Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations

Tavasoli, Ali Reza; Parvaneh, Nima; Ashrafi, Mahmoud Reza; Rezaei, Zahra; Zschocke, Johannes; Rostami, Parastoo

doi:10.1186/s13023-018-0876-5

Cited by 19 publications

(22 citation statements)

References 17 publications

(24 reference statements)

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“…Upon activation, astrocyte secretes the chemokines CCL2 and CXCL10 which is consistent with a robust microglial activation as wells as an invasion of peripheral immune cells. It could allow the degeneration of myelinating oligodendrocytes and its death, promoting active demyelination [89,90], which is frequently observed in infantile forms of GM2 gangliosidosis [4,91,92]. Together, these findings highlight the pivotal interplay between microglia and astrocytes in the inflammatory response observed in the GM2 gangliosidosis, which could be the functional consequence of neuronal injury due to GM2 ganglioside accumulation contributing to the neurodegenerative process.…”

Section: Neural Death and Neuroinflammationmentioning

confidence: 84%

“…Using this approach, the authors found that ICV administration of the chimeric enzyme on SD mice allowed a significant reduction of GM2 ganglioside in the brain (77%) and cerebellum (57%), compared to untreated SD mice. Likewise, a 2-fold increase in Hex activity and a marked reduction of GM2 ganglioside was observed in liver; which could have a Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 July 2020 doi:10.20944/preprints202007.0137.v1 significant impact on the disease [111], since, unlike to TSD, hepatosplenomegaly can be found in SD patients [92].…”

Section: Current Proposals For the Treatment Of Gm2 Gangliosidosismentioning

confidence: 99%

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GM2 Gangliosidosis: Clinical Features and Current Therapies

Leal¹,

Benincore-Flórez²,

Solano-Galarza³

et al. 2020

Preprint

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GM2 gangliosidosis 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 gangliosidosis have been described: Tay-Sachs disease, Sandhoff disease, and AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidosis patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidosis, 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 gangliosidosis, 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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Section: Neural Death and Neuroinflammationmentioning

confidence: 84%

Section: Current Proposals For the Treatment Of Gm2 Gangliosidosismentioning

confidence: 99%

GM2 Gangliosidosis: Clinical Features and Current Therapies

Leal¹,

Benincore-Flórez²,

Solano-Galarza³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Upon activation, astrocyte secretes the chemokines CCL2 and CXCL10, which correlates with a robust microglial activation and the invasion of peripheral immune cells. This astrocytes activation could lead to degeneration and death of myelinating oligodendrocytes, promoting active demyelination [ 84 , 85 ], which is frequently observed in infantile forms of GM2 gangliosidoses [ 4 , 86 , 87 ]. Together, these findings highlight the pivotal interplay between microglia and astrocytes in the inflammatory response observed in GM2 gangliosidoses, which could be the functional consequence of neuronal injury due to GM2 ganglioside accumulation and that may contribute to the neurodegenerative process.…”

Section: Physiopathology Of Gm2 Gangliosidosesmentioning

confidence: 99%

“…This approach, led to a significant reduction of GM2 ganglioside in the brain and cerebellum and a 2-fold increase in Hex activity. Noteworthy, a marked reduction of GM2 ganglioside was also observed in liver; which could have a significant impact on the disease, since hepatosplenomegaly is a common clinical finding of SD patients [ 87 ]. Together, these results suggest that ICV ERT is a potential strategy for the treatment of GM2 gangliosidoses and that N-glycans modifications may have a positive effect on enzyme uptake, biodistribution, and substrate reduction throughout the brain.…”

Section: Current Proposals For the Treatment Of Gm2 Gangliosidosesmentioning

confidence: 99%

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

Leal

Benincore-Flórez

Solano-Galarza

et al. 2020

IJMS

View full text Add to dashboard Cite

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 blood samples from patient was collected and spotted on filter paper and placed in 3 mm diameter. After addition of elution liquid and substrate solution then incubate of the samples at 37°C , the enzyme activity quantified by comparing the amount of hydrolyzed product with a calibrator [17] [18].…”

Section: β-Hexosaminidase Activity Assaymentioning

confidence: 99%

Novel homozygous HEXB mutation identified in a consanguineous Iranian pedigree with Sandhoff disease

Rahmani

Banisadr

Ghodsinezhad

et al. 2020

Preprint

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Background Sandhoff disease is a rare neurodegenerative and autosomal recessive disorder, characterized by a defect in ganglioside metabolism. It is caused by mutations in the HEXB gene for the β-subunit of β-N-acetyl hexosaminidase. Results In the present study, an Iranian 14- month -old girl with an 8- month history of unsteady walking and involuntary movements is described. Biochemical testing showed defects in the normal activity of beta-hexosaminidase protein. Following sequencing of HEXB gene, a novel homozygous p.A278V mutation was identified in the patient’s DNA. Conclusions The p.A278V mutation is pathogenic because of amino acid change and changing in biochemical activity. this mutation has not been reported previously, but based on In silico analysis and structural analysis, was predicted to be disease causing.

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Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations

Cited by 19 publications

References 17 publications

GM2 Gangliosidosis: Clinical Features and Current Therapies

GM2 Gangliosidosis: Clinical Features and Current Therapies

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

Novel homozygous HEXB mutation identified in a consanguineous Iranian pedigree with Sandhoff disease

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