Current management of the gastrointestinal complications of systemic sclerosis.

Systemic sclerosis is a multisystem autoimmune disorder that involves the gastrointestinal tract in more than 90% of patients. This involvement can extend from the mouth to the anus, with the oesophagus and anorectum most frequently affected. Gut complications result in a plethora of presentations that impair oral intake and faecal continence and, consequently, have an adverse effect on patient quality of life, resulting in referral to gastroenterologists. The cornerstones of gastrointestinal symptom management are to optimize symptom relief and monitor for complications, in particular anaemia and malabsorption. Early intervention in patients who develop these complications is critical to minimize disease progression and improve prognosis. In the future, enhanced therapeutic strategies should be developed, based on an ever-improving understanding of the intestinal pathophysiology of systemic sclerosis. This Review describes the most commonly occurring clinical scenarios of gastrointestinal involvement in patients with systemic sclerosis as they present to the gastroenterologist, with recommendations for the suggested assessment protocol and therapy in each situation

A novel deep-intronic de novo WDR45/WIPI4 mutation causes impaired selective autophagy in BPAN

Here we report the first deep-intronic de novo mutation in WDR45 (splice, c.235+159C>G) which was found by a phenotypically driven sequencing approach leveraging the unique MRI features of BPAN. mRNA analysis of the splice effect revealed an aberrant WDR45 transcript resulting in a frameshift with significantly reduced WDR45 mRNA levels. We next studied this loss-of-function mutation in patient derived fibroblasts as a paradigmatic model to elucidate the process of autophagy underlying BPAN. Altered LC3-I and LC3-II levels confirmed a block in autophagic flux. Automated image-based analysis unravelled a decrease of WIPI2-positive autophagosomal membranes. Likewise, despite overall increased p62 levels, less WIPI2 colocalized with the autophagy cargo receptor p62, suggesting that selective autophagy is compromised in BPAN fibroblasts. In sum, our results indicate that (i) identifying de novo variations in the deep-intronic space might allow molecular diagnosis in so far unsolved BPAN/NBIA patients, and (ii) that deficits in particular in selective autophagy may present a key mechanism causative for BPAN