Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant of the AAAS gene

Abstract Allgrove syndrome is a rare, multisystem, autosomal recessive disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency. Various and nonspecific neurological symptoms can also develop over time, “blurring” the typical course of this underdiagnosed condition. The incidence of Allgrove syndrome is unknown, Orphanet reports fewer than 100 published cases, but according to literature review, at least 206 patients have been already described. The pathogenic variant p.Ser263Pro is one of the most recurrent aberration affecting AAAS gene and have been reported in several families of Slavic origin. We investigated genotype-phenotype correlation in 206 patients with AS described in literature (including two novel Polish siblings carrying a homozygous p.Ser263Pro variant in the AAAS gene) and found that neurological symptoms were significantly more common among carriers of p.Ser236Pro variant (33 out of 34; 97.05%) as compared to other AAAS mutation carriers (133 out of172; 77.3%, p = 0.006). While the incidence of the classical clinical triad of AS was similar and observed in 110 out of 206 AS patients (53.4%) and in 18 out of 34 (52.9%) among p.Ser263Pro variant carriers. Furthermore our report supports the hypothesis of a founder mutation p.Ser263Pro of AAAS gene in a European Caucasian population, probably of Slavic origin- since 25out of 36 reported variant carriers were of Slavic origin (69.4%) and 17 out of 23(73.9%) who were homozygous for p.Ser263Pro mutation came from Slavic region. Summarizing, neurological manifestations of AS predominate in patients carrying a potentially founder p.Ser263Pro variant with the AAAS gene.