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Journal of Lipid Research Dec 2023
Topics: Humans; Lysosomal Storage Diseases; Lipids; Lysosomes
PubMed: 37972730
DOI: 10.1016/j.jlr.2023.100476 -
Movement Disorders : Official Journal... May 2019Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal-recessive or X-linked genetic syndromes caused by disruption of lysosomal biogenesis...
Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal-recessive or X-linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult-onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society.
Topics: Adult; Child; Galactosylceramidase; Gaucher Disease; Glucosylceramidase; Humans; Leukodystrophy, Globoid Cell; Lysosomal Storage Diseases; Mucopolysaccharidosis III; Mutation; Neuronal Ceroid-Lipofuscinoses; Niemann-Pick Diseases; Parkinson Disease; Parkinsonian Disorders; Phenotype; Proton-Translocating ATPases; Sandhoff Disease; Sphingomyelin Phosphodiesterase
PubMed: 30726573
DOI: 10.1002/mds.27631 -
Gene Therapy Apr 2021Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that...
Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside. Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV-gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV-gene therapy for human SD.
Topics: Animals; Cats; Dependovirus; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Humans; Sandhoff Disease; beta-N-Acetylhexosaminidases
PubMed: 32884151
DOI: 10.1038/s41434-020-00190-1 -
Polish Journal of Radiology 2016Sandhoff disease is an autosomal recessive disorder caused by β-hexosaminidase deficiency in which the ganglioside GM2 and other glycolipids accumulate intracellularly...
BACKGROUND
Sandhoff disease is an autosomal recessive disorder caused by β-hexosaminidase deficiency in which the ganglioside GM2 and other glycolipids accumulate intracellularly within lysosomes. This process results in progressive motor neuron manifestations, death from respiratory failure and infections in infantiles.
CASE REPORT
This report presents a 22-month-old girl with infantile type Sandhoff disease that was hospitalized for generalized seizures and psychomotor retardation. She was diagnosed with a genetically proven novel mutation and by demonstrating it's specific imaging findings.
CONCLUSIONS
Determination of spesific changes in neuroimaging which are initial findings for GM2 gangliosidosis is important from the point of diagnosis and follow-up in infants suspected of having a neurodegenerative disease.
PubMed: 26985245
DOI: 10.12659/PJR.895911 -
Genetics in Medicine : Official Journal... Dec 2022Gangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental...
PURPOSE
Gangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay, and regression, leading to significant morbidity and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies.
METHODS
Single disease registry of 8 gangliosidoses (NCT04624789). Cross-sectional analysis of baseline data in N = 26 patients. Primary end point: disease severity assessed by the 8-in-1 score. Secondary end points: first neurologic sign or symptom observed (1) by parents and (2) by physicians, diagnostic delay, as well as phenotypical characterization. Tertiary end points: neurologic outcomes (development, ataxia, dexterity) and disability.
RESULTS
The 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 (interquartile range 0.69-6.25) years. In total, 8 patients presented with late-infantile phenotypes.
CONCLUSION
Data in this registry raise awareness of these rare and fatal conditions to accelerate diagnosis, inform counseling of afflicted families, define quantitative end points for clinical trials, and can serve as historical controls for future therapeutic studies. We provide further insight into the rare late-infantile phenotype for G-gangliosidosis. Longitudinal follow up is planned.
Topics: Humans; Cross-Sectional Studies; Gangliosidoses, GM2; Delayed Diagnosis; Gangliosidoses; Registries; Tay-Sachs Disease
PubMed: 36194207
DOI: 10.1016/j.gim.2022.09.001 -
Journal of Lipid Research Jun 2019The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs...
The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis), with GM2 as the major lysosomal storage compound. GM2 is also a secondary storage compound in lysosomal storage diseases such as Niemann-Pick disease types A-C, with primary storage of SM in type A and cholesterol in types B and C, respectively. The reconstitution of GM2 catabolism at liposomal surfaces carrying GM2 revealed that incorporating lipids into the GM2-carrying membrane such as cholesterol, SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by β-hexosaminidase A assisted by GM2 activator protein, while anionic lipids, ceramide, fatty acids, lysophosphatidylcholine, and diacylglycerol stimulate GM2 catabolism. In contrast, the hydrolysis of the synthetic, water-soluble substrate 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-d-glucopyranoside was neither significantly affected by membrane lipids such as ceramide or SM nor stimulated by anionic lipids such as bis(monoacylglycero)phosphate added as liposomes, detergent micelles, or lipid aggregates. Moreover, hydrolysis-inhibiting lipids also had an inhibiting effect on the solubilization and mobilization of membrane-bound lipids by the GM2 activator protein, while the stimulating lipids enhanced lipid mobilization.
Topics: Cholesterol; G(M2) Activator Protein; G(M2) Ganglioside; Gangliosides; Humans; Liposomes; Lysophospholipids; Membrane Lipids; Monoglycerides; Niemann-Pick Diseases; Sphingolipids; Sphingomyelins; Sphingosine; Stearic Acids
PubMed: 30988135
DOI: 10.1194/jlr.M092551 -
Biochimica Et Biophysica Acta.... Feb 2019GM2-gangliosidosis, a subgroup of lysosomal storage disorders, is caused by deficiency of hexosaminidase activity, and comprises the closely related Tay-Sachs and...
