Materiały źródłowe

• #1 Ataxia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562284/

  Ataxia is a neurological sign that manifests in a lack of coordination in the movement of different muscles in the body. […] It results from dysfunction of the brain areas, responsible for the coordination of movements, and, most commonly, the cerebellum. […] Ataxia may occur due to abnormalities in the nervous system’s different areas, including the brain, spinal cord, nerves, and nerve roots. […] Ataxia may be due to an interference in the sensory transmission to the cerebellum caused by a lesion. This condition can lead to sensory or spinal ataxia. An interruption in cortical signals from the cerebellum causes cerebellar ataxia. Spinocerebellar ataxias are a result of both of the above mentioned pathologies. They are autosomal dominant and result from CAG repetition on chromosomes.

• #2 Mechanisms of ataxia – PubMed

  https://pubmed.ncbi.nlm.nih.gov/9184691/

  Ataxia, or incoordination of movement, is a disorder that can be caused by damage to several different nervous system structures. Common causes of ataxia include damage of the cerebellum and damage of sensory structures. […] The basic mechanism underlying ataxia is not yet understood, although studies indicate that ataxia may be due in part to an inability to coordinate the relative activity of multiple muscles and adjust movements at a given joint for the effects of other moving joints (interaction torques). […] Based on these findings, it could be reasoned that treatments focusing on strategies to reduce the complexity of a movement by minimizing the number of moving joints or by stabilizing against the inertial effects of limb movement will improve function. […] Ataxia may be best treated by teaching people to avoid rapid multijoint movements and instead make slower movements limited to single joints.

• #3 Ataxia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/ataxia/symptoms-causes/syc-20355652

  Lasting ataxia usually results from damage to the part of the brain that controls muscle coordination, known as the cerebellum. […] Ataxia usually results from damage to the part of the brain called the cerebellum or its connections. The cerebellum controls muscle coordination. […] Ataxia is caused by damage to the part of the brain called the cerebellum or its connections. The cerebellum is located at the base of the brain and connects to the brainstem. The cerebellum helps control balance, eye movements, swallowing and speech. […] The irregular proteins affect the function of nerve cells, primarily in the cerebellum and spinal cord. They cause the nerve cells to break down and die, known as degeneration. As the disease progresses, coordination problems worsen. […] Different gene changes cause different types of ataxia. Most types get worse over time. Each type causes poor coordination but also has other specific symptoms.

• #4 Ataxia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562284/

  Friedreich’s ataxia is the most common of the inherited ataxias. It has an autosomal recessive pattern of inheritance. It involves the frataxin gene. There is degeneration of peripheral nerve axons and loss of sensory cells. […] Depending on the location of the lesion, characteristic findings are as follows: Lesions in the lateral cerebellum cause symptoms on the same side as the lesion (ipsilateral), whereas diffuse lesions cause generalized symptoms. […] Ataxia frequently leads to complex decision making due to the multiple causes and nonspecific signs and symptoms.

• #5 Friedreich Ataxia: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1150420-overview

  The major pathophysiologic finding in Friedreich ataxia is a „dying back phenomena” of axons, beginning in the periphery with ultimate loss of neurons and a secondary gliosis. The primary sites of these changes are the spinal cord and spinal roots. This results in loss of large myelinated axons in peripheral nerves, which increases with age and disease duration. Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared. […] The posterior columns and corticospinal, ventral, and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents. This is accompanied by a fibrous gliosis that does not replace the bulk of the lost fibers. Overall, the spinal cord becomes thin and the anteroposterior (AP) and transverse diameters of the thoracic cord are reduced. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells. The posterior column degeneration accounts for the loss of position and vibration senses and the sensory ataxia. The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes.

