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Lysosomal Storage Disease (lysosomal + storage_disease)
Selected AbstractsSeventh International Symposium on Lysosomal Storage DiseasesACTA PAEDIATRICA, Issue 2008Johannes Aerts No abstract is available for this article. [source] Lysosomal storage disease in Sida carpinifolia toxicosis: an induced mannosidosis in horsesEQUINE VETERINARY JOURNAL, Issue 5 2003A. P. LORETTI Summary Reasons for performing study: This study reports a neurological disease unrecognised until now in ponies in southern Brazil. Hypothesis: Epidemiological data strongly suggests that the ingestion of Sida carpinifolia is involved in the aetiology. We tested the hypothesis that it is an acquired lyosomal storage disease. Methods: Following the death of 3 ponies, all ponies from the premises were closely monitored; epidemiological data and clinical findings carefully recorded. Fragments of several organs, including CNS, were fixed in neutral formalin and embedded in paraffin-wax. Sections were stained with haematoxylin and eosin. Representative sections of the cerebellum and trigeminal ganglia were submitted to lectin histochemical procedures. Results: The neurological disorder, characterised by stiff gait, muscle tremors, abdominal pain and death, was observed on a farm with 3 hectares of pasture. Three of 11 ponies died 15,20 days after they had been introduced into a new paddock heavily infested by the plant Sida carpinifolia. No significant gross lesions were observed. The main histological findings included multiple cytoplasmatic vacuoles in swollen neurones in the brain, cerebellum, spinal cord, autonomic ganglia (trigeminal and celiac ganglia), and submucosal and myenteric plexus of the intestines. In the kidneys, there was marked vacuolation of the proximal convoluted tubular cells. Sections of cerebellum and trigeminal ganglion were submitted to lectin histochemistry. The vacuoles in different cerebellar and ganglion cells reacted strongly to the following lectins: Concanavalia ensiformis, Triticum vulgaris and succinylated- Triticum vulgaris. Conclusions: The pattern of staining coincides with that of both swainsonine toxicosis and inherited mannosidosis reports. The histopathological changes were similar to those described in S. carpinifolia spontaneous and experimental poisoning in goats. This disease seems to be similar to Swainsona, Oxytropis and Astragalus toxicosis. Potential relevance: S. carpinifolia should be evaluated as a possible cause in the diagnosis of equine neuropathies. [source] Is there a role for dynamic retinal vessel analysis in internal medicine?ACTA OPHTHALMOLOGICA, Issue 2008IM LANZL Purpose Human retinal vessels and their reaction to stimuli change during life and in disease due to physiological, genetic and pathological influences. Using the Dynamic Vessel Analyzer (DVA, Fa. IMEDOS, Jena) it is possible to assess changes in retinal vessel diameters in response to vasoactive stimuli in real time and non-invasively. Methods Retinal arterial vessel reaction in the natural time course and to the average of 3 consecutive monochromatic flicker stimulations (530-600 nm, 12,5 Hz, 20 s) with a 80 s observation pause between stimulations was investigated in healthy volunteers of different age groups, obese patients, diabetes type 1 patients, systemic hypertensive patients and patients with lysosomal storage disease. Statistical data analysis of vessel reactions independent from the DVA program was performed. Results There is a statistically significant difference in retinal vascular behaviour in different age groups in a healthy population. The same is true between a healthy population and each of the diseases investigated. Lysosomal storage disease however demonstrated an increase in dilation following flicker stimulation compared to normal persons. Conclusion Flicker stimulation of the retina light evokes a prompt vessel reaction in all healthy subjects. We could demonstrate an age dependence of the retinal arterial reaction in medically healthy persons and in hypertension, diabetes and obese patients. From the increased reaction in lysosomal storage disease further understanding of different factors leading to the vascular reaction to stimuli may be derived. Application of flicker stimulus to retinal vessels represents a method to assess the endothelial function of vessels which is important to understand in systemic