Materiały źródłowe

• #1 Tay-Sachs Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/29887

  Tay-Sachs disease is a progressive, lethal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase-A that results in the accumulation of GM2 gangliosides. […] Tay-Sachs disease belongs to a group of autosomal recessively inherited lysosomal storage disorders called GM2 gangliosidoses. GM2 gangliosides accumulate inside lysosomes, primarily affecting the nervous system and resulting in neuronal dysfunction and neurodegeneration. […] Tay-Sachs disease is an autosomal recessive disorder caused by a mutation in HEXA, which encodes the enzymes beta-hexosaminidase A. HEXA is located at 15q23. More than 130 mutations have been identified, including single gene deletions, substitution, insertion splicing alteration, duplication, and complex gene rearrangements. […] Tay-Sachs disease is caused by beta-hexosaminidase A (Hex A) deficiency, responsible for GM2 ganglioside degradation. Alpha and beta subunits of Hex A are synthesized at the endoplasmic reticulum. The enzyme is transported to the Golgi network following glycosylation, intramolecular disulfide bond formation, and dimerization in the endoplasmic reticulum. The most important step is posttranslational modification of the enzyme with mannose-6-phosphate, which helps the lysosome recognize the enzyme. The presentation of GM2 ganglioside to the active site of Hex A requires an activator protein GM2A, which makes the enzyme lipophilic.

• #2 Tay-Sachs disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/tay-sachs-disease/

  Tay-Sachs disease is a rare, inherited disorder that is characterized by neurological problems caused by the death of nerve cells (neurons) in the brain and spinal cord (central nervous system). […] Variants in the HEXA gene cause Tay-Sachs disease. The HEXA gene provides instructions for making one part (the alpha subunit) of an enzyme called beta-hexosaminidase A. Beta-hexosaminidase A is located in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside found in cell membranes. […] HEXA gene variants affect the ability of the beta-hexosaminidase A enzyme to break down GM2 ganglioside. As a result, GM2 ganglioside accumulates to toxic levels, particularly in neurons in the central nervous system. Damage caused by the buildup of GM2 ganglioside leads to the dysfunction and eventual death of these neurons, which causes the signs and symptoms of Tay-Sachs disease. […] Because Tay-Sachs disease impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.

• #3 Orphanet: Tay-Sachs disease

  https://www.orpha.net/en/disease/detail/845

  A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A deficiency as a consequence of biallelic pathogenic variants in the HEXA gene. […] The causative gene HEXA encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23). […] When Tay-Sachs is suspected, hexosaminidase A enzymatic activity on blood leukocytes is always very low compared to normal values (around 0% for the severe infantile form, around 10-15% for the late-onset form). This should be confirmed by HEXA gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome, and should be confirmed by hexosaminidase A enzymatic activity measurement. […] There is no specific efficient treatment for Tay-Sachs disease. Treatment is symptomatic.

• #4 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Tay-Sachs-Disease-Pathophysiology.aspx

  Tay-Sachs Disease is a progressive and fatal genetic condition that involves a complete deficiency of the hexosaminidase-A (HEXA) enzyme. This enzyme is needed in healthy individuals for the process of hydrolysis of GM2 ganglioside to occur. For individuals with Tay-Sachs disease that lack this enzyme, the fatty substance of GM2 ganglioside accumulates in the brain and leads to the symptoms of the disease. […] The hydrolytic HEXA enzyme usually plays an essential role in the process to break down glycolipids in the lysosomes. Alongside other enzymes, it is responsible for the breakdown of specific fatty acid derivatives known as gangliosides. […] It is the absence of the alpha subunit, known as HEXA, that plays a particularly important role in the pathophysiology of Tay-Sachs disease. […] In the absence of the HEXA enzyme, the natural hydrolysis reaction of the gangliosides cannot occur as normal. This can lead to an accumulation of the lipids in the brain, central nervous system and the retina of the eyes. […] The build-up of gangliosides in the neurons disrupts the normal physiological processes and leads to the presentation of symptoms of Tay-Sachs disease.

• #5 Tay-Sachs disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/tay-sachs-disease/symptoms-causes/syc-20378190

  Tay-Sachs disease is a rare genetic disorder passed from parents to child. It’s caused by the absence of an enzyme that helps break down fatty substances. These fatty substances, called gangliosides, build up to toxic levels in the brain and spinal cord and affect the function of the nerve cells. […] The genetic change that causes Tay-Sachs disease results in a deficiency of the enzyme beta-hexosaminidase A. This enzyme is required to break down the fatty substance GM2 ganglioside. The buildup of fatty substances damages nerve cells in the brain and spinal cord. Severity and age of onset of the disease relates to how much enzyme is still produced.

• #6 Tay-Sachs Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK564432/

  Tay-Sachs disease is a fatal, inherited neurodegenerative disorder caused by a deficiency in the enzyme hexosaminidase-A, leading to progressive neuronal damage. […] Tay-Sachs disease is caused by beta-hexosaminidase A (Hex A) deficiency, responsible for GM2 ganglioside degradation. […] The most important step is posttranslational modification of the enzyme with mannose-6-phosphate, which helps the lysosome recognize the enzyme. […] However, deficiency of Hex A causes an accumulation of the gangliosides up to toxic levels, especially in the neurons. While it is clear that the accumulation of ganglioside is the cause, the exact mechanism that translates the primary insult into neuronal death is unclear. […] Progressive neurodegeneration, microglia proliferation, and accumulation of the complex lipids in neuronal macrophages occur. […] Other pathological processes in the disease include abnormal endosomal transport, impaired autophagy, progressive accumulation of alpha-synuclein, and anti-ganglioside antibodies.

• #7 Tay-Sachs Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/29887

  Tay-Sachs disease is a progressive, lethal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase-A that results in the accumulation of GM2 gangliosides. […] Tay-Sachs disease belongs to a group of autosomal recessively inherited lysosomal storage disorders called GM2 gangliosidoses. GM2 gangliosides accumulate inside lysosomes, primarily affecting the nervous system and resulting in neuronal dysfunction and neurodegeneration. […] Tay-Sachs disease is an autosomal recessive disorder caused by a mutation in HEXA, which encodes the enzymes beta-hexosaminidase A. HEXA is located at 15q23. More than 130 mutations have been identified, including single gene deletions, substitution, insertion splicing alteration, duplication, and complex gene rearrangements. […] Tay-Sachs disease is caused by beta-hexosaminidase A (Hex A) deficiency, responsible for GM2 ganglioside degradation. Alpha and beta subunits of Hex A are synthesized at the endoplasmic reticulum. The enzyme is transported to the Golgi network following glycosylation, intramolecular disulfide bond formation, and dimerization in the endoplasmic reticulum. The most important step is posttranslational modification of the enzyme with mannose-6-phosphate, which helps the lysosome recognize the enzyme. The presentation of GM2 ganglioside to the active site of Hex A requires an activator protein GM2A, which makes the enzyme lipophilic.

