ESPE Abstracts (2015) 84 P-1-5


Genetic Heterogeneity in Triple A Syndrome: Discrimination of the Classic Syndrome from Two Triple A-Like Syndromes

Angela Huebnera, Felix Reschkea, Ingo Kurthb, Susann Kutznera, Eda Utinec, Filiz Hazand, Dana Landgrafa, Christian A Hübnerb & Katrin Koehlera


aDepartment of Paediatrics, Technische Universität, Dresden, Germany; bDepartment of Human Genetics, University Hospital, Jena, Germany; cDepartment of Pediatric Genetics, Ihsan Dogramaci Childrens Hospital, Hacettepe University, Ankara, Turkey; dDepartment of Medical Genetics, Dr Behçet Uz Children’s Hospital, Izmir, Turkey

Background: Triple A syndrome is a rare autosomal recessive disorder characterized by adrenal failure, alacrima, achalasia, and a variety of neurological features. In 70% of the families it is caused by mutations in the AAAS gene. Linkage analyses indicated genetic heterogeneity and exome sequencing revealed two further genes causing triple A-like syndromes.

Objective and hypotheses: To summarise the genotypes and phenotypes of classic triple A syndrome in comparison to two novel triple A-like syndromes.

Method: Clinical and genetic analysis of more than 250 patients with suspected triple A syndrome.

Results: In classic triple A syndrome due to AAAS mutations adrenal insufficiency occurs in 77.1%, achalasia in 85.1%, and alacrima in 89.7% of all patients. Most patients (72.8%) display neurological impairment, most frequently distal muscular weakness, hyperreflexia, nasal speech, and autonomic dysfunction. Mutations in GDP-mannose pyrophosphorylase A (GMPPA) cause a triple A-like syndrome characterized by alacrima, delayed developmental milestones, and speech delay (each 100%), intellectual disability (91.6%) and achalasia (84.6%). None of the worldwide 13 known patients developed adrenal insufficiency. The disorder caused by GMPPA mutations represents a novel congenital disorder of glycosylation. Recently we identified a homozygous splice mutation in a novel gene in four patients from two independent families. These patients suffer from achalasia, alacrima, short stature, developmental delay, seizures, and cerebral atrophy, but also lack adrenal insufficiency. The protein product seems to be important for an intact Golgi apparatus.

Conclusion: There are at least two novel diseases who display overlapping features with classic triple A syndrome. Protein products are involved in different cellular pathways. Clinicians should be aware of this genetic heterogeneity in terms of genetic and clinical counselling. All known patients with triple A-like disorders are still young so that we cannot exclude that they develop adrenal failure at a later time.

Funding: This work was supported by the German Research Society (HU 895/3-3, 3-4, 3-5, 4-1, 5-1, 5-2).

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