In the arena of uncommon and intricate genetic illnesses, Ataxia-Telangiectasia (A-T) presents a significant challenge to both medical researchers and healthcare practitioners. A-T is a complex conundrum that requires careful investigation because it is characterized by a confluence of immune system failure, neurological impairments, and a propensity for cancer.
According to NIH, between 1:40,000 to 1:100,000 is the incidence of A-T. In certain groups, the ailment is as uncommon as 1 in 300,000. The ATM gene mutation is carried by around 1% of people in the US. Equally impacted by A-T are men and women. Atherosclerosis telangiectasia is the most prevalent hereditary ataxia that manifests in the first ten years of life. It is the second most frequent autosomal recessive ataxia in children, following Friedreich's ataxia. Numerous populations, particularly the Jewish community in North Africa, have documented a notable founder impact.
Ataxia-Telangiectasia (AT) is a multifaceted neurodegenerative disease. It is also known as Louis-Bar Syndrome. Typically, between the ages of one and four, throughout the preschool years, symptoms related to AT emerge. AT frequently manifests as ataxia, or an unstable stride. An inability to coordinate eye movements (oculomotor apraxia) and episodes of uncontrollable movements (choreoathetosis) are two symptoms that set AT apart from other illnesses. Cerebellar degeneration is linked to the progression of ataxia, and many school-age children with AT require wheelchair assistance.
Children with AT have telangiectasias, or dilated blood vessels, in their skin, eyes, or mucous membranes. The most prevalent kind of telangiectasias, ocular telangiectasias, often manifest between the ages of 4 and 6. Many patients with AT have impaired immune system functioning, often known as cellular and humoral immunodeficiency, and many of them are more susceptible to lung and sinus infections. Additionally, those who have AT are more likely to develop some cancers, especially lymphomas, leukemias, and solid organ tumors in their early adult years as well as throughout the first two decades of life.
Causes
Pathogenic variations, or mutations, in the ATM gene are the cause of AT. Protein kinase with serine/threonine coding is encoded by the ATM gene. An enzyme known as a kinase is a biological catalyst that accelerates the phosphate group addition process to other molecules.
Oxidative stress in the cell also causes the ATM proteins to become active. The ATM gene is mutated in AT patients in a way that impacts the kinase activity and functionality of the ATM protein. As a result, the signaling networks that react to DNA double strand breaks or a decrease in oxidative stress are flawed. Some symptoms of AT are brought on by mutations in the ATM gene that result in an ATM protein that is faulty.
As an autosomal recessive condition, AT is inherited. A single gene is often inherited in two copies, one from each father. Being a recessive disorder, AT only manifests in a person who carries two copies of the faulty gene.
AT does not occur in individuals with one mutant gene and one normal gene. These peoples are referred as carriers. An ATM mutation is thought to affect one person out of every 100. Compared to people without any ATM gene mutations, carriers have a higher risk of cancer and heart disease even when they do not have AT. AT carriers pass on the mutated gene to their offspring, although they usually do not exhibit any symptoms.
Symptoms
Many conditions have symptoms or test results that are comparable to those of AT. Usually associated with the loss of motor capabilities are these symptoms.
A physical evaluation of the patient's symptoms is the first step in the diagnosis of ataxia-telangiectasia. Imaging and blood tests are then performed to confirm the genetic mutation causing the symptoms.
Laboratory Test
Blood Test- Although it is not limited to A-T, elevated alpha-fetoprotein is a distinctive hallmark of this disease. Additionally, blood tests reveal a drop in IgG and IgA concentrations overall as well as varying IgM levels.
Genetic Test- The identification of homozygous or compound heterozygous mutations in the ATM gene—which is using targeted sequencing, sequencing included in ataxia panels, or whole-exome sequencing—is the final step towards the diagnosis of A-T. This test is also called the Karyotype test. When a new gene variant is discovered, immunoblotting of the ATM protein is carried out to verify whether the mutation results in a notable decrease in ATM levels.
Magnetic Resonance Imaging
One useful tool for identifying potential causes is brain MRI. In some cases, ataxia sufferers' MRIs reveals cerebellar and other brain structural reduction. It also reveals additional discoveries that are curable, including a benign tumor or blood clot.
Lumbar puncture
This is a useful test for ataxia in certain instances. A little sample of cerebrospinal fluid is taken by inserting a needle between two lumbar bones (vertebrae) in the lower back. The fluid that envelops and shields your spinal cord and brain is transported to a lab for analysis.
Diagnostic Market players |
Diagnostic Products |
Teleflex |
SURTEX® Quincke |
Avanos Medical |
BD® Quincke spinal needles |
ICU Medical |
BD® spinal kits and sets |
Cardinal Health |
SOMATOM® |
LSL Healthcare, Inc. |
GE Discovery MR450 |
Rocket Medical |
Magnifico Open 0.4 T |
Busse Hospital Disposables |
AncestryDNA® |
Boston Scientific Corporation |
Cellient™ |
Stryker Corporation |
Affirm™ |
Medtronic plc. |
Cobas® |
ARGON MEDICAL |
Aptima™ |
EXELINT International, Co. |
Phadia™ |
APC International, Ltd. (U.S.) |
RealTime® |
Becton, Dickinson, and Company (BD) |
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Foundation Medicine, Inc. |
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Danaher Corporation |
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Genomic Health, Inc. |
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F. Hoffmann-La Roche Ltd |
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Biocept, Inc. |
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Canon Medical Systems Corporation |
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Hitachi, Ltd. |
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Toshiba Corporation |
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Siemens Healthineers |
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GSK plc (U.K.), |
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Philips Healthcare |
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As there is presently no known cure for AT, treatment focuses on managing symptoms.
Thus, it's critical to treat the disease's particular symptoms and conduct surveillance to avert consequences. Thus, it's critical to treat the disease's particular symptoms and conduct surveillance to avert consequences. There hasn't been a controlled study on the use of medications to lessen AT patients' ataxia symptoms for the past few years. The lack of universal grading scales to evaluate the complicated neurological dysfunction in AT and the varying contributions of various movement disorders to patient morbidity are obstacles to interventional trials. Thus far, there has been no success in preventing the initial signs and symptoms of AT.
Following are some treatment approaches based on the symptoms of AT:
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Phase 1 |
Phase 2 |
Phase 3 |
Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness |
N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T) |
The Cancer of the Pancreas Screening-5 CAPS5)Study |
A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors |
Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness |
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A Study to Assess the Safety and Tolerability of AZD1390 Given with Radiation Therapy in Patients with Brain Cancer |
A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors |
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M1774 in Combination with Cemiplimab in Participants with Non-Squamous NSCLC (DDRiver NSCLC 322) |
A Study of Reduced-dose Radiation in People with Metastatic Tumors with a Genetic Change |
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M1774 in Combination with Cemiplimab in Participants with Non-Squamous NSCLC (DDRiver NSCLC 322) |
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