• #6 Friedreich Ataxia Inheritance and Mechanism of Disease

  https://www.thinkfa.com/fa-inheritance-and-pathology.html

  Friedreich ataxia (FA) is caused by a genetic mutation of the frataxin (FXN) gene. A mutation in the frataxin gene in people with FA causes deficiency in the frataxin protein, which disrupts mitochondrial iron metabolism. This mitochondrial dysfunction leads to impaired adenosine triphosphate production and oxidative stress, which are thought to be the key drivers of FA pathogenesis. […] FA is most often caused by a variant within the frataxin gene called a GAA triplet-repeat expansion. […] The number of GAA triplet repeats can be as high as 1800, typically corresponding to very severe disease and rapid progression.

• #7 Friedreich Ataxia: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1150420-overview

  Large neurons of the dorsal root ganglia, especially lumbosacral, and nerve cells in the Clarke column are reduced in number. The posterior roots become thin. The dentate nuclei exhibit mild to moderate neuronal loss and the middle and superior cerebellar peduncles are reduced in size. Patchy loss of Purkinje cells in the superior vermis of the cerebellum and of neurons in corresponding portions of the inferior olivary nuclei is typical. Mild degenerative changes occur in the pontine and medullary nuclei and optic tracts. The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar tracts and involvement of the Clarke column, dentate nucleus, superior vermis, and dentatorubral pathways. […] The corticospinal tracts are relatively spared down to the level of the cervicomedullary junction. Beyond this point, the corticospinal tracts are severely degenerated, which becomes progressively more severe moving down the spinal cord. This explains the common finding of bilateral extensor plantar responses and weakness late in the disease.

• #8 Friedreich ataxia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/friedreich-ataxia/

  Friedreich ataxia is a genetic condition that affects the nervous system and causes movement problems. […] Mutations in the FXN gene cause Friedreich ataxia. This gene provides instructions for making a protein called frataxin. […] The abnormally long GAA trinucleotide repeat disrupts the production of frataxin, which severely reduces the amount of this protein in cells. Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the characteristic signs and symptoms of Friedreich ataxia. […] The pathogenesis of Friedreich ataxia and the structure and function of frataxin.

• #9 Novel Frataxin Isoforms May Contribute to the Pathological Mechanism of Friedreich Ataxia | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047847

  Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. […] In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. […] Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA. […] Cells derived from FRDA patients have a partial defect in ISC-containing proteins, with consequent mitochondrial damage, lower ATP production, and impaired iron utilization, leading to mitochondrial iron accumulation. […] We suspected that the tissue-specific pathology of FRDA might arise from tissue-specific expression of FXN isoforms and that the extra-mitochondrial isoforms might contribute to molecular pathogenesis.

• #10 Ataxia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/ataxia/symptoms-causes/syc-20355652

  Spinocerebellar ataxias. Researchers have identified more than 40 spinocerebellar ataxia genes, and the number continues to grow. Ataxia and cerebellar degeneration are common to all types, and there may be other symptoms. […] Friedreich ataxia. This is the most common hereditary ataxia. It involves damage to the cerebellum, spinal cord and peripheral nerves. Peripheral nerves carry signals from the arms and legs to the brain and spinal cord. Symptoms typically appear well before age 25. […] Ataxia-telangiectasia. This rare childhood disease causes degeneration in the brain and immune system. This increases the risk of other diseases, including infections and tumors.

• #11

  https://link.springer.com/article/10.1080/14734220510007950

  Six forms of spinocerebellar ataxia (SCA) are caused by pathological cytosine-adenine-guanine (CAG) trinucleotide repeat expansions in the coding region of the mutated genes. The translated proteins contain abnormally long polyglutamine stretches, and SCA-1, SCA-2, SCA-3/Machado-Joseph disease (MJD), SCA-6, SCA-7, and SCA-17 are polyglutamine diseases. […] The role of polyglutamine-containing intranuclear and cytoplasmic inclusion bodies in SCA remains unknown but protein aggregation may be the common step in the pathogenesis of these otherwise rather heterogeneous disorders.

