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We described a case of a patient with autosomal dominant progressive external ophthalmoplegia (PEO) who presented with the acute onset dysphagia, quadriparesis, ptosis and respiratory insufficiency following a cardiac procedure and mimicking a myasthenic crisis. A pathogenic mutation in the C10orf2 (PEO1) gene was confirmed. The unusual presentation of our patient contributes to expand the clinical phenotype of PEO1 mutations and reinforces the need to consider mitochondrial myopathy as differential diagnosis of myasthenia gravis even in the case of acute onset symptoms.

Dravet C.,Center Saint Paul Hopital Henri Gastaut | Dravet C.,Neurogenetics Unit
Epilepsia | Year: 2011

Dravet syndrome was described in 1978 by Dravet (1978) under the name of severe myoclonic epilepsy in infancy (SMEI). The characteristics of the syndrome were confirmed and further delineated by other authors over the years. According to the semiologic features, two forms have been individualized: (1) the typical, core, SMEI; and (2) the borderline form, SMEIB, in which the myoclonic component is absent or subtle. Clinical manifestations at the onset, at the steady state, and during the course of the disease are analyzed in detail for the typical Dravet syndrome, and the differential diagnosis is discussed. Onset in the first year of life by febrile or afebrile clonic and tonic-clonic, generalized, and unilateral seizures, often prolonged, in an apparently normal infant is the first symptom, suggesting the diagnosis. Later on, multiple seizure types, mainly myoclonic, atypical absences, and focal seizures appear, as well as a slowing of developmental and cognitive skills, and the appearance of behavioral disorders. Mutation screening for the SCN1A gene confirms the diagnosis in 70-80% of patients. All seizure types are pharmacoresistent, but a trend toward less severe epilepsy and cognitive impairment is usually observed after the age of 5 years. © Wiley Periodicals, Inc. 2011 International League Against Epilepsy.

Fratta P.,University College London | Nirmalananthan N.,University College London | Masset L.,University College London | Skorupinska I.,University College London | And 7 more authors.
Neurology | Year: 2014

Objectives: To characterize the clinical and genetic features of spinal bulbar muscular atrophy (SBMA), a rare neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene, in the United Kingdom. Methods: We created a national register for SBMA in the United Kingdom and recruited 61 patients between 2005 and 2013. In our cross-sectional study, we assessed, by direct questioning, impairment of activities of daily living (ADL) milestones, functional rating, and subjective disease impact, and performed correlations with both CAG repeat size and degree of somatic mosaicism. Ten patients were deceased, 46 patients participated in the study, and = declined. Results: Subjects had an average age at onset of 43.4 years, and weakness onset most frequently occurred in the lower limbs (87%). Impaired mobility was the most frequently reported problem by patients, followed by bulbar dysfunction. Age distribution of the impairment of ADL milestones showed remarkable overlap with a Japanese study. We have identified a significant correlation between the number of CAG repeats and both age at onset and ADL milestones. Somatic mosaicism also showed a correlation with CAG expansion size and age at onset. Conclusions: Clinical features in SBMA show a substantial overlap when comparing populations with different genetic backgrounds. This finding has major implications, because multicenter trials will be necessary to obtain sufficient power in future clinical trials. Clinical-genetic correlations are strong in SBMA and should inform any clinical research strategy in this condition. © 2014 American Academy of Neurology.

Melas P.A.,Neurogenetics Unit | Rogdaki M.,Neurogenetics Unit | Osby U.,Neurogenetics Unit | Osby U.,TioHundra AB | And 3 more authors.
FASEB Journal | Year: 2012

Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene-specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0×10-6) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R 2=0.11, ANOVA P<0.001). Specifically, haloperidol was associated with higher ("control-like") methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future. © FASEB.

Arena G.,Neurogenetics Unit | Arena G.,University of Rome La Sapienza | Gelmetti V.,Neurogenetics Unit | Torosantucci L.,Neurogenetics Unit | And 8 more authors.
Cell Death and Differentiation | Year: 2013

Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer. © 2013 Macmillan Publishers Limited.

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