Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe.

The triple A syndrome is caused by autosomal recessively inherited mutations in the AAAS gene and is characterized by achalasia, alacrima and adrenal insufficiency as well as progressive neurological impairment. We report on a 14-year-old girl with slowly progressive axonal motor neuropathy with conspicuous muscle wasting of hypothenars and calves as well as alacrima. The mutation analysis of the AAAS gene revealed a compound heterozygous mutation: a c.251G>A mutation in exon 2 that had been reported previously, and a novel c.1288C>T mutation in exon 14. At the transcriptional level, the c.251G>A transition results in an aberrant splicing and decay of this RNA strand so that the particular clinical picture results from the novel c.1288C>T, (p.Leu430Phe, L430F) mutation in a hemizygous form. With transfection experiments, we demonstrate that GFP-ALADIN(L430F) correctly localizes to nuclear pore complexes. Therefore, we conclude that this point mutation impairs ALADIN function at the nuclear pore.