on Neuromuscular disorders : NMD
by Savarese M, Torella A, Musumeci O, Angelini C, Astrea G, Bello L, Bruno C, Comi GP, Di Fruscio G, Piluso G, Di Iorio G, Ergoli M, Esposito G, Fanin M, Farina O, Fiorillo C, Garofalo A, Giugliano T, Magri F, Minetti C, Moggio M, Passamano L, Pegoraro E, Picillo E, Sampaolo S, Santorelli FM, Semplicini C, Udd B, Toscano A, Politano L, Nigro V
Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.
on Journal of neurology, neurosurgery, and psychiatry
by Terracciano C, Farina O, Esposito T, Lombardi L, Napolitano F, De Blasiis P, Ciccone G, Todisco V, Tuccillo F, Bernardini S, Di Iorio G, Melone MAB, Sampaolo S
on Clinical genetics
by Napolitano F, Di Iorio V, Testa F, Tirozzi A, Reccia MG, Lombardi L, Farina O, Simonelli F, Gianfrancesco F, Di Iorio G, Melone MAB, Esposito T, Sampaolo S
We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A>G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.
on Journal of cellular physiology
by Pascarella A, Terracciano C, Farina O, Lombardi L, Esposito T, Napolitano F, Franzese G, Panella G, Tuccillo F, la Marca G, Bernardini S, Boffo S, Giordano A, Melone MAB, Di Iorio G, Sampaolo S
Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-α-glucosidase (GAA) gene. Deficiency of GAA enzyme leads to glycogen accumulation and autophagy impairment in cardiac and skeletal muscles, but also in lymphocytes. Since an effective therapy is available, a rapid, sensitive and specific test is crucial to early identify affected subjects. Number of lymphocytes containing PAS-positive vacuoles was evaluated on blood films from 72 consecutive adult patients with hyperckemia and/or muscle weakness, 13 genetically confirmed late-onset-Pompe-disease (LOPD) and 13 of their offspring. GAA activity, measured on dried blood spot (DBS) in all patients inversely correlated with number of PAS-positive lymphocytes. More than 4 PAS-positive lymphocytes were found in 11 out of the 72 patients (6 new diagnosis of LOPD, 3 different glycogen storage myopathies, 1 glucose-6-phosphate dehydrogenase deficiency, 1 caveolinopathy), in all 13 LOPD patients and in the 13 LOPD offspring. These latter resulted to have all a single GAA mutation but low GAA levels. Immunostaining with the autophagy markers LC3 and p62 confirmed the autophagic nature of lymphocytes vacuoles. ROC curve assessment of PAS-positive lymphocytes disclosed 100% of sensitivity and 94% of specificity in recognizing both compound heterozygous and heterozygous GAA carriers. The other myopathies with more than 4 PAS-positive lymphocytes appeared to be all related to impaired autophagy, which seems to be responsible of PAS-positive vacuolated lymphocytes formation. Quantification of PAS-positive lymphocytes in blood films is useful to identify autophagic vacuolar myopathies and should be routinely used as first level test for Pompe disease. This article is protected by copyright. All rights reserved.
on Journal of medical genetics
by Sampaolo S, Napolitano F, Tirozzi A, Reccia MG, Lombardi L, Farina O, Barra A, Cirillo F, Melone MAB, Gianfrancesco F, Iorio GD, Esposito T
The laminin alpha 5 gene (LAMA5) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in LAMA5 gene to a novel multisystem syndrome.
on Journal of cellular physiology
by Squillaro T, Schettino C, Sampaolo S, Galderisi U, Di Iorio G, Giordano A, Melone MAB
Aging is a primary risk factor for both neurodegenerative disorders (NDs) and tumors such as adult-onset brain tumors. Since NDs and tumors are severe, disabling, progressive and often incurable conditions, they represent a pressing problem in terms of human suffering and economic costs to the healthcare systems. The current challenge for physicians and researchers is to develop new therapeutic strategies in both areas to improve the patients' quality of life. In addition to genetics and environmental stressors, the increase in cellular oxidative stress as one of the potential common etiologies has been reported for both disorders. Recently, the scientific community has focused on the beneficial effects of dietary antioxidant classes, known as nutraceuticals, such as carotenoids, vitamins, and polyphenols. Among these compounds, polyphenols are considered to be one of the most bioactive agents in neurodegeneration and tumor prevention. Despite the beneficial activity of polyphenols, their poor bioavailability and inefficient delivery systems are the main factors limiting their use in medicine and functional food. The development of polymeric nanoparticle-based delivery systems able to encapsulate and preserve polyphenolic compounds may represent a promising tool to enhance their stability, solubility, and cell membrane permeation. In the present review we provide an overview of the main polyphenolic compounds used for ND and brain tumor prevention and treatment that explores their mechanisms of action, recent clinical findings and principal factors limiting their application in medicine.
