A Comprehensive, Targeted NGS Approach to Assessing Molecular Diagnosis of Lysosomal Storage Diseases

With over 60 different disorders and a combined incidence occurring in 1:5000–7000 live births, lysosomal storage diseases (LSDs) represent a major public health problem and constitute an enormous burden for affected individuals and their families. Several reasons make the diagnosis of LSDs an arduous task for clinicians, including the phenotype and penetrance variability, the shared signs and symptoms, and the uncertainties related to biochemical enzymatic assay results. Developing a powerful diagnostic tool based on next generation sequencing (NGS) technology may help reduce the delayed diagnostic process for these families, leading to better outcomes for current therapies and providing the basis for more appropriate genetic counseling. Herein, we employed a targeted NGS-based panel to scan the coding regions of 65 LSD-causative genes. A reference group sample (n = 26) with previously known genetic mutations was used to test and validate the entire workflow. Our approach demonstrated elevated analytical accuracy, sensitivity, and specificity. We believe the adoption of comprehensive targeted sequencing strategies into a routine diagnostic route may accelerate both the identification and management of LSDs with overlapping clinical profiles, producing a significant reduction in delayed diagnostic response with beneficial results in the treatment outcome.

Download Full-text

Highlights on Genomics Applications for Lysosomal Storage Diseases

Cells ◽

10.3390/cells9081902 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1902

Author(s):

Valentina La Cognata ◽

Maria Guarnaccia ◽

Agata Polizzi ◽

Martino Ruggieri ◽

Sebastiano Cavallaro

Keyword(s):

Genetic Disorders ◽

Treatment Strategies ◽

Lysosomal Storage Diseases ◽

Diagnostic Methods ◽

Diagnostic Process ◽

Lysosomal Storage ◽

Storage Diseases ◽

Infancy And Childhood ◽

Gradual Accumulation ◽

Cellular Pathogenesis

Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem genetic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the lysosome. Although the cellular pathogenesis of LSDs is complex and still not fully understood, the approval of disease-specific therapies and the rapid emergence of novel diagnostic methods led to the implementation of extensive national newborn screening (NBS) programs in several countries. In the near future, this will help the development of standardized workflows aimed to more timely diagnose these conditions. Hereby, we report an overview of LSD diagnostic process and treatment strategies, provide an update on the worldwide NBS programs, and discuss the opportunities and challenges arising from genomics applications in screening, diagnosis, and research.

Download Full-text

Inherited metabolic diseases

Oxford Textbook of Rheumatology ◽

10.1093/med/9780199642489.003.0170 ◽

2013 ◽

pp. 1451-1456

Author(s):

Bernhard Manger

Keyword(s):

Metabolic Diseases ◽

Signs And Symptoms ◽

Lysosomal Storage Diseases ◽

Organ Damage ◽

Lysosomal Storage ◽

Storage Diseases ◽

Enzyme Replacement ◽

Hereditary Disorders ◽

Enzymatic Pathways

A variety of hereditary disorders can present with structural or functional alterations of the musculoskeletal system. In particular, genetic defects within enzymatic pathways involved in the lysosomal degradation of various substrates can manifest with bone or joint symptoms. Because musculoskeletal complaints are frequently the first reason for the patient to seek medical advice, the rheumatologist may play a crucial role in the early diagnosis of these diseases. Lysosomal storage diseases are a heterogeneous group of individually very rare disorders, but taken together they have a prevalence of more than 1 in 8000 live births. Some of these lysosomal storage diseases can nowadays be treated very effectively by enzyme replacement therapies; however, a timely start of treatment is essential to avoid irreversible organ damage and deterioration of the quality of life. Therefore, the rheumatologist should be able to recognize signs and symptoms of the most frequent treatable lysosomal storage diseases.

