Phenotype–genotype spectrum of AAA syndrome from Western India and systematic review of literature

Abstract

ObjectiveTo study genotype–phenotype spectrum of triple A syndrome (TAS).MethodsRetrospective chart analysis of Indian TAS patients (cohort 1, n = 8) and review of genotyped TAS cases reported in world literature (cohort 2, n = 133, 68 publications).ResultsMedian age at presentation was 4.75 years (range: 4–10) and 5 years (range: 1–42) for cohorts 1 and 2, respectively. Alacrima, adrenal insufficiency (AI), achalasia and neurological dysfunction (ND) were seen in 8/8, 8/8, 7/8 and 4/8 patients in cohort 1, and in 99, 91, 93 and 79% patients in cohort 2, respectively. In both cohorts, alacrima was present since birth while AI and achalasia manifested before ND. Mineralocorticoid deficiency (MC) was uncommon (absent in cohort 1, 12.5% in cohort 2). In cohort 1, splice-site mutation in exon 1 (p.G14Vfs*45) was commonest, followed by a deletion in exon 8 (p.S255Vfs*36). Out of 65 mutations in cohort 2, 14 were recurrent and five exhibited regional clustering. AI was more prevalent, more often a presenting feature, and was diagnosed at younger age in T group (those with truncating mutations) as compared to NT (non-truncating mutations) group. ND was more prevalent, more common a presenting feature, with later age at onset in NT as compared to T group.ConclusionClinical profile of our patients is similar to that of patients worldwide. Alacrima is the earliest and most consistent finding. MC deficiency is uncommon. Some recurrent mutations show regional clustering. p.G14Vfs*45 and p.S255Vfs*36 account for majority of AAAS mutations in our cohort. Phenotype of T group differs from that of NT group and merits future research.

Two novel truncating variants of the AAAS gene causative of the triple A syndrome

“…The AAAS diagnosis is difficult because of its rarity (the prevalence of disease is unknown) and clinical onset heterogeneity. Being AAAS a multisystem and progressive disease, the diagnosis could be delayed, due to the long latency observed between the first and the others known signs of the pathognomonic triad [27].…”

Triple A syndrome presenting as complicated hereditary spastic paraplegia

“…Our current findings support this suggestion, and it is possible that earlier diagnosis could have been achieved, especially in family B, had these been the recommendations. Of note, early genetic testing and diagnosis can prevent lethal adrenal crises, as patients are at risk for cortisol deficiency (Grant et al, ; Patt et al, ). Therefore, we reiterate the need to consider triple A syndrome in patients diagnosed with complicated HSP or other neurological disorders with at least one of the classical triple A syndrome symptoms.…”

Genetic Heterogeneity in Adrenal Insufficiency

“…AS, or Triple-A syndrome, a specific form of adrenal unresponsiveness to ACTH, is a rare autosomal recessive disease caused by mutations in "ALacrima Achalasia aDrenal Insufficiency Neurologic disorder" (ALADIN) protein, a tryptophan/aspartate WD-repeat-containing protein of the nuclear pore complex, encoded by gene AAAS, which is located on chromosome 12. ALADIN mutations are mainly missense and nonsense mutations, but also deletions have been reported (Sarathi and Shah 2010;Patt et al 2017). These mutations seem to induce DNA damage through the lack of repair mechanisms and the increase in oxidative DNA injury (Sarathi and Shah 2010).…”

“…Alacrimia usually occurs as first AS manifestation, since neonatal age or during early infancy, although it is rarely identified. Conversely, achalasia and PAI occur during the first decade of life, from infancy to childhood (Sarathi and Shah 2010;Patt et al 2017). Achalasia usually manifests in infants with recurrent pulmonary diseases due to aspiration, whereas in older children and adults with dysphagia (Sarathi and Shah 2010).…”

“…Achalasia usually manifests in infants with recurrent pulmonary diseases due to aspiration, whereas in older children and adults with dysphagia (Sarathi and Shah 2010). In the majority of cases, PAI is characterized by isolated glucocorticoid deficiency, although up to 26% of patients may also show mineralocorticoid deficiency; other specific clinical features are represented by hypoglycemic episodes and skin hyperpigmentation (Sarathi and Shah 2010;Patt et al 2017). Besides the disease-specific classic clinical triad, AS patients also experience neurological impairment, including autonomic alterations, distal sensory and motor polyneuropathy, and mental retardation.…”