Pancreatic involvement in EPG5-related disorders

TL;DR

This paper reports pancreatic involvement in patients with EPG5-related Vici syndrome, highlighting the role of autophagy in pancreatic health.

Contribution

The study identifies previously unrecognized pancreatic manifestations in EPG5-related disorders.

Findings

Three patients with EPG5-related Vici syndrome showed pancreatic involvement, including amylase elevations and insufficiency.

Autophagy defects may contribute to pancreatitis through mechanisms like vacuole formation and mitochondrial dysfunction.

The findings expand the known phenotypic spectrum of EPG5-related disorders to include pancreatic dysfunction.

Abstract

Vici syndrome is a severe neurodevelopmental multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. There may be additional variable involvement of other organs. VS is caused by recessive mutations in EPG5, encoding a tethering factor with important roles in autophagy, an essential cellular homeostatic mechanism involved in metabolic adaptation, infection defence and quality control of proteins and organelles.

Acute pancreatitis is an inflammatory syndrome caused by an acute injury resulting in failure of safeguarding mechanisms preventing autodigestion. Chronic pancreatitis is characterized by replacement of pancreatic parenchyma with fibrotic tissue following repeated injury, resulting in endocrine and exocrine insufficiency. In addition to common causes such as excessive ethanol consumption, gallstones and pharmacological factors, there are likely to be additional genetic contributors.

Here we report 3 patients with EPG5-related Vici syndrome and not previously recognized pancreatic involvement, ranging from otherwise asymptomatic amylase elevations to acute pancreatitis and pancreatic insufficiency. A topical literature review on the role of autophagy and autophagy-related genes in the pancreas suggested that autophagy defects may affect critical pathological events involved in pancreatitis, in particular abnormal vacuole formation in acinar cells, inappropriate intra-acinar trypsinogen activation, mitochondrial dysfunction and disturbed calcium homeostasis.

These findings illustrate the importance of EPG5 and other autophagy-related genes in normal pancreatic function and expand the phenotypical spectrum of EPG5-related disorders.

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