The role of epigenetics in lysosomal storage disorders: Uncharted territory

Hassan, Shahzeb; Sidransky, Ellen; Tayebi, Nahid

doi:10.1016/j.ymgme.2017.07.012

Cited by 44 publications

(33 citation statements)

References 168 publications

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“…Non-protein coding regions such as enhancer/silencer regions and those that encode non-coding RNAs have been increasingly implicated in the pathogenesis of diseases as GWASs continue to find hits in these non-coding regions, and great effort is being placed in creating new techniques which allow study of their function (Cech & Steitz, 2014;Elkon & Agami, 2017). The contribution of epigenetics to GD and lysosomal storage disorders as a whole, has been recently reviewed (Hassan, Sidransky, & Tayebi, 2017).…”

Section: Siebert Et Al Performed a Screen Of 875 Mirna Mimics In Gaumentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.

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Section: Siebert Et Al Performed a Screen Of 875 Mirna Mimics In Gaumentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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“…Selecting appropriate candidate biomarkers has been hampered by the complexity of this monogenetic disorder, in which modifier genes, epigenetics, and external factors give rise to vast clinical and biochemical heterogeneity [ 6 , 13 , 14 , 15 , 16 , 17 ]. This phenomenon partly explains why there are such poor correlations between the GBA genotype and residual GBA activity as a diagnostic and prognostic tool [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Revel‐Vilk

Fuller

Zimran

2020

IJMS

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The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.

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“…Finally, epigenetics should be also considered in GM2 gangliosidoses. Although the role of epigenetic mechanisms in lysosomal diseases has not been well stablished, it has been proposed that these mechanisms may contribute to the clinical heterogeneity observed in these disorders [ 176 ]. However, to the best of our knowledge, no studies on this field has been performed for GM2 gangliosidoses.…”

Section: Discussionmentioning

confidence: 99%

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Leal

Benincore-Flórez

Solano-Galarza

et al. 2020

IJMS

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GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

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The role of epigenetics in lysosomal storage disorders: Uncharted territory

Cited by 44 publications

References 168 publications

Exploring genetic modifiers of Gaucher disease: The next horizon

Exploring genetic modifiers of Gaucher disease: The next horizon

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

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