disease. [source] Exclusion of NEU1 and PPGB from candidate genes for a lysosomal storage disease in Japanese Black cattleANIMAL SCIENCE JOURNAL, Issue 5 2009Ali Akbar MASOUDI ABSTRACT A case of lysosomal storage disease has been reported in a calf of Japanese Black cattle. Lysosomal storage diseases are hereditary diseases caused by deficiency of lysosomal hydrolases. The clinical and pathological features and accumulated substrates of the affected animal indicated a possibility of sialidosis or galactosialidosis caused by deficiency of neuraminidase (NEU1) or protective protein for ,-galactosidase (PPGB). In the present study, we investigated nucleotide sequences of the genes encoding these two proteins to evaluate whether mutation of these genes is involved in this disease. We determined cattle genomic sequences of these two genes by using bovine EST sequences and the nucleotide sequences of all exons of these genes were compared between affected and normal animals. The results showed several nucleotide substitutions, but none of them was a functional mutation or specific to the affected animal. Furthermore, genotyping of the microsatellite markers in the vicinity of these two genes revealed no homozygosity of the chromosomal regions including these genes in the affected animal. These findings indicated that neither NEU1 nor PPGB gene is responsible for the lysosomal storage disease of Japanese Black cattle and therefore the disease is neither sialidosis nor galactosialidosis. [source] Advances in the treatment of lysosomal storage diseaseDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 9 2001J E Wraith MB ChB FRCP FRCPCH First page of article [source] A novel aspartylglucosaminuria mutation affects translocation of aspartylglucosaminidase,,HUMAN MUTATION, Issue 4 2004Jani Saarela Abstract The AGA gene is mutated in patients with aspartylglucosaminuria (AGU), a lysosomal storage disease enriched in the Finnish population. The disease mechanism of AGU and the biochemistry and cell biology of the lysosomal aspartylglucosaminidase (AGA) enzyme are well characterized. Here, we have investigated a novel AGU mutation found in a Finnish patient. The mutation was detected as a compound heterozygote with the Finnish major mutation in the other allele. The novel point mutation, c.44T>G, causes the L15R amino acid substitution in the signal sequence of the AGA enzyme. The mutated AGA enzyme was here analyzed by over expression in BHK and COS-1 cells. The L15R AGA protein was only faintly detectable by immunofluorescence analysis and observed in the endoplasmic reticulum. Metabolic labeling and immunoprecipitation revealed only a small amount of AGA polypeptides but the specific activity of the mutant enzyme was surprisingly high, 37% of the wild type. The amino acid substitution probably affects translocation of AGA polypeptides by altering a critical hydrophobic core structure of the signal sequence. It appears that the small amounts of active enzyme are not able to reach the lysosomes thus explaining the development of AGU disease in the patient. © 2004 Wiley-Liss, Inc. [source] Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients,,HUMAN MUTATION, Issue 3 2002Mirella Filocamo Abstract Gaucher disease (GD), the most prevalent lysosomal storage disease characterized by a remarkable degree of clinical variability, results from deleterious mutations in the glucocerebrosidase gene (GBA). In this paper we report the molecular characterization of 144 unrelated Italian GD patients with the three types of the disease. The allelic frequencies of Italians are reported and the mutation profile is analyzed. Besides the common N370S, L444P, RecNciI, G202R, IVS2+1G>A, D409H, F213I mutations, the different molecular strategies, used for the mutation detection, identified the rare N107L, R131C, R170C, R170P, N188S, S196P, R285C, R285H, W312C, D399N, A446P, IVS10-1G>A, Rec,55, total gene deletion, as well as 12 mutant alleles that were exclusively present in the Italian population until now: the previously reported R353G, N370S+S488P mosaicism, IVS8(-11delC)-14T>A), Rec I, Y418C, and the seven novel alleles D127X, P159T, V214X, T231R, L354X, H451R, and G202R+M361I. The wide phenotypic differences observed within the genotypic groups as well as between siblings implicate a significant contribution of other modifying genetic and/or non-genetic factors and claim a comprehensive valuation of the