• #12 Research reveals mechanism that drives ataxia type 1 | Texas Children’s

  https://www.texaschildrens.org/content/media/research-reveals-mechanism-drives-ataxia-type-1

  Research reveals mechanism that drives ataxia type 1 […] When the protein ATAXIN1 accumulates in neurons it causes a neurodegenerative condition called spinocerebellar ataxia type 1 (SCA1), a rare disease characterized by progressive problems with balance and breathing difficulties. […] ATAXIN1 accumulates because of a mutation that produces an abnormal, very long version of the protein that forms clumps inside neurons. […] However, how accumulation of longer ATAXIN1, called polyQ-ATAXIN1, leads to neurodegeneration has remained a mystery. […] A group of researchers at Baylor College of Medicine, Texas Children’s Hospital and the University of Minnesota reports in the journal Neuron that polyQ-ATAXIN1 and a partner molecule called capicua form a complex that is essential for neurodegeneration. […] They discovered that this complex is able to disrupt the expression of a number of genes in neurons in animal models of the disease. […] Patients with SCA1 present with similar disruption of gene expression. […] This discovery can potentially lead to the design of novel therapies to treat the condition. […] The researchers found that when polyQ-ATAXIN1 accumulates, it remains longer inside neurons, which provides opportunities for interacting more with its usual molecular partners. […] One of them is capicua, a protein that is important for the regulation of gene expression. […] The normal ATAXIN1-capicua complex is known to be crucial for various developmental functions in other bodily tissues, so the researchers investigated whether this complex was also important for cerebellar function. […] On the other hand, the authors thought that the formation of polyQ-ATAXIN1-capicua complexes in the cerebellum may underlie some of the typical features of SCA1. […] The researchers showed that the formation of this complex is sufficient to trigger SCA1 in mice. […] When they altered polyQ-ATAXIN1 so it could not form a complex with capicua, the animals did not develop the condition, even though polyQ-ATAXIN1 still accumulated in their neurons. […] Having pinpointed that it is this protein interaction that drives toxicity, the researchers were able to discard the possibility that other mechanisms, such as ATAXIN1 RNA, also participate in the development of SCA1. […] We have learned that only when polyQ-ATAXIN1 can form a complex with capicua does it dampen the expression of a number of genes and leads to neurodegeneration. […] If we disrupt the interaction between polyQ-ATAXIN-1 and capicua, polyQ-ATAXIN1 is no longer toxic. […] These data give us insight into the factors, in this case capicua, that make certain cells more vulnerable in SCA1. […] When the researchers studied samples from patients with SCA1, they found that some of the genes whose expression was dampened in the cerebellum of mice were also dampened in the cerebellum of human patients. […] This tells us that the gain of function of the polyQ-ATAXIN1-capicua complexes we are deducing from the mice seems to also apply to the human condition. […] We hope our findings will open the possibility of developing future therapeutic strategies for SCA1 by partially blocking the interaction between polyQ-ATAXIN1 and capicua. […]

• #13 Research reveals a mechanism that drives ataxia type 1

  https://medicalxpress.com/news/2018-03-reveals-mechanism-ataxia.html

  When the protein ATAXIN1 accumulates in neurons it causes a neurodegenerative condition called spinocerebellar ataxia type 1 (SCA1), a rare disease characterized by progressive problems with balance and breathing difficulties. […] A group of researchers at Baylor College of Medicine, Texas Children’s Hospital and the University of Minnesota reports in the journal Neuron that polyQ-ATAXIN1 and a partner molecule called capicua form a complex that is essential for neurodegeneration. […] The researchers found that when polyQ-ATAXIN1 accumulates, it remains longer inside neurons, which provides opportunities for interacting more with its usual molecular partners. One of them is capicua, a protein that is important for the regulation of gene expression. […] The normal ATAXIN1-capicua complex is known to be crucial for various developmental functions in other bodily tissues, so the researchers investigated whether this complex was also important for cerebellar function.

