Expanding the Neurological Phenotype of Anderson–Fabry Disease: Proof of Concept for an Extrapyramidal Neurodegenerative Pattern and Comparison with Monogenic Vascular Parkinsonism

Anderson–Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson’s disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients’ information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations

Neurosyphilis: An Important Cause of Recurrent Strokes

Background: Neurosyphilis can manifest as recurrent brain infarction, although not frequently, but can be challenging to diagnose due to atypical presentations. Case report: A 43-year-old male with history of smoking presented to the Midland Regional Hospital, Tullamore (MRHT), Offaly, Ireland, with focal speech deficit and arm/leg weakness for 3 days. Neuroimaging showed acute cerebral infarction. He denied any high-risk sexual contacts. Forty-eight hour telemetry, trans-thoracic echocardiogram, cerebral catheter angiogram, and magnetic resonance angiogram were normal. He was treated with high-dose aspirin for 14 days and then discharged on aspirin with a follow-up plan. Trans-oesophageal echocardiogram performed after 2 weeks showed no evidence of subacute bacterial endocarditis, but there was evidence of fibroelastoma on the aortic valve. The cardiology department felt this was not a likely cardioembolic source. The patient presented 2 months later with recurrent stroke symptoms of loss of speech to another hospital. However, he was discharged for follow-up in MRHT as symptoms resolved. Brain computed tomography (CT) showed ‘old’ stroke. One week later he re-presented to MRHT with dysarthria, ataxia, and a National Institute of Health Stroke Scale (NIHSS) score of three. Repeated neuroimaging showed multiple ‘new’ and ‘old’ cerebral infarcts. The patient was anticoagulated based on recurrent thromboembolic events and magnetic resonance imaging was repeated. CT aortogram and 48-hour Holter results were normal. A repeated magnetic resonance angiogram showed multiple stenosis areas due to vasculitis. As aetiology was complex, a lumbar puncture was performed and blood tests repeated (viral serology, vasculitic and thrombophilia screens). Cerebrospinal fluid and serum analysis displayed a diagnosis of neurosyphilis with co-infection of HIV. Treatment with penicillin was commenced, after which the patient greatly improved and is now under long-term follow-up. Conclusion: Stroke in a young patient is rare and recurrent stroke-like events in a young person raise the clinical suspicion of an alternative diagnosis. It is therefore imperative to investigate neurosyphilis in all HIV-positive patients, as it can cause early clinical manifestation in such patients

Neurological manifestations of Fabry disease

Neurologické projevy Fabryho nemoci Abstrakt Práce se zabývá cerebrovaskulárními projevy vzácného X-vázaného onemocnění, Fabryho choroby (FCh). Screeningové programy mohou odhalit nepoznané onemocnění, zvyšují