patient including clinical., biochemical and molecular investigations for prognosis, appropriate interventive therapy and reliable genetic counseling. © 2002 Wiley-Liss, Inc. [source] The expanding clinical spectrum of Anderson,Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapyJOURNAL OF INTERNAL MEDICINE, Issue 6 2004A. C. Hauser Abstract. Anderson,Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient ,-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding ,-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease. [source] Innate and adaptive immune activation in the brain of MPS IIIB mouse modelJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2009Julianne DiRosario Abstract Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with severe neurological manifestations due to ,- N -acetylglucosaminidase (NaGlu) deficiency. The mechanism of neuropathology in MPS IIIB is unclear. This study investigates the role of immune responses in neurological disease of MPS IIIB in mice. By means of gene expression microarrays and real-time quantitative reverse transcriptase,polymerase chain reaction, we demonstrated significant up-regulation of numerous immune-related genes in MPS IIIB mouse brain involving a broad range of immune cells and molecules, including T cells, B cells, microglia/macrophages, complement, major histocompatibility complex class I, immunoglobulin, Toll-like receptors, and molecules essential for antigen presentation. The significantly enlarged spleen and lymph nodes in MPS IIIB mice were due to an increase in splenocytes/lymphocytes, and functional assays indicated that the T cells were activated. An autoimmune component to the disease was further suggested by the presence of putative autoantigen or autoantigens in brain extracts that reacted specifically with serum IgG from MPS IIIB mice. We also demonstrated for the first time that immunosuppression with prednisolone alone can significantly slow the central nervous system disease progression. Our data indicate that immune responses contribute greatly to the neuropathology of MPS IIIB and should be considered as an adjunct treatment in future therapeutic developments for optimal therapeutic effect. © 2008 Wiley-Liss, Inc. [source] Reduced rates of axonal and dendritic growth in embryonic hippocampal neurones cultured from a mouse model of Sandhoff diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2003D. Pelled Sandhoff disease is a lysosomal storage disease in which ganglioside GM2 accumulates because of a defective ,-subunit of ,-hexosaminidase. This disease is characterized by neurological manifestations, although the pathogenic mechanisms leading from GM2 accumulation to neuropathology are largely unknown. We now examine the viability, development and rates of neurite growth of embryonic hippocampal neurones cultured from a mouse model of Sandhoff disease, the Hexb,/, mouse. GM2 was detected by metabolic labelling at low levels in wild type (Hexb+/+) neurones, and increased by approximately three-fold in Hexb,/, neurones. Hexb,/, hippocampal neurones were as viable as their wild type counterparts and, moreover, their developmental programme was unaltered because the formation of axons and of the minor processes which eventually become dendrites was similar in Hexb,/, and Hexb+/+ neurones. In contrast, once formed, a striking difference in the rate of axonal and minor process growth was observed, with changes becoming apparent after 3 days in culture and highly significant after 5 days in culture. Analysis of various parameters of axonal growth suggested that a key reason for the decreased rate of axonal growth was because of a decrease in the formation of collateral axonal branches, the major mechanism by which hippocampal axons elongate in culture. Thus, although the developmental programme with respect to axon and minor process formation and the viability of hippocampal neurones are unaltered, a significant decrease occurs in the rate of axonal and minor process growth in Hexb,/, neurones. These results appear to be in contrast to dorsal root ganglion neurones cultured from 1-month-old Sandhoff mice, in which cell survival is impaired but normal outgrowth of neurones occurs. The possible reasons for these differences are discussed. [source] Restoration of central nervous system ,- N -acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector deliveryTHE JOURNAL OF GENE MEDICINE, Issue 