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Triple A syndrome


Other Names for this Disease
  • AAA
  • AAA syndrome
  • Achalasia Addisonianism Alacrimia syndrome
  • Achalasia alacrima syndrome
  • Addisonian achalasia syndrome
More Names
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Your Question

I am trying to research current information for my friend who has been diagnosed with Triple A syndrome. She is looking for understandable information about the disease and possible treatment options. Is there recent information about what might help to treat neuropathy? How can we reach out to other people affected by the condition? How can we find out about current research that is being done to find better treatment alternatives?

Our Answer

We have identified the following information that we hope you find helpful. If you still have questions, please contact us.

What is triple A syndrome?

Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima (a reduced or absent ability to secrete tears). Most people with triple A syndrome have all three of these features, although some have only two. Affected individuals may also have dysautonomia, developmental delay, intellectual disability, speech problems, a small head size, muscle weakness, movement problems, peripheral neuropathy, and optic atrophy. Many of the neurological symptoms of triple A syndrome worsen over time. Triple A syndrome is caused by mutations in the AAAS gene and is inherited in an autosomal recessive pattern.[1]
Last updated: 8/16/2010

What are the signs and symptoms of triple A syndrome?

Triple A syndrome is characterized by three specific features: achalasia, Addison disease, and alacrima (reduced or absent ability to secrete tears). Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is alacrima. Most people with triple A syndrome have all three of these features, although some have only two.

Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia). People with this condition may have other neurological abnormalities such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time. People with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.

Alacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. Individuals typically develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.[2] Cases of parkinsonism, peripheral neuropathy, and seizures developing in individuals have been reported, but whether this also occurs in individuals who received an early diagnosis and long-term effective medical and surgical management is unclear.[3]
Last updated: 2/9/2011

What causes triple A syndrome?

Mutations in the AAAS gene cause triple A syndrome in many affected individuals. This gene provides instructions for making a protein called ALADIN, whose function is not well understood. Within cells, ALADIN is found in the nuclear envelope, the structure that surrounds the nucleus and separates it from the rest of the cell. Based on its location, ALADIN is thought to be involved in the movement of molecules into and out of the nucleus of the cell. Mutations in the AAAS gene prevent this protein from reaching its proper location in the cell, which may disrupt the movement of molecules. Researchers suspect that DNA repair proteins may be unable to enter the nucleus if ALADIN is missing from the nuclear envelope. DNA damage that is not repaired can cause the cell to become unstable and lead to cell death. Although the nervous system is particularly vulnerable to DNA damage, it remains unknown exactly how mutations in the AAAS gene lead to the signs and symptoms of triple A syndrome. Some individuals with triple A syndrome do not have an identified mutation in the AAAS gene; in these individuals, the genetic cause of the disorder is unknown.[4]
Last updated: 2/9/2011

How is triple A syndrome inherited?

Triple A syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene and are referred to as "carriers" but they typically do not show signs and symptoms of the condition.[2] When 2 carriers for the same autosomal recessive condition have a child, there is a 25% (1 in 4) chance that the child will have the condition, a 50% (1 in 2) chance that the child will be a carrier like each of the parents, and a 25% chance that the child will not have the condition and not be a carrier for the condition.
Last updated: 2/9/2011

How might triple A syndrome be treated?

There is no cure for triple A syndrome at this time; treatment typically focuses on managing individual signs and symptoms of the condition.

Glucocorticoid deficiency in individuals with known adrenal insufficiency (present with Addison disease) is typically treated by replacement of glucocorticoids. This may be important for avoiding an adrenal crisis and allowing for normal growth in children. In adult individuals, as well as those who have difficulty with compliance, replacing hydrocortisone with prednisone or dexamethasone is sometimes recommended. It is usually recommended that affected individuals wear a medical alert bracelet or necklace and carry the emergency medical information card supplied with it.

Achalasia is typically managed with surgical correction. Individuals may be monitored for pulmonary complications (due to reflux and aspiration). Gastric acid reduction therapy in individuals with reflux after surgical intervention is usually recommended. The symptoms in individuals with achalasia may be improved partially with pneumatic dilatation (also called balloon dilation). For those who remain symptomatic after this, other surgeries may be recommended.

Alacrima is typically managed by applying topical lubricants (such as artificial tears or ointments), and with punctal occlusion (a procedure used to close the tear ducts that drain tears from the eye). The symptoms of alacrima typically improve with punctal occlusion. However, this procedure is usually only done when therapy with topical lubricants is unsuccessful.[3]
Last updated: 2/9/2011

How might neuropathy associated with triple A syndrome be treated?