• #14 Research reveals a mechanism that drives ataxia type 1

  https://medicalxpress.com/news/2018-03-reveals-mechanism-ataxia.html

  On the other hand, the authors thought that the formation of polyQ-ATAXIN1-capicua complexes in the cerebellum may underlie some of the typical features of SCA1. […] When they altered polyQ-ATAXIN1 so it could not form a complex with capicua, the animals did not develop the condition, even though polyQ-ATAXIN1 still accumulated in their neurons. […] We have learned that only when polyQ-ATAXIN1 can form a complex with capicua does it dampen the expression of a number of genes and leads to neurodegeneration. […] This tells us that the gain of function of the polyQ-ATAXIN1-capicua complexes we are deducing from the mice seems to also apply to the human condition. […] We hope our findings will open the possibility of developing future therapeutic strategies for SCA1 by partially blocking the interaction between polyQ-ATAXIN1 and capicua.

• #15 Alternative splicing: Potential disease mechanism for SCA1 – National Ataxia Foundation

  https://www.ataxia.org/scasourceposts/alternative-splicing-potential-disease-mechanism-for-sca1/

  Ever since the CAG expansion of the Ataxin-1 (ATXN1) gene has been identified as the cause of spinocerebellar ataxia type 1 (SCA1), researchers have been on the hunt for the mechanism of the disease. How does this mutation cause SCA1? So far, there have been many clues to the effect of mutant ATXN1 on the brain. A research group at Yale School of Medicine has found a novel mechanism that gives us more insight into how the CAG expansion may cause disease. […] The Yale researchers were interested in how the mutant ATXN1 may affect gene expression in the brain. There are a couple of ways gene expression is regulated. One such way is a process called alternative splicing, in which the RNA that is waiting to be translated into a protein is modified by having certain RNA sections cut out. This can result in different forms of the same protein that may carry out different functions or result in proteins that can no longer perform their proper function and get degraded.

• #16 Alternative splicing: Potential disease mechanism for SCA1 – National Ataxia Foundation

  https://www.ataxia.org/scasourceposts/alternative-splicing-potential-disease-mechanism-for-sca1/

  The Yale researchers utilized a mouse model that expresses the human mutant ATXN1 protein only in Purkinje cells, the predominantly affected cell type in SCA1. The research group first confirmed the progressive neurodegeneration of Purkinje cells in this mouse model. Using a technique called RNA sequencing, the group then identified genes that are downregulated and upregulated in the SCA1 mouse model. […] In summary, the study showed evidence of the dysregulation of alternative splicing events SCA1, identifying a new mechanism of interest for disease progression. The authors identified RBFOX1 as a potential mediator of the alternative splicing defects and confirmed its role in modulating degenerative phenotypes in SCA1 fruit fly models. Future studies will have to follow up on the role of RBFOX1 and the identified alternative splicing events in causing SCA1 pathogenesis.

• #17 Friedreich’s ataxia and frataxin: Molecular genetics, evolution and pathogenesis (Review)

  https://www.spandidos-publications.com/10.3892/ijmm.7.6.581

  Friedreich’s ataxia patho-genesis is not solved yet. […] Substantial data from organism models, such the S. cerevisae yeast and more recently conditioned knock-outs in mouse, and studies in heart biopsies and fibroblast cultures from patients suggest an important role of mitochondrial iron in the development of the disease. […] It has been postulated that iron-induced oxygen radical affects the oxidative phosphorylation in frataxin deficiency states favouring the disease pathology. […] A second hypothesis postulates a direct role of frataxin in the mitochondrial energy activation and oxidative phosphorylation.