• #8 Tay-Sachs disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001417.htm

  Tay-Sachs disease occurs when the body lacks hexosaminidase A. This is a protein that helps break down a group of chemicals found in nerve tissue called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, often nerve cells in the brain. […] Tay-Sachs disease is caused by a variant gene on chromosome 15. When both parents carry the variant Tay-Sachs gene, a child has a 25% chance of developing the disease. The child must receive two copies of the variant gene, one from each parent, in order to become sick. If only one parent passes the variant gene to the child, the child is called a carrier. They will not be sick, but may pass the disease to their own children. […] Late-onset Tay-Sachs disease, which affects adults, is very rare.

• #9 Tay-Sachs disease | College of Medicine

  https://med.fsu.edu/iprd/tay-sachs-disease

  Tay-Sachs disease (TSD) is an ultra-rare genetic disorder caused by mutations in the HEXA gene. The subunit of lysosomal -hexosaminidase (HEXA) enzyme is critical for converting GM2 gangliosides to GM3 gangliosides. When the HEXA enzyme availability is severely reduced an abnormal buildup of GM2 occurs, causing neurological symptoms. […] A recent expanded-access clinical trial used adeno-associated virus (AAV) to deliver the HEXA gene intracerebrally to two patients with infantile TSD. The results demonstrated good overall safety and feasibility of gene therapy for TSD. However, the safety and efficacy was compromised significantly by immune-mediated toxicity. The goal of this project is to test a new generation of AAV vectors that have the potential to evade the host’s immune defenses.

• #10 Orphanet: Tay-Sachs disease

  https://www.orpha.net/en/disease/detail/845

  A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A deficiency as a consequence of biallelic pathogenic variants in the HEXA gene. […] The causative gene HEXA encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23). […] When Tay-Sachs is suspected, hexosaminidase A enzymatic activity on blood leukocytes is always very low compared to normal values (around 0% for the severe infantile form, around 10-15% for the late-onset form). This should be confirmed by HEXA gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome, and should be confirmed by hexosaminidase A enzymatic activity measurement. […] There is no specific efficient treatment for Tay-Sachs disease. Treatment is symptomatic.

• #11 Tay-Sachs Disease (HEXA) Sequencing and Deletion/Duplication | Test Fact Sheet

  https://arupconsult.com/ati/tay-sachs-disease-testing

  Tay-Sachs disease is a genetic disorder caused by a deficiency of the hexosaminidase A (HEX A) enzyme. […] Molecular testing can identify pathogenic and pseudodeficiency HEXA gene variant(s) in individuals with abnormal HEX A activity. […] Over 130 HEXA variants have been identified. The majority are null alleles that result in no HEX A enzymatic activity. […] The 7.6kb deletion is the only recurring large deletion. […] The 7.6kb deletion is the most common pathogenic variant. […] A negative result does not exclude a diagnosis of Tay-Sachs disease. […] This assay detects the 7.6kb deletion at a reduced sensitivity. Therefore, individuals of French Canadian descent may benefit from targeted screening; refer to the Laboratory Test Directory for available test options.

• #12 Tay–Sachs disease – Wikipedia

  https://en.wikipedia.org/wiki/Tay%E2%80%93Sachs_disease

  TaySachs disease is caused by a genetic mutation in the HEXA gene on chromosome 15, which codes a subunit of the hexosaminidase enzyme known as hexosaminidase A. […] The mutation disrupts the activity of the enzyme, which results in the build-up of the molecule GM2 ganglioside within cells, leading to toxicity. […] TaySachs disease is caused by insufficient activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down sphingolipids. […] When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. […] Deficiency in any one of these proteins leads to ganglioside storage, primarily in the lysosomes of neurons. […] TaySachs disease occurs because a mutation inherited from both parents deactivates or inhibits this process. […] Most TaySachs mutations probably do not directly affect protein functional elements (e.g., the active site). Instead, they cause incorrect folding (disrupting function) or disable intracellular transport.

• #13 Molecular Mechanism of Tay–Sachs Disease | Nature

  https://www.nature.com/articles/236032a0

  TAYSACHS disease is an inherited disorder of the central nervous system which becomes clinically evident in the fourth to sixth month of life, is characterized by progressive neurological impairment, and leads to death usually before the age of 4. […] The development of pathological changes in the brain is associated with the accumulation of excess GM2 * ganglioside. […] The gangliosides are a class of sialic acid-containing glycosphingolipids normally found at highest concentration in the ganglion-cell-rich fraction of the brain. GM2 is a monosialo form present in only minute quantities in normal brain.

• #14 Molecular Mechanism of Tay-Sachs Disease – ADS

  https://ui.adsabs.harvard.edu/abs/1972Natur.236…32L/abstract

  TAY-SACHS disease is an inherited disorder of the central nervous system which becomes clinically evident in the fourth to sixth month of life, is characterized by progressive neurological impairment, and leads to death usually before the age of 4. […] The development of pathological changes in the brain is associated with the accumulation of excess GM2 * ganglioside. […] The gangliosides are a class of sialic acid-containing glycosphingolipids normally found at highest concentration in the ganglion-cell-rich fraction of the brain. GM2 is a monosialo form present in only minute quantities in normal brain.

• #15 Tay-Sachs disease / Metabolic Diseases / Types of brain injury – brain disorders | Braininjury-explanation.com

  https://www.braininjury-explanation.com/types-of-brain-injury-brain-disorders/metabolic-diseases/tay-sachs-disease

  If GM2 ganglioside cannot be broken down, it accumulates in the body cells, so that these cells can no longer function properly. It is known that in people suffering from Tay-Sachs disease there were 100 to 1000 times more GM2 gangliosides in the brain than in healthy people. […] In Tay-Sachs disease, there is a change (mutation) in the HEXA gene on chromosome 15 (15q23). HEXA is short for the enzyme Hexosaminidase A. […] More than a hundred errors in the gene are known that can cause Tay-Sachs disease.

• #16 Tay-Sachs disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/tay-sachs-disease/

  Tay-Sachs disease is a rare, inherited disorder that is characterized by neurological problems caused by the death of nerve cells (neurons) in the brain and spinal cord (central nervous system). […] Variants in the HEXA gene cause Tay-Sachs disease. The HEXA gene provides instructions for making one part (the alpha subunit) of an enzyme called beta-hexosaminidase A. Beta-hexosaminidase A is located in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside found in cell membranes. […] HEXA gene variants affect the ability of the beta-hexosaminidase A enzyme to break down GM2 ganglioside. As a result, GM2 ganglioside accumulates to toxic levels, particularly in neurons in the central nervous system. Damage caused by the buildup of GM2 ganglioside leads to the dysfunction and eventual death of these neurons, which causes the signs and symptoms of Tay-Sachs disease. […] Because Tay-Sachs disease impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.