There is limited information available regarding the treatment of neuropathy specific to triple A syndrome. However, the following is general information about how the symptoms of peripheral and autonomic neuropathies are sometimes managed. Individuals that are interested in learning about how to treat their own neuropathy should speak with their health care provider or a neurologist for individual treatment options.

For peripheral neuropathy, a major goal of treatment is to first manage the condition causing the neuropathy. Another goal of treatment is to relieve the painful symptoms. Medications may be used to relieve the pain of peripheral neuropathy. Mild symptoms may be relieved by over-the-counter pain medications. For more severe symptoms, a doctor may recommend prescription painkillers. Anti-seizure medications were originally developed to treat epilepsy; however, some doctors also prescribe them for nerve pain. Tricyclic antidepressant medications were originally developed to treat depression; however, they have been found to help relieve pain as well. Another type of therapy called transcutaneous electrical nerve stimulation (TENS) uses electrodes that are placed on the skin, sending a gentle electric current through the electrodes; some people report this therapy improves symptoms. Other potential remedies include exercise, which may reduce neuropathy pain and can help control blood sugar levels; and massaging of hands and feet, which may improve circulation, stimulate nerves and temporarily relieve pain.[2995]

The National Institute of Neurological Disorders and Stroke (NINDS) has a Peripheral Neuropathy Fact Sheet that includes information about treatments that are available and research that is being done; it can be accessed by clicking here.

Treatment of autonomic neuropathy, like that of peripheral neuropathy, also includes treating the underlying disease and managing the specific symptoms. Gastrointestinal symptoms may be managed by modifying the diet or using dietary supplements. Medications to ease constipation such as laxatives may help ease constipation; increasing the amount of fiber in the diet may also ease constipation. Some doctors may prescribe tricyclic antidepressants to treat diarrhea and abdominal pain. Autonomic neuropathy can cause a number of heart rate and blood pressure problems, which may be managed with medication. For individuals that experience excessive sweating, a doctor may prescribe a medication that decreases perspiration. There is no medication to increase sweating if an individual has lost the ability to sweat.[2996]

Last updated: 2/9/2011

How can we connect with other individuals or families who are affected by triple A syndrome?

Groups that may provide services, supportive resources, and information regarding Addison's disease, achalasia, and/or alacrima are listed under the "Support Groups" tab of this Web page. Some of these groups may have additional information about how to connect with other individuals and/or families affected by triple A syndrome. A list of all of the resources listed for this condition may be accessed by clicking here.
Last updated: 2/9/2011

How can we find out about current research being done regarding treatment for triple A syndrome?

The National Institutes of Health, through the National Library of Medicine, developed ClinicalTrials.gov to provide patients, family members, and members of the public with current information on clinical research studies. While there may not be studies involving triple A syndrome listed at a particular time, there are studies involving the disorders and symptoms associated with triple A syndrome. This site should be checkled often for updates. To search for a study specifically regarding triple A syndrome, you may use "triple A syndrome," "Allgrove," or other names for this condition (which are listed on the left side of this Web site) as your search term. To search for a study involving treatment for a specific symptom or condition associated with triple A syndrome, type in the name of the condition or symptom of interest as your search term.

To see clinical research studies involving achalasia, click here.
To see clinical research studies involving alacrima, click here.
To see clinical research studies involving Addison's disease, click here.
To see clinical reserach studies involving dysautonomia, click here.

You can also contact the Patient Recruitment and Public Liaison (PRPL) Office at the National Institutes of Health (NIH). We recommend calling the toll-free number listed below to speak with a specialist, who can help you determine if you are eligible for any clinical trials.

Patient Recruitment and Public Liaison Office (PRPL)
NIH Clinical Center
Bethesda, Maryland 20892-2655
Toll-free: 1-800-411-1222
Fax: 301-480-9793
E-mail: prpl@mail.cc.nih.gov
Web site: http://clinicalcenter.nih.gov/

If you are interested in enrolling in a clinical trial, you can find helpful general information on clinical trials at the following ClinicalTrials.gov Web page.http://clinicaltrials.gov/ct2/info/understand\

Resources on many charitable or special-fare flights to research and treatment sites and low-cost hospitality accommodations for outpatients and family members, as well as ambulance services, are listed on the Web site of the Office of Rare Diseases Research (ORDR), part of the National Institutes of Health. http://rarediseases.info.nih.gov/Resources.aspx?PageID=8
Last updated: 2/9/2011

References