Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes.

BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia-parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD). OBJECTIVES: Our aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants. METHODS: We collected clinical, imaging, and molecular information of eight individuals from four AD-MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD-MPAN patients, AR-MPAN patients, and controls. RESULTS: We identified four heterozygous C19orf12 variants in eight AD-MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late-onset phenotype. Fibroblasts from AD-MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR-MPAN cells. CONCLUSION: Our data add strong evidence of the realness of AD-MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD-MPAN than in AR-MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Case report: Parsonage-turner syndrome in a melanoma patient treated by BRAF/MEK inhibitors after immune checkpoint inhibitors.

Introduction: Combination molecular BRAF/MEK inhibitors targeted therapy has been shown to improve overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events but neurological adverse events (nAEs) remain rare. Case report: A 42-year-old woman diagnosed with metastatic melanoma presented with an intense pain in the left shoulder 7 days after the beginning of encorafenib/binimetinib after immune checkpoint inhibitors (ICI) combination. No other triggering factors were identified. Electromyogram performed one month after the pain onset revealed a left brachial plexopathy suggestive of a Parsonage-Turner syndrome. The weakness slowly improved with intensive rehabilitation and targeted therapies were continued. Conclusion: We report the first case of Parsonage-Turner syndrome in a melanoma patient treated with encorafenib/binimetinib following checkpoint inhibitors combination.We cannot rule out the implication of ICI in the development of this syndrome but the rapid onset of the symptoms after the beginning of targeted therapies makes their involvment more likely.Given the increased use of BRAF/MEK inhibitors in managing of stage III and IV melanoma, as well as the development in stage II, clinicians should be aware of this potential side effect.

The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors.

Toll-like receptors (TLRs) are key players in the innate immune system. Recent studies have suggested that they may affect the growth of pancreatic cancer, a disease with no cure. Among them, TLR7 shows promise for therapy but may also promotes tumor growth. Thus, we aimed to clarify the therapeutic potential of TLR7 ligands in experimental pancreatic cancer models, to open the door for clinical applications. In vitro, we found that TLR7 ligands strongly inhibit the proliferation of both human and murine pancreatic cancer cells, compared with TLR2 agonists. Hence, TLR7 treatment alters cancer cells' cell cycle and induces cell death by apoptosis. In vivo, TLR7 agonist therapy significantly delays the growth of murine pancreatic tumors engrafted in immunodeficient mice. Remarkably, TLR7 ligands administration instead increases tumor growth and accelerates animal death when tumors are engrafted in immunocompetent models. Further investigations revealed that TLR7 agonists modulate the intratumoral content and phenotype of macrophages and that depleting such tumor-associated macrophages strongly hampers TLR7 agonist-induced tumor growth. Collectively, our findings shine a light on the duality of action of TLR7 agonists in experimental cancer models and call into question their use for pancreatic cancer therapy.

Endothelial Cell Indoleamine 2, 3-Dioxygenase 1 Alters Cardiac Function After Myocardial Infarction Through Kynurenine.

BACKGROUND: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI. METHODS: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction. RESULTS: We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism. CONCLUSIONS: These data suggest that IDO could constitute a new therapeutic target during acute MI.

Natural history of SPINK1 germline mutation related-pancreatitis.

BACKGROUND: The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP). METHODS: All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected. FINDINGS: 209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7-17.4) vs 5.3 (2.5-8.8)). The median age at onset of symptoms was 20.1 years (17.5-22.8) in the SPINK1 group versus 41.2 (35.2-45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5-54.6) years vs. 65.2 (62.1-68.3), p < 0.001. SPINK1 patients with EPI were 5.3%, 14.7%, 28.3% and 52.4% at 20, 30, 40 and 50 years. Diabetes occurred 37.7 (33.3-42.1) years following the onset of symptoms in the SPINK1 group vs. 30.6 (17.3-43.8) (p = 0.002). SPINK1 patients with diabetes were 7.8%, 13.4%, 26.3% and 43.4% at 30, 40, 50 and 60 years. Seven patients (3.3%) developed pancreatic cancer in the SPINK1 group (versus 3 (0.99%), p = 0.1), at a median age of 60 vs 66 years. The cancer risk was 0.8% before 50 years, 11.9%, 27.7%, 51.8% at 60, 70 and 80 years and was 12 times higher than in controls (Cox HR 12.0 (3.0-47.8), p < 0.001). INTERPRETATION: SPINK1 related pancreatitis is associated with earlier onset and pancreatic insufficiencies. p.N34S SPINK1 may well be associated with cancer.

Acute Brachial Radiculoplexopathy and Giant Cell Arteritis.

INTRODUCTION: Giant cell arteritis (GCA), a vasculitis involving large-sized and medium-sized vessels (which most commonly involves temporal arteries), is easily recognized in older patients presenting with headache, scalp tenderness, and raised inflammatory markers. Neurological complications (either central or peripheral) are classically described in GCA. CASE REPORT: We report the case of an 85-year-old woman with bilateral acute brachial radiculoplexopathy, a rare neurological complication of GCA. She also presented right oculomotor palsy (with ptosis) and raised inflammatory markers, but she did not complain of the other classic cranial symptoms of the disease. We compare this case with 16 similar cases reported in the medical literature. CONCLUSIONS: In assessing a patient over 50 years of age with unexplained (unilateral or bilateral) brachial radiculoplexopathy (especially if C5-C6 nerve roots are affected) and elevated inflammatory markers, we would recommend specific enquiries with regard to the manifestations of GCA. The purpose is to reduce the risk of missing the wider spectrum of this condition and minimize the subsequent risk for disability of this treatable disease.

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.

Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor.

BACKGROUND: In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. METHODS AND RESULTS: We generated double-deficient mice for Mertk and Mfge8 (Mertk(-/-)/Mfge8(-/-)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk(-/-)), or Mfge8-deficient (Mfge8(-/-)) animals, Mertk(-/-)/Mfge8(-/-) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C(High and Low) monocytes and macrophages. In parallel, Mertk(-/-)/Mfge8(-/-) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C(High) and Ly6C(How) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C(High)/Ly6C(Low) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre(+)/VEGFA(fl/fl) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. CONCLUSIONS: After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart.

MicroRNA-21 coordinates human multipotent cardiovascular progenitors therapeutic potential.

Published clinical trials in patients with ischemic diseases show limited benefit of adult stem cell-based therapy, likely due to their restricted plasticity and commitment toward vascular cell lineage. We aim to uncover the potent regenerative ability of MesP1/stage-specific embryonic antigen 1 (SSEA-1)-expressing cardiovascular progenitors enriched from human embryonic stem cells (hESCs). Injection of only 10(4) hESC-derived SSEA-1(+) /MesP1(+) cells, or their progeny obtained after treatment with VEGF-A or PDGF-BB, was effective enough to enhance postischemic revascularization in immunodeficient mice with critical limb ischemia (CLI). However, the rate of incorporation of hESC-derived SSEA-1(+) /MesP1(+) cells and their derivatives in ischemic tissues was modest. Alternatively, these cells possessed a unique miR-21 signature that inhibited phosphotase and tensin homolog (PTEN) thereby activating HIF-1α and the systemic release of VEGF-A. Targeting miR-21 limited cell survival and inhibited their proangiogenic capacities both in the Matrigel model and in mice with CLI. We next assessed the impact of mR-21 in adult angiogenesis-promoting cells. We observed an impaired postischemic angiogenesis in miR-21-deficient mice. Notably, miR-21 was highly expressed in circulating and infiltrated monocytes where it targeted PTEN/HIF-1α/VEGF-A signaling and cell survival. As a result, miR-21-deficient mice displayed an impaired number of infiltrated monocytes and a defective angiogenic phenotype that could be partially restored by retransplantation of bone marrow-derived cells from wild-type littermates. hESC-derived SSEA-1(+) /MesP1(+) cells progenitor cells are powerful key integrators of therapeutic angiogenesis in ischemic milieu and miR-21 is instrumental in this process as well as in the orchestration of the biological activity of adult angiogenesis-promoting cells.

A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations.

Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy. The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot-Marie-Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband's mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband's father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation.

Axonal sensory motor neuropathy in copper-deficient Wilson's disease.

Copper deficiency may cause myeloneuropathy or progressive limb weakness. By contrast, Wilson's disease (WD) is characterized by progressive copper accumulation with hepatic and neurological impairment and requires life-long treatment with zinc and/or chelator agents. We report a WD patient who developed axonal sensory motor neuropathy in the context of copper deficiency due to his treatment with zinc and chelators. Exhaustive testing for other etiologies was negative. After treatment adjustment, only mild clinical improvement was noted during long-term follow-up. Muscle Nerve 40: 294-296, 2009.