Therapeutic Strategies For Tay-Sachs Disease

Picache, Jaqueline A.; Zheng, Wei; Chen, Catherine Z.

doi:10.3389/fphar.2022.906647

Cited by 19 publications

(8 citation statements)

References 99 publications

(168 reference statements)

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“…With now a growing number of therapeutic approaches for GM2 gangliosidoses on the horizon (e.g., 2 gene therapy trials [NCT04669535 and NCT04798235]), 7,8,13-16 an accurate stratification of disease course and phenotypic progression clusters is now no longer only a conceptual effort but indeed a prerequisite to identify the window of opportunity for therapies and to inform promising trial designs. The lack of clarity and consistence in classification of GM2 gangliosidoses interferes with both efficient trial designs and appropriate selection of patients for clinical trial cohorts, particularly as early start of treatment is the key for clinical efficacy of disease-modifying therapies in neurometabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis

Kern,

Böhringer,

Timmann

et al. 2024

Neurology

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Background and Objectives GM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from β-hexosaminidase (HEX) deficiency with GM2 ganglioside as its main substrate. Historically, GM2 gangliosidoses have been classified into infantile, juvenile, and late-onset forms. With disease-modifying treatment trials now on the horizon, a more fine-grained understanding of the disease course is needed. Methods We aimed to map and stratify the clinical course of GM2 gangliosidoses in a multicenter cohort of pediatric and adult patients. Patients were stratified according to age at onset and age at diagnosis. The 2 resulting GM2 disease clusters were characterized in-depth for respective disease features (detailed standardized clinical, laboratory, and MRI assessments) and disease evolution. Results In 21 patients with GM2 gangliosidosis (17 Tay-Sachs, 2 GM2 activator deficiency, 2 Sandhoff disease), 2 disease clusters were discriminated: an early-onset and early diagnosis cluster (type I; n = 8, including activator deficiency and Sandhoff disease) and a cluster with very variable onset and long interval until diagnosis (type II; n = 13 patients). In type I, rapid onset of developmental stagnation and regression, spasticity, and seizures dominated the clinical picture. Cherry red spot, startle reactions, and elevated AST were only seen in this cluster. In type II, problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms were specific and frequent symptoms. Ocular signs were common, including supranuclear vertical gaze palsy in 30%. MRI involvement of basal ganglia and peritrigonal hyperintensity was seen only in type I, whereas predominant infratentorial atrophy (or normal MRI) was characteristic in type II. These types were, at least in part, associated with certain genetic variants. Discussion Age at onset alone seems not sufficient to adequately predict different disease courses in GM2 gangliosidosis, as required for upcoming trial planning. We propose an alternative classification based on age at disease onset and dynamics, predicted by clinical features and biomarkers, into type I—an early-onset, rapid progression cluster—and type II—a variable onset, slow progression cluster. Specific diagnostic workup, including GM2 gangliosidosis, should be performed in patients with combined ataxia plus lower motor neuron weakness to identify type II patients.

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Section: Introductionmentioning

confidence: 99%

Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis

Kern,

Böhringer,

Timmann

et al. 2024

Neurology

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“…Public awareness about Tay-Sachs disease and continued research into novel therapeutic interventions is essential. Advances such as gene therapy and enzyme replacement therapy are promising avenues that could transform the management of this disease, making them more broadly available to the public [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Infantile Monosialoganglioside2 (GM2) Gangliosidosis With Concurrent Bronchopneumonia: An Extraordinary Case of Tay-Sachs Disease

Grezenko,

Al-Deir,

Eshete

et al. 2024

Cureus

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Tay-Sachs disease (TSD) is a rare, fatal neurodegenerative disorder characterized by the deficiency of the enzyme hexosaminidase-A (Hex A), which results in the accumulation of monosialoganglioside2 (GM2) ganglioside within nerve cells, predominantly affecting individuals of Ashkenazi Jewish descent. We report a remarkable case of a three-year-old South Asian male with infantile GM2 gangliosidosis, compounded by bronchopneumonia, a rarely documented complication in Tay-Sachs patients. The patient presented with recurrent seizures, fever, cough, and developmental delay. Confirmation of the diagnosis was obtained through reduced Hex A enzyme activity, corroborated by imaging and blood and urine analyses. Family history was significant for consanguinity and similar sibling fatalities. Despite the progressive nature of the disease, symptomatic management, including antiepileptic drugs, antibiotic therapy, and supportive care, led to an improvement in clinical condition, though ongoing monitoring remains essential. In this case, the coexistence of bronchopneumonia with Tay-Sachs disease is unusual, reflecting the necessity for this case report. The patient's response highlights the potential for symptomatic management, the importance of genetic counseling, and the imperative for research into gene and enzyme replacement therapies. The uniqueness of this case provides novel insights into the disease's spectrum, enhancing awareness, encouraging early diagnosis, and refining care strategies for Tay-Sachs disease, aligning with the broader goals of improving patient outcomes and advancing medical research.

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“…Ganglioside dysregulation is observed in several lysosomal storage disorders diseases, including Tay Sach's disease (Platt et al, 2018). The imino sugars used here have been developed in the context of research focused on providing help to patients with such diseases (Picache et al, 2022). Altered ganglioside patterns are also found in the aging brain as well as in several neurodegenerative injuries and diseases such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease (Ariga et al, 2008; Sipione et al, 2020; Yamashita et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Use of metabolic glycoengineering and pharmacological inhibitors to assess lipid and protein sialylation on cells

Kranaster

Blum

Dold

et al. 2022

Journal of Neurochemistry

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Therapeutic Strategies For Tay-Sachs Disease

Cited by 19 publications

References 99 publications

Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis

Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis

Infantile Monosialoganglioside2 (GM2) Gangliosidosis With Concurrent Bronchopneumonia: An Extraordinary Case of Tay-Sachs Disease

Use of metabolic glycoengineering and pharmacological inhibitors to assess lipid and protein sialylation on cells

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