Identification of two novel and four known mutation in the AAAS gene in unrelated Turkish Families

Abstract

Abstract Aim Triple-A Syndrome(TAS) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia, and alacrimia. This disorder is caused by mutations in the AAAS gene. The aim of this study is to discuss the clinical, laboratory and molecular genetic analysis results of who were diagnosed with TAS. Method We evaluated 12 patients from 8 families. All exons and exon-intron junctions of the AAAS gene were evaluated by next generation sequencing method. Detected variants were classified according to American Collage of Medical Genetics criteria. Results Alacrimia was found in all of them(100%); achalasia was found in 10 patients(83.3%) and adrenal insufficiency was found in 10 patients(83.3%). In addition, hyperreflexia(6/12), learning disability(5/12), hypernasal speech(5/12), muscle weakness(8/12), delayed walking(7/12), delayed speech(6/12), excessive sweating(7/12), optic atrophy(1/12), epilepsy(1/12), palmoplantar hyperkeratosis(5/12), multiple dental caries(9/12), atrophy of the thenar/hypothenar muscles(4/12) and short stature(4/12) were detected. The DHEA-S levels were measured in 10 patients and were found to be low in 8 of them. In all patients, the sodium and potassium levels were found to be normal. Six different homozygous pathogenic variants, 2 of which had not been previously reported, were detected. Conclusion We detected two novel variants in the AAAS gene. The earliest sign of TAS is alacrimia. In all cases, particularly with alacrimia or achalasia, adrenal insufficiency should be investigated and if necessary, genetic analysis should be performed for TAS. Additionally, in patients diagnosed with TAS, apart from the classic triad, especially neurological dysfunction and skin and dental pathologies should be investigated and followed up with a multidisciplinary approach.