7 2010Haiyan Fu Abstract Background Finding efficient central nervous system (CNS) delivery approaches has been the major challenge facing therapeutic development for treating diseases with global neurological manifestation, such as mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease, caused by autosomal recessive defect of ,- N -acetylglucosaminidase (NaGlu). Previously, we developed an approach, intracisternal (i.c.) injection, to deliver recombinant adeno-associated viral (rAAV) vector to the CNS of mice, leading to a widespread periventricular distribution of transduction. Methods In the present study, we delivered rAAV2 vector expressing human NaGlu into the CNS of MPS IIIB mice by an i.c. injection approach, to test its therapeutic efficacy and feasibility for treating the neurological manifestation of the disease. Results We demonstrated significant functional neurological benefits of a single i.c. vector infusion in adult MPS IIIB mice. The treatment slowed the disease progression by mediating widespread recombinant NaGlu expression in the CNS, resulting in the reduction of brain lysosomal storage pathology, significantly improved cognitive function and prolonged survival. However, persisting motor function deficits suggested that pathology in areas outside the CNS contributes to the MPS IIIB behavioral phenotype. The therapeutic benefit of i.c. rAAV2 delivery was dose-dependent and could be attribute solely to the CNS transduction because the procedure did not lead to detectable transduction in somatic tissues. Conclusions A single IC rAAV2 gene delivery is functionally beneficial for treating the CNS disease of MPS IIIB in mice. It is immediately clinically translatable, with the potential of improving the quality of life for patients with MPS IIIB. Copyright © 2010 John Wiley & Sons, Ltd. [source] Exclusion of NEU1 and PPGB from candidate genes for a lysosomal storage disease in Japanese Black cattleANIMAL SCIENCE JOURNAL, Issue 5 2009Ali Akbar MASOUDI ABSTRACT A case of lysosomal storage disease has been reported in a calf of Japanese Black cattle. Lysosomal storage diseases are hereditary diseases caused by deficiency of lysosomal hydrolases. The clinical and pathological features and accumulated substrates of the affected animal indicated a possibility of sialidosis or galactosialidosis caused by deficiency of neuraminidase (NEU1) or protective protein for ,-galactosidase (PPGB). In the present study, we investigated nucleotide sequences of the genes encoding these two proteins to evaluate whether mutation of these genes is involved in this disease. We determined cattle genomic sequences of these two genes by using bovine EST sequences and the nucleotide sequences of all exons of these genes were compared between affected and normal animals. The results showed several nucleotide substitutions, but none of them was a functional mutation or specific to the affected animal. Furthermore, genotyping of the microsatellite markers in the vicinity of these two genes revealed no homozygosity of the chromosomal regions including these genes in the affected animal. These findings indicated that neither NEU1 nor PPGB gene is responsible for the lysosomal storage disease of Japanese Black cattle and therefore the disease is neither sialidosis nor galactosialidosis. [source] A case of multiple angiomas without any angiokeratomas in a female heterozygote with Fabry diseaseAUSTRALASIAN JOURNAL OF DERMATOLOGY, Issue 1 2010Vesna Mirceva ABSTRACT Fabry disease is a rare, X-chromosome-linked lysosomal storage disease caused by a deficient ,-galactosidase A enzyme. The disease manifests primarily in affected hemizygous males and to some extent in heterozygous females (,carrier'). A 45-year-old female Fabry disease patient without angiokeratomas but with numerous angiomas is presented. Her leukocyte ,-galactosidase A activity was reduced (0.35 nmol/min/mg protein; normal range: 0.4,1). The analysis of her ,-galactosidase A gene (exon 1,7) showed the transition c.427 G>A. An intrafamilial follow-up search detected a reduced leukocyte ,-galactosidase A activity in her father, who suffered exclusively from coronary heart disease. Our case report underlines the possible wide range of clinical signs in Fabry disease patients, sometimes complicated by missing typical lesions (e.g. angiokeratomas). In oligosymptomatic Fabry disease cases, genetic analysis is recommended. [source] Is