Triple A Syndrome
Edit

Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima.

genetic conditions

1. Introduction

Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. 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 a reduced or absent ability to secrete tears (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. They 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. Frequency

Triple A syndrome is a rare condition, although its exact prevalence is unknown.

3. Causes

Mutations in the AAAS gene cause triple A syndrome. 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.

Mutations in the AAAS gene change the structure of ALADIN in different ways; however, almost all mutations prevent this protein from reaching its proper location in the nuclear envelope. The absence of ALADIN in the nuclear envelope likely disrupts the movement of molecules across this membrane. 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. The genetic cause of the disorder is unknown in these individuals.

4. Inheritance

This condition 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, but they typically do not show signs and symptoms of the condition.

5. Other Names for This Condition

  • AAA
  • AAA syndrome
  • Achalasia-addisonian syndrome
  • Achalasia-Addisonianism-Alacrima syndrome
  • Achalasia-alacrima syndrome
  • Alacrima-achalasia-adrenal insufficiency neurologic disorder
  • Allgrove syndrome

References

  1. Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, Bei T,Bjornson B, Russell L, Chanoine JP, Tsagarakis S, Kalsner L, Stratakis C.Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005. Clin Genet. 2005 Sep;68(3):215-21.
  2. Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple Asyndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum MolGenet. 2001 Feb 1;10(3):283-90.
  3. Kind B, Koehler K, Lorenz M, Huebner A. The nuclear pore complex proteinALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope.Biochem Biophys Res Commun. 2009 Dec 11;390(2):205-10. doi:10.1016/j.bbrc.2009.09.080.
  4. Kiriyama T, Hirano M, Asai H, Ikeda M, Furiya Y, Ueno S. Restoration ofnuclear-import failure caused by triple A syndrome and oxidative stress. Biochem Biophys Res Commun. 2008 Oct 3;374(4):631-4. doi: 10.1016/j.bbrc.2008.07.088.
  5. Prpic I, Huebner A, Persic M, Handschug K, Pavletic M. Triple A syndrome:genotype-phenotype assessment. Clin Genet. 2003 May;63(5):415-7.
  6. Storr HL, Kind B, Parfitt DA, Chapple JP, Lorenz M, Koehler K, Huebner A,Clark AJ. Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism. MolEndocrinol. 2009 Dec;23(12):2086-94. doi: 10.1210/me.2009-0056.
  7. Tullio-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, de Laet MH, Chaouachi B,Bakiri F, Brottier P, Cattolico L, Penet C, Bégeot M, Naville D, Nicolino M,Chaussain JL, Weissenbach J, Munnich A, Lyonnet S. Mutant WD-repeat protein intriple-A syndrome. Nat Genet. 2000 Nov;26(3):332-5.
More
Related Content
This entry reviews the health condition known as Roemheld syndrome, or gastrocardiac syndrome in modern medicine. A pathology of gastrointestinal origin, the syndrome relies on a gut–brain–heart triad, interconnected by the vagus nerve. Pressure from the intestines pushes the stomach into the diaphragm and activates the vagus nerve, which affects the heart rate and gives the perception of cardiac issues. This distressing sensation, which usually comes after meals or with other digestive problems, causes anxiety or panic. Although events not arising from anatomic abnormalities are relatively harmless, hypersensitivity to these uncomfortable sensations may precipitate psychiatric problems (anxiety or depression) that cause repeated gastrocardiac events through sympathetic activation and the disruption of peristalsis. Treatment is usually symptomatic and may include diet, lifestyle changes, probiotics, or prescriptions that increase gut motility, but this specific set of reproducible symptoms may also be caused by hiatal hernia or side effects from medication/surgery and treated with respect to those mechanical causes. This review highlights details from the most current knowledge of the condition and offers suggestions for clinical management based on the literature.
Keywords: Roemheld; gastrocardiac; IBS; SIBO; vagus
The human gut is a complex ecosystem that supports billions of living species, including bacteria, viruses, archaea, phages, fungi, and unicellular eukaryotes. Bacteria give genes and enzymes for microbial and host-produced compounds, establishing a symbiotic link between the external environment and the host at both the gut and systemic levels. The gut microbiome, which is primarily made up of commensal bacteria, is critical for maintaining the healthy host’s immune system, aiding digestion, synthesizing essential nutrients, and protecting against pathogenic bacteria, as well as influencing endocrine, neural, humoral, and immunological functions and metabolic pathways. Qualitative, quantitative, and/or topographic shifts can alter the gut microbiome, resulting in dysbiosis and microbial dysfunction, which can contribute to a variety of noncommunicable illnesses, including hypertension, cardiovascular disease, obesity, diabetes, inflammatory bowel disease, cancer, and irritable bowel syndrome. While most evidence to date is observational and does not establish direct causation, ongoing clinical trials and advanced genomic techniques are steadily enhancing our understanding of these intricate interactions. This video will explore key aspects of the relationship between gut microbiota, eubiosis, and dysbiosis in human health and disease, highlighting emerging strategies for microbiome engineering as potential therapeutic approaches for various conditions.
Keywords: gut barrier; gut microbes; intestinal permeability; leaky gut; microbiome
Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G>A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G>C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients.
Keywords: Wolfram syndrome type 1; optic atrophy; insulin-requiring diabetes mellitus; sensorineural deafness
In this video, we get to understand how pathological changes are reflected in clinical signs.
Keywords: Amoebiasis; Dysentery; Entamoeba histolytica; Protozoan infections; Pathology; Clinical presentation
Understand the stages of heart failure and learn how early detection can improve outcomes and potentially save lives.
Keywords: Systolic and diastolic heart failure; Maintaining good heart health; appropriate management
Information
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 583
Entry Collection: MedlinePlus
Revision: 1 time (View History)
Update Date: 23 Dec 2020
Video Production Service