Do Not Miss the (Genetic) Diagnosis of Gaucher Syndrome: A Narrative Review on Diagnostic Clues and Management in Severe Prenatal and Perinatal-Lethal Sporadic Cases

With a growing number of proved therapies and clinical trials for many lysosomal storage disorders (LSDs), a lot of hope for many patients and families exists. However, there are sometimes cases with poor prognosis, fatal outcomes when our efforts must be directed towards a prompt and correct genetic diagnosis, which offers the only possibility of providing the family with appropriate prevention and treatment. To address this issue, in this article, we present the clinical and genetic hallmarks of the lethal form of Gaucher disease (PLGD) and discuss the potential management. We hope that this will draw attention to its specific manifestations (such as collodion-baby phenotype, ichthyosis, arthrogryposis), which differ from best-known GD complications and ensure appropriate diagnostic assessment to provide families at risk with reliable counselling and treatment to avoid the medical complication of GD.

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Biomarkers in Lysosomal storage disorders with reference to Gaucher disease

Clinical Therapeutics ◽

10.1016/s0149-2918(09)00428-7 ◽

2009 ◽

Vol 31 ◽

pp. S183-S184

Author(s):

Timothy M. Cox

Keyword(s):

Gaucher Disease ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Storage Disorders

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Therapeutic strategies to ameliorate lysosomal storage disorders – a focus on Gaucher disease

Cellular and Molecular Life Sciences ◽

10.1007/s00018-005-5437-0 ◽

2006 ◽

Vol 63 (10) ◽

pp. 1179-1192 ◽

Cited By ~ 93

Author(s):

A. R. Sawkar ◽

W. D’Haeze ◽

J. W. Kelly

Keyword(s):

Gaucher Disease ◽

Therapeutic Strategies ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Storage Disorders

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Ocular Features of Treatable Lysosomal Storage Disorders—Fabry Disease, Mucopolysaccharidoses I, II and VI and Gaucher Disease

US Ophthalmic Review ◽

10.17925/usor.2007.03.00.44 ◽

2012 ◽

Vol 03 ◽

pp. 44 ◽

Cited By ~ 1

Author(s):

Ines M Lanzl ◽

Bart P Leroy ◽

◽

Keyword(s):

Fabry Disease ◽

Gaucher Disease ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Storage Disorders

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Prevention of Lysosomal Storage Diseases and Derivation of Mutant Stem Cell Lines by Preimplantation Genetic Diagnosis

Molecular Biology International ◽

10.1155/2012/797342 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Gheona Altarescu ◽

Rachel Beeri ◽

Rachel Eiges ◽

Silvina Epsztejn-Litman ◽

Talia Eldar-Geva ◽

...

Keyword(s):

Stem Cell ◽

Cell Lines ◽

Preimplantation Genetic Diagnosis ◽

Genetic Disorder ◽

Genetic Diagnosis ◽

Subsequent Development ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Stem Cell Lines ◽

Storage Disorders

Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research.

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Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease

PLoS ONE ◽

10.1371/journal.pone.0217780 ◽

2019 ◽

Vol 14 (5) ◽

pp. e0217780 ◽

Cited By ~ 5

Author(s):

Andrea N. Crivaro ◽

Juan M. Mucci ◽

Constanza M. Bondar ◽

Maximiliano E. Ormazabal ◽

Romina Ceci ◽

...

Keyword(s):

Gaucher Disease ◽

In Vitro Models ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Pentosan Polysulfate ◽

Storage Disorders

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Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders

Brain Communications ◽

10.1093/braincomms/fcaa200 ◽

2020 ◽

Author(s):

Azucena Perez-Canamas ◽

Hideyuki Takahashi ◽

Jane A Lindborg ◽

Stephen M Strittmatter

Keyword(s):

Gaucher Disease ◽

Neuronal Ceroid Lipofuscinosis ◽

Vacuolar Atpase ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Lysosomal Compartment ◽

Lysosomal Ph ◽

Ceroid Lipofuscinosis ◽

Storage Disorders

Abstract TMEM106B is a transmembrane protein localized to the endo-lysosomal compartment. Genome-wide association studies have identified TMEM106B as a risk modifier of Alzheimer’s disease and frontotemporal lobar degeneration, especially with progranulin haploinsufficiency. We recently demonstrated that TMEM106B loss rescues progranulin null mouse phenotypes including lysosomal enzyme dysregulation, neurodegeneration and behavioural alterations. However, the reason whether TMEM106B is involved in other neurodegenerative lysosomal diseases is unknown. Here, we evaluate the potential role of TMEM106B in modifying the progression of lysosomal storage disorders using progranulin-independent models of Gaucher disease and neuronal ceroid lipofuscinosis. To study Gaucher disease, we employ a pharmacological approach using the inhibitor conduritol B epoxide in wild-type and hypomorphic Tmem106b−/− mice. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in the pharmacological model of Gaucher disease, similar to its effect on certain progranulin null phenotypes. In order to examine the role of TMEM106B in neuronal ceroid lipofuscinosis, we crossbred Tmem106b−/− mice with Ppt1−/−, a genetic model of the disease. In contrast to its conduritol B epoxide-rescuing effect, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in Ppt1−/− mice. Mechanistically, TMEM106B is known to interact with subunits of the vacuolar ATPase and influence lysosomal acidification. In the pharmacological Gaucher disease model, the acidified lysosomal compartment is enhanced and TMEM106B loss rescues in vivo phenotypes. In contrast, gene-edited neuronal loss of Ppt1 causes a reduction in vacuolar ATPase levels and impairment of the acidified lysosomal compartment, and TMEM106B deletion exacerbates the mouse Ppt1−/− phenotype. Our findings indicate that TMEM106B differentially modulates the progression of the lysosomal storage disorders Gaucher disease and neuronal ceroid lipofuscinosis. The effect of TMEM106B in neurodegeneration varies depending on vacuolar ATPase state and modulation of lysosomal pH. These data suggest TMEM106B as a target for correcting lysosomal pH alterations, and in particular for therapeutic intervention in Gaucher disease and neuronal ceroid lipofuscinosis.

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FDA orphan drug designations for lysosomal storage disorders – a cross sectional analysis

10.1101/2020.01.05.20016568 ◽

2020 ◽

Author(s):

Sven F. Garbade ◽

Matthias Zielonka ◽

Konstantin Mechler ◽

Stefan Kölker ◽

Georg F. Hoffmann ◽

...

Keyword(s):

Fabry Disease ◽

Small Molecules ◽

Orphan Drug ◽

Pompe Disease ◽

Gaucher Disease ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Mps I ◽

Storage Disorders

AbstractPurposeTo provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSD’s).MethodsAssessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics.ResultsBetween 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N=16), Pompe disease (N=16), Fabry disease (N=10), MPS II (N=10), MPS I (N=9), and MPS IIIA (N=9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N=6), cystinosis (N=5), Pompe disease (N=3), and Fabry disease (N=2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSD’s (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N=23) months.ConclusionsThe development pipeline is growing and evolving into diversified small molecules and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included “me-too” – enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

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