• #17 Tay-Sachs Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK564432/

  Tay-Sachs disease is a fatal, inherited neurodegenerative disorder caused by a deficiency in the enzyme hexosaminidase-A, leading to progressive neuronal damage. […] Tay-Sachs disease is caused by beta-hexosaminidase A (Hex A) deficiency, responsible for GM2 ganglioside degradation. […] The most important step is posttranslational modification of the enzyme with mannose-6-phosphate, which helps the lysosome recognize the enzyme. […] However, deficiency of Hex A causes an accumulation of the gangliosides up to toxic levels, especially in the neurons. While it is clear that the accumulation of ganglioside is the cause, the exact mechanism that translates the primary insult into neuronal death is unclear. […] Progressive neurodegeneration, microglia proliferation, and accumulation of the complex lipids in neuronal macrophages occur. […] Other pathological processes in the disease include abnormal endosomal transport, impaired autophagy, progressive accumulation of alpha-synuclein, and anti-ganglioside antibodies.

• #18 Tay-Sachs Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/29887

  However, deficiency of Hex A causes an accumulation of the gangliosides up to toxic levels, especially in the neurons. While it is clear that the accumulation of ganglioside is the cause, the exact mechanism that translates the primary insult into neuronal death is unclear. […] Progressive neurodegeneration, microglia proliferation, and accumulation of the complex lipids in neuronal macrophages occur. Other pathological processes in the disease include abnormal endosomal transport, impaired autophagy, progressive accumulation of alpha-synuclein, and anti-ganglioside antibodies.

• #19

  https://omim.org/entry/272800

  Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

• #20

  https://www.omim.org/entry/272800

  A number sign (#) is used with this entry because Tay-Sachs disease (TSD) is caused by homozygous or compound heterozygous mutation in the alpha subunit of the hexosaminidase A gene (HEXA; 606869) on chromosome 15q23. […] Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

• #21 GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01947-6

  It has been shown that the accumulation of undegraded gangliosides is linked to activation of microglial cells. Here, we demonstrated that an accumulation of GM2 ganglioside led to the activation of the microglial/macrophage system in the brain and retina of Hexa/Neu3 mice, compared with that in age-matched WT, Hexa-/-, and Neu3-/- mice. Activation of this cellular system led to an altered expression profile of both pro- and anti-inflammatory cytokines, as well as chemokines, in the cortex and cerebellum. […] Our data suggest that abnormal GM2 ganglioside accumulation in the CNS of early onset Tay-Sachs disease mouse model activates neuroinflammation, by triggering the release of pro-inflammatory cytokines and chemokines, microgliosis, astrogliosis, and the infiltration of PBMC in the CNS. This inflammatory cascade results in a loss of neurons and oligodendrocytes.

• #22 GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01947-6

  It has been shown that the accumulation of undegraded gangliosides is linked to activation of microglial cells. Here, we demonstrated that an accumulation of GM2 ganglioside led to the activation of the microglial/macrophage system in the brain and retina of Hexa/Neu3 mice, compared with that in age-matched WT, Hexa-/-, and Neu3-/- mice. Activation of this cellular system led to an altered expression profile of both pro- and anti-inflammatory cytokines, as well as chemokines, in the cortex and cerebellum. […] Our data suggest that abnormal GM2 ganglioside accumulation in the CNS of early onset Tay-Sachs disease mouse model activates neuroinflammation, by triggering the release of pro-inflammatory cytokines and chemokines, microgliosis, astrogliosis, and the infiltration of PBMC in the CNS. This inflammatory cascade results in a loss of neurons and oligodendrocytes.

• #23

  https://omim.org/entry/272800

  Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

• #24 Lipid-Lowering Drug Gemfibrozil Protects Mice from Tay-Sachs Disease via Peroxisome Proliferator-Activated Receptor α

  https://www.mdpi.com/2073-4409/12/24/2791

  Our results indicate a beneficial function of GFB that employs a PPARα-dependent mechanism to halt the progression of TSD and increase longevity in Tay-Sachs mice. […] Glial activation and dysfunction are salient features of neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). […] Here, we examined the effect of GFB on inflammation and overall glycoconjugate induced pathology in a mouse model of TSD, and observed that oral administration of GFB was capable of reducing glial inflammation and lowering glycoconjugates in the motor cortex of Tay-Sachs mice. […] Our results suggest that oral GFB may have therapeutic importance for TSD. […] The mechanism by which GFB may reduce ganglioside accumulation from the brain is also becoming clear. […] Therefore, it appears that GFB-mediated activation of PPARα is perhaps the underlying reason behind the neuroprotective effect of GFB in Tay-Sachs mice.

• #25 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  There is a wide spectrum of clinical signs and symptoms in TSD patients. Generally, TSD patients have neurological signs and symptoms and do not present systemic issues. The TSD clinical spectrum is delineated into three main types of TSD based on symptom severity and age of onset of disease. The first type of TSD is the acute infantile form which is the most prevalent type. Acute infantile TSD signs and symptoms begin to manifest around 6 months of age and progress until lethality around age four. […] The next type of TSD is the juvenile subacute form. This type has an age of onset of three to 5 years old and is usually lethal by age 15. The third type of TSD is the adult chronic form characterized by its later onset of symptoms. Patients usually demonstrate signs and symptoms in their late adolescence/early adulthood.

• #26 Tay-Sachs disease Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/tay-sachs-disease

  Tay-Sachs disease occurs when the body lacks hexosaminidase A. This is a protein that helps break down a group of chemicals found in nerve tissue called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, often nerve cells in the brain. […] Tay-Sachs disease is caused by a variant gene on chromosome 15. When both parents carry the variant Tay-Sachs gene, a child has a 25% chance of developing the disease. The child must receive two copies of the variant gene, one from each parent, in order to become sick. If only one parent passes the variant gene to the child, the child is called a carrier. They will not be sick, but may pass the disease to their own children. […] Tay-Sachs disease is divided into infantile, juvenile, and adult forms, depending on the symptoms and when they first appear. Most people with Tay-Sachs have the infantile form. In this form, the nerve damage usually begins while the baby is still in the womb. Symptoms usually appear when the child is 3 to 6 months old. The disease tends to get worse very quickly, and the child usually dies by age 4 or 5. […] Late-onset Tay-Sachs disease, which affects adults, is very rare.

