Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three
cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity.
Various progressive neurological abnormalities and skin changes have been described in association
with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome
12q13. Mutations in AAAS were identified in more than 90% of individuals and families with TAS.
The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of
proteins, that have been found to be involved in many different functions such as protein-protein
interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction
and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes
to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the
mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless,
recent studies provided some insights on the role of ALADIN as a member of the Nuclear
Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative
stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification
of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity
even among members of the same family. In this review, we aim to summarize the current
knowledge of clinical and molecular profile of patients with TAS and recommendations for the
diagnosis, management, and follow-up of patients.
Keywords: Triple-A Syndrome, AAAS gene, aladin, adrenal insufficiency, achalasia, alacrimia, 4A syndrome, 5A syndrome.
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