Download Full-text

Electron Microscopy in the diagnosis of lysosomal storage diseases

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100156316 ◽

1989 ◽

Vol 47 ◽

pp. 866-867

Author(s):

Carole Vogler ◽

Harvey S. Rosenberg

Keyword(s):

Electron Microscopy ◽

Lysosomal Enzyme ◽

Rectal Mucosa ◽

Lysosomal Storage Diseases ◽

Cell Types ◽

Lysosomal Storage ◽

Storage Material ◽

Ultrastructural Examination ◽

Blood Leukocytes ◽

Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

Download Full-text

Substrate reduction therapy for lysosomal storage diseases

Acta Paediatrica ◽

10.1080/08035320510028157 ◽

2005 ◽

Vol 94 (0) ◽

pp. 69-75 ◽

Cited By ~ 34

Author(s):

T Cox

Keyword(s):

Lysosomal Storage Diseases ◽

Substrate Reduction Therapy ◽

Lysosomal Storage ◽

Storage Diseases ◽

Substrate Reduction

Download Full-text

Bone Marrow Transplantation in the Treatment of Lysosomal Storage Diseases

Inborn Metabolic Diseases ◽

10.1007/978-3-662-02613-7_52 ◽

1990 ◽

pp. 659-670 ◽

Cited By ~ 5

Author(s):

P. M. Hoogerbrugge ◽

J. M. J. J. Vossen

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Storage Diseases

Download Full-text

The role of surfactant and distal lung dysfunction in the pathology of lysosomal storage diseases

Current Opinion in Physiology ◽

10.1016/j.cophys.2021.100467 ◽

2021 ◽

pp. 100467

Author(s):

Tamara L Paget ◽

Emma J Parkinson-Lawrence ◽

Sandra Orgeig

Keyword(s):

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Storage Diseases ◽

Lung Dysfunction ◽

Distal Lung

Download Full-text

Sphingolipid lysosomal storage diseases: from bench to bedside

Lipids in Health and Disease ◽

10.1186/s12944-021-01466-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Muna Abed Rabbo ◽

Yara Khodour ◽

Laurie S. Kaguni ◽

Johnny Stiban

Keyword(s):

Basic Research ◽

Lysosomal Storage Diseases ◽

Therapeutic Strategies ◽

Clinical Applications ◽

Late Nineteenth Century ◽

Lysosomal Storage ◽

Storage Diseases ◽

The Past ◽

Health And Disease ◽

General Aspects

AbstractJohann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.

Download Full-text

Knowledge, Awareness and Perception on Malaria in Tribal Regions of Vadodara District, Gujarat (India)

Journal of Health Management ◽

10.1177/0972063419868580 ◽

2019 ◽

Vol 21 (3) ◽

pp. 406-416

Author(s):

Bindu Bhatt ◽

Janak P. Joshi

Keyword(s):

Malaria Control ◽

Control Measure ◽

Health Sector ◽

Public Health Problem ◽

Signs And Symptoms ◽

Well Being ◽

Clear Understanding ◽

Major Public Health Problem ◽

Health Seeking ◽

Tropical Regions

Malaria affects health and general well-being of many people in the developing world. In India also, malaria is a major public health problem. It continues to be a leading cause of morbidity and mortality in many tropical regions of the world, despite global efforts to eradicate the disease. To achieve the targets of reducing malaria prevalence and preventing malaria epidemic, it is essential to have active community participation. Therefore, clear understanding of the Knowledge, Awareness and Perception (KAPs) of a particular community can help in framing the policy of prevention and promotion of any malaria control measure. In this context, the decision makers in the health sector are recognizing the importance of community’s KAPs on malaria and, thus, is gaining stimulus as one of the methods for malaria control. KAPs, however, play an important role in the improvement of health and health-seeking behaviour of a disease-burdened group. This study, therefore, investigates a local community’s KAPs on malaria in tribal areas of Vadodara District. The KAP investigates the community’s understanding of malaria transmission, their recognition of signs and symptoms, their treatment-seeking behaviours and community preventive measures and practices.

Download Full-text