• #27 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  There is a wide spectrum of clinical signs and symptoms in TSD patients. Generally, TSD patients have neurological signs and symptoms and do not present systemic issues. The TSD clinical spectrum is delineated into three main types of TSD based on symptom severity and age of onset of disease. The first type of TSD is the acute infantile form which is the most prevalent type. Acute infantile TSD signs and symptoms begin to manifest around 6 months of age and progress until lethality around age four. […] The next type of TSD is the juvenile subacute form. This type has an age of onset of three to 5 years old and is usually lethal by age 15. The third type of TSD is the adult chronic form characterized by its later onset of symptoms. Patients usually demonstrate signs and symptoms in their late adolescence/early adulthood.

• #28 Tay-Sachs Disease (VIII.137) – The Cambridge World History of Human Disease

  https://www.cambridge.org/core/books/cambridge-world-history-of-human-disease/taysachs-disease/1F20EA0E4E6738533642BDB87E92CBC5

  Tay-Sachs disease (TSD) is the best known of the sphingolipidoses, a group of genetic disorders that includes Niemann-Pick disease, Gauchers disease, and others. Specifically, TSD is GM2 (beta) gangliosidosis, an autosomal recessive disease with complete penetrance. Affected individuals (recessive homozygotes) produce virtually no functional hexosaminidase A (hex A), an enzyme necessary for normal neurological development and function. […] Persons with the disease usually show clinical symptoms of neurological degeneration by 6 months of age. Their condition steadily deteriorates, and they seldom live beyond the age of 4 years. […] It was Sachs who first noted the familial nature of the disease, and its seemingly exclusive occurrence in Jewish families. However, reports were soon made of non-Jewish cases. D. Slome (1933) was the first to survey the literature on the population characteristics of TSD and confirmed the diseases autosomal recessive mode of transmission as well as the TSD genes higher frequency among Jews.

• #29 Tay-Sachs Disease | Hereditary Ocular Diseases

  https://disorders.eyes.arizona.edu/disorders/tay-sachs-disease

  Retinal ganglion cells become dysfunctional as a result of the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms. […] Tay-Sachs disease is an autosomal recessive disorder caused by mutations in the hexosaminidase A gene, HEXA, (15q23-q24). The altered enzyme is unable to break down GM2 ganglioside which accumulates in lysosomes and leads to neuronal death. […] Mutations in the HEXA gene renders the hexosaminidase A subunit less effective and interferes with the function of the combined enzyme in the breakdown of gangliosides.

• #30 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  There is a wide spectrum of clinical signs and symptoms in TSD patients. Generally, TSD patients have neurological signs and symptoms and do not present systemic issues. The TSD clinical spectrum is delineated into three main types of TSD based on symptom severity and age of onset of disease. The first type of TSD is the acute infantile form which is the most prevalent type. Acute infantile TSD signs and symptoms begin to manifest around 6 months of age and progress until lethality around age four. […] The next type of TSD is the juvenile subacute form. This type has an age of onset of three to 5 years old and is usually lethal by age 15. The third type of TSD is the adult chronic form characterized by its later onset of symptoms. Patients usually demonstrate signs and symptoms in their late adolescence/early adulthood.

• #31 Tay-Sachs disease Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/tay-sachs-disease

  Tay-Sachs disease occurs when the body lacks hexosaminidase A. This is a protein that helps break down a group of chemicals found in nerve tissue called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, often nerve cells in the brain. […] Tay-Sachs disease is caused by a variant gene on chromosome 15. When both parents carry the variant Tay-Sachs gene, a child has a 25% chance of developing the disease. The child must receive two copies of the variant gene, one from each parent, in order to become sick. If only one parent passes the variant gene to the child, the child is called a carrier. They will not be sick, but may pass the disease to their own children. […] Tay-Sachs disease is divided into infantile, juvenile, and adult forms, depending on the symptoms and when they first appear. Most people with Tay-Sachs have the infantile form. In this form, the nerve damage usually begins while the baby is still in the womb. Symptoms usually appear when the child is 3 to 6 months old. The disease tends to get worse very quickly, and the child usually dies by age 4 or 5. […] Late-onset Tay-Sachs disease, which affects adults, is very rare.

• #32 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  There is a wide spectrum of clinical signs and symptoms in TSD patients. Generally, TSD patients have neurological signs and symptoms and do not present systemic issues. The TSD clinical spectrum is delineated into three main types of TSD based on symptom severity and age of onset of disease. The first type of TSD is the acute infantile form which is the most prevalent type. Acute infantile TSD signs and symptoms begin to manifest around 6 months of age and progress until lethality around age four. […] The next type of TSD is the juvenile subacute form. This type has an age of onset of three to 5 years old and is usually lethal by age 15. The third type of TSD is the adult chronic form characterized by its later onset of symptoms. Patients usually demonstrate signs and symptoms in their late adolescence/early adulthood.

• #33 Orphanet: Tay-Sachs disease

  https://www.orpha.net/en/disease/detail/845

  A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A deficiency as a consequence of biallelic pathogenic variants in the HEXA gene. […] The causative gene HEXA encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23). […] When Tay-Sachs is suspected, hexosaminidase A enzymatic activity on blood leukocytes is always very low compared to normal values (around 0% for the severe infantile form, around 10-15% for the late-onset form). This should be confirmed by HEXA gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome, and should be confirmed by hexosaminidase A enzymatic activity measurement. […] There is no specific efficient treatment for Tay-Sachs disease. Treatment is symptomatic.

• #34

  https://myhealth.alberta.ca/Health/pages/conditions.aspx?hwid=hw182975

  Tay-Sachs is a rare disease. A person with Tay-Sachs has changed (mutated) genes that don’t make any or enough of an enzyme called hexosaminidase A (hex A). Hex A breaks down fatty compounds (called GM2 gangliosides). Without it, fatty compounds build up in the nerve cells of the brain and cause damage. […] Tay-Sachs occurs due to very low levels of hex A. Low levels of hex A happen when parents pass on a changed gene to their child. […] In late-onset Tay-Sachs (LOTS), the body makes a small amount of hex A. People with LOTS inherit the late-onset hex A gene change from both parents. […] The changed gene that causes Tay-Sachs disease is more commonly found in people of Ashkenazi Jewish descent. About 1 out of 30 people in this population is a carrier of the disease.

• #35 Tay-Sachs disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001417.htm

  Tay-Sachs disease occurs when the body lacks hexosaminidase A. This is a protein that helps break down a group of chemicals found in nerve tissue called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, often nerve cells in the brain. […] Tay-Sachs disease is caused by a variant gene on chromosome 15. When both parents carry the variant Tay-Sachs gene, a child has a 25% chance of developing the disease. The child must receive two copies of the variant gene, one from each parent, in order to become sick. If only one parent passes the variant gene to the child, the child is called a carrier. They will not be sick, but may pass the disease to their own children. […] Late-onset Tay-Sachs disease, which affects adults, is very rare.

