Triple A syndrome - Rare Neurology News

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Disease Profile

Triple A syndrome

<1 >

US Estimated

Europe Estimated

Age of onset

All ages

ICD-10

E27.4

Inheritance

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.

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Achalasia Addisonianism Alacrimia syndrome; AAA syndrome; AAA;

Summary

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. Several authors published descriptions of a more global autonomic disturbance associated with the original three characteristics, leading one author to suggest the name 4A syndrome (adrenal insufficiency, achalasia, alacrima, autonomic abnormalities). Specific autonomic disturbances described in this syndrome include abnormal pupillary reflexes, poor heart rate variability, and orthostatic hypotension. Affected individuals may also have 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]^[2] Alacrimia is treated with artificial tears while achalasia may need surgery with either pneumatic dilatation or Heller's myotomy. Adrenal insufficiency is treated with glucocorticoid and if necessary mineralocorticoid replacement.^[1]

Symptoms

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.^[2]^[1]

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. Adults may exhibit progressive neural degenearation, parkinsonism features and cognitive impairment.^[1] 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.^[2]^[1]

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]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Achalasia		0002571
Adrenal insufficiency		0000846
Generalized hyperpigmentation		0007440
Seizure		0001250
30%-79% of people have these symptoms
Palmoplantar keratoderma	Thickening of palms and soles	0000982
Short stature	Decreased body height Small stature [ more ]	0004322
Visual impairment	Impaired vision Loss of eyesight Poor vision [ more ]	0000505
5%-29% of people have these symptoms
Abnormality of the calf musculature	Abnormal calf muscles	0001430
Abnormality of the hypothenar eminence		0010486
Anterior hypopituitarism		0000830
Ataxia		0001251
Developmental regression	Loss of developmental milestones Mental deterioration in childhood [ more ]	0002376
Hyperreflexia	Increased reflexes	0001347
Iris coloboma	Cat eye	0000612
Microcephaly	Abnormally small skull Decreased circumference of cranium Decreased size of skull Reduced head circumference Small head circumference [ more ]	0000252
Motor axonal neuropathy		0007002
Muscular hypotonia	Low or weak muscle tone	0001252
Optic atrophy		0000648
Pes cavus	High-arched foot	0001761
Plantar hyperkeratosis		0007556
Respiratory insufficiency	Respiratory impairment	0002093
Sensorineural hearing impairment		0000407
Percent of people who have these symptoms is not available through HPO
Abnormal autonomic nervous system physiology		0012332
Abnormality of visual evoked potentials		0000649
Adrenocorticotropin receptor defect		0008259
Anisocoria	Asymmetric pupil sizes Asymmetry of the pupils Unequal pupil size [ more ]	0009916
Autosomal recessive inheritance		0000007
Babinski sign		0003487
Childhood onset	Symptoms begin in childhood	0011463
Decreased circulating aldosterone level	Low blood aldosterone level	0004319
Decreased circulating cortisol level	Low blood cortisol level	0008163
Dysarthria	Difficulty articulating speech	0001260
Global developmental delay		0001263
Hyperpigmentation of the skin	Patchy darkened skin	0000953
Intellectual disability	Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ]	0001249
Muscle weakness	Muscular weakness	0001324
Orthostatic hypotension	Decrease in blood pressure upon standing up	0001278
Palmoplantar hyperkeratosis	Thickening of the outer layer of the skin of the palms and soles	0000972
Progressive	Worsens with time	0003676

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Cause

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.^[2]

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Orphanet lists international laboratories offering diagnostic testing for this condition.

Treatment

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.^[1]

Related diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Given that the presence of 2 among the 3 main clinical signs (achalasia, alacrima or adrenal insufficiency) is pathognomonic, differential diagnosis can be considered when only one clinical sign is observed, for example at the onset of the disease. Differential diagnosis thus includes other causes of adrenal insufficiency, achalasia or alacrima such as frequent forms of congenital adrenal hyperplasia (easily excluded with dosage of adrenal hormones precursors), and rare peripheral forms of congenital adrenal insufficiency or adrenoleukodystrophy, which might be associated with neurological features. Visit the Orphanet disease page for more information.

Conditions with similar signs and symptoms from Orphanet

Given that the presence of 2 among the 3 main clinical signs (achalasia, alacrima or adrenal insufficiency) is pathognomonic, differential diagnosis can be considered when only one clinical sign is observed, for example at the onset of the disease. Differential diagnosis thus includes other causes of adrenal insufficiency, achalasia or alacrima such as frequent forms of congenital adrenal hyperplasia (easily excluded with dosage of adrenal hormones precursors), and rare peripheral forms of congenital adrenal insufficiency or adrenoleukodystrophy, which might be associated with neurological features.

Visit the Orphanet disease page for more information.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Addison's Disease Self Help Group
Website: https://www.addisons.org.uk/
Martin Mueller IV Achalasia Awareness Foundation, Inc
111 Hampton Meadows Dr
Bonaire, GA 31005
Telephone: (478) 293-1822
E-mail: [email protected]
Website: https://www.achalasiainfo.com/
National Dysautonomia Research Foundation
P.O. Box 301
Red Wing, MN 55066-0301
Telephone: 651-267-0525
Fax: 651-267-0524
E-mail: [email protected]
Website: https://www.ndrf.org

Organizations Providing General Support

International Foundation for Functional Gastrointestinal Disorders (IFFGD)
3015 Dunes West Blvd. Suite 512
Mount Pleasant, SC 29466
Telephone: +1-414-964-1799
Website: https://iffgd.org/

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

Genetics Home Reference (GHR) contains information on Triple A syndrome. This website is maintained by the National Library of Medicine.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Triple A syndrome. Click on the link to view a sample search on this topic.

References

Boston BA & Marks DL. Allgrove (AAA) Syndrome. Medscape Reference. February 27, 2013; https://emedicine.medscape.com/article/919360-treatment.
Triple A syndrome. Genetics Home Reference. February 2010; https://ghr.nlm.nih.gov/condition/triple-a-syndrome. Accessed 9/24/2015.

Rare Neurology News

Rare Neurology News

Rare Neurology News

All ages

E27.4

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Cause

Diagnosis

Testing Resources

Treatment

Related diseases

Organizations

Organizations Supporting this Disease

Organizations Providing General Support

Learn more

Where to Start

In-Depth Information

References

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.