G.P.59: Muscle pathology as a diagnostic clue to Allgrove syndrome

Abstract

Allgrove or triple A syndrome is an autosomal-recessive disorder caused by mutations in the AAAS gene, coding for the nucleoporin ALADIN. While the eponymous combination of Achalasia, Addisonianism and Alacrimia seems hard to miss, these cases are a diagnostic challenge when this trias is incomplete and other neurological signs from a broad range of associated symptoms predominate. This was the case with a 15year old boy from a consanguineous family suffering from progressive distal limb muscle weakness and atrophy as well as mild learning disability, whose muscle and sural nerve biopsy samples we received. No abnormalities of the sural nerve were found, but the gastrocnemius muscle sample showed considerable fatty replacement, increased endo- and perimysial connective tissue, rounded fibre profiles, increased fibre size variability, increased internalised myonuclei and nuclear clumps, numerous degenerating and some regenerating fibres, massive fibre splitting and many whirled fibres as well as some rimmed vacuoles, few target fibres, but more frequent targetoid/ core-like lesions. Conspicuous nuclear inclusions in electron microscopy and particularly reduced immunoreactivity with an antibody against lamin A/C led us to suspect a nuclear pathology. When he developed dysphagia due to achalasia, sequencing of the AAAS gene was initiated, revealing homozygous c.762delC mutations in exon 8 leading to a premature stop of translation due to frameshift (p.S255V fs ∗ 35). Adrenal deficiency and autonomic dysfunction can result in life threatening situations for these patients, but can be addressed by symptomatic medication. Thus making the diagnosis in time is important. Triple A syndrome with its variable, multi-system symptoms including optic atrophy, cerebellar ataxia, upper and lower motoneuron signs and various neuropathic presentations is a differential diagnosis for mixed pathologies with signs of nuclear changes that myopathologists need to be aware of.