N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice

Enzymic cleavage of beta-N-acetylglucosamine residues of keratan sulphate was studied in vitro by using substrate a [3H]glucosamine-labelled desulphated keratan sulphate with N-acetylglucosamine residues at the non-reducing end. Both lysosomal beta-N-acetylhexosaminidases A and B are proposed to participate in the degradation of keratan sulphate on the basis of the following observations. Homogenates of fibroblasts from patients with Sandhoff disease, but not those from patients with Tay–Sachs disease, were unable to release significant amounts of N-acetyl[3H]glucosamine. On isoelectric focusing of beta-N-acetylhexosaminidase from human liver the peaks of keratan sulphate-degrading activity coincided with the activity towards p-nitrophenyl beta-N-acetylglucosaminide. A monospecific antibody against the human enzyme reacted with both enzyme forms and precipitated the keratan sulphate-degrading activity. Both isoenzymes had the same apparent Km of 4mM, but the B form was approximately twice as active as the A form when compared with the activity towards a chromogenic substrate. Differences were noted in the pH–activity profiles of both isoenzymes. Thermal inactivation of isoenzyme B was less pronounced towards the polymeric substrate than towards the p-nitrophenyl derivative.

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Late onset Sandhoff disease presenting with lower motor neuron disease and stuttering

Neuromuscular Disorders ◽

10.1016/j.nmd.2021.04.011 ◽

2021 ◽

Author(s):

Jorge Alonso-Pérez ◽

Ana Casasús ◽

Álvaro Gimenez-Muñoz ◽

Jennifer Duff ◽

Ricard Rojas-Garcia ◽

...

Keyword(s):

Motor Neuron ◽

Motor Neuron Disease ◽

Late Onset ◽

Sandhoff Disease ◽

Lower Motor Neuron ◽

Lower Motor Neuron Disease

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Effect of Yuzu (Citrus junos) Seed Limonoids and Spermine on Intestinal Microbiota and Hypothalamic Tissue in the Sandhoff Disease Mouse Model

Medical Sciences ◽

10.3390/medsci9010017 ◽

2021 ◽

Vol 9 (1) ◽

pp. 17

Author(s):

Mayumi Minamisawa ◽

Takuma Suzumura ◽

Sudeep Bose ◽

Tetsuyuki Taniai ◽

Gota Kawai ◽

...

Keyword(s):

Mouse Model ◽

Intestinal Microbiota ◽

Neuronal Degeneration ◽

Sandhoff Disease ◽

Short Chain Fatty Acids ◽

Rrna Gene ◽

Wild Type ◽

Degrading Bacteria ◽

Citrus Junos ◽

Hypothalamic Tissue

The effect of limonoids and spermine (Spm) extracted from yuzu (Citrus junos) seeds on the gut and the brain in a mouse model with Sandhoff disease (SD) was investigated. Wild-type and SD mice were fed a normal diet, or a diet supplemented with limonoid, Spm, or limonoid + Spm for 14–18 weeks, and then 16S rRNA gene amplicon sequencing with extracted DNA from their feces was executed. For SD control mice, intestinal microbiota was mostly composed of Lactobacillus and linked to dysbiosis. For SD and wild-type mice fed with limonoids + Spm or limonoids alone, intestinal microbiota was rich in mucin-degrading bacteria, including Bacteroidetes, Verrucomicrobia, and Firmicutes, and displayed a higher production of short-chain fatty acids and immunoglobulin A. Additionally, SD mice fed with limonoids + Spm or limonoids alone had less inflammation in hypothalamic tissues and displayed a greater number of neurons. Administration of limonoids and/or Spm improved the proportions of beneficial intestinal microbiota to host health and reduced neuronal degeneration in SD mice. Yuzu seed limonoids and Spermine may help to maintain the homeostasis of intestinal microbiota and hypothalamic tissue in the SD mouse model.

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Two patients from Turkey with a novel variant in the GM2A gene and review of the literature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0655 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Aslı İnci ◽

Filiz Başak Cengiz Ergin ◽

Gürsel Biberoğlu ◽

İlyas Okur ◽

Fatih Süheyl Ezgü ◽

...

Keyword(s):

Sandhoff Disease ◽

Pathogenic Variant ◽

Protein Deficiency ◽

Gm2 Gangliosidosis ◽

Infantile Form ◽

Rare Form ◽

Inborn Errors ◽

Activator Protein ◽

Gm2 Activator ◽

Gm2 Activator Protein

Abstract Objectives GM2 gangliosidosis is a rare form of inborn errors of metabolism including Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. GM2 activator protein deficiency is an ultra-rare form of GM2 gangliosidosis. To date, 16 cases of GM2 activator protein deficiency have been reported in the literature, and among them, 11 cases were the infantile form of the disease. Here we report the first two patients from Turkey with the infantile form of the disease with a novel likely pathogenic variant. Case presentation A boy of eight months old presented to the metabolic department with very mild neurological deterioration, although he had achieved early developmental milestones at the appropriate time. The parents also had a daughter who had lost skills progressively before one year of age. The boy was evaluated and bilateral cherry-red spots were found with no abnormality in either metabolic screening including β-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant in GM2A was detected in a next-generation sequence panel revealing GM2 activator protein deficiency. His sister was investigated after he was diagnosed with GM2 activator deficiency and it was found that she had the same variant as her brother. Conclusions This case report emphasizes that in the event of normal β-hexosaminidase activity, GM2 activator protein deficiency could be underdiagnosed, and further molecular analysis should be performed. To the best of our knowledge, this boy is one of the youngest patient diagnosed with very mild symptoms. With this novel pathogenic variant, these patients have expanded the mutation spectrum of GM2 activator protein deficiency.

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Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Journal of Clinical Medicine ◽

10.3390/jcm9041050 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1050 ◽

Cited By ~ 3

Author(s):

Ecem Kaya ◽

David A. Smith ◽

Claire Smith ◽

Barry Boland ◽

Michael Strupp ◽

...

Keyword(s):

Mouse Model ◽

Sandhoff Disease ◽

Lysosomal Storage ◽

Gm2 Ganglioside ◽

Beneficial Effects ◽

New Therapeutic Approaches ◽

Late Endosomes ◽

Altered Glucose ◽

Cerebellar Ataxias ◽

Niemann Pick

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

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