. Patients report an average delay of > 10 years between symptom onset and diagnosis. Newborn screening studies suggest a much higher prevalence than that found on population studies supporting the notion that FD is under-diagnosed. Four key challenges in the diagnosis of FD and strategies to overcome them are discussed. The clinical features of FD are highly heterogeneous resulting in patients presenting to many different specialists, often with non-specific symptoms with a wide differential diagnosis. The pathophysiological mechanisms underlying this are poorly understood and the prediction of pathogenicity on the basis of gene mutation analysis can be problematic. While the availability of treatment adds an impetus to make the correct diagnosis, our understanding of when and if treatment may be required in a specific individual is incomplete. Improving diagnostic rates of FD requires a greater awareness of the disorder among physicians to whom patients may present, new strategies to determine the pathogenicity of novel mutations and a greater understanding of the natural history of FD across the phenotypic spectrum. Collaborative clinical and laboratory research is vital in furthering knowledge of the underlying mechanisms of this disorder and how they may be impacted by current or future therapies.
Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-g... more Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS-the Fabry Outcome Survey-and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy. Conclusion: Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.
Multiple myeloma (MM) in three human immunodeficiency virus (HIV)-infected patients is reported. ... more Multiple myeloma (MM) in three human immunodeficiency virus (HIV)-infected patients is reported. HIV infection predisposes to the development of high-grade B-cell lymphomas, but few cases of plasma cell tumours in association with HIV have been reported. The coincidence of HIV infection and neoplasia highlights the distinct roles of immunodeficiency and infection with herpesviridae, including HIV itself, in the pathogenesis of HIVrelated tumours. In addition, a number of cytokines (e.g., interleukin-6 [IL-6]) and angiogenic factors (e.g., vascular endothelial growth factor [VEGF] and basic fibroblastic growth factor [bFGF]) may play a role in the initiation, maintenance, and progression of multiple myeloma (MM). Infection was the first clinical consideration to the cause of the illness in two of our HIV-seropositive patients. The diagnosis of MM may be difficult in patients with advanced HIV infection as they often have renal failure, bone marrow plasmacytosis, repeated infections, and polyclonal hypergammaglobulinaemia, due to HIV infection itself, opportunistic pathogens, and/or medication. Am.
Journal of Inherited Metabolic Disease, Sep 1, 2013
Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individu... more Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individuals with GBA1 mutations develop neurological involvement raising the possibility that other factors may provide compensatory protection. One factor may be the activity of the non-lysosomal β-glucosidase (GBA2) which exhibits catalytic activity towards glucosylceramide and is reported to be highly expressed in brain tissue. Here, we assessed brain GBA2 enzymatic activity in wild type, heterozygote and GBA1 deficient mice. Additionally, we determined activity in leucocytes obtained from 13 patients with Gaucher disease, 10 patients with enzymology consistent with heterozygote status and 19 controls. For wild type animals, GBA2 accounted for over 85 % of total brain GBA activity and was significantly elevated in GBA1 deficient mice when compared to heterozygote and wild types (GBA1 deficient; 92.4 ± 5.6, heterozygote; 71.5 ± 2.4, wild type 76.8 ± 5.1 nmol/h/mg protein). For the patient samples, five Gaucher patients had GBA2 leucocyte activities markedly greater than controls. No difference in GBA2 activity was apparent between the control and carrier groups. Undetectable GBA2 activity was identified in four leucocyte preparations; one in the control group, two in the carrier group and one from the Gaucher disease group. Work is now required to ascertain whether GBA2 activity is a disease modifying factor in Gaucher disease and to identify the mechanism(s) responsible for triggering increased GBA2 activity in GBA1 deficiency states.
Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha... more Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha galactosidase A. Enzyme replacement therapy (ERT) is commercially available and has been demonstrated to improve cardiac and renal outcomes. Predictive scores, such as the Fabry International Prognostic Index (FIPI), have been developed to stratify disease severity; however, these have not been validated to predict outcomes in patients receiving ERT. We show that the FIPI score at baseline can predict outcomes in a group of patients on long-term ERT.
Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficie... more Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficient β-glucocerebrosidase activity and accumulation of its substrate glucosylceramide. Bone disease is present in around 84% of GD patients, ranging from bone loss including osteopenia and osteonecrosis to abnormal bone remodelling in the form of Erlenmeyer flask formation. The range of severity and variety of types of bone disease found in GD patients indicate the involvement of several mechanisms. Here we investigate the effects of exogenous sphingolipids on osteoclasts, osteoblasts, plasma cells and mesenchymal stem cells (MSC) and the interactions between these cell types. Osteoclasts were differentiated from the peripheral blood of Gaucher patients and control subjects. Osteoblasts were differentiated from mesenchymal stem cells isolated from bone marrow aspirates of Gaucher patients and control subjects. The human osteoblast cell line SaOS-2 was also investigated. Osteoclasts, osteob...
Gaucher disease (GD) is a rare autosomal recessive disorder caused by deficient activity of β-glu... more Gaucher disease (GD) is a rare autosomal recessive disorder caused by deficient activity of β-glucocerebrosidase resulting in the accumulation of glucosylceramide. Bone disease is a common feature with radiological evidence in up to 93% of patients. Severity of bone involvement ranges from osteoporosis to pathological fractures. The progressive course of type 1 GD is largely mitigated by treatment with enzyme replacement therapy (ERT) or substrate reduction. A number of studies have shown some patients suffer bone events while receiving ERT. Studies of biochemical markers of bone turnover have generated varied results and as a consequence are not generally used to assess bone disease in GD. In vitro osteoclast generation from peripheral blood samples of 74 Gaucher patients followed over a period of up to 10 years was correlated with bone events, reports of bone pain, anaemia, spleen status, bone mineral density, chitotriosidase activity, treatment with Gaucher specific therapies, bi...
... Atul Mehta Royal Free Hospital and University College Medical School, Pond Street, NW3 2QG, L... more ... Atul Mehta Royal Free Hospital and University College Medical School, Pond Street, NW3 2QG, London, UK Tel.: +44 207 830 2814 Fax: +44 207 830 2313 [email protected] ... Page 2. Expert Rev. Endocrinol. Metab. 5(5), (2010) 642 Mehta Drug Profile ...
Sequence analysis of the 3&am... more Sequence analysis of the 3' end of the 16S rRNA gene of mitochondrial DNA (mtDNA) revealed a single base change G----A, at position 3010. This mutation was first identified in a patient who had recovered from chloramphenicol-induced aplastic anaemia (CAP-induced AA). A link between this mutation and CAP-induced AA was ruled out by investigating three other similar patients, none of whom had the mutation. This mutation lies within or near the chloramphenicol binding site in a part of the 16S rRNA gene which shows high evolutionary conservation and where polymorphisms have not been previously reported. Hybridization tests with appropriate oligonucleotide probes in 114 individuals reveal that this mutation has a polymorphic frequency of about 14% in Europeans.
Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of a-ga... more Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of a-galactosidase A. Storage of globotriaosylceramide ultimately results in multiorgan pathology, including cerebrovascular, cardiovascular and renal disease. Vascular involvement is evident throughout the body but the mechanisms by which storage on a cellular level leads to endorgan pathology are unknown. Here the evidence for abnormal blood flow, vessel architecture and endothelial function will be reviewed and possible models of vascular pathology discussed. The effects of reversal of storage within vessels by enzyme replacement therapy (ERT) and the possibilities for intervention with additional agents will be considered. Conclusion: The pathology of Fabry disease has an important vascular component, although the underlying pathophysiology is unclear. Preliminary evidence suggests that ERT may have beneficial effects on the vascular component of this multisystem disease.
