Brachial and subclavian arteries aneurysms due to tuberous sclerosis complex mechanisms - case report and literature review.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant condition characterized by cutaneous, cerebral, and other multiorgan involvement. Aneurysms due to TSC pathogenic mechanism are rarely present, mainly aortic, renal, or intracranial and very few associated with peripheral circulation. A TSC patient, aged 31 years, who developed brachial and subclavian arteries aneurysms is presented. The question of a random association of the aneurysms with TSC versus aneurysms within pathogenic released mammalian target of rapamycin (mTOR) pathway effect was raised. CASE PRESENTATION: Patient's file, available from the age of six months, was analyzed for demonstration of the TSC diagnosis. Patient was examined, and cerebral magnetic resonance imaging (MRI) was repeated. Surgery and angiographic reports and images were reviewed. Pathology of the aneurysmal wall available from surgery was reexamined and special stainings and immunohistochemistry markers were applied. Genetic characterization of the patient was performed. Definite TSC was diagnosed based on major criteria [ungual fibromas, shagreen patch, cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytoma (SEGA)], minor criteria (confetti skin lesions, dental enamel pits, gingival fibromas), genetic result showing heterozygous variant in exon 8 of TSC1 gene (c.733C>T-p.Arg245*). Pathology analysis revealed markedly thickened aneurysmal wall due to smooth muscle cells (SMCs) proliferation in media and neoformation vessels with similar characteristics in the aneurysmal wall. DISCUSSIONS AND CONCLUSIONS: This is a rare case with aneurysms related to TSC, with an exceptional peripheral localization. Pathology exam is the key investigation in demonstrating the TSC-related pathogenic mechanism. A literature review showed 73 TSC cases presenting aneurysms published until now.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Diagnostic Usefulness of MLPA Techniques for Recurrent Copy Number Variants Detection in Global Developmental Delay/Intellectual Disability.

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.

Societal Cost of Ischemic Stroke in Romania: Results from a Retrospective County-Level Study.

BACKGROUND: Health policies in transitioning health systems are rarely informed by the economic burden of disease due to scanty access to data. This study aimed to estimate direct and indirect costs for first-ever acute ischemic stroke (AIS) during the first year for patients residing in Cluj, Romania, and hospitalized in 2019 at the County Emergency Hospital (CEH). METHODS: The study was conducted using a mixed, retrospective costing methodology from a societal perspective to measure the cost of first-ever AIS in the first year after onset. Patient pathways for AIS were reconstructed to aid in mapping inpatient and outpatient cost items. We used anonymized administrative and clinical data at the hospital level and publicly available databases. RESULTS: The average cost per patient in the first year after stroke onset was RON 25,297.83 (EUR 5226.82), out of which 80.87% were direct costs. The total cost in Cluj, Romania in 2019 was RON 17,455,502.7 (EUR 3,606,505.8). CONCLUSIONS: Our costing exercise uncovered shortcomings of stroke management in Romania, particularly related to acute care and neurorehabilitation service provision. Romania spends significantly less on healthcare than other countries (5.5% of GDP vs. 9.8% European Union average), exposing stroke survivors to a disproportionately high risk for preventable and treatable post-stroke disability.

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries.

OBJECTIVE: Genetic 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Our 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.

A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis.

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.

Electrophysiological and structural aspects in the frontal cortex after the bee (Apis mellifera) venom experimental treatment.

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.