ObjectiveGenetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries.MethodsWe performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers.ResultsWe identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations.ConclusionsOur data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.
The aim of this study is to evaluate the bioelectrical and structural-functional changes in frontal cortex after the bee venom (BV) experimental treatments simulating both an acute envenomation and a subchronic BV therapy. Wistar rats were subcutaneously injected once with three different BV doses: 700 μg/kg (T(1) group), 2100 μg/kg (T(3) group), and 62 mg/kg (sublethal dose-in T(SL) group), and repeated for 30 days with the lowest dose (700 μg/kg-in T(S) group). BV effects were assessed by electrophysiological, histological, histochemical, and ultrastructural methods. Single BV doses produced discharges of negative and biphasic sharp waves, and epileptiform spike-wave complexes. The increasing frequency of these elements suggested a dose-dependent neuronal hyperexcitation or irritation. As compared to the lower doses, the sublethal dose was responsible for a pronounced toxic effect, confirmed by ultrastructural data in both neurons and glial cells that underwent extensive, irreversible changes, triggering the cellular death. Subchronic BV treatment in T(S) group resulted in a slower frequency and increased amplitude of cortical activity suggesting neuronal loss. However, neurons were still stimulated by the last BV dose. Structural-functional data showed a reduced cellular density in frontal cortex of animals in this group, while the remaining neurons displayed both specific (stimulation of neuronal activity) and unspecific modifications (moderate alterations to necrotic phenomena). Molecular mechanisms involved in BV interactions with the nervous tissue are also discussed. We consider all these data very important for clinicians who manage patients with multiple bee stings, or who intend to set an appropriate BV therapy.
Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.
Background Genetic testing has become a standardized practice in the diagnosis of patients with global developmental delay/intellectual disability (GDD/ID). The aim of this study is to observe the frequency of recurrent copy number variations (CNVs) in patients diagnosed with GDD/ID, using MLPA technique. Methods A total of 501 paediatric patients with GDD/ID were analysed using SALSA MLPA probemix P245 Microdeletion Syndromes-1A, and the technical steps were performed according to the MRC Holland MLPA general protocol. Results Twenty-five of 501 patients (5%) were diagnosed with a microdeletion/microduplication syndrome. Amongst them, 7 of 25 (30%) with clinical suggestion have a confirmed diagnosis, for the other cases the clinical features were not evocative for a specific syndrome. Conclusion This study showed that in cases with a specific clinical diagnosis the MLPA technique could be a useful alternative, less expensive and more efficient to indicate as first intention of a targeted diagnostic test, as it is the case of Williams syndrome, Prader–Willi syndrome or DiGeorge syndrome.
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