• #36 MacSphere: Molecular mechanisms of Tay Sachs Disease: calcium, excitotoxicity, and apoptosis

  https://macsphere.mcmaster.ca/handle/11375/21662

  The objective is to investigate the molecular mechanisms leading to neurodegeneration in Tay Sachs disease, a lysosomal storage disorder caused by a deficiency in the enzyme hexosaminidase A. […] Neuronal pentraxin 1 (NPTX1), potassium channel, subfamily K, member 2 (KCNK2), and prostaglandin synthase 1 (PTGS 1) were found to be upregulated in Tay Sachs neuroglia while heme oxygenase (HMOX1) was downregulated. […] In this study, our genetic profiling experiment led to the identification of NPTX1 as a marker of pathogenesis in Tay Sachs Cells. The role of NPTX1 in excitotoxicity implicates the latter in disease mechanism associated with Tay Sachs disease. Furthermore, this study provides evidence that TSD cells undergo programmed cell death in response to increased intracellular calcium as a result of increased glutamate receptor stimulation.

• #37 MacSphere: Molecular mechanisms of Tay Sachs Disease: calcium, excitotoxicity, and apoptosis

  https://macsphere.mcmaster.ca/handle/11375/21662

  The objective is to investigate the molecular mechanisms leading to neurodegeneration in Tay Sachs disease, a lysosomal storage disorder caused by a deficiency in the enzyme hexosaminidase A. […] Neuronal pentraxin 1 (NPTX1), potassium channel, subfamily K, member 2 (KCNK2), and prostaglandin synthase 1 (PTGS 1) were found to be upregulated in Tay Sachs neuroglia while heme oxygenase (HMOX1) was downregulated. […] In this study, our genetic profiling experiment led to the identification of NPTX1 as a marker of pathogenesis in Tay Sachs Cells. The role of NPTX1 in excitotoxicity implicates the latter in disease mechanism associated with Tay Sachs disease. Furthermore, this study provides evidence that TSD cells undergo programmed cell death in response to increased intracellular calcium as a result of increased glutamate receptor stimulation.

• #38 MacSphere: Molecular mechanisms of Tay Sachs Disease: calcium, excitotoxicity, and apoptosis

  https://macsphere.mcmaster.ca/handle/11375/21662

  The objective is to investigate the molecular mechanisms leading to neurodegeneration in Tay Sachs disease, a lysosomal storage disorder caused by a deficiency in the enzyme hexosaminidase A. […] Neuronal pentraxin 1 (NPTX1), potassium channel, subfamily K, member 2 (KCNK2), and prostaglandin synthase 1 (PTGS 1) were found to be upregulated in Tay Sachs neuroglia while heme oxygenase (HMOX1) was downregulated. […] In this study, our genetic profiling experiment led to the identification of NPTX1 as a marker of pathogenesis in Tay Sachs Cells. The role of NPTX1 in excitotoxicity implicates the latter in disease mechanism associated with Tay Sachs disease. Furthermore, this study provides evidence that TSD cells undergo programmed cell death in response to increased intracellular calcium as a result of increased glutamate receptor stimulation.

• #39 Tay-Sachs Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK564432/

  Tay-Sachs disease is a fatal, inherited neurodegenerative disorder caused by a deficiency in the enzyme hexosaminidase-A, leading to progressive neuronal damage. […] Tay-Sachs disease is caused by beta-hexosaminidase A (Hex A) deficiency, responsible for GM2 ganglioside degradation. […] The most important step is posttranslational modification of the enzyme with mannose-6-phosphate, which helps the lysosome recognize the enzyme. […] However, deficiency of Hex A causes an accumulation of the gangliosides up to toxic levels, especially in the neurons. While it is clear that the accumulation of ganglioside is the cause, the exact mechanism that translates the primary insult into neuronal death is unclear. […] Progressive neurodegeneration, microglia proliferation, and accumulation of the complex lipids in neuronal macrophages occur. […] Other pathological processes in the disease include abnormal endosomal transport, impaired autophagy, progressive accumulation of alpha-synuclein, and anti-ganglioside antibodies.

• #40 Tay-Sachs Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/29887

  However, deficiency of Hex A causes an accumulation of the gangliosides up to toxic levels, especially in the neurons. While it is clear that the accumulation of ganglioside is the cause, the exact mechanism that translates the primary insult into neuronal death is unclear. […] Progressive neurodegeneration, microglia proliferation, and accumulation of the complex lipids in neuronal macrophages occur. Other pathological processes in the disease include abnormal endosomal transport, impaired autophagy, progressive accumulation of alpha-synuclein, and anti-ganglioside antibodies.

• #41 Tay-Sachs disease

  https://www.redalyc.org/journal/5763/576366816018/html/

  The pathophysiological mechanism of GM2 gangliosidosis involves the storage of lipids in neurons with neuronal loss and dendritic changes, indicating an alteration of synaptic function and altered brain microconnectivity. […] Research on molecular pathogenesis and the development of possible treatments for TSD based on the pathophysiological mechanism are limited due to the fact that endogenous accumulation of GM2 is not observed in the peripheral cells of the patients.

• #42 Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0886-3

  Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes -hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. […] The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. […] Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. […] In TSD patients, mutations in the HEXA gene result in misfolded -subunits that render Hex A and Hex S non-functional. Deficiency of Hex A activity in TSD causes accumulation of GM2 ganglioside in lysosomes, which ultimately results in progressive neurodegeneration.

• #43 Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0886-3

  The treatment of these patient cells with recombinant human Hex A protein dramatically reduced the lipid accumulation in the TSD cells. […] The results demonstrate that the TSD NSCs differentiated from patient iPSCs are a useful disease model for further study of disease pathophysiology and for use as a cell-based model in drug development. […] We found that the increased Nile Red dye staining in TSD patient NSCs could be rescued by recombinant human Hex A protein. Thus, these patient cells can be used as a cell-based disease model and Nile Red staining offers a valid method for evaluating drug efficacy and compound screening. […] In this study, we found that patient NSCs treated with Hex A exhibited decreased lipid accumulation.

• #44 Characterization of Inducible Models of Tay-Sachs and Related Disease | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002943

  Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid -N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. […] The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb/ (Sandhoff) mice that lack -hexosaminidases A and B. […] Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. […] Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis.

• #45 Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system | Cell Discovery

  https://www.nature.com/articles/s41421-021-00276-z

  TaySachs disease (TSD) is a progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of -hexosaminidase A (HexA). The four-bases (TATC) insertion in exon 11 of the HEXA (HEXAins TATC) accounts for 80% of TaySachs disease from the Ashkenazi Jewish population. […] The HEXAins TATC introduces a premature termination codon (PTC) in exon 11, which leads to deficient activity of the hexosaminidase A (HexA). […] This ideal and novel HEXA ins TATC rabbit model would be beneficial for the pathogenic mechanism study and drug screening to treat TSD in the future.

