Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience

Fischetto, Rita; Palladino, Valentina; Mancardi, Maria Margherita; Giacomini, Thea; Palladino, Stefano; Gaeta, Alberto; Rocco, Maja Di; Zampini, Lucia; Lassandro, Giuseppe; Favia, Vito; Tripaldi, Maria E; Strisciuglio, Pietro; Romano, Alfonso; Severino, Mariasavina; Morrone, Amelia; Giordano, Paola

doi:10.1002/mgg3.1371

Cited by 21 publications

(14 citation statements)

References 53 publications

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“…Miglustat showed efficacy in correcting some clinical and biochemical parameters in Gaucher disease patients (Cox, 2005; Charrow & Scott, 2015). For its effect on this early step of the glycosphingolipid biosynthetic pathway, Miglustat has also been proposed for the treatment of GM1 and GM2 gangliosidoses, with a slowed disease progression (Poswar et al , 2019; Fischetto et al , 2020), and is approved for the treatment Niemann‐Pick disease type, in which gangliosides GM2, GM3 gangliosides, and other glycosphingolipids play a role in the pathogenesis of neurological manifestations (Zervas et al , 2001). Other substrate‐reducing molecules are now in clinical development or approved for the treatment of Gaucher and Fabry disease, such as eliglustat tartrate, venglustat, and lucerastat (Felis et al , 2019; Poswar et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

The rapidly evolving view of lysosomal storage diseases

2021

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Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic‐lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high‐throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

The rapidly evolving view of lysosomal storage diseases

2021

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“…Deodato et al (2017) described similar neurological improvement in the juvenile form of the disease (Deodato et al, 2017). Stabilization and/or slowing of neurological progression in three of four patients was observed by Fischetto et al (2020).…”

Section: Substrate Reduction Therapymentioning

confidence: 72%

GM1 Gangliosidosis—A Mini-Review

et al. 2021

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GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).

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“…Miglustat administration in four children (20-125 months) from Italy affected by the GM1 gangliosidosis type I was safe and relatively well tolerated. Three children had stabilized and/or slowed down neurological progression [42].…”

Section: Substrate Reduction Therapymentioning

confidence: 98%

GLB1-related disorders: GM1 gangliosidosis and Morquio B disease

Cho

Jin

2021

J Genet Med

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GLB1-related disorders comprise two phenotypically unique disorders: GM1 gangliosidosis and Morquio B disease. These autosomal recessive disorders are caused by b-galactosidase deficiency. A hallmark of GM1 gangliosidosis is central nervous system degeneration where ganglioside synthesis is highest. The accumulation of keratan sulfate is the suspected cause of the bone findings in Morquio B disease. GM1 gangliosidosis is clinically characterized by a neurodegenerative disorder associated with dysostosis multiplex, while Morquio B disease is characterized by severe skeletal manifestations and the preservation of intelligence. Morquio B disease and GM1 gangliosidosis may be on a continuum of skeletal involvement. There is currently no effective treatment for GLB1-related disorders. Recently, multiple interventions have been developed and there are several ongoing clinical trials.

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Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 21 publications

References 53 publications

The rapidly evolving view of lysosomal storage diseases

The rapidly evolving view of lysosomal storage diseases

GM1 Gangliosidosis—A Mini-Review

GLB1-related disorders: GM1 gangliosidosis and Morquio B disease

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