there a role for dynamic retinal vessel analysis in internal medicine?ACTA OPHTHALMOLOGICA, Issue 2008IM LANZL Purpose Human retinal vessels and their reaction to stimuli change during life and in disease due to physiological, genetic and pathological influences. Using the Dynamic Vessel Analyzer (DVA, Fa. IMEDOS, Jena) it is possible to assess changes in retinal vessel diameters in response to vasoactive stimuli in real time and non-invasively. Methods Retinal arterial vessel reaction in the natural time course and to the average of 3 consecutive monochromatic flicker stimulations (530-600 nm, 12,5 Hz, 20 s) with a 80 s observation pause between stimulations was investigated in healthy volunteers of different age groups, obese patients, diabetes type 1 patients, systemic hypertensive patients and patients with lysosomal storage disease. Statistical data analysis of vessel reactions independent from the DVA program was performed. Results There is a statistically significant difference in retinal vascular behaviour in different age groups in a healthy population. The same is true between a healthy population and each of the diseases investigated. Lysosomal storage disease however demonstrated an increase in dilation following flicker stimulation compared to normal persons. Conclusion Flicker stimulation of the retina light evokes a prompt vessel reaction in all healthy subjects. We could demonstrate an age dependence of the retinal arterial reaction in medically healthy persons and in hypertension, diabetes and obese patients. From the increased reaction in lysosomal storage disease further understanding of different factors leading to the vascular reaction to stimuli may be derived. Application of flicker stimulus to retinal vessels represents a method to assess the endothelial function of vessels which is important to understand in systemic disease. [source] Fetal hydrops in GM1 gangliosidosis: A case reportACTA PAEDIATRICA, Issue 12 2005Maria Teresa Sinelli Abstract GM1 gangliosidosis is a rare disorder characterized by deficiency of the ,-galactosidase enzyme, with the resulting accumulation of glycolipids, oligosaccharides and especially GM1 ganglioside. It can be classified into three clinical types according to the time of onset: infantile, juvenile and adult form. We report a case of GM1 gangliosidosis presenting with fetal hydrops at 24 wk of gestation. The parents were consanguineous; the baby, born at 35 wk of gestation, was dysmorphic and presented severe generalized oedema. The most common cause of fetal hydrops was excluded. A lysosomal storage disease was suspected, and GM1 gangliosidosis was diagnosed. The child developed severe growth and mental retardation and died when she was 21 mo old. Conclusion: We suggest that the possible association between inborn errors of metabolism and antenatal ascites should be considered, in order to offer genetic counselling due to the high recurrence risk and the availability of early antenatal diagnosis. [source] Treatment of neutral glycosphingolipid lysosomal storage diseases via inhibition of the ABC drug transporter, MDR1FEBS JOURNAL, Issue 9 2006Cyclosporin A can lower serum, liver globotriaosyl ceramide levels in the Fabry mouse model We have shown that the ABC transporter, multiple drug resistance protein 1 (MDR1, P-glycoprotein) translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral, but not acidic, glycosphingolipid (GSL) synthesis. Here we show that the MDR1 inhibitor, cyclosporin A (CsA) can deplete Gaucher lymphoid cell lines of accumulated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide (Gb3), by preventing de novo synthesis. In the Fabry mouse model, Gb3 is increased in the heart, liver, spleen, brain and kidney. The lack of renal glomerular Gb3 is retained, but the number of verotoxin 1 (VT1)-staining renal tubules, and VT1 tubular targeting in vivo, is markedly increased in Fabry mice. Adult Fabry mice were treated with ,-galactosidase (enzyme-replacement therapy, ERT) to eliminate serum Gb3 and lower Gb3 levels in some tissues. Serum Gb3 was monitored using a VT1 ELISA during a post-ERT recovery phase ± biweekly intra peritoneal CsA. After 9 weeks, tissue Gb3 content and localization were determined using VT1/TLC overlay and histochemistry. Serum Gb3 recovered to lower levels after CsA treatment. Gb3 was undetected in wild-type liver, and the levels of Gb3 (but not gangliosides) in Fabry mouse