SnapShot: Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) represent a group of monogenic inherited metabolic disorders characterized by the progressive accumulation of undegraded substrates inside lysosomes, resulting in aberrant lysosomal activity and homeostasis. This SnapShot summarizes the intracellular localization and function of proteins implicated in LSDs. Common aspects of LSD pathogenesis and the major current therapeutic approaches are noted. To view this SnapShot, open or download the PDF.

Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: A nationwide survey in Japan.

INTRODUCTION: Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. METHODS: A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy. DISCUSSION: Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan. CONCLUSION: We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.

Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry.

BACKGROUND: There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. OBJECTIVE: To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic activity assay of 6 lysosomal enzymes in a NBS laboratory for the identification of newborns at risk for developing Pompe, Mucopolysaccharidosis-I (MPS-I), Fabry, Gaucher, Niemann Pick-A/B, and Krabbe diseases. METHODS AND RESULTS: Enzyme activities (acid α-glucosidase (GAA), galactocerebrosidase (GALC), glucocerebrosidase (GBA), α-galactosidase A (GLA), α-iduronidase (IDUA) and sphingomyeline phosphodiesterase-1 (SMPD-1)) were measured on ~43,000 de-identified dried blood spot (DBS) punches, and screen positive samples were submitted for DNA sequencing to obtain genotype confirmation of disease risk. The 6-plex assay was efficiently performed in the Washington state NBS laboratory by a single laboratory technician at the bench using a single MS/MS instrument. The number of screen positive samples per 100,000 newborns were as follows: GAA (4.5), IDUA (13.6), GLA (18.2), SMPD1 (11.4), GBA (6.8), and GALC (25.0). DISCUSSION: A 6-plex MS/MS assay for 6 lysosomal enzymes can be successfully performed in a NBS laboratory. The analytical ranges (enzyme-dependent assay response for the quality control HIGH sample divided by that for all enzyme-independent processes) for the 6-enzymes with the MS/MS is 5- to 15-fold higher than comparable fluorimetric assays using 4-methylumbelliferyl substrates. The rate of screen positive detection is consistently lower for the MS/MS assay compared to the fluorimetric assay using a digital microfluidics platform.

Demographic characteristics and distribution of lysosomal storage disorder subtypes in Eastern China.

Lysosomal storage disorders (LSDs) are a group of >50 different types of inherited metabolic disorders that result from defects in the lysosome. The aim of this study was to investigate the distribution and demographic characteristics of the different subtypes of LSDs in Eastern China. From 2006 to 2012, 376 out of 1331 clinically suspected patients were diagnosed with 17 different subtypes of LSDs at our hospital. Mucopolysaccharidoses (MPS) were the most common group of LSDs (50.5%), followed by sphingolipidoses (25.4%) and Pompe disease (19.8%). Mucolipidosis type II/III accounted for the remaining 4% of diagnosed LSDs. MPS II was the most common form of MPS, comprising 47.4% of all MPS cases diagnosed, followed by MPS IVA (26.8%) and MPS I (16.3%). Gaucher disease and Niemann-Pick disease type A/B were the two most common forms of sphingolipidoses. There was a large variation in the time between disease onset and eventual diagnosis, from 0.3 years in infantile-onset Pompe disease to 30 years in Fabry disease, highlighting timely and accurate diagnosis of LSDs as the main challenge in China.

Case definition and classification of leukodystrophies and leukoencephalopathies.

OBJECTIVE: An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. METHOD: Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. RESULTS: A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). INTERPRETATION: A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.

Ophthalmic manifestations of Gaucher disease: the most common lysosomal storage disorder.