• #46 Characterization of Inducible Models of Tay-Sachs and Related Disease | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002943

  Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid -N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. […] The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb/ (Sandhoff) mice that lack -hexosaminidases A and B. […] Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. […] Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis.

• #47 Characterization of Inducible Models of Tay-Sachs and Related Disease | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002943

  As in germline Hexb/ mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system. […] However, questions as to the pathogenesis, mechanisms inducing progression of disease, and the true extent of therapeutic reversibility remain. […] To accomplish this, we developed a reversible transgenic murine counterpart of human Sandhoff disease which utilizes the tetracycline-inducible gene expression system. […] Unexpectedly, doxycycline-induced suppression of -hexosaminidase expression in the adult animal caused acute neurodegeneration with the stereotypical murine simulacrum of Sandhoff disease and a course indistinguishable from the unmodified germline Hexb/ background strain.

• #48 Characterization of Inducible Models of Tay-Sachs and Related Disease | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002943

  As in germline Hexb/ mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system. […] However, questions as to the pathogenesis, mechanisms inducing progression of disease, and the true extent of therapeutic reversibility remain. […] To accomplish this, we developed a reversible transgenic murine counterpart of human Sandhoff disease which utilizes the tetracycline-inducible gene expression system. […] Unexpectedly, doxycycline-induced suppression of -hexosaminidase expression in the adult animal caused acute neurodegeneration with the stereotypical murine simulacrum of Sandhoff disease and a course indistinguishable from the unmodified germline Hexb/ background strain.

• #49 Characterization of Inducible Models of Tay-Sachs and Related Disease | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002943

  These findings may inform the timing and clinical stage at which therapeutic interventions such as gene therapy are considered for patients with GM2 gangliosidoses. […] The most obvious aspect of residual neurological disease in the transgenic animals was increased limb tone (spasticity) – observed as clasping of the limbs when the mice were lifted by their tails. […] Suppression of -hexosaminidase expression in the adult mouse induced an acute phenotype of Sandhoff disease. […] The fact that Sandhoff disease progressed largely unmodified when initiated in the adult mouse suggests that either developmental changes in ganglioside synthesis are insignificant compared with adult neuronal output of ganglioside, or that lysosomal disorder disease processes are resilient to fluctuations in the absolute amount of storage material.

• #50 Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system | Cell Discovery

  https://www.nature.com/articles/s41421-021-00276-z

  TaySachs disease (TSD) is a progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of -hexosaminidase A (HexA). The four-bases (TATC) insertion in exon 11 of the HEXA (HEXAins TATC) accounts for 80% of TaySachs disease from the Ashkenazi Jewish population. […] The HEXAins TATC introduces a premature termination codon (PTC) in exon 11, which leads to deficient activity of the hexosaminidase A (HexA). […] This ideal and novel HEXA ins TATC rabbit model would be beneficial for the pathogenic mechanism study and drug screening to treat TSD in the future.

• #51 Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system | Cell Discovery

  https://www.nature.com/articles/s41421-021-00276-z

  TaySachs disease (TSD) is a progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of -hexosaminidase A (HexA). The four-bases (TATC) insertion in exon 11 of the HEXA (HEXAins TATC) accounts for 80% of TaySachs disease from the Ashkenazi Jewish population. […] The HEXAins TATC introduces a premature termination codon (PTC) in exon 11, which leads to deficient activity of the hexosaminidase A (HexA). […] This ideal and novel HEXA ins TATC rabbit model would be beneficial for the pathogenic mechanism study and drug screening to treat TSD in the future.

• #52 GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01947-6

  Tay-Sachs disease (TSD), a type of GM2-gangliosidosis, is a progressive neurodegenerative lysosomal storage disorder caused by mutations in the subunit of the lysosomal -hexosaminidase enzyme. This disease is characterized by excessive accumulation of GM2 ganglioside, predominantly in the central nervous system. […] GM2-gangliosidosis is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage, and astrocyte activation, along with the production of inflammatory mediators. However, the mechanism of disease progression in Hexa/Neu3 mice, relevant to neuroinflammation is poorly understood. […] Our data suggest that Hexa/Neu3 mice display a phenotype similar to Tay-Sachs patients suffering from chronic neuroinflammation triggered by GM2 accumulation. Furthermore, our work contributes to better understanding of the neuropathology in a mouse model of early onset Tay-Sachs disease.

• #53 GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01947-6

  It has been shown that the accumulation of undegraded gangliosides is linked to activation of microglial cells. Here, we demonstrated that an accumulation of GM2 ganglioside led to the activation of the microglial/macrophage system in the brain and retina of Hexa/Neu3 mice, compared with that in age-matched WT, Hexa-/-, and Neu3-/- mice. Activation of this cellular system led to an altered expression profile of both pro- and anti-inflammatory cytokines, as well as chemokines, in the cortex and cerebellum. […] Our data suggest that abnormal GM2 ganglioside accumulation in the CNS of early onset Tay-Sachs disease mouse model activates neuroinflammation, by triggering the release of pro-inflammatory cytokines and chemokines, microgliosis, astrogliosis, and the infiltration of PBMC in the CNS. This inflammatory cascade results in a loss of neurons and oligodendrocytes.

• #54 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  Tay-Sachs disease (TSD) is an autosomal recessive disease that features progressive neurodegenerative presentations. It affects one in 100,000 live births. Currently, there is no approved therapy or cure. This review summarizes multiple drug development strategies for TSD, including enzyme replacement therapy, pharmaceutical chaperone therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell replacement therapy. […] GM2-gangliosidoses are a group of three lysosomal storage disorders (LSDs) that result from a deficiency in one of the lysosomal enzymes β-hexosaminidases (Hex A, B, or S) or the GM2 activator protein (GM2A). This deficiency prevents the degradation of GM2 ganglioside (GM2) into GM3 ganglioside and causes a cytotoxic accumulation of GM2. TSD is a congenital, autosomal recessive, neurodegenerative disease caused by mutations in the hexosaminidase A (HEXA) gene.

• #55 Tay-Sachs Disease – Blu Genes Foundation

  https://blugenes.org/tay-sachs-disease/

  Tay-Sachs disease is a rare and fatal inherited genetic disorder that causes a progressive build-up of a fatty substance in the nerve cells (neurons) of the brain and spinal cord because of a defect in a gene called HEXA. […] The HEXA gene produces an enzyme called -hexosaminidase A, which plays critical role in breaking down a fatty substance called GM2 ganglioside in the central nervous system. Mutations in the HEXA gene disrupt production of the -hexosaminidase A enzyme, resulting in a toxic build-up of the GM2 ganglioside in the cells of the central nervous system. […] One of the most promising avenues of research is gene therapy. Gene therapy is complex, but the idea is to find a way of packaging a correct version of the defective gene (HEXA in the case of Tay-Sachs disease) so that it can be delivered into the affected cells (nerve cells in the central nervous system in the case of Tay-Sachs disease), much like a patch in the case of faulty software. The goal would be for the correct gene to become functional and permanently incorporated into the affected cells.