liver were significantly depleted by CsA treatment. VT1 liver histochemistry showed Gb3 accumulated in Kupffer cells, endothelial cell subsets within the central and portal vein and within the portal triad. Hepatic venule endothelial and Kupffer cell VT1 staining was considerably reduced by in vivo CsA treatment. We conclude that MDR1 inhibition warrants consideration as a novel adjunct treatment for neutral GSL storage diseases. [source] GAP43 overexpression and enhanced neurite outgrowth in mucopolysaccharidosis type IIIB cortical neuron culturesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2010Michaël Hocquemiller Abstract Behavioral manifestations mark the onset of disease expression in children with mucopolysaccharidosis type III (MPSIII, Sanfilippo syndrome), a genetic disorder resulting from interruption of the lysosomal degradation of heparan sulfate. In the mouse model of MPSIII type B (MPSIIIB), cortical neuron pathology and dysfunction occur several months before neuronal loss and are primarily cell autonomous. The gene coding for GAP43, a neurite growth potentiator, is overexpressed in the MPSIIIB mouse cortex, and neurite dystrophy was reported in other types of lysosomal storage diseases. We therefore examined the development of the neuritic trees in pure populations of MPSIIIB mouse embryo cortical neurons grown for up to 12 days in primary culture. Dynamic observation of living neurons and quantification of neurite growth parameters indicated more frequent neurite elongation and branching and less frequent neurite retraction, resulting in a relative overgrowth of MPSIIIB neuron neuritic trees, involving both dendrites and axons, compared with normal controls. Neurite overgrowth was concomitant with more than twofold increased expression of GAP43 mRNAs and proteins. Correction of the genetic defect leads to expression of the missing lysosomal enzyme, normal GAP43 mRNA expression, and reduced neurite outgrowth. These results indicate that heparan sulfate oligosaccharide storage modifies GAP43 expression in MPSIIIB cortical neurons with potential consequences for neurite development and neuronal functions that may be relevant to clinical manifestations. © 2009 Wiley-Liss, Inc. [source] Glycosphingolipid lysosomal storage diseases: therapy and pathogenesisNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2002M. Jeyakumar Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies. [source] Prenatal diagnosis of free sialic acid storage disorders (SASD)PRENATAL DIAGNOSIS, Issue 8 2006Nina Aula Abstract Free sialic acid storage disorders, Salla disease (SD) and Infantile sialic acid storage disease (ISSD), are lysosomal storage diseases due to impaired function of a sialic acid transporter, sialin, at the lysosomal membrane. Several mutations of the sialin gene, SLC17A5, are known, leading either to the severe neonatal/infantile disease or to the milder, adult-type developmental disorder, Salla disease. Free sialic acid accumulation in lysosomes causes increased tissue concentration and consequently elevated urinary excretion. Prenatal diagnosis of SASD is possible either by determination of free sialic acid concentration or by mutation analysis of the SLC17A5 gene in fetal specimen, in chorionic villus biopsy particularly. Both techniques have been successfully applied in several cases, sialic acid assay more often in ISSD cases but mutation analysis preferentially in SD. Sialic acid assay of amniotic fluid supernatant or cultured amniotic fluid cells may give erroneous results and should not be used for prenatal diagnosis of these disorders. The present comments are mainly based on our experience of prenatal diagnosis of SD in Finnish families. A founder mutation in SLC17A5 gene, 115C-> T, represents 95% of the disease alleles in the Finnish SD patients, which provides a unique possibility to apply mutation analysis. Therefore, molecular studies have successfully been used in 17 families since the identification of the gene and the characterization of the SD mutations. Earlier, eight prenatal studies were performed by measuring the free sialic acid concentration in chorionic villus samples. Copyright © 2006 John Wiley & Sons, Ltd. [source] Investigation of lysosomal storage diseases in nonimmune hydrops fetalisPRENATAL DIAGNOSIS, Issue 8 2004Maira G. Burin Abstract Objective To investigate lysosomal storage diseases (LSD) in cases of nonimmune hydrops