by Sampaolo S, Liguori G, Vittoria A, Napolitano F, Lombardi L, Figols J, Melone MAB, Esposito T, Di Iorio G
The superior sagittal sinus (SSS) of the mammalian brain is a pain-sensitive intracranial vessel thought to play a role in the pathogenesis of migraine headaches. Here, we aimed to investigate the presence and the potential co-localization of some neurotransmitters in the human SSS. Immunohistochemical and double-labeling immunofluorescence analyses were applied to paraformaldehyde-fixed, paraffin-embedded, coronal sections of the SSS. Protein extraction and Western blotting technique were performed on the same material to confirm the morphological data. Our results showed nerve fibers clustered mainly in large bundles tracking parallel to the longitudinal axis of the sinus, close in proximity to the vascular endothelium. Smaller fascicles of fibers encircled the vascular lumen in a spiral fashion, extending through the subendothelial connective tissue. Isolated nerve fibers were observed around the openings of bridging veins in the sinus or around small vessels extending into the perisinusal dura. The neurotransmitters calcitonin gene related peptide (CGRP), substance P (SP), neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), and neuropeptide Y (NPY) were found in parietal nerve structures, distributed all along the length of the SSS. Overall, CGRP- and TH-containing nerve fibers were the most abundant. Neurotransmitters co-localized in the same fibers in the following pairs: CGRP/SP, CGRP/NOS, CGRP/VIP, and TH/NPY. Western blotting analysis confirmed the presence of such neurosubstances in the SSS wall. Overall our data provide the first evidence of the presence and co-localization of critical neurotransmitters in the SSS of the human brain, thus contributing to a better understanding of the sinus functional role.
on Neuropsychiatric disease and treatment
by Schettino C, Dato C, Capaldo G, Sampaolo S, Di Iorio G, Melone MA
Rasagiline is a selective, irreversible monoamine oxidase B inhibitor that ameliorates the symptoms of Parkinson's disease (PD) by inhibiting striatal dopamine metabolism. There is also evidence that monoamine oxidase B inhibitors increase melatonin levels in the pineal gland and may have a beneficial effect on sleep disorders, which are a common feature in patients with PD.
on The neuroradiology journal
by Scuotto A, Saracino D, Rotondo M, Izzo A, Urraro F, Cappabianca S, Sampaolo S
We report on two patients disclosing a pneumosinus dilatans (PSD) and an anterior skull base meningioma. Our findings, together with those from the pertinent literature, support the thought that this infrequent anomaly of paranasal sinuses is a useful clue to suspect a concomitant meningioma. Moreover, hypotheses concerning the pathophysiology of PSD are discussed.
on Neuromuscular disorders : NMD
by Sampaolo S, Esposito T, Gianfrancesco F, Napolitano F, Lombardi L, Lucà R, Roperto F, Di Iorio G
We report the clinical, neuro-imaging, pathological and biochemical features of an Italian family in which two siblings have the Adult Polyglucosan Body Disease (APBD). APBD is a rare autosomal recessive disorder characterized by a gradually progressive involvement of both the central and peripheral nervous systems caused by the deficiency of the glycogen branching enzyme (GBE1). The two affected siblings, a 64-year-old man and his 67-year-old sister who had complained of urinary urgency and sporadic incontinence and also progressive gait difficulty for 6 and 7 years respectively, had severely impaired deep sensations on direct examination and a moderately severe symmetrical, axonal sensory-motor neuropathy on electrophysiological testing. GBE1 activity was below 25% of the normal rate in leukocytes and sural nerves. The siblings were homozygous for the novel GBE1 mutation p.N541D. All other members of the pedigree are heterozygous and manifest no symptoms, even in the very elderly. The affected siblings showed polyglucosan bodies (PBs) included within non-myelinating Schwann cells and within lymphocyte vesicles, which were positive for the autophagy markers P62 and LC3-II at immunofluorescence microscopy.