• #56 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  The unique challenge of gene therapy for TSD is the fact that HEXA encodes one subunit of the heterodimer HexA enzyme, and needs to complex with the beta subunit, encoded by HEXB, in order to be functionally active. Therefore, gene therapy development for TSD requires the delivery of two subunits to form a functional enzyme. […] Tay-Sachs disease is an autosomal recessive disease caused by HEXA mutations. It is mainly characterized by neurodegenerative clinical manifestations in patients. While there is a wide gradient of signs and symptoms, the age of onset generally indicates disease severity and patient outcome. While there exist some therapies for symptom management, especially for late onset TSD patients, currently, there is no cure for TSD. Several approaches have been reported to develop therapies for TSD including enzyme replacement therapy, enzyme enhancement therapy via the use of chaperones, substrate reduction therapy, gene therapy, and stem cell replacement therapy.

• #57 Gene Therapy for Tay-Sachs Disease – Horae Gene Therapy Center

  https://www.umassmed.edu/gtc/our-research/tay-sachs-disease/

  Dr. Sena-Esteves has devised new ways to deliver therapeutic levels of the missing enzymes to the entire brain by injection of adeno-associated virus (AAV) vectors into specific structures in the Central Nervous System (CNS). Based on the exceptional results that he and his lab members have obtained in animal models and pre-clinical studies they hope to soon move on to a human clinical trial for Tay-Sachs disease. […] The proposed trial will employ a recombinant adeno-associated virus vector (rAAV) to replace the faulty gene that produces the enzyme responsible for removing and recycling waste products in cells. Once introduced into brain, the functioning gene begins making the missing enzyme, turning parts of the brain into mini-factories. Capitalizing on the natural pathways of the brain, those enzymes are then distributed throughout the brain, allowing cells to resume their natural metabolic functions and remove waste products.

• #58 First gene therapy for Tay-Sachs disease successfully given to two children

  https://www.umassmed.edu/news/news-archives/2022/02/first-gene-therapy-for-tay-sachs-disease-successfully-given-to-two-children/

  Tay-Sachs is a severe neurological disease caused by a deficiency in an enzyme called HexA. This enzyme breaks down a fatlike substance that normally exists in very small, harmless amounts in the brain. Without HexA, however, this fatlike substance can accumulate to toxic levels that damage and kill neurons. […] The only effective way to treat Tay-Sachs is to restore the HexA enzyme in the brain. This is difficult, however, because the blood-brain barrier prevents most molecules from passing into the brain. […] Our treatment uses two harmless viral vectors to deliver DNA instructions to brain cells that teach them how to produce the missing enzyme. […] In the case of Tay-Sachs, these DNA instructions enter the nucleus of these cells and stay there, allowing for long-term production of HexA.

• #59 Tay-Sachs disease | College of Medicine

  https://med.fsu.edu/iprd/tay-sachs-disease

  Tay-Sachs disease (TSD) is an ultra-rare genetic disorder caused by mutations in the HEXA gene. The subunit of lysosomal -hexosaminidase (HEXA) enzyme is critical for converting GM2 gangliosides to GM3 gangliosides. When the HEXA enzyme availability is severely reduced an abnormal buildup of GM2 occurs, causing neurological symptoms. […] A recent expanded-access clinical trial used adeno-associated virus (AAV) to deliver the HEXA gene intracerebrally to two patients with infantile TSD. The results demonstrated good overall safety and feasibility of gene therapy for TSD. However, the safety and efficacy was compromised significantly by immune-mediated toxicity. The goal of this project is to test a new generation of AAV vectors that have the potential to evade the host’s immune defenses.

• #60 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  For TSD, ERT remains challenging because a successful ERT must comprise of both a functional alpha and beta subunit of HexA. Several groups have developed functional HexA enzyme which have alleviated disease phenotypes in vitro. Due to the large size of HexA, it is unable to cross the blood brain barrier and therefore traditional intravenous administration has not been effective in alleviating central nervous system symptoms. […] Pharmacological chaperones are small molecule drugs that bind to mutant proteins after their synthesis to correct their conformation such that the mutant proteins can be transported correctly to their cellular site for their biological functions. For TSD, some mutations cause misfolded HexA enzymes that are degraded quickly before the enzyme can move to the lysosome. One potential solution for these misfolded HexA enzymes is the use of pharmacological chaperones to promote proper folding in patient cells.

• #61 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  For TSD, ERT remains challenging because a successful ERT must comprise of both a functional alpha and beta subunit of HexA. Several groups have developed functional HexA enzyme which have alleviated disease phenotypes in vitro. Due to the large size of HexA, it is unable to cross the blood brain barrier and therefore traditional intravenous administration has not been effective in alleviating central nervous system symptoms. […] Pharmacological chaperones are small molecule drugs that bind to mutant proteins after their synthesis to correct their conformation such that the mutant proteins can be transported correctly to their cellular site for their biological functions. For TSD, some mutations cause misfolded HexA enzymes that are degraded quickly before the enzyme can move to the lysosome. One potential solution for these misfolded HexA enzymes is the use of pharmacological chaperones to promote proper folding in patient cells.

• #62 Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0886-3

  The treatment of these patient cells with recombinant human Hex A protein dramatically reduced the lipid accumulation in the TSD cells. […] The results demonstrate that the TSD NSCs differentiated from patient iPSCs are a useful disease model for further study of disease pathophysiology and for use as a cell-based model in drug development. […] We found that the increased Nile Red dye staining in TSD patient NSCs could be rescued by recombinant human Hex A protein. Thus, these patient cells can be used as a cell-based disease model and Nile Red staining offers a valid method for evaluating drug efficacy and compound screening. […] In this study, we found that patient NSCs treated with Hex A exhibited decreased lipid accumulation.

• #63 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  Substrate reduction therapy (SRT) is a therapeutic strategy to inhibit the formation of specific substrates of a mutant enzyme that reduces the need of this enzyme to hydrolyze its substrate, resulting in a decrease in the substrate accumulation of the lysosomal storage disease. For TSD, SRT involves inhibiting the production of the accumulating substrate, e.g. reducing GM2 produced in TSD. […] HSCT is mainly achieved through transplantation of stem cells from peripheral blood, bone marrow, or umbilical cord blood. This is possible because Hex enzymes are able to pass from cell to cell through the M6PR-mediated process. Gene therapy utilizes viral vectors for the delivery of a functional gene to correct a genetic defect. Since TSD defects are monogenic, gene therapy is a promising treatment for this disease.