GM2-gangliosidosis, a subgroup of lysosomal storage disorders, is caused by deficiency of hexosaminidase activity, and comprises the closely related Tay-Sachs and Sandhoff diseases. The enzyme deficiency prevents normal metabolization of ganglioside GM2, usually resulting in progressive neurodegenerative disease. The molecular mechanisms whereby GM2 accumulation in neurons triggers neurodegeneration remain unclear. In vitro experiments, using microsomes from Sandhoff mouse model brain, showed that increase of GM2 content negatively modulates sarco/endoplasmic reticulum Ca-ATPase (SERCA) (Pelled et al., 2003). Furthermore, Ca depletion in endoplasmic reticulum (ER) triggers Unfolded Protein Response (UPR), which tends to restore homeostasis in the ER; however, if cellular damage persists, an apoptotic response is initiated. We found that ER GM2 accumulation in cultured neurons induces luminal Ca depletion, which in turn activates PERK (protein kinase RNA [PKR]-like ER kinase), one of three UPR sensors. PERK signaling displayed biphasic activation; i.e., early upregulation of cytoprotective calcineurin (CN) and, under prolonged ER stress, enhanced expression of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Moreover, GM2 accumulation in neuronal cells induced neurite atrophy and apoptosis. Both processes were effectively modulated by treatment with the selective PERK inhibitor GSK2606414, by CN knockdown, and by CHOP knockdown. Overall, our findings demonstrate the essential role of PERK signaling pathway contributing to neurodegeneration in a model of GM2-gangliosidosis.
Topics: Adenine; Animals; Apoptosis; Atrophy; Cell Line, Tumor; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; G(M2) Ganglioside; Gangliosidoses, GM2; Indoles; Mice; Neurites; Neurodegenerative Diseases; Neurons; Signal Transduction; Transcription Factor CHOP; Unfolded Protein Response; eIF-2 Kinase
PubMed: 30389374
DOI: 10.1016/j.bbamcr.2018.10.014 -
International Journal of Molecular... Apr 2023The Unfolded protein response (UPR), triggered by stress in the endoplasmic reticulum (ER), is a key driver of neurodegenerative diseases. GM2 gangliosidosis, which...
The Unfolded protein response (UPR), triggered by stress in the endoplasmic reticulum (ER), is a key driver of neurodegenerative diseases. GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff disease, is caused by an accumulation of GM2, mainly in the brain, that leads to progressive neurodegeneration. Previously, we demonstrated in a cellular model of GM2 gangliosidosis that PERK, a UPR sensor, contributes to neuronal death. There is currently no approved treatment for these disorders. Chemical chaperones, such as ursodeoxycholic acid (UDCA), have been found to alleviate ER stress in cell and animal models. UDCA's ability to move across the blood-brain barrier makes it interesting as a therapeutic tool. Here, we found that UDCA significantly diminished the neurite atrophy induced by GM2 accumulation in primary neuron cultures. It also decreased the up-regulation of pro-apoptotic CHOP, a downstream PERK-signaling component. To explore its potential mechanisms of action, in vitro kinase assays and crosslinking experiments were performed with different variants of recombinant protein PERK, either in solution or in reconstituted liposomes. The results suggest a direct interaction between UDCA and the cytosolic domain of PERK, which promotes kinase phosphorylation and dimerization.
Topics: Animals; Atrophy; Gangliosidoses, GM2; Neurites; Sandhoff Disease; Ursodeoxycholic Acid; eIF-2 Kinase
PubMed: 37108372
DOI: 10.3390/ijms24087209 -
Trials Jan 2021The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new...
A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.
BACKGROUND
The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T).
METHODS/DESIGN
The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase.
DISCUSSION
The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases.
TRIAL REGISTRATION
The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).
Topics: Ataxia Telangiectasia; Female; Gangliosidoses, GM2; Humans; Leucine; Male; Neurodegenerative Diseases; Quality of Life
PubMed: 33482890
DOI: 10.1186/s13063-020-05009-3 -
BMC Pediatrics Jul 2016GM2 gangliosidosis-AB variants a rare autosomal recessive neurodegenerative disorder occurring due to deficiency of GM2 activator protein resulting from the mutation in... (Review)
Review
BACKGROUND
GM2 gangliosidosis-AB variants a rare autosomal recessive neurodegenerative disorder occurring due to deficiency of GM2 activator protein resulting from the mutation in GM2A gene. Only seven mutations in nine cases have been reported from different population except India.
CASE PRESENTATION
Present case is a one year old male born to 3rd degree consanguineous Indian parents from Maharashtra. He was presented with global developmental delay, hypotonia and sensitive to hyperacusis. Horizontal nystagmus and cherry red spot was detected during ophthalmic examination. MRI of brain revealed putaminal hyperintensity and thalamic hypointensity with some unmyelinated white matter in T2/T1 weighted images. Initially he was suspected having Tay-Sachs disease and finally diagnosed as GM2 gangliosidosis, AB variant due to truncated protein caused by nonsense mutation c.472 G > T (p.E158X) in GM2Agene.
CONCLUSION
Children with phenotypic presentation as GM2 gangliosidosis (Tay-Sachs or Sandhoff disease) and normal enzyme activity of β-hexosaminidase-A and -B in leucocytes need to be investigated for GM2 activator protein deficiency.
Topics: Codon, Nonsense; G(M2) Activator Protein; Genetic Markers; Genetic Testing; Humans; Infant; Male; Tay-Sachs Disease, AB Variant
PubMed: 27402091
DOI: 10.1186/s12887-016-0626-6