Ataxia Telangiectasia

What Causes Ataxia Telangiectasia?

AT is caused by an abnormal change (mutation) in the ATM gene. This gene contains instructions for making a protein vital to normal cell function. In particular, the ATM protein helps to repair damaged DNA and prevent cells with DNA damage from reproducing. The mutation appears to cause a deficiency of functional ATM protein, leading to unstable cells prone to death.

Lack of ATM protein also allows cells with damaged DNA to divide unchecked, explaining why people with AT are more likely to get certain cancers. The disorder’s movement symptoms result from cells in the brain’s coordination center (the cerebellum) being particularly sensitive to ATM deficiency.

Is Ataxia Telangiectasia Hereditary?

AT is inherited in an autosomal recessive pattern. This means a child will develop the disorder only if they inherit two copies of the ATM mutation, one from each parent. A person with only one copy of the mutated gene will not develop the disorder but may pass the mutation on to their children.

When both parents have the ATM mutation, each of their children has a 25 percent chance of developing AT. Each child has a 50 percent chance of inheriting only one mutated gene and being a carrier. Each child has a 25 percent chance of inheriting two normal genes and being unaffected.

How Is Ataxia Telangiectasia Detected?

The symptoms of AT are progressive and develop gradually over time. The first symptoms are usually movement- and coordination-related (ataxia). These symptoms may mimic those of other neurological disorders, sometimes making early diagnosis difficult.

Early signs of AT include:

• Delayed walking
• Unsteady walking
• Unsteady sitting
• Difficulty standing still in one place

The progressive nature of the neurological symptoms, which distinguishes AT from disorders such as cerebral palsy, often doesn’t become noticeable until later in childhood.

How Is Ataxia Telangiectasia Diagnosed?

The process of diagnosing AT typically includes an evaluation of the child’s medical history and physical and neurological exams to look for symptoms of the disorder. Some laboratory tests may be able to detect common characteristics of AT.

Diagnostic steps often include:

• Blood tests to measure serum alpha-fetoprotein (AFP) levels. This protein is elevated in children with AT, but the test may be inconclusive in very young children.
• Tests to measure the level of ATM protein
• Tests to look for abnormal chromosomes that are more common in children with AT
• Tests to measure liver enzymes, which may be elevated in children with AT
• Magnetic resonance imaging (MRI) or other imaging scans to look for abnormalities in the cerebellum
• Tests to measure the child’s sensitivity to radiation
• Genetic testing to look for mutations in the ATM gene

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Ataxia Telangiectasia Treated?

AT has no cure, and no treatment will stop the progression of symptoms. Standard treatments and therapies are directed toward managing the severity of symptoms and preventing complications.

Common treatment options include:

• Antibiotics to treat infections
• Avoidance of sunlight to prevent worsening of telangiectasias
• Vitamin E for mild relief of symptoms, as directed by a doctor
• Diazepam (Valium) to treat muscle stiffness and speech impairments. High doses may worsen symptoms.
• Physical therapy

How Does Ataxia Telangiectasia Progress?

AT’s movement-related symptoms worsen over time, and other symptoms may begin to appear years after the onset of the disorder. Problems with the immune system may cause complications that can be life-threatening.

Progressive symptoms of AT include:

• Loss of the ability to walk
• Development of telangiectasias, often between the ages of three and six
• Problems with swallowing, coughing, breathing, or choking
• Slow growth caused by hormone deficiencies
• Premature aging (gray hair or wrinkles in adolescence)
• Incomplete sexual development
• Sinus and lung infections (pneumonia, bronchitis)
• Diabetes
• Lymphoma or leukemia. Approximately a third of people with AT develop some form of cancer.

How Is Ataxia Telangiectasia Prevented?

There is no known way to prevent AT when the disease-causing gene mutations are present. Parents with a family history of the disorder, or who have had another child with AT, are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Prenatal testing may be able to detect AT gene mutations during pregnancy. For parents using in vitro fertilization, pre-implantation testing can detect affected embryos before transferring them to the mother’s uterus.

Ataxia Telangiectasia Caregiver Tips

• Know what to watch for. AT brings the potential for many severe complications, including lung infections, diabetes, and cancer. Educate yourself about the disorder; know how to decrease your child’s risk of long-term problems.
• Find your community. Living with AT is easier when you’re in contact with people who know about the disorder’s challenges. Online support groups can give you valuable information and insight and let you know you’re not alone.
• Get involved. The AT Children’s Project provides resources for education, research updates, and fundraising for families who are living with AT.  