Gaucher disease (GD) results from a deficiency of glucocerebrosidase activity and the subsequent accumulation of the enzyme's metabolites, principally glucosylsphingosine and glucosylceramide. There are three principal forms: Type I, which is the most common, is usually considered non-neuronopathic. Type II, III and IIIc manifest earlier and have neurological sequelae due to markedly reduced enzyme activity. Gaucher's can be associated with ophthalmological sequelae but these have not been systematically reviewed. We therefore performed a comprehensive literature review of all such ophthalmic abnormalities associated with the different types of Gaucher disease. We systematically searched the literature (1950 - present) for functional and structural ocular abnormalities arising in patients with Gaucher disease and found that all subtypes can be associated with ophthalmic abnormalities; these range from recently described intraocular lesions to disease involving the adnexae, peripheral nerves and brain. In summary, Gaucher can affect most parts of the eye. Rarely is it sight-threatening; some but not all manifestations are amenable to treatment, including with enzyme replacement and substrate reduction therapy. Retinal involvement is rare but patients with ocular manifestations should be monitored and treated early to reduce the risk of progression and further complications. As Gaucher disease is also associated with Parkinsons disease and may also confer an increased risk of malignancy (particularly haematological forms and melanoma), any ocular abnormalities should be fully investigated to exclude these potential underlying conditions.

[Treatment prospects of lysosomal storage disorders]. / Lizoszomális tárolási rendellenességek kezelési lehetoségei.

Lysosomal storage disorders are caused either by deficiencies or decreased activity of enzymes localised in lysosomal vesicles or transport failure of these enzymes or their substrates. Accumulation of macromolecules destroy cell function presenting in clinical symptoms. Up to date, there are about 40 different lysosomal storage disorders according to the accumulated macromolecules. Till the last decades supportive therapy was the only option by these disorders. Enhanced researches in the last decades have presented some breakthrough results in the field of storage disease therapy. The review briefly introduces the lysosomal storage disorders, summarizes the actual therapy possibilities, as enzyme replacement therapy, substrate deprivation therapy, bone marrow transplantation. Finally, the review outlines future therapeutic potentials, like stem-cell and gene therapy.

Update on treatment of lysosomal storage diseases.

Lysosomal storage diseases (LSDs) are a large group of disorders caused by a deficiency of specific enzymes responsible for the degradation of substances present in lysosomes. In the past few years, treatments for LSDs were non specific and could only cope with signs and symptoms of the diseases. A successful therapeutic approach to LSDs should instead address to the underlying causes of the diseases, thus helping the degradation of the accumulated metabolites in the various organs, and at the same time preventing their further deposition. One way is to see to an available source of the deficient enzyme: bone marrow transplantation, enzyme replacement therapy and gene therapy are based on this rationale. The purpose of substrate reduction therapy is to down regulate the formation of the lysosomal substance to a rate at which the residual enzyme activity can catabolize the stored and de novo produced lysosomal substrate. Chemical chaperone therapy is based on small molecules able to bind and stabilize the misfolded enzymes. This paper offers a historical overview on the therapeutic strategies for LSDs.

[Neurological presentations of lysosomal diseases in adult patients]. / Présentations neurologiques des maladies lysosomales chez l'adulte.

Lysosomal diseases represent a large group of genetic storage disorders characterized by a defect in the catabolism of complex molecules within the lysosome. Effective treatments are now possible for some of them given progresses in bone-marrow transplantation, enzyme replacement therapy and substrate reduction therapy. Neurologists and psychiatrists are concerned by these diseases because they can present in adolescence or adulthood with progressive neuropsychiatric signs. Here we focus on late-onset clinical forms which can be met in an adult neurology or psychiatric department. Lysosomal diseases were classified into 3 groups: (1) leukodystrophies (metachromatic leukodystrophy, Krabbe's disease and Salla's disease); (2) Neurodegenerative or psychiatric-like diseases (GM1 and GM2 gangliosidoses, Niemann Pick type C disease, sialidosis type I, ceroid-lipofuscinosis, mucopolysaccharidosis type III); (3) multisystemic diseases (Gaucher's disease, Fabry's disease, alpha and B mannosidosis, Niemann Pick disease type B, fucosidosis, Schindler/Kanzaki disease, and mucopolysaccharidosis type I and II. We propose a diagnostic approach guided by clinical examination, brain MRI, electrodiagnostic studies and abdominal echography.

[Lysosomal storage diseases: functional classification and treatment principles]. / Maladies de surcharge lysosomale: classification fonctionnelle et principes thérapeutiques.

