Description
Allgrove et al, for the first time in 1978 described two pairs of siblings with glucocorticoid deficiency and achalasia cardia. Three of them also had alacrimia and hence, a new term ‘Triple-A syndrome’ or ‘Allgrove syndrome’ was coined for the combination of these three manifestations.1 Although Triple-A syndrome is classically described as a triad of adrenal insufficiency, alacrimia and achalasia cardia, spectrum of the disease varies widely. Some times it is partially characterized and expressed by only two of the three manifestations (2A syndrome) while most often it is asso-ciated with autonomic neuropathy, deserving the term ‘4A syndrome’.2,3 Some authors suggested the eponym ‘5A syndrome’ to include amyotrophy and other neurological manifestations as fifth component of the syndrome.4
Epidemiology
Triple-A syndrome is a rare disorder and is usually described as case reports, often in fa-milial clusters. It has been reported from different parts of the world. The actual incidence is difficult to estimate because of its rarity and widely variable presentation. Allgrove syndrome is characterized by autosomal recessive pattern of inheritance and most patients have consan-guineous parents. Owing to its autosomal recessive inheritance pattern, the recurrence risk of Allgrove syndrome in future pregnancies of parents with an affected child is 25%. Penetrance of the identified AAAS gene (gene mutated in Triple-A syndrome) defects is close to 100% for Allgrove syndrome (albeit with variable clinical expression) and is characterized by absence of any symptoms in heterozygote carriers.5
Mutation in AAAS gene is a relatively common. An analysis of nine patients with Triple-A, who were carriers of the IVS 14 1G A mutation suggested an estimated age of the mutation of 1000-1175 years.6
Etiology
Common etiologic factor affecting the three organ systems (esophagus, lacrimal glands and adrenal glands) with different function and location remained enigmatous until recently. Although initially it appeared that mutations in the ACTH receptor gene would provide the link for the association of the triad manifestations of Allgrove syndrome, it could not be proven.8,9 Triple-A syndrome was also considered to be a variant of familial glucocorticoid deficiency (FGD) due to the presence of ACTH insensitivity in both the disorders. However, no abnormality was found in the ACTH receptor gene, located on the short arm of chromosome 18 (18p11.2), which is responsible for FGD.9
Several initial linkage analyses failed to localize the gene for Triple-A syndrome. In 1996 Weber et al succeeded to locate the gene for the Triple-A syndrome to chromosome 12q13 near the type II keratin gene cluster.10 The gene was located on a chromosomal segment, flanked by the mark-ers D12S1629 and D12S312, which are 6cM apart.10 In 2001, Handschug et al identified the 16 exons in AAAS gene.11
AAAS gene shows ubiquitous expression in human tissues with particularly abundant ex-pression in the adrenal gland, gastrointestinal structures, pituitary gland, cerebellum and fetal lung.11 It codes for a protein called ALADIN for alacrima, achalasia, adrenal insufficiency and neurological disorder.12
ALADIN is a protein belonging to the WD repeat family.13 Proteins, belonging to this family, have a wide functional diversity and are involved in protein-protein interactions, signal transduc-tion, RNA processing, vesicular trafficking, cytoskeleton assembly and cell division control.11 The exact function of ALADIN protein is not known but proteomic analysis has shown it to be a part of the mammalian nuclear pore complex (NPC). NPC is critical for communication between the nucleus and the cytoplasm of cells.14 When AAAS gene is mutated, ALADIN protein mislocalizes to the cytoplasm, rather than to NPC.15 However microscopic analysis of cells from a Triple-A syndrome patient showed no morphologic abnormalities in NPC, suggesting that mutation in AAAS results in a functional rather than a structural abnormality in NPC.15
Hirano et al16 reported impaired nuclear import of DNA repair proteins, including DNA ligase I and the cerebellar ataxia causative protein ‘aprataxin’ in a patient with Allgrove syn-drome. They also proposed that oxidative stress aggravates nuclear import failure which is already compromised in patient cells and consequent DNA damage may participate in trig-gering cell death. Takao et al17 showed that nuclear import dysfunction could be overcome by fusing classical nuclear localization signal (NLS) and 137-aa downstream sequence of XRCC1, designated stretched NLS (stNLS). They found that minimum essential sequence of stNLS (mstNLS) is residues 239-276, downsized by more than 100 amino acids and mstNLS enables efficient nuclear import of DNA repair proteins in patient fibroblasts, functioned under oxidative stress and reduced oxidative-stress-induced cell death, more effectively than stNLS. They concluded that this finding may have some therapeutic implications in the management of Allgrove syndrome.
Various mutations have been reported in AAAS gene including both coding regions and inter-vening sequences (Table 1). Most of the reported mutations produce a truncated protein, although missense and point-mutations have also been reported.18 Most commonly reported mutation is IVS 14 1 G A which leads to premature termination of predicted protein.19 Chromosome and/or chromatid breaks, whole chromosome arm deletions, marker chromosomes involving 9q12, a heterochromatic region known to be a fragile site, have also been demonstrated in subjects with Triple-A syndrome.20