Ataxia Telangiectasia Brain Science

Scientists don’t yet fully understand how AT affects the brain. Studies have shown that the disorder causes degeneration of the cerebellum that gets worse over time. In particular, AT causes the loss of nerve cells called Purkinje cells and small neurons called granule cells, which help transmit nerve signals in the cerebellum. Researchers have put forth several different hypotheses to explain why these cells are lost, including:

• Problems with cell repair when nerve cell DNA is damaged
• Abnormal responses to stresses on cells
• Problems with mitochondria, the energy-producing structures inside cells
• Biochemical imbalances that damage cells

Not all of the neurological AT symptoms appear to be directly related to cerebellar degeneration, suggesting that other parts of the brain might be affected as well.

Ataxia Telangiectasia Research

Title:  MBM-01 (Tempol) for the Treatment of Ataxia Telangiectasia

Stage: Not yet recruiting

Principal investigator: Nicholas Russo, MD

University of Texas Health Science Center at Houston

Houston, TX

Ataxia Telangiectasia (A-T) is an autosomal recessively inherited neurodegenerative disorder that also dramatically affects the immune and endocrine systems. The disorder results from mutations in the A-T mutated gene (ATM), leading to a loss in the production of the ATM protein.

The active compound in MBM-01 (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) may substitute for the loss of ATM by protecting cells from DNA damage, preventing and reducing oxidative damage, triggering an increase in cellular survival proteins, and preserving the brain and peripheral immune system.

Cells lacking ATM are left defenseless and unable to: repair damaged cellular DNA; exhibit normal cell cycle control; effectively respond to oxidative damage, ionizing radiation, and alkylating agents; and maintain a healthy immune response, among others. A-T patients have increased oxidative stress and significantly reduced total antioxidant levels. In an early study directed to oxidative stress in A-T patients, a decrease in total antioxidant capacity levels has been observed.

There is currently no cure for A-T, and current treatments are limited to palliative care. Therapies include rehabilitative care, infection prevention and treatment, and screening for pulmonary dysfunction and malignancies. Symptomatic treatments generally fall short and leave A-T patients debilitated and in a progressively wasting state. Patients suffering from A-T are in dire need of treatment to alleviate the conditions of this disease. A drug product that can substitute for the loss of ATM has the potential to provide these patients with this critically unmet need. The active compound in MBM-01 has been shown to supplant the overall role of ATM by reducing oxidative stress, reducing DNA double-strand breaks, and decreasing programmed cell death (in healthy cells).

Title: N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T)

Stage: Recruiting

Contact: Susan Perlman, MD

University of California Los Angeles

Los Angeles, CA

The study’s primary purpose is to evaluate the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the treatment of A-T, investigating the efficacy in terms of improving symptoms, functioning, and quality of life against the defined endpoints in patients with A-T.

Patients will be assessed during three study phases: a baseline period, a 6-week treatment period, and a 6-week post-treatment washout period. If within (6) weeks prior to the initial screening visit, a patient has received any prohibited medications defined in the eligibility criteria (irrespective of the preceding treatment duration), a wash-out study-run in 6 weeks is required before the first baseline assessment.

All patients will receive the study drug during this study.

For each patient, the study lasts for approximately 3.5 – 4 months, during which there are 6 study visits to the study site.

This Extension Phase allows patients who have completed the Parent Study to, at the discretion of the Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001). Patients will receive treatment with IB1001 for two one-year treatment periods, separated by a 6-week washout. All patients will receive the study drug during the treatment period. For each patient, the Extension Phase lasts for approximately 25.5 months, during which there are (6) visits to the study site.

Title: A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors

Stage: Recruiting

Contact: Manish Patel, MD

Florida Cancer Specialists

Sarasota, FL

ART0380 is a new investigational medicinal product that is a potent and selective inhibitor of Ataxia telangiectasia and Rad3-related (ATR). ART0380 is being developed as an oral anti-cancer agent for treating participants with cancers that harbor defects in deoxyribonucleic acid (DNA) repair and in combination with agents, including those that cause DNA damage.

This study is an open-label Phase I/IIa study designed to evaluate the safety, tolerability, PK, and preliminary efficacy of ART0380 as monotherapy or in combination with gemcitabine in participants with advanced or metastatic solid tumors, advanced or solid tumors that fail to express Ataxia-Telangiectasia Mutated protein kinase (ATM) by immunohistochemistry, and high grade serous ovarian, primary peritoneal or fallopian tube carcinoma.