Until recently, lysosomes were only considered as the place of macromolecules degradation. To date, these organelles are considered as playing a key role in cellular homeostasis. The knowledge of their complex role allows a better understanding of the physiopathology of the diseases resulting from their dysfunction. Biosynthesis of lysosomal enzymes and routes for macromolecules influx within lysosomes are briefly described and a functional classification of lysosomal diseases, which allows a comprehensive approach of treatment rationale, is proposed. Except cystinosis which is a lysosomal membrane transport disorder the majority of current treatments aim at treating enzymatic defects. Normal enzyme can be brought by hoematopoietic cell transplant (or other cell therapies) or by infusions of human recombinant enzyme. The normal enzyme can be also produced in situ by bringing the normal gene: it is the objective of gene therapy The other therapeutic approaches aim at decreasing the quantity of non degraded substrate reaching the lysosomes by limiting its biosynthesis or thanks to small pharmacologic molecules, at increasing the residual enzyme activity by stabilizing the protein (chaperones) or by improving read through possibilities of some stop codons in special contexts. The better knowledge of secondary phenomena set by the cell in order to try to restore homeostasis which are sometimes more deleterious than the storage itself should allow to develop complementary treatments. The rationale of these different therapeutic approaches and their limits are described in this paper

Lysosomal storage disorders: Morphologic appraisal in Indian population.

BACKGROUND: Lysosomal storage disorders (LSDs) comprise a group of at least 50 distinct genetic diseases, each one resulting from the deficiency of a particular lysosomal enzyme involved in metabolism. We attempt to study and further subclassify pediatric LSDs into Gaucher's and non-Gaucher's category based on the morphologic variables seen in the bone marrow aspiration smears and trephine biopsy sections. MATERIALS AND METHODS: Pediatric (<12 years age) cases of LSDs diagnosed by bone marrow aspiration and trephine biopsy specimens, in the last 12 years period, were retrieved. The archival material and the relevant clinical as well as hematologic parameters were reviewed. RESULTS: From January 1997 to December 2008, 55 cases were diagnosed as LSDs. Based on bone marrow morphology, 56% (n = 31) cases were diagnosed as non-Gaucher's and the remaining 44% (n = 24) cases as Gaucher's disease, the ratio being 1.29:1. Anemia and thrombocytopenia were more commonly observed in Gaucher's disease (91.67 and 62.5%) as compared to non-Gaucher's group (74.19 and 19.35%). Neurologic symptoms and signs were more frequently present in non-Gaucher's cases (45.16%) as compared to Gaucher's group (29.17%). CONCLUSION: LSDs can be classified into Gaucher's and non-Gaucher's subtypes based on the characteristic cytomorphology of the storage cells in Giemsa-stained bone marrow aspiration smears and on hematoxylin and eosin-stained trephine biopsy sections. This approach would be fairly adequate for therapeutic and prognostic purposes in resource.constrained settings, where enzyme studies and mutational analysis may not be easily available.

Lactosylceramide in lysosomal storage disorders: a comparative immunohistochemical and biochemical study.

Immunohistochemical studies of the presence of lactosylceramide (LacCer) in lysosomal storage disorders (LSDs) were done using anti-LacCer monoclonal antibody of the CDw 17 type (clone MG-2). No sign of an association between LacCer and the lysosomal system in normal cells was observed, except for histiocytes active in phagocytosis. A comparative study of a group of LSDs showed a general tendency for LacCer to increase in storage cells in Niemann-Pick disease type C (NPC), and types A and B, GM1 gangliosidosis, acid lipase deficiency, glycogen storage disease type II and mucopolysaccharidoses. LacCer accumulated in storage cells despite normal activity of relevant lysosomal degrading enzymes. The accumulation of LacCer displayed variability within storage cell populations, and was mostly expressed in neurons in NPC. An absence of the increase in LacCer in storage cells above control levels was seen in neuronal ceroid lipofuscinoses (neurons and cardiocytes) and in Fabry disease. Gaucher and Krabbe cells showed significantly lower levels, or even the absence, of LacCer compared with control macrophages. Results of immunohistochemistry were corroborated by semiquantitative lipid thin-layer chromatography (TLC). It is suggested that different associations of LacCer with the lysosomal storage process may reflect differences in glycosphingolipid turnover induced by the storage-compromised lysosomal/endosomal system.

