scholarly journals Highlights on Genomics Applications for Lysosomal Storage Diseases

Cells ◽  
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.

The mucopolysaccharidoses: a success of molecular medicine

2008 ◽  
Vol 10 ◽  
Author(s):  
Lorne A. Clarke
Keyword(s):  
Genetic Disorders ◽  
Specific Treatment ◽  
Lysosomal Storage Diseases ◽  
Molecular Medicine ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Enzyme Replacement ◽  
Treatment Regimens ◽  
The Past ◽  
Development Evaluation

The mucopolysaccharidoses represent a devastating group of lysosomal storage diseases affecting approximately 1 in 25 000 individuals. Advances in biochemistry and genetics over the past 25 years have resulted in the identification of the key hydrolases underlying the mucopolysaccharidoses, with subsequent isolation and characterisation of the genes involved. Ultimately these advances have led to the recent development of specific treatment regimens for some of the mucopolysaccharidoses, in the form of direct enzyme replacement. Direct replacement of the defective gene product has been attempted for very few genetic disorders, and thus the experience gained in the lysosomal storage diseases by the development, evaluation and integration of treatment regimens into healthcare is instructive for other rare genetic disorders. This review focuses on the pathophysiology of the mucopolysaccharidoses and highlights the complex biochemical and physiological perturbations that underlie the disease phenotype.

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

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1750
Author(s):  
Valentina La Cognata ◽  
Sebastiano Cavallaro
Keyword(s):  
Reference Group ◽  
Public Health Problem ◽  
Signs And Symptoms ◽  
Lysosomal Storage Diseases ◽  
Diagnostic Process ◽  
Major Public Health Problem ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Targeted Ngs ◽  
Analytical Accuracy

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.

scholarly journals Design and Validation of a Custom NGS Panel Targeting a Set of Lysosomal Storage Diseases Candidate for NBS Applications

2021 ◽  
Vol 22 (18) ◽  
pp. 10064
Author(s):  
Valentina La Cognata ◽  
Maria Guarnaccia ◽  
Giovanna Morello ◽  
Martino Ruggieri ◽  
Agata Polizzi ◽  
...  
Keyword(s):  
Ad Hoc ◽  
Diagnostic Delay ◽  
Clinical Manifestations ◽  
Cost Effective ◽  
Lysosomal Storage Diseases ◽  
Turnaround Time ◽  
Diagnostic Methods ◽  
Standard Group ◽  
Lysosomal Storage ◽  
Storage Diseases

Lysosomal storage diseases (LSDs) are a heterogeneous group of approximately 70 monogenic metabolic disorders whose diagnosis represents an arduous challenge for clinicians due to their variability in phenotype penetrance, clinical manifestations, and high allelic heterogeneity. In recent years, the approval of disease-specific therapies and the rapid emergence of novel rapid diagnostic methods has opened, for a set of selected LSDs, the possibility for inclusion in extensive national newborn screening (NBS) programs. Herein, we evaluated the clinical utility and diagnostic validity of a targeted next-generation sequencing (tNGS) panel (called NBS_LSDs), designed ad hoc to scan the coding regions of six genes (GBA, GAA, SMPD1, IDUA1, GLA, GALC) relevant for a group of LSDs candidate for inclusion in national NBS programs (MPSI, Pompe, Fabry, Krabbe, Niemann Pick A-B and Gaucher diseases). A standard group of 15 samples with previously known genetic mutations was used to test and validate the entire flowchart. Analytical accuracy, sensitivity, and specificity, as well as turnaround time and costs, were assessed. Results showed that the Ion AmpliSeq and Ion Chef System-based high-throughput NBS_LSDs tNGS panel is a fast, accurate, and cost-effective process. The introduction of this technology into routine NBS procedures as a second-tier test along with primary biochemical assays will allow facilitating the identification and management of selected LSDs and reducing diagnostic delay.

Electron Microscopy in the diagnosis of lysosomal storage diseases

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.

scholarly journals Sphingolipid lysosomal storage diseases: from bench to bedside

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.

Prenatal diagnosis of lysosomal storage diseases: A review of 23 cases

Pathology ◽  
1980 ◽  
Vol 12 (1) ◽  
pp. 139
Author(s):  
W.F. Carey ◽  
P.V. Nelson ◽  
A.C. Pollard
Keyword(s):  
Prenatal Diagnosis ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Storage Diseases
Sign in / Sign up

Export Citation Format

Share Document