• #18 Oxidative Stress is Involved in Friedreich’s Ataxia PathogenesisEnvelope icon

  https://friedreichsataxianews.com/news/oxidative-stress-involved-friedreichs-ataxia-pathogenesis/

  Researchers at the University of California, Davis (UC Davis) recently conducted a review study on data concerning the link between oxidative stress and inherited mitochondrial diseases like Friedreich’s ataxia. […] In this study, UC Davis researchers reviewed the involvement of oxidative stress in the pathogenesis of the most common mitochondrial diseases. […] Friedreich’s ataxia, in particular, is a rare inherited neurodegenerative disease characterized by progressive damage of the nervous system with degeneration of the spinal cord and peripheral nerves that leads to muscle weakness, sensory loss, balance deficits and lack of voluntary coordination of muscle movements. […] Studies using Friedreich’s ataxia patient cells and animal models have shown that the antioxidant responses for protection against ROS are deficient in the context of the disease.

• #19 Oxidative Stress is Involved in Friedreich’s Ataxia PathogenesisEnvelope icon

  https://friedreichsataxianews.com/news/oxidative-stress-involved-friedreichs-ataxia-pathogenesis/

  According to the authors, the current model of Friedreich’s ataxia is that the decrease in frataxin protein levels leads to a reduction of the antioxidant protection triggering neuro-inflammatory and neurodegenerative effects that result in the clinical symptoms of the disease. […] Given the evidence for the involvement of oxidative stress in disease pathogenesis, therapeutic strategies based on antioxidants (like idebenone, an analog of coenzyme Q10 antioxidant) are being evaluated. […] The team suggests that given the fact that oxidative stress underlies the pathogenesis of mitochondrial diseases, antioxidant therapies should be considered as a potential treatment strategy, particularly for Friedreich’s ataxia patients.

• #20 Molecular Mechanism behind Purkinje Cell Toxicity in SCA1 Uncovered – National Ataxia Foundation

  https://www.ataxia.org/scasourceposts/molecular-mechanism-behind-purkinje-cell-toxicity-in-sca1-uncovered/

  One of the most interesting of these results was that the levels of Homer-3 protein were reduced. […] The authors predicted that the reduction in Homer-3 levels is a consequence of abnormal glutamate signaling in SCA1. […] As a proof of principle, authors chemically destroyed the inputs from climbing fibers and found that the Homer-3 levels were further reduced. […] Activation of neurons by glutamate signaling is associated with activation of critical downstream signaling pathway such as mTORC1. […] So, the authors next investigated the mTORC1 signaling pathway in SCA1 Purkinje cells. […] In conclusion, the authors demonstrated here that the levels of mTORC1/Homer-3 signaling was reduced to below normal levels in SCA1 mouse Purkinje cells. […] Furthermore, they found that glutamatergic transmission from climbing fibers (which determines the levels of mTORC1/Homer-3 in Purkinje cells) was compromised, and that restoration of levels of Homer-3 protein is enough to diminish SCA1 symptoms in mice. […] This discovery of a novel mechanism of degeneration (mTORC1 dysfunction) in the Purkinje cells of the cerebellum leads us closer to understanding SCA1.

• #21 Researchers Discover Pathway Important for Friedreich’s Ataxia Pathogenesis: TORC1Envelope icon

  https://friedreichsataxianews.com/news/researchers-discover-pathway-important-friedreichs-ataxia-pathogenesis-torc1/

  Researchers at the University of Valencia in Spain and Baylor College of Medicine in the United States recently discovered a new pathway involved with Friedreich’s ataxia pathogenesis, providing new therapeutic targets for the disorder. […] Studies on Friedreich’s ataxia patients and animal models have suggested a key role for oxidative stress in disease pathogenesis. […] The authors concluded that reducing TORC1 signaling activity in the Drosophila model of Friedreich’s ataxia can improve motor abilities and increase lifespan. As such, they propose that the TORC1 pathway might represent a new potential therapeutic target for Friedreich’s ataxia.