• #64 Tay-Sachs Disease: Treatments, Symptoms, Risks, and More

  https://www.healthline.com/health/neurological-health/tay-sachs-disease

  Tay-Sachs is caused by problems with an enzyme known as hexosaminidase A (Hex-A) that’s important for your brain. People with Tay-Sachs don’t have enough of this enzyme. As a result, a fatty substance (lipid) builds up and causes damage to the brain and spinal cord. […] Without this enzyme, a lipid called GM2 ganglioside builds up in nerve cells in the brain, destroying these cells. […] Since Tay-Sachs is caused by the lack of the Hex-A enzyme, this treatment seeks to replace the enzyme. So far, several complications have kept this from being effective for Tay-Sachs. […] This therapy uses molecules to stabilize enzymes and increase their activity. More research is needed on this treatment. […] Instead of trying to increase the Hex-A enzyme, this uses small molecules to reduce the lipid buildup that damages nerve cells in people with Tay-Sachs.

• #65 Frontiers | Therapeutic Strategies For Tay-Sachs Disease

  https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.906647/full

  For TSD, ERT remains challenging because a successful ERT must comprise of both a functional alpha and beta subunit of HexA. Several groups have developed functional HexA enzyme which have alleviated disease phenotypes in vitro. Due to the large size of HexA, it is unable to cross the blood brain barrier and therefore traditional intravenous administration has not been effective in alleviating central nervous system symptoms. […] Pharmacological chaperones are small molecule drugs that bind to mutant proteins after their synthesis to correct their conformation such that the mutant proteins can be transported correctly to their cellular site for their biological functions. For TSD, some mutations cause misfolded HexA enzymes that are degraded quickly before the enzyme can move to the lysosome. One potential solution for these misfolded HexA enzymes is the use of pharmacological chaperones to promote proper folding in patient cells.

• #66 Tay-Sachs Disease: Treatments, Symptoms, Risks, and More

  https://www.healthline.com/health/neurological-health/tay-sachs-disease

  Tay-Sachs is caused by problems with an enzyme known as hexosaminidase A (Hex-A) that’s important for your brain. People with Tay-Sachs don’t have enough of this enzyme. As a result, a fatty substance (lipid) builds up and causes damage to the brain and spinal cord. […] Without this enzyme, a lipid called GM2 ganglioside builds up in nerve cells in the brain, destroying these cells. […] Since Tay-Sachs is caused by the lack of the Hex-A enzyme, this treatment seeks to replace the enzyme. So far, several complications have kept this from being effective for Tay-Sachs. […] This therapy uses molecules to stabilize enzymes and increase their activity. More research is needed on this treatment. […] Instead of trying to increase the Hex-A enzyme, this uses small molecules to reduce the lipid buildup that damages nerve cells in people with Tay-Sachs.

• #67 Lipid-Lowering Drug Gemfibrozil Protects Mice from Tay-Sachs Disease via Peroxisome Proliferator-Activated Receptor α

  https://www.mdpi.com/2073-4409/12/24/2791

  Tay-Sachs disease (TSD) is a progressive heritable neurodegenerative disorder characterized by the deficiency of the lysosomal β-hexosaminidase enzyme (Hex−/−) and the storage of GM2 ganglioside, as well as other related glycoconjugates. […] This study underlines the importance of gemfibrozil (GFB), an FDA-approved lipid-lowering drug, in inhibiting the disease process in a transgenic mouse model of Tay-Sachs. […] Oral administration of GFB significantly suppressed glial activation and inflammation, while also reducing the accumulation of GM2 gangliosides/glycoconjugates in the motor cortex of Tay-Sachs mice. […] While investigating the mechanism, we found that oral administration of GFB increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Tay-Sachs mice, and that GFB remained unable to reduce glycoconjugates and improve behavior and survival in Tay-Sachs mice lacking PPARα.

• #68 Lipid-Lowering Drug Gemfibrozil Protects Mice from Tay-Sachs Disease via Peroxisome Proliferator-Activated Receptor α

  https://www.mdpi.com/2073-4409/12/24/2791

  Tay-Sachs disease (TSD) is a progressive heritable neurodegenerative disorder characterized by the deficiency of the lysosomal β-hexosaminidase enzyme (Hex−/−) and the storage of GM2 ganglioside, as well as other related glycoconjugates. […] This study underlines the importance of gemfibrozil (GFB), an FDA-approved lipid-lowering drug, in inhibiting the disease process in a transgenic mouse model of Tay-Sachs. […] Oral administration of GFB significantly suppressed glial activation and inflammation, while also reducing the accumulation of GM2 gangliosides/glycoconjugates in the motor cortex of Tay-Sachs mice. […] While investigating the mechanism, we found that oral administration of GFB increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Tay-Sachs mice, and that GFB remained unable to reduce glycoconjugates and improve behavior and survival in Tay-Sachs mice lacking PPARα.

• #69 Lipid-Lowering Drug Gemfibrozil Protects Mice from Tay-Sachs Disease via Peroxisome Proliferator-Activated Receptor α

  https://www.mdpi.com/2073-4409/12/24/2791

  Our results indicate a beneficial function of GFB that employs a PPARα-dependent mechanism to halt the progression of TSD and increase longevity in Tay-Sachs mice. […] Glial activation and dysfunction are salient features of neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). […] Here, we examined the effect of GFB on inflammation and overall glycoconjugate induced pathology in a mouse model of TSD, and observed that oral administration of GFB was capable of reducing glial inflammation and lowering glycoconjugates in the motor cortex of Tay-Sachs mice. […] Our results suggest that oral GFB may have therapeutic importance for TSD. […] The mechanism by which GFB may reduce ganglioside accumulation from the brain is also becoming clear. […] Therefore, it appears that GFB-mediated activation of PPARα is perhaps the underlying reason behind the neuroprotective effect of GFB in Tay-Sachs mice.

• #70 Lipid-Lowering Drug Gemfibrozil Protects Mice from Tay-Sachs Disease via Peroxisome Proliferator-Activated Receptor α

  https://www.mdpi.com/2073-4409/12/24/2791

  Our results indicate a beneficial function of GFB that employs a PPARα-dependent mechanism to halt the progression of TSD and increase longevity in Tay-Sachs mice. […] Glial activation and dysfunction are salient features of neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). […] Here, we examined the effect of GFB on inflammation and overall glycoconjugate induced pathology in a mouse model of TSD, and observed that oral administration of GFB was capable of reducing glial inflammation and lowering glycoconjugates in the motor cortex of Tay-Sachs mice. […] Our results suggest that oral GFB may have therapeutic importance for TSD. […] The mechanism by which GFB may reduce ganglioside accumulation from the brain is also becoming clear. […] Therefore, it appears that GFB-mediated activation of PPARα is perhaps the underlying reason behind the neuroprotective effect of GFB in Tay-Sachs mice.

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