Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

2019 ◽  
Vol 98 (4) ◽  
pp. 718-733 ◽  
Author(s):  
Claudia Landi ◽  
Alice Luddi ◽  
Laura Bianchi ◽  
Giovanna Pannuzzo ◽  
Valentina Pavone ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lysosomal Storage Disorders ◽  
Krabbe Disease ◽  
Lysosomal Storage ◽  
Storage Disorders

scholarly journals Newborn Screening of Lysosomal Storage Disorders

2010 ◽  
Vol 56 (7) ◽  
pp. 1071-1079 ◽  
Author(s):  
Deborah Marsden ◽  
Harvey Levy
Keyword(s):  
Newborn Screening ◽  
Screening Method ◽  
Lysosomal Storage Disorders ◽  
Krabbe Disease ◽  
Lysosomal Storage ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Mucopolysaccharidosis I ◽  
Technological Advances ◽  
Storage Disorders

Abstract Background: Newborn screening is a state-based public health program established as a means for the early detection and treatment of certain medical conditions to minimize developmental disability and mortality. The program was initiated more than 40 years ago to detect and prevent phenylketonuria. Recent technological advances have expanded the scope of newborn screening to include more than 30 inborn errors of metabolism. Consideration is now being given to inclusion of screening for lysosomal storage disorders (LSDs). Content: Some lysosomal storage disorders (LSDs) express early in infancy or childhood and are treatable. Initiation of treatment in presymptomatic patients or in syptomatic patients before important symptoms are present may improve the long-term outcome. Therefore, early diagnosis is critical. Based on the availability of therapy and development of a screening method, 6 of the more than 40 known LSDs are candidates for newborn screening in the US: Gaucher disease, Pompe disease, Fabry disease, Niemann-Pick disease, mucopolysaccharidosis I, and Krabbe disease. This report reviews the history of newborn screening, the technology that has allowed for expanded screening during the last decade, LSDs and their treatment, and the evolving methods that might allow additional expansion of newborn screening to include certain LSDs. Summary: Recent and evolving technological advances may be implemented for newborn screening for LSDs. This screening will identify presymptomatic newborns, allowing for early treatment and prevention or limitation of morbidity otherwise associated with these inherited rare diseases.

scholarly journals Simplified Newborn Screening Protocol for Lysosomal Storage Disorders

2011 ◽  
Vol 57 (9) ◽  
pp. 1286-1294 ◽  
Author(s):  
Thomas F Metz ◽  
Thomas P Mechtler ◽  
Joseph J Orsini ◽  
Monica Martin ◽  
Bori Shushan ◽  
...  
Keyword(s):  
Sample Preparation ◽  
Lysosomal Enzyme ◽  
Enzyme Activities ◽  
Solid Phase ◽  
New York State ◽  
Lysosomal Storage Disorders ◽  
Krabbe Disease ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Storage Disorders

BACKGROUND Interest in lysosomal storage disorders, a collection of more than 40 inherited metabolic disorders, has increased because of new therapy options such as enzyme replacement, stem cell transplantation, and substrate reduction therapy. We developed a high-throughput protocol that simplifies analytical challenges such as complex sample preparation and potential interference from excess residual substrate associated with previously reported assays. METHODS After overnight incubation (16–20 h) of dried blood spots with a cassette of substrates and deuterated internal standards, we used a TLX-2 system to quantify 6 lysosomal enzyme activities for Fabry, Gaucher, Niemann-Pick A/B, Pompe, Krabbe, and mucopolysaccharidosis I disease. This multiplexed, multidimensional ultra-HPLC–tandem mass spectrometry assay included Cyclone P Turbo Flow and Hypersil Gold C8 columns. The method did not require offline sample preparation such as liquid–liquid and solid-phase extraction, or hazardous reagents such as ethyl acetate. RESULTS Obviating the offline sample preparation steps led to substantial savings in analytical time (approximately 70%) and reagent costs (approximately 50%). In a pilot study, lysosomal enzyme activities of 8586 newborns were measured, including 51 positive controls, and the results demonstrated 100% diagnostic sensitivity and high specificity. The results for Krabbe disease were validated with parallel measurements by the New York State Screening Laboratory. CONCLUSIONS Turboflow online sample cleanup and the use of an additional analytical column enabled the implementation of lysosomal storage disorder testing in a nationwide screening program while keeping the total analysis time to <2 min per sample.

scholarly journals Potential resistance to SARS-CoV-2 infection in lysosomal storage disorders

2021 ◽  
Author(s):  
Maurizio Pieroni ◽  
Federico Pieruzzi ◽  
Renzo Mignani ◽  
Francesca Graziani ◽  
Iacopo Olivotto ◽  
...  
Keyword(s):  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

scholarly journals Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria De Risi ◽  
Michele Tufano ◽  
Filomena Grazia Alvino ◽  
Maria Grazia Ferraro ◽  
Giulia Torromino ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Sch 23390 ◽  
Lysosomal Storage Disorders ◽  
Dopamine Neurons ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Cellular Models ◽  
Mps Ii ◽  
Mps Iiia ◽  
Storage Disorders

AbstractLysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

Lysosomal Storage Disorders as an Etiology of Nonimmune Hydrops Fetalis: A Systematic Review

2021 ◽  
Author(s):  
Neel S. Iyer ◽  
Alexis C. Gimovsky ◽  
Carlos R. Ferreira ◽  
Elizabeth J. Critchlow ◽  
Huda B. Al‐kouatly
Keyword(s):  
Systematic Review ◽  
Lysosomal Storage Disorders ◽  
Hydrops Fetalis ◽  
Lysosomal Storage ◽  
Nonimmune Hydrops ◽  
Storage Disorders

scholarly journals A charitable access program for patients with lysosomal storage disorders in underserved communities worldwide

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Atul Mehta ◽  
Uma Ramaswami ◽  
Joseph Muenzer ◽  
Roberto Giugliani ◽  
Kurt Ullrich ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Clinical Manifestations ◽  
Lysosomal Storage Disorders ◽  
Expert Committee ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Access Program ◽  
Storage Disorders

Abstract Background Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs. Methods The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company. Results As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year. Conclusions The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.

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