Triplan (Italy)

Background: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum levels of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vasopermeability, are considered to be responsible for many of POEMS syndrome’s symptoms, such as edema, pleural effusion/ascites, angiomata, organomegaly, and polyneuropathy itself. The insufficient clinical effects obtained by suppression of VEGF alone, as obtained using an anti-VEGF specific antibody, suggests a more complex pathogenesis of POEMS syndrome. Pentraxin 3 (PTX3), 3 is a multimeric glycoprotein acting as a soluble receptor with a non-redundant protective role against selected pathogens in innate response and playing a role in regulating inflammation through a cross-talk between innate immunity, extracellular matrix deposition and vascular biology. PTX3 is already a candidate marker for monitoring progression of small vessel vasculitis. Objective: To assess whether plasma PTX3 levels would correlate with VEGF levels and whether the combined analysis would increases the diagnostic power. Methods: We measured longitudinally (mean follow-up 2 years) VEGF serum and PTX 3 plasma levels in 8 POEMS patients (5 men, 3 women, 40-78 age range). As controls, sera from 20 age-matched patients with inflammatory or paraproteinemic neuropathies have been studied. Results: On an average, there was a low linear correlation between plasma PTX3 levels and VEGF serum levels (r= 0.2, p< 0.0001), not present in the control group (r=0.16 p=0.56). A higher correlation (p< 0.05) was instead present when VEGF serum levels were higher than 1000 pg/mL. Conclusions: Our data confirms VEGF as a very useful and more specific marker in the diagnostic and monitoring process of POEMS’s syndrome, also when compared to other marker of vascular inflammation, such as PTX 3.

OBJECTIVE: The aim of the study was to develop therapeutic strategies based on RNA modulation for Spinal Muscular Atrophy (SMA) using a stem cell model. BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations of the survival motor neuron gene (SMN1) leading to the degeneration of motor neurons, and clinically causing paralysis and death. No effective treatment is available so far, but antisense therapy to increase the SMN level is a promising strategy. DESIGN/METHODS: We generated induced pluripotent stem cell (iPSC) lines derived from human skin fibroblasts with lentiviral constructs and with a non-viral non integrating method based on the expression of reprogramming factors with episomal vectors. We differentiated iPSCs using a protocol to promote motor neuronal phenotype. The phenotype of these cells was analyzed by morphological, functional, gene expression, and protein analysis. RNA strategy based on antisense morpholino, ExSpeU1 and siRNA aiming at increasing SMN level or inhibiting Fas activation were tested. RESULTS: We show here that SMA iPSC-motor neurons recapitulate the disease phenotype with a significantly fewer and smaller motor neurons at later time periods in culture compared to wild-type subject iPSC lines. These features were ameliorated in SMA motor neurons treated with antisense morpholino or ExSpeU1 that rescue SMN level. During motor neuron development, SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 activation. Importantly, this could be mitigated by Fas silencing with siRNA. CONCLUSIONS: Our data confirm the utility of SMA iPSCs as in vitro disease model, suggesting that RNA therapy can be a possible therapeutic strategy for SMA trough SMN up-regulation and modulation of disease pathways that can be achieved with different therapeutic tools.

OBJECTIVE: To report a novel homozygous mutation in ADCK3 in a patient with adult onset cerebellar ataxia BACKGROUND: Inherited ataxias are a group of heterogeneous disorders affecting children and adults. In almost half of the patients, the genetic cause of the disorder is unknown. CoQ10 deficiency has been commonly associated with cerebellar ataxias, often as part of multisystem disorder. Mutations in ADCK3, a putative kinase that modulates CoQ10 biosynthesis, have been associated with cerebellar ataxia and CoQ10 deficiency. CASE REPORT:We report a 48 years old man, born from unrelated parents, who had difficulties in walking and dysarthria. Since age 20 years old, he noticed mild gait imbalance. Neurological examination revealed dysarthria, bilateral ptosis, mild dysmetria and dysdiadochokinesia. Brain MRI revealed mild diffuse cerebellar atrophy. Electromyography showed slight neurogenic changes. Serum lactate was increased. Muscle and skin biopsy were performed. RESULTS: Muscle biopsy revealed increased fiber size variation, and a severe reduction of complex II+III activity. Fibroblasts showes spare capacity and coupling efficiency in the lower range of controls and normal mitochondrial respiratory chanin enzymes activities. CoQ10 was severely decreased in muscle while normal in fibroblasts. Molecular studies revealed a homozygous novel two base deletion (p.504del_CT) in ADCK3 gene causing a premature stop codon in the kinase domain of the protein. Patients started supplementation with 100 mg/day of CoQ10. CONCLUSIONS: Molecular diagnosis of cerebellar ataxic syndromes represent a challenge for the neurologist. COQ10 deficiency in muscle need to be investigated when the other most common causes of recessive ataxias has been excluded, becaouse potentially treatable.