The status of hematopoietic stem cell transplantation in lysosomal storage disease.

Lysosomal storage diseases are a group of disorders which have in common an inherited defect in lysosomal function-in most cases, a missing intralysosomal enzyme. Research into potential treatment options for this group of disorders has focused on enzyme replacement. Over the past two decades, hematopoietic stem cell transplantation has been used with increasing frequency to treat patients with lysosomal storage disease by providing a population of cells with the capacity to produce the missing enzyme. The success of marrow transplantation depends on the specific enzyme deficiency and the stage of the disease. Generally, visceral symptoms can be improved, whereas skeletal lesions remain relatively unaffected. The effect on neurologic symptoms varies. Hematopoietic stem cell transplantation remains a viable treatment option in those lysosomal storage diseases where data supportive of disease stabilization or amelioration are known. Early transplantation is the goal so that enzyme replacement may occur before extensive central nervous system injury becomes evident. When inadequate clinical data are available, the decision to perform transplantation requires experimental data demonstrating that the enzyme in question is both excreted from normal cells and taken up by affected cells as evidenced by elimination of storage material in vitro.

Lipidoses detected in Poland through 1993.

It is estimated that 70-100 children suffering from a lysosomal storage disease are born in Poland every year. From 1975 to 1993, the activity of various lysosomal enzymes was determined in the leukocytes, cultured skin fibroblasts, or hair roots from 5,594 patients, mainly children, in whom the diagnosis of a lipidosis was suspected. In that material 162 cases of a lipidosis were diagnosed. Metachromatic leukodystrophy seems to be the most frequent of the lipidoses; GM1 gangliosidosis is more frequent than GM2 gangliosidosis and Gaucher and Niemann-Pick diseases appear to be almost as frequent as the former.

Lysosomal storage disorders in Thailand: the Siriraj experience.

Lysosomal storage disorders are a heterogeneous group of biochemical genetic disorders; currently 40-50 are known. The clinical phenotype is determined by the tissue distribution of the storage material and degree of enzyme deficiency. The genetic transmission is mostly autosomal recessive. Lysosomal storage disorders can be divided into three groups according to the major organ system pathology: (1) Primary involvement of the central nervous system without significant somatic or skeletal pathology. Disorders of grey matter, eg gangliosidosis and disorders of white matter eg the leucodystrophy are the most common; (2) Primary involvement of the reticuloendothelial system with or without associated neuropathology, eg Niemann-Pick disease and Gaucher disease; (3) Multisystem involvement in which skeletal manifestations are prominent features. The mucopolysaccharidosis and mucolipidoses are the two major forms with this clinical phenotype. Lysosomal storage disorders identified at Siriraj Hospital are neuronal ceroid lipofuscinosis, GMI gangliosidosis, mucolipidosis II, Maroteaux-Lamy, sialidosis, Sly syndrome, Hunter syndrome, Morquio syndrome, Gaucher disease, Niemann-Pick, Sandhoff disease, Pompe's disease and many more. Most patients came from the provinces where consanguinity is common. Confirmation usually is done by enzyme assays using skin fibroblast culture or leucocytes. Genetic counseling is extremely important and prenatal diagnosis is recommended to high-risk couple.

Hydrops fetalis: lysosomal storage disorders in extremis.