fetalis (NIHF). Methods Thirty-three cases of NIHF were investigated, 28 in the prenatal period and 5 in hydropic newborns. In addition to a general investigation for NIHF, specific enzymatic analyses for the detection of LSD were performed. Results In our sample, we detected five patients (15%) with LSD, each patient having one of the following diseases: mucolipidosis, Niemann,Pick disease, galactosialidosis, sialidosis and mucopolysaccharidosis type IV A. Conclusion Although LSDs are rare disorders as a group, they should be considered as a possible cause of NIHF, even in the absence of consanguinity or of a previous family history. By excluding the more frequent causes of NIHF, an LSD investigation assists in clarifying the etiology of many hydropic cases, making more appropriate genetic counseling for parents possible. Copyright © 2004 John Wiley & Sons, Ltd. [source] Gene therapy for lysosomal storage diseases: the lessons and promise of animal modelsTHE JOURNAL OF GENE MEDICINE, Issue 5 2004N. Matthew Ellinwood Abstract There are more than 40 different forms of inherited lysosomal storage diseases (LSDs) known to occur in humans and the aggregate incidence has been estimated to approach 1 in 7000 live births. Most LSDs are associated with high morbidity and mortality and represent a significant burden on patients, their families, and health care providers. Except for symptomatic therapies, many LSDs remain untreatable, and gene therapy is among the only viable treatment options potentially available. Therapies for some LSDs do exist, or are under evaluation, including heterologous bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and substrate reduction therapy (SRT), but these treatment options are associated with significant concerns, including high morbidity and mortality (BMT), limited positive outcomes (BMT), incomplete response to therapy (BMT, ERT, and SRT), life-long therapy (ERT, SRT), and cost (BMT, ERT, SRT). Gene therapy represents a potential alternative therapy, albeit a therapy with its own attendant concerns. Animal models of LSDs play a critical role in evaluating the efficacy and safety of therapy for many of these conditions. Naturally occurring animal homologs of LSDs have been described in the mouse, rat, dog, cat, guinea pig, emu, quail, goat, cattle, sheep, and pig. In this review we discuss those animal models that have been used in gene therapy experiments and those with promise for future evaluations. Copyright © 2004 John Wiley & Sons, Ltd. [source] Molecular facets of sphingolipids: Mediators of diseasesBIOTECHNOLOGY JOURNAL, Issue 7 2009Fatma Betul Kavun Ozbayraktar Abstract Sphingolipids constitute a biologically active lipid class that is significantly important from both structural and regulatory aspects. The manipulation of sphingolipid metabolism is currently being studied as a novel strategy for cancer therapy. The basics of this therapeutic approach lie in the regulation property of sphingolipids on cellular processes, which are important in a cell's fate, such as cell proliferation, apoptosis, cell cycle arrest, senescence, and inflammation. Furthermore, the mutations in the enzymes catalyzing some specific reactions in the sphingolipid metabolism cause mortal lysosomal storage diseases like Fabry, Gaucher, Niemann-Pick, Farber, Krabbe, and Metachromatic Leukodystrophy. Therefore, the alteration of the sphingolipid metabolic pathway determines the choice between life and death. Understanding the sphingolipid metabolism and regulation is significant for the development of new therapeutic approaches for all sphingolipid-related diseases, as well as for cancer. An important feature of the sphingolipid metabolic pathway is the compartmentalization into endoplasmic reticulum, the Golgi apparatus, lysosome and plasma membrane, and this compartmentalization makes the transport of sphingolipids critical for proper functioning. This paper focuses on the structures, metabolic pathways, localization, transport mechanisms, and diseases of sphingolipids in Saccharomyces cerevisiae and humans, and provides the latest comprehensive information on sphingolipid research. [source] Hippocampal Pathology in the Human Neuronal Ceroid-Lipofuscinoses: Distinct Patterns of Storage Deposition, Neurodegeneration and Glial ActivationBRAIN PATHOLOGY, Issue 4 2004Jaana Tyynelä The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies. [source] | |||||||||||||