Aim: Mutations of the gene (GLA) encoding a-galactosidase A are implicated in Fabry disease, a pr... more Aim: Mutations of the gene (GLA) encoding a-galactosidase A are implicated in Fabry disease, a progressive, X-chromosomal inherited lysosomal storage disorder. FOS-the Fabry Outcome Survey-was established as a long-term surveillance study to describe the natural course of Fabry disease and its response to enzyme replacement therapy in a large cohort of European patients. Clinical phenotype, age of onset and course of Fabry disease are very variable, even within the same family, which makes it difficult to define a genotype-phenotype relationship by analysing individual patients. The FOS database contains detailed medical information on a large cohort of patients and thus has the potential to provide important information to address this question. Methods: At the time of analysis, information on 545 patients belonging to 157 families from nine European countries had been entered into the FOS database. A GLA mutation has been reported in 365 individuals (65% and 68% of all males and females, respectively) in FOS. These data were used to analyse the relationship between genotype and phenotype in Fabry disease. Results: A highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index in male patients with GLA missense mutations (p50.001) as well as in those carrying other types of mutations (p50.001). A positive correlation was also found between the age at entry into FOS and the number of affected organs in male patients with missense mutations, irrespective of whether the change in the amino acid side chain predicted in the a-galactosidase A protein was classified as a conservative or non-conservative change. Conclusion: The data presented here suggest that there is a correlation between genotype and clinical severity.
Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-g... more Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS-the Fabry Outcome Survey-and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy. Conclusion: Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.
We report an unusual dermatological reaction to bortezomib in a 61-year-old man with AL amyloidos... more We report an unusual dermatological reaction to bortezomib in a 61-year-old man with AL amyloidosis. Systemic AL amyloidosis is a rare complication of monoclonal gammopathy or myeloma in which abnormally unstable free light chains cause fibrillary deposits in organs leading to multisystem disease. The treatment of AL amyloidosis is directed at the underlying plasma cell dyscrasia and most regimes have been adapted from myeloma, but drug toxicity is more common in AL amyloidosis because of the more extensive nature of the disease. We report a patient who developed asymptomatic purple discolouration of the veins of his left arm several days after receiving the infusion in his left hand, although the infusion itself had been uncomplicated with no extravasation. The discolouration resolved completely within 2 weeks; there was recurrence on a subsequent dose of bortezomib but this also subsided spontaneously. This reaction may have been transient phlebitis or a local vasogenic reaction; its transient nature and the lack of systemic features suggest it is a benign phenomenon. There appears to be no indication for discontinuation of bortezomib treatment or dose alteration in such cases.
Background: Most male and about 20% of female Fabry patients eventually develop end stage renal d... more Background: Most male and about 20% of female Fabry patients eventually develop end stage renal disease (ESRD). However, pathophysiology of FN is not well-understood. SFR studies can lead to the discovery of FN progression predictors. Aim: To study FN natural history and renal function and structure in 50-60 Fabry patients with a broad range of age from childhood to adulthood before starting enzyme replacement therapy. Preliminary data: We have so far studies renal biopsies from 20 (male/female = 2/ 1) Fabry patients, age 4-44 years; Glomerular structural parameters, including volume fraction of globotriaosylceramide (GL3) inclusions in podocytes [Vv(Inc/PC)], Abstracts/Molecular Genetics and Metabolism 99 (2010) S8-S41 S27
Finding a clone in the bone marrow of a patient with a hematologic disorder is important to confi... more Finding a clone in the bone marrow of a patient with a hematologic disorder is important to confirm the neoplastic nature of the disease and may be indicative of prognosis. Since cytogenetic analysis detects only ectively dividing clones, the presence of a single abnormal cell among 20 cells analyzed raises doubts about its clonal nature. Fluorescence in situ hybridization (FISH) enables rapid detection of certain chromosomal abnormalities in metaphase and interphase cells, thus enabling detection of minor or inactive clones. Seven patients with hematologic malignancy each having random cell(s) were investigated thus: at diagnosis, with MDS and a cell with + 8 (two cases) or + 9 (one case) and with AML and a cell with +4 (one case), +7 lone case), or two cells with + 9, +22/+ 10, + 1Z + 17 (one case). One patient with ALL in remission had one cell with trisomy 4. One patient, a male aged 66 years with refractory anemia with ringed sideroblasts, was found to have a minor trisomy 8 clone in his diagnostic marrow. A follow-up marrow 42 months later showed no trisomy 8 cell among 62 metaphases analyzed, and the percentage of trisomic cells using FISH on interphase cells was within the control range. This patient has survived for more than 42 months requiring no treatment. Single-cell abnormalities in the other six cases proved to be random events. Thus it appears that single-cell abnormalities may not be clonal or at most indicate the presence of a minor clone well below the level of cytogenetic detection. The prognostic significance of s~!ch minor clones is at present unclear.
Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency o... more Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the lysosomal enzyme alpha galactosidase A. Clinical features include neuropathic pain, rash, proteinuria renal failure, stroke and cardiomyopathy accompanied by a reduced life expectancy. Patients report an average delay of > 10 years between symptom onset and diagnosis. Newborn screening studies suggest a much higher prevalence than that found on population studies supporting the notion that FD is under-diagnosed. Four key challenges in the diagnosis of FD and strategies to overcome them are discussed. The clinical features of FD are highly heterogeneous resulting in patients presenting to many different specialists, often with non-specific symptoms with a wide differential diagnosis. The pathophysiological mechanisms underlying this are poorly understood and the prediction of pathogenicity on the basis of gene mutation analysis can be problematic. While the availability of treatment adds an impetus to make the correct diagnosis, our understanding of when and if treatment may be required in a specific individual is incomplete. Improving diagnostic rates of FD requires a greater awareness of the disorder among physicians to whom patients may present, new strategies to determine the pathogenicity of novel mutations and a greater understanding of the natural history of FD across the phenotypic spectrum. Collaborative clinical and laboratory research is vital in furthering knowledge of the underlying mechanisms of this disorder and how they may be impacted by current or future therapies.
Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-g... more Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of a-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS-the Fabry Outcome Survey-and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy. Conclusion: Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.
Multiple myeloma (MM) in three human immunodeficiency virus (HIV)-infected patients is reported. ... more Multiple myeloma (MM) in three human immunodeficiency virus (HIV)-infected patients is reported. HIV infection predisposes to the development of high-grade B-cell lymphomas, but few cases of plasma cell tumours in association with HIV have been reported. The coincidence of HIV infection and neoplasia highlights the distinct roles of immunodeficiency and infection with herpesviridae, including HIV itself, in the pathogenesis of HIVrelated tumours. In addition, a number of cytokines (e.g., interleukin-6 [IL-6]) and angiogenic factors (e.g., vascular endothelial growth factor [VEGF] and basic fibroblastic growth factor [bFGF]) may play a role in the initiation, maintenance, and progression of multiple myeloma (MM). Infection was the first clinical consideration to the cause of the illness in two of our HIV-seropositive patients. The diagnosis of MM may be difficult in patients with advanced HIV infection as they often have renal failure, bone marrow plasmacytosis, repeated infections, and polyclonal hypergammaglobulinaemia, due to HIV infection itself, opportunistic pathogens, and/or medication. Am.
Journal of Inherited Metabolic Disease, Sep 1, 2013
Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individu... more Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individuals with GBA1 mutations develop neurological involvement raising the possibility that other factors may provide compensatory protection. One factor may be the activity of the non-lysosomal β-glucosidase (GBA2) which exhibits catalytic activity towards glucosylceramide and is reported to be highly expressed in brain tissue. Here, we assessed brain GBA2 enzymatic activity in wild type, heterozygote and GBA1 deficient mice. Additionally, we determined activity in leucocytes obtained from 13 patients with Gaucher disease, 10 patients with enzymology consistent with heterozygote status and 19 controls. For wild type animals, GBA2 accounted for over 85 % of total brain GBA activity and was significantly elevated in GBA1 deficient mice when compared to heterozygote and wild types (GBA1 deficient; 92.4 ± 5.6, heterozygote; 71.5 ± 2.4, wild type 76.8 ± 5.1 nmol/h/mg protein). For the patient samples, five Gaucher patients had GBA2 leucocyte activities markedly greater than controls. No difference in GBA2 activity was apparent between the control and carrier groups. Undetectable GBA2 activity was identified in four leucocyte preparations; one in the control group, two in the carrier group and one from the Gaucher disease group. Work is now required to ascertain whether GBA2 activity is a disease modifying factor in Gaucher disease and to identify the mechanism(s) responsible for triggering increased GBA2 activity in GBA1 deficiency states.
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Papers by Atul Mehta