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Arzuffi P.,The Foundation Carlo Besta Institute of Neurology IRCCS | Lamperti C.,The Foundation Carlo Besta Institute of Neurology IRCCS | Fernandez-Vizarra E.,University Institute of Health Sciences | Tonin P.,University of Verona | And 2 more authors.
Neuromuscular Disorders | Year: 2012

An 80-year-old woman (PI) has been suffering of late onset progressive weakness and wasting of lower-limb muscles, accompanied by high creatine kinase levels in blood. A muscle biopsy, performed at 63years, showed myopathic features with partial deficiency of cytochrome c oxidase. A second biopsy taken 7years later confirmed the presence of a mitochondrial myopathy but also of vacuolar degeneration and other morphological features resembling inclusion body myopathy. Her 46-year-old daughter (PII) and 50-year-old son (PIII) are clinically normal, but the creatine kinase levels were moderately elevated and the EMG was consistently myopathic in both. Analysis of mitochondrial DNA sequence revealed in all three patients a novel, homoplasmic 15bp tandem duplication adjacent to the 5' end of mitochondrial tRNA Phe gene, encompassing the first 11 nucleotides of this gene and the four terminal nucleotides of the adjacent D-loop region. Both mutant fibroblasts and cybrids showed low oxygen consumption rate, reduced mitochondrial protein synthesis, and decreased mitochondrial tRNA Phe amount. These findings are consistent with an unconventional pathogenic mechanism causing the tandem duplication to interfere with the maturation of the mitochondrial tRNA Phe transcript. © 2011 Elsevier B.V. Source


Saetre E.,University of Oslo | Abdelnoor M.,University of Oslo | Perucca E.,University of Pavia | Perucca E.,Institute of Neurology IRCCS | And 4 more authors.
Epilepsy and Behavior | Year: 2010

During an international double-blind trial evaluating the efficacy and tolerability of lamotrigine and carbamazepine in patients aged ≥65 with newly diagnosed epilepsy, the comparative effects of the drugs on health-related quality of life were investigated based on screening and 12-, 28-, and 40-week data, using the modified Side Effect and Life Satisfaction (SEALS) Inventory and the Liverpool Adverse Event Profile. Of 167 patients, 29 discontinued before first follow-up, and data were incomplete for 13. In 125 eligible subjects (62 taking carbamazepine, 63 taking lamotrigine), comparable baseline data did not change significantly during medication, within or across treatments. A borderline difference in the SEALS Dysphoria subscores favored lamotrigine. No difference between completers and noncompleters was identified. Twelve-week data for noncompleters were comparable across treatments. Changes in the inventories up to 40 weeks correlated moderately. Neither lamotrigine nor carbamazepine seems likely to cause significant changes in health-related quality of life measures after 40 weeks at therapeutic doses. © 2009 Elsevier Inc. All rights reserved. Source


Mancuso M.,University of Pisa | Orsucci D.,University of Pisa | Angelini C.,University of Padua | Bertini E.,Bambino Gesu Hospital | And 25 more authors.
Neurology | Year: 2013

Objectives: Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with the 8344A>G mutation. The secondary aim was revision of the previously published data. Methods: Retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) and systematic revision. Results: Forty-two patients carrying the mutation were identified. The great majority did not have full-blown MERRF syndrome. Myoclonus was present in 1 of 5 patients, whereas myopathic signs and symptoms, generalized seizures, hearing loss, eyelid ptosis, and multiple lipomatosis represented the most common clinical features. Some asymptomatic mutation carriers have also been observed. Myoclonus was more strictly associated with ataxia than generalized seizures in adult 8344A.G subjects. Considering all of the 321 patients so far available, including our dataset and previously published cases, at the mean age of approximately 35 years, the clinical picture was characterized by the following signs/symptoms, in descending order: myoclonus, muscle weakness, ataxia (35%-45% of patients); generalized seizures, hearing loss (25%-34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%-24.9%); and increased creatine kinase levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, migraine (5%-14.9%). Conclusions: Our results showed higher clinical heterogeneity than commonly thought. Moreover, MERRF could be better defined as a myoclonic ataxia rather than a myoclonic epilepsy. © 2013 American Academy of Neurology. Source


Lamperti C.,Institute of Neurology IRCCS | Invernizzi F.,Institute of Neurology IRCCS | Solazzi R.,Institute of Neurology IRCCS | Freri E.,Institute of Neurology IRCCS | And 8 more authors.
European Journal of Paediatric Neurology | Year: 2016

Background Paroxysmal Kinesigenic Dyskinesia (PKD, OMIM 128200) is the most common type of autosomal dominant Paroxysmal Dyskinesias characterized by attacks of dystonia and choreoathetosis triggered by sudden movements. Recently PRRT2, encoding proline-rich transmembrane protein 2, has been described as the most frequent causative gene for PKD. Methods We studied the incidence of PRRT2 mutations in a cohort of 16 PKD patients and their relatives for a total of 39 individuals. Results We identify mutations in 10/16 patients and 23 relatives. In 27/33 the mutation was the c.insC649 p.Arg217Profs∗8. In 6 individuals from 3 families we found three new mutations: c.insT27 p.Ser9∗, c.G967A p.Gly323Arg and c.delCA215-216 p.Thr72Argfs∗62. Family history was positive in 9 patients. The mean age of onset was 10 years. Attacks lasted from a few seconds to 1 min and ranged from several per day to some per week, and were generalised in all patients. The main distinctive features of mutation-negative patients were the sporadic occurrence, the absence of association with epilepsy or EEG abnormalities and the poor response to Carbamazepine or other antiepileptic agents. Conclusions We report the first cohort of Italian patients mutated in PRRT2 and we confirm that this is the most frequent gene involved in PKD. © 2015 European Paediatric Neurology Society. Source


Cerutti R.,Institute of Neurology IRCCS | Cerutti R.,MRC Mitochondrial Biology Unit | Pirinen E.,Ecole Polytechnique Federale de Lausanne | Pirinen E.,University of Eastern Finland | And 12 more authors.
Cell Metabolism | Year: 2014

Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD+-dependent protein deacetylase. As NAD+ boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD+ play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD+ precursor, or reduction of NAD+ consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans. © 2014 The Authors. Source

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