THU232 Genetic Study In A Series Of 29 Triple A Syndrome Patients From 19 Sudanese Families - Identification Of Two Novel AAAS Mutations

Abstract Disclosure: K. Koehler: None. F. Quitter: None. D. Landgraf: None. E. Streiff: None. M.A. Abdullah: None. S.S. Hassan: None. A. Huebner: None. S.A. Musa: None. Triple A syndrome (MIM*231550) is a rare autosomal recessive multisystemic disorder characterized by adrenal insufficiency, achalasia, alacrima and neurologic impairments. It is caused by defects in the nucleoporin ALADIN due to mutations in the encoding AAAS gene. We report the genetic and clinical data of triple A syndrome in a series of Sudanese children treated at the Gaafar Ibn Auf Children’s Tertiary Hospital, the largest children's referral hospital in Sudan. The initial diagnosis of triple A syndrome was based on pathognomonic clinical signs and symptoms. Furthermore, early morning serum cortisol levels below the reference range (<6 μg/dl) with high ACTH levels (>100 pg/ml) and/or cortisol below 500 nmol/l in an ACTH stimulation test as well as pathological barium swallow and Schirmer-test were criteria for diagnosis. The medical diagnosis was finally confirmed by mutation detection in the AAAS gene.We genetically investigated 19 families including 29 patients with clinically diagnosed triple A syndrome. We identified six different AAAS mutations mainly in a homozygous form including three nonsense mutations, one frameshift mutation leading to a truncated protein and two splice defects, among them the North African founder mutation c.1331+1G>A (intron 14) in 32 % (6 families). An 8 bp-deletion at the junction of exon 4/intron 4 in two families is a novel, yet undescribed mutation (c.394_399+2delCTGTCTGT). As this mutation destroys a donor splice site, it results in alternative splicing skipping exon 4, altering the protein sequence after amino acid E102 and leading to a premature stop codon shortly after. This is most likely associated with functional impairment of the truncated ALADIN protein. The second novel AAAS mutation is a 1 bp-deletion in exon 9 in three families, which results in a frameshift at amino acid tryptophan 284 and consequently a premature stop codon at position 7 of the new reading frame (c.852_852delG, p.Trp284Cysfs*7, or shortly p.W284fs). The most frequent mutation in this large Sudanese patient series was a previously described mutation in exon 9 (c.934C>T, p.Arg312*) present in 37 % (seven families).Genotype/phenotype analyses revealed a highly variable occurrence of the three main symptoms, age of onset and severity of the disease between patients with the same AAAS mutation and even within one family. The rate of 95 % mutations in a homozygous form reflects the high rate of consanguinity in the Sudanese population.In summary, triple A syndrome seems to be an underdiagnosed disease outside a specialized paediatric endocrinological department in Sudan as many cases presented late with adrenal crises. An early molecular genetic diagnosis, e.g. in siblings, can be important to avoid hypoglycaemic crises with a potential lethal outcome. Presentation: Thursday, June 15, 2023