• #22 Immune Ataxias: The Continuum of Latent Ataxia, Primary Ataxia and Clinical Ataxia

  https://www.imrpress.com/journal/JIN/23/4/10.31083/j.jin2304079/htm

  The clinical category of immune-mediated cerebellar ataxias (IMCAs) is now recognized after 3 decades of clinical and experimental research. […] Cerebellar circuitry is especially vulnerable to immune attacks. After the loss of immune tolerance, IMCAs present in an acute or subacute manner with various combinations of a vestibulocerebellar syndrome (VCS), a cerebellar motor syndrome (CMS), and a cerebellar cognitive affective syndrome/Schmahmann’s syndrome (CCAS/SS). […] Immune ataxias represent a model to elucidate the sequence of events leading to destruction of cerebellar neuronal reserve and develop novel strategies aiming to restore plasticity mechanisms. […] The group of IMCAs present typically with a subacute or acute disease course evolving from days to weeks, leading to several blends of a vestibulocerebellar syndrome (VCS; the main initial complaint is dizziness/vertigo and the lesion is located at the level of cerebellar lobules V–VII/IX–X), a cerebellar motor syndrome (CMS; the main initial complaint is clumsiness/irregular gait and the lesion is located at the level of lobules I–VI/VIII), and a cerebellar cognitive affective syndrome/Schmahmann’s syndrome (CCAS/SS; the main observation is an aberrant behavior and the lesion is located at the level of lobules VI–IX in the posterior lobe).

• #23 Immune Ataxias: The Continuum of Latent Ataxia, Primary Ataxia and Clinical Ataxia

  https://www.imrpress.com/journal/JIN/23/4/10.31083/j.jin2304079/htm

  The core deficit is dysmetria (motor, cognitive, and even social function) and is currently explained by the impact of an immune attack on internal models generated and updated by the cerebellum. […] As the immune attack progresses (activation of lymphocytes and monocytes, cellular invasion through the blood-brain barrier, release of cytokines and antibodies) more antigens from neural/glial cells become accessible to attack, and the neuroinflammation process continues. […] Inflammation impairs neurotransmission of the mossy fibers coming from numerous extra-cerebellar sources, the climbing fibers originating from the inferior olive, the cerebellar cortex, and cerebellar nuclei. Long-term depression (LTD) at parallel fibers-Purkinje cells (PF-PC LTD), a key-mechanism of cerebellar motor learning, is also impaired in IMCAs.

• #24 Gluten Ataxia Associated with Dietary Protein Cross-Reactivity with GAD-65

  https://www.mdpi.com/2571-841X/3/3/24

  Gluten ataxia results from immunological damage to the cerebellum from gluten antibodies that cross-react with cerebellum tissue in genetically susceptible subgroups. […] Individuals suffering from gluten ataxia have been found to clinically improve when implementing a gluten-free diet due to cross-reactivity of dietary proteins with ataxia target sites, such as GAD-65 within the cerebellum in clinical settings. […] The clinical impression, at this time, was the development of both latent autoimmune diabetes of adulthood and cerebellum ataxia associated with GAD-65 antibodies that express in both cerebellum and pancreatic tissue with increased risk due to blood–brain barrier permeability. GAD-65 autoimmunity is associated with cerebellum disease and ataxia. […] The concern for cross-reactivity with other food proteins to GAD-65 and IA-2 have been reported in the literature.

• #25 Gluten Ataxia Associated with Dietary Protein Cross-Reactivity with GAD-65

  https://www.mdpi.com/2571-841X/3/3/24

  This mechanism in combination with his findings of a compromised blood-brain barrier leads to the clinical investigation of other dietary proteins that may also cross-react with GAD-65. […] In some susceptible individuals, other dietary proteins may also cross-react with cerebellum target proteins (GAD-65) and lead to cerebellum degeneration and the presentation of cerebellar disease clinical findings, such as ataxia, intention tremor, and nystagmus, as noted with our clinical case. […] Gluten ataxia is one of the rare forms of ataxias in which a gluten-free diet alone can effectively stop the progression of the disease. […] Early detection and removal of the antigen is essential to preserve cerebellum tissue integrity and to avoid refractory patterns of cerebellum injury. […] A novel finding of this case report is that dietary proteins besides gluten may also cross-react with gluten-ataxia target sites.

