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Ardissone A.,Unit of Child Neurology | Invernizzi F.,Unit of Molecular Neurogenetics | Nasca A.,Unit of Molecular Neurogenetics | Moroni I.,Unit of Child Neurology | And 2 more authors.
Molecular Genetics and Metabolism Reports | Year: 2015

Mitochondrial disease involving complex II is rare among respiratory chain deficiencies and its genetic cause remains often unknown. Two main clinical presentations are associated with this biochemical defect: mitochondrial encephalomyopathy and susceptibility to tumors. Only one homozygous SDHBmutation has been described in a patient with mitochondrial disorder. We report here two sisters, who presented highly different phenotypes (neurological impairmentwith leukoencephalopathy vs. asymptomatic status) and harbored the same homozygous SDHB mutation, suggesting reduced penetrance. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.


Invernizzi F.,Unit of Molecular Neurogenetics | Ardissone A.,Unit of Child Neurology | Lamantea E.,Unit of Molecular Neurogenetics | Garavaglia B.,Unit of Molecular Neurogenetics | And 4 more authors.
Frontiers in Genetics | Year: 2014

Multiple Mitochondrial Dysfunction Syndrome (MMDS) comprises a group of severe autosomal recessive diseases with onset in early infancy and characterized by a systemic disorder of energy metabolism, resulting in weakness, respiratory failure, lack of neurological development, lactic acidosis, and early death. Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc). Three genes have been associated with MMDS since now: NFU1, BOLA3, and IBA57. We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity. He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues. A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene. © 2014 Invernizzi, Ardissone, Lamantea, Garavaglia, Zeviani, Farina, Ghezzi and Moroni.


Steffens M.,University of Bonn | Leu C.,University of Cologne | Ruppert A.,University of Cologne | Zara F.,University of Genoa | And 105 more authors.
Human Molecular Genetics | Year: 2012

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10-9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10-9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10-9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10-8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10-6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes. © The Author 2012. Published by Oxford University Press. All rights reserved.


Roosing S.,Howard Hughes Medical Institute | Hofree M.,University of California at San Diego | Kim S.,New York University | Kim S.,Howard Hughes Medical Institute | And 41 more authors.
eLife | Year: 2015

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies. © 2015, eLife Sciences Publications Ltd. All rights reserved.


Zorzi G.,Unit of Child Neurology
Movement disorders : official journal of the Movement Disorder Society | Year: 2011

The safety and efficacy of the oral iron-chelating agent deferiprone on magnetic resonance pallida iron concentration and on clinical status were investigated in 10 patients affected by pantothenate kinase-associated neurodegeneration. Nine patients (age range, 7-39 years) completed the study. A significant median reduction in globus pallidus iron content as assessed by T2* relaxometry (and calculated R2* maps; P=.008) was observed at the end of the study. None of the patients demonstrated a change in clinical status as assessed by the Burke-Fahn and Marsden Dystonia Rating scales and by a health-related quality-of-life scale. Deferiprone was well tolerated, and no serious adverse events occurred. Future trials assessing the clinical efficacy of chelating therapy should consider early symptomatic patients and a longer treatment period. Copyright © 2011 Movement Disorder Society.

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