Adult Proinsulinomatosis Associated With a MAFA Germline Mutation as a Rare Cause of Recurrent Hypoglycemia.

ABSTRACT: Sporadic adult insulinomatosis is an extremely rare clinical condition. Adult proinsulinomatosis has not yet been described. We report the case of a 48-year-old female patient with recurrent hypoglycemia caused by benign proinsulin-secreting pancreatic neuroendocrine neoplasias (pNENs) with no history of multiple endocrine neoplasia type 1. Initial workup revealed elevated serum proinsulin levels and a positive fasting test. Magnetic resonance imaging and endosonography visualized 2 pNENs in the pancreatic body and tail that were treated by robotic-assisted enucleation. After initial biochemical cure, the patient's hypoglycemia recurred 3 months after surgery. Imaging showed a new lesion in the pancreatic body, so that now a spleen-preserving subtotal distal pancreatectomy was performed. The pathological examination revealed 17 neuroendocrine microadenomas and 1 well-differentiated pNEN (Ki-67% 1%-2%) of 22-mm size as well as more than 200 (pro)insulin-producing ß-cell precursor lesions, confirming the diagnosis of adult proinsulinomatosis. Mutation analysis of the germline DNA identified the in-frame deletion mutation (p.His207del) in the MAFA gene on chromosome 8. The patient was biochemically cured 16 months after the last surgical resection. Similarly to adult insulinomatosis, the presence of proinsulin-secreting tumors causes recurrent hypoglycemia and might be associated with germline mutations in the MAFA gene.

Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells.

α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) in insulinomas: Indications and clinical relevance in a single investigator cohort of 47 patients.

PURPOSE: This study was aimed to investigate the role and relevance of endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of insulinomas. METHODS: We have analysed the frequency, clinical indications, success rate (obtaining diagnostic tissue), diagnostic accuracy (in comparison to the pathological diagnosis after surgery), complications, and tolerability of endoscopic ultrasound-guided fine-needle aspiration biopsy and the localization and size of the lesions in 47 consecutive patients (29 females, 18 males; 46 ± 15 years) who had surgery for insulinoma following fasting test and were explored by single investigator EUS 1994-2015. RESULTS: Endoscopic ultrasound-guided fine-needle aspiration biopsy was performed in 21 % (10/47) of the patients. The clinical indications for endoscopic ultrasound-guided fine-needle aspiration biopsy were non-conclusive result of fasting test (n = 7), missing toxicology (n = 2), suspected malignancy at EUS (n = 1), suspicious extra-pancreatic localization of the lesion (n = 1). The diagnostic success rate of the procedure was 80 % (8/10 cases), the diagnostic accuracy of the fine-needle aspiration biopsy 70 % (7/10 cases). The lesions undergoing endoscopic ultrasound-guided fine-needle aspiration biopsy were localized in the cauda (n = 5), corpus (n = 2), caput/processus uncinatus (n = 3), the diameter of the tumors was 21 ± 18 (10-70) mm. Only one accidental vascular puncture without any clinical complication occurred and all patients tolerated the procedure well. CONCLUSIONS: In the majority of cases, positive fasting test, negative toxicology, and detection of a typical pancreatic lesion at endoscopic ultrasound is sufficient for the diagnosis of insulinoma and the definition of the appropriate surgical strategy. Based on our data, we suggest including endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of organic hyperinsulinism in selected patients with inconclusive or uncertain diagnosis before surgery.

Trifluoperazine rescues human dopaminergic cells from wild-type α-synuclein-induced toxicity.

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species.