In recent years there has been an increased recognition that hydrops fetalis may be an extreme presentation of many of the lysosomal storage disorders. Hydrops fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues and serous cavities of the fetus, has many possible etiologies, providing a diagnostic challenge for the physician. Ten different lysosomal storage disorders have now been diagnosed in infants with hydrops fetalis, including mucopolysaccharidosis (MPS) VII and IVA, type 2 Gaucher disease, sialidosis, GMI gangliosidosis, galactosialidosis, Niemann-Pick disease type C, disseminated lipogranulomatosis (Farber disease), infantile free sialic acid storage disease (ISSD), and mucolipidosis II (I-cell disease). Frequently, these inborn errors of metabolism are recognized only after the unfortunate recurrence of hydrops fetalis in several pregnancies of a family. Making the diagnosis relies on the physician having a high index of suspicion and ordering appropriate testing, which can often be performed prenatally. In several of these disorders, including MPS VII, infantile galactosialidosis, type 2 Gaucher disease, and ISSD, hydrops fetalis is a relatively common presentation. A greater physician awareness of hydrops fetalis as a presentation of lysosomal disease will facilitate establishing a diagnosis in cases that would have previously been considered idiopathic and will enable a better estimation of the incidence of this association. Lysosomal disorders are among the few causes of nonimmune hydrops fetalis in which an accurate recurrence risk can be ascertained. With an early and accurate diagnosis, genetic counseling and family planning can be offered in these difficult cases.

[Lysosomal disorders. Diagnostic role of extra-cerebral biopsy]. / Maladies lysosomales. Apport diagnostique de la biopsie extra-cérébrale.

Lysosomal disorders are related to dysfunctions of lysosomes which may affect enzymes, transporters or activators. Their clinical features are varied. This is due to several mechanisms, the metabolism of nervous tissue explaining its particular involvement in sphingolipidosis. The classifications are still changing and, recently, some ceroid-lipofuscinosis were included in this group. Biological diagnosis relies on biochemical study of accumulated substrate or on enzymatic assays. It remains sometimes difficult. The analysis of tissue is then a useful tool. Biopsies from extraneural tissues, essentially skin and conjunctival biopsies, are nowadays preferred to brain biopsies. However, the location of the biopsy varies according to the suspected disease. The specimen must be adequately prepared and electron microscopy is necessary. Results of this examination are summarized. The interest of the biopsy is not restricted to diagnosis, it is useful in follow-up of treated patients and for understanding the underlying pathophysiology.

[Lysosomal diseases]. / Les maladies lysosomales.

Lysosomal diseases are severe genetic enzymopathies generally affecting the child, with a progressively fatal issue in the first few years of life. The group is very heterogeneous regarding: the number of included affections (about 30), as well as the clinical, biological and molecular manifestations. The responsible genes for the respective enzyme deficiencies are located or cloned and the recently developed research allows to characterise the causal mutations and to elucidate the involved molecular mechanisms. In the absence of an efficient therapy a reliable prenatal diagnosis can be proposed. However, therapeutic prospects concerning substitutive therapy, bone marrow transplantation and, in a more long-term, gene therapy are encouraging.

[Lysosomal storage disease].

Lysosomes are the principal sites of intracellular digestion. In Lysosomes approximately 40 hydrolytic enzymes are contained. Lysosomal storage diseases are mainly caused by genetic defects that affect one or more of the lysosomal hydrolases, and result in accumulation of their undigested substrates in lysosomes, with profound pathological consequences. In this paper clinical features, diagnostic methods, and trend of the present research for lysosomal storage diseases are reviewed.

[Galactosialidosis--protective protein and related enzymes].

Galactosialidosis is the inherited metabolic disease with autosomal recessive trait. This disease classifies into three classical subtypes and a variant type in clinically. In enzymatic assay, we observe the decreasing activities of both beta-galactosidase and neuraminidase, but now we know that the primarily cause of this disease is abnormality of protective protein. In 1988, the cDNA of human protective protein was cloned. From the cloning, the genetically abnormalities of this disease were detected and the difference of abnormalities about the proteins were studied between the clinical subtypes. Then, the abnormalities within the subtypes were confirmed the difference about the mature process of protective protein in expression study. The structure of this protein was shown in 1994-1995 and the abnormal mutated proteins were studied about stoichiometrical features. On the other hand, the functions of protective protein are identified to have the role of deamidase, esterase, and carboxypeptidase besides the protective function. In the galactosialidosis patients, these activities decrease in fact. We knew the reason of the difference within the subtypes of this disease using molecular biology methods at present. In the future, the model mouse will be prepared and we hope to produce the medicine for this disease.