• #26 Acute cerebellar ataxia in children – UpToDate

  https://www.uptodate.com/contents/acute-cerebellar-ataxia-in-children

  Acute cerebellar ataxia usually occurs after an acute febrile illness, though it may occur unheralded. […] Numerous other infectious agents have been implicated in the pathogenesis of acute cerebellar ataxia, including coxsackievirus, echovirus, enteroviruses, Epstein-Barr virus, hepatitis A, herpes simplex virus I, human herpesvirus 6, measles, mumps, parvovirus B19, Borrelia burgdorferi (Lyme disease), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), malaria, Mycoplasma pneumoniae, and typhoid fever. […] The pathogenic mechanisms that underlie acute cerebellar ataxia have not been definitively established but are believed to be autoimmune. Antiviral antibodies and autoantibodies against centrosomes, glutamate receptor delta 2, myelin-associated glycoprotein, neurons, and triosephosphate isomerase have been isolated from serum and/or cerebrospinal fluid (CSF) in affected patients. However, in other case reports, viral nucleic acids have been identified in the CSF, suggesting that infection of brain tissue may contribute.

• #27 Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

  https://www.mdpi.com/2076-3425/12/3/367

  The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia. […] In contrast, animal models with neurodegeneration of the cerebellar Purkinje cells and hypoexcitability of the neurons show cerebellar ataxia. The suppression of the Ca2+-activated K+ channels in vivo is associated with a type of ataxia. Therefore, there is a gap in our interpretation between the very early phase of cerebellar inflammation and the emergence of cerebellar ataxia. […] In a recent model of acute inflammation in the cerebellar cortex, rodents showed multiple depressive-like behaviors associated with hyperexcitability of Purkinje cells.

• #28 Ataxia-telangiectasia (A-T) | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/ataxia-telangiectasia-t

  Ataxia-telangiectasia (A-T) is an autosomal recessive disorder that causes neurological symptoms (like unsteady gait), dilated corkscrew-shaped blood vessels in the white of the eyes and on sun-exposed skin, combined immune deficiency, and high risk of cancer. […] DNA breakage syndromes are characterized by chromosomal instability and breakage, as well as a defect in the DNA repair mechanism. […] The ataxia is caused by abnormalities in the cerebellum, the part of the brain that controls balance and movement. […] A-T causes a progressive decline in motor function, which may not become apparent until children are 4-8 years old. […] The immunodeficiency in individuals with A-T generally remains stable over time but does worsen in approximately 15% of individuals. […] The ATM gene controls the production of the ATM protein, an essential enzyme involved in cellular responses to DNA damage and other forms of cellular stress.

• #29 Ataxia-telangiectasia (A-T) | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/ataxia-telangiectasia-t

  Diagnostic A-T is a disorder of DNA breakage, and thus, there is a theoretical risk of chromosomal damage from radiation. […] DNA breakage syndromes are a rare group of disorders characterized by radiation sensitivity, and varying degrees of immunodeficiency, as well as cognitive and/or physical developmental problems.

• #30 Omaveloxolone for the Treatment of Friedreich’s Ataxia – touchNEUROLOGY

  https://touchneurology.com/neurodegenerative-diseases/journal-articles/omaveloxolone-for-the-treatment-of-friedreichs-ataxia/

  Omaveloxolone is a second-generation semisynthetic oleanane triterpenoid compound that binds to adapter protein Kelch-like ECH associated protein 1 to decrease ubiquitination of Nrf2, thus increasing cellular Nrf2 levels and improving both the cells ability to handle oxidative stress and produce energy. […] The MOXIe study evaluated the clinical effect of omaveloxolone and will be discussed in detail below. […] The basic pathological mechanism underlying FRDA reflects its decreased FXN expression. […] The success of omaveloxolone is due in part to how the trials were designed to overcome these challenges. […] The MOXIe study was carefully designed to address many of the difficulties faced by rare disease clinical trials, including prior FRDA studies. […] Overall, the success of MOXIe can be summarized in a few concepts: Well-defined mechanism, Relatively safe drug, Long follow-up to demonstrate endurance, Optimized dose and subject population, Detailed analysis with multiple statistical paradigms demonstrating consistent results.

• #31 LX2006 – Lexeo Therapeutics

  https://www.lexeotx.com/programs/cardiac-programs/friedreichs-ataxia/

  Friedreichs ataxia is caused by a mutation in the FXN gene that disrupts the normal production of the protein frataxin, which is critical to the function of mitochondria in a cell and to the maintenance of cardiac function. […] LX2006 is designed to transfer the FXN gene to myocardial cells and increase frataxin levels in the mitochondria. The increase in frataxin levels in the mitochondria restores mitochondrial function and energy production in cardiac myocytes. […] LX2006 has demonstrated the ability to significantly reverse the cardiac phenotype in preclinical studies.

• #32 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200106/New-molecular-mechanism-can-reverse-genetic-defect-responsible-for-Friedreichs-ataxia.aspx

  Scientists at Tufts University have identified a molecular mechanism that could reverse the genetic defect responsible for Friedreich’s ataxia, a neurodegenerative disease that leaves its victims with difficulty walking, a loss of sensation in the arms and legs and impaired speech caused by degeneration of nerve tissue in the spinal cord. […] The researchers report today in the Proceedings of the National Academy of Sciences that the genetic anomaly that causes the disease — the multiple repetition of a three letter DNA sequence — could potentially be reversed by enhancing a natural process that contracts the repetitive sequences in living tissue. […] Friedreich’s ataxia is a genetic disease caused by the presence of an expanded repetition of a three letter genetic sequence, GAA in the FXN gene, which encodes for frataxin, a protein required for proper function of the mitochondria — the cell’s „batteries” that generate the fuel to keep all other cell functions running.

• #33 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200106/New-molecular-mechanism-can-reverse-genetic-defect-responsible-for-Friedreichs-ataxia.aspx

  It is known that in patients’ tissues, the GAA repeats are unstable and continuously expand and contract. Understanding the mechanism of GAA repeat expansion and contraction — especially contraction — is important to developing this strategy for battling the currently incurable disease. […] The Tufts researchers found that the contraction of repeats depends on the ability of the DNA repeat to form an unusual triple-helical DNA structure along the lagging strand. […] When the replication machinery jumps over this triple helix hurdle, the copied DNA strand ends up with fewer GAA repeats. […] „While these results were uncovered in a yeast model, they do provide us with a clue into the mechanism of DNA repeat instability in Friedreich’s ataxia,” said Alexandra Khristich, graduate student in Mirkin’s lab and first author of the study. […] „I hope that our discovery would become a starting point for the potential development of therapeutic strategies that tip the balance toward DNA repeat contraction in patient tissues.”

• #34 A protective mechanism against spinocerebellar ataxia | The Neuro – McGill University

  https://www.mcgill.ca/neuro/article/research/protective-mechanism-against-spinocerebellar-ataxia

  A recent study published in Nature Genetics led by Dr. Bernard Brais from The Neuro and Dr. Stephan Zuchner from the University of Miamis Miller School of Medicine has discovered a genetic mechanism that protects people from developing a type of spinocerebellar ataxia, a mechanism that one third of the population lack. […] In this most recent study, the research team discovered that a short DNA sequence in the FGF14 gene blocks the expansion of tandem repeats, preventing spinocerebellar ataxia 27B. […] This most recent study shows for the first time that a short DNA sequence located next to the repeat expansion prevents intergenerational growth of the FGF14 repeat. A third of humans do not have this protective element and so are at risk of transmitting to their children an enlarged expansion. […] While we always suspected such stabilizing sequences for repeat expansion disorders, this is the first time such an element has been identified, says Dr. Zuchner. Astoundingly, this rather common sequence does not appear in any of the popular reference genomes.

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