DiMauro S.,York College |
Schon E.A.,York College |
Carelli V.,CNR Institute of Neurological Sciences |
Hirano M.,York College
Nature Reviews Neurology | Year: 2013
Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category - defects of mtDNA maintenance - combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot-Marie-Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed. © 2013 Macmillan Publishers Limited. All rights reserved.
Tomson T.,Karolinska Institutet |
Battino D.,CNR Institute of Neurological Sciences
Handbook of Experimental Pharmacology | Year: 2011
It is well established that children exposed to antiepileptic drugs (AEDs) in utero have an increased risk of adverse pregnancy outcomes including foetal growth retardation, major congenital malformations and impaired postnatal cognitive development. However, due to the significant maternal and foetal risks associated with uncontrolled epileptic seizures, AED treatment is generally maintained during pregnancy in the majority of women with active epilepsy. The prevalence of major malformations in children exposed to AEDs has ranged from 4 to 10%, 2-4 times higher than in the general population. More recent studies suggest a smaller increase in malformation rates. Malformation rates have consistently been higher in association with exposure to valproate than with carbamazepine and lamotrigine. Some prospective cohort studies also indicate reduced cognitive outcome in children exposed to valproate compared to carbamazepine and possibly lamotrigine. Information on pregnancy outcomes with newer generation AEDs other than lamotrigine are still insufficient. © 2011 Springer-Verlag Berlin Heidelberg.
Partinen M.,Vitalmed Research Center |
Partinen M.,University of Helsinki |
Kornum B.R.,Molecular Sleep Laboratory |
Plazzi G.,University of Bologna |
And 5 more authors.
The Lancet Neurology | Year: 2014
Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12-16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger. © 2014 Elsevier Ltd.
Citraro R.,University of Catanzaro |
Leo A.,University of Catanzaro |
Marra R.,CNR Institute of Neurological Sciences |
De Sarro G.,University of Catanzaro |
Russo E.,University of Catanzaro
Brain Research Bulletin | Year: 2015
Different data suggest the involvement of specific inflammatory pathways in the pathogenesis of epilepsy. Cyclooxygenase (COX), which catalyses the production of pro-inflammatory prostaglandins, may play a significant role in seizure-induced neuroinflammation and neuronal hyperexcitability. COX-2 is constitutively expressed in the brain and also increased during/after seizures. COX-2 inhibitors may thus attenuate inflammation associated with brain disorders. We studied whether early long-term treatment (17 consecutive weeks starting from 45 days postnatal age) with the non-steroidal anti-inflammatory drug etoricoxib (10. mg/kg/day per os), a selective COX-2 inhibitor, was able to prevent/reduce the development of absence seizures in WAG/Rij rats, a recognized animal model of absence epilepsy and epileptogenesis. Drug effects on the incidence, duration and properties of absence seizure spike-wave discharges (SWDs) were measured both 1 and 5 months after treatment withdrawal; furthermore, the acute effects of etoricoxib on SWDs in 6-month-old WAG/Rij rats were measured. Early long-term treatment (ELTT) with etoricoxib led to an ~40% long-lasting (5 months) reduction in the development of spontaneous absence seizures in adult WAG/Rij rats thus exhibiting antiepileptogenic effects. Acutely administered etoricoxib (10 and 20. mg/kg i.p.) also had anti-absence properties, significantly reducing the number and duration of SWDs by ~50%. These results confirm the antiepileptogenic effects of COX-2 inhibitors and suggest the possible role of COX-2, prostaglandin synthesis and consequent neuroinflammation in the epileptogenic process underlying the development of absence seizures in WAG/Rij rats. © 2015 Elsevier Inc.
Alessandria M.,University of Bologna |
Provini F.,University of Bologna |
Provini F.,CNR Institute of Neurological Sciences
Frontiers in Neurology | Year: 2013
In recent years, a growing body of evidence suggests that periodic limb movements during sleep (PLMS) are associated with hypertension, cardiovascular, and cerebrovascular risk. However, several non-mutually exclusive mechanisms may determine a higher cardiovascular risk in patients with PLMS and the link between the two remains controversial. Prospective data are scant and the temporal relationship between PLMS and acute vascular events is difficult to ascertain because although PLMS may lead to acute vascular events such as stroke, stroke may also give rise to PLMS. This article describes the clinical and polygraphic features of PLMS and examines the literature evidence linking PLMS with an increased risk for the development and progression of cardiovascular diseases, discussing the possible pathways of this association. © 2013 Alessandria and Provini.