OBJECTIVE: to assess normative data for the Italian population, providing corrections for demographics and educational level and test-retest reliability of the Brief International Cognitive Assessment for MS (BICAMS). BACKGROUND: an international expert consensus committee recently recommended a brief battery of tests for cognitive evaluation in multiple sclerosis (MS). BICAMS battery includes the Symbol Digit Modalities Test (SDMT), the Brief Visuospatial Memory Test-Revised (BVMTR) and the California Verbal Learning Test (CVLT2). However, normative data are lacking in the Italian population. METHODS: we administered the BICAMS battery to healthy volunteers recruited from the community in nine Italian sites at baseline and after three weeks, using the same versions of the tests. Significant demographic predictors of test score were assessed through multivariate linear regression model. Thereafter corrected scores were calculated for each test. RESULTS: the BICAMS battery was administered to 251 subjects at baseline (165 females, 86 males, mean age 39.9+/-13.6 years, range 17.5-78 and mean education 14.7+/-3.1 years, range 5-21). Mean raw scores on the neuropsychological test battery were: SDMT 56.2+/-11.7, CVLT2: 56+/-9.0 and BVMTR: 27.8+/-5.8. In the 218 subjects re-assessed after three weeks, mean scores were significantly higher on all the tests for both raw and corrected tests (p Disclosure: Dr. Amato has received personal compensation for activities with Biogen Idec, Merck & Co., Inc., Serono, Inc., Teva Neuroscience, Genzyme Corporation, Novartis, Bayer Pharmaceuticals Corporation, and Almirall. Dr. Portaccio has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corp., and Merck Serono as a scientific advisory board member and speaker. Dr. Portaccio has received research support from Biogen Idec, Bayer Schering, Merck Serono, and Sanofi-Aventis Pharmaceuticals Inc. Dr. Niccolai has received research support from Biogen Idec. Dr. Hakiki has nothing to disclose. Dr. Goretti has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Goretti has received research support from Biogen Idec and Novartis. Dr. Sturchio has nothing to disclose. Dr. Martinelli has received personal compensation for activities with Biogen Idec, Merck Serono, and Bayer Schering. Dr. Falautano has nothing to disclose. Dr. Minacapelli has nothing to disclose. Dr. Nocentini has nothing to disclose. Dr. Incerti has nothing to disclose. Dr. Marrosu has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Marrosu has received personal compensation in an editorial capacity for Neurological Sciences. Dr. Marrosu has received research support from Serono Foundation, Biogen Idec, Schering AG, Sanofi-Aventis Pharmaceuticals Inc. Dr. Cocco has nothing to disclose. Dr. Murgia has nothing to disclose. Dr. Fenu has nothing to disclose. Dr. Ambra has nothing to disclose. Dr. Garofalo has nothing to disclose. Dr. Maddestra has nothing to disclose. Dr. Consalvo has nothing to disclose. Dr. Zimatore has nothing to disclose. Dr. Losignore has nothing to disclose. Dr. Lugaresi has received personal compensation for activities with Biogen Idec, Bayer Schering, Merck Serono, Novartis and Sanofi-Aventis Pharmaceuticals Inc. as a speaker. Dr. Lugaresi has received research support from Biogen Idec, Bayer Schering, Merck Serono, Novartis and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Pietrolongo has nothing to disclose. Dr. Viterbo has received personal compensation for activities with Biogen Idec as a scientific advisory board member and speaker, and with Novartis as a speaker. Dr. Trojano has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Biogen Idec, Novartis and Bayer Schering as a consultant or speaker. Dr. Trojano has received research support from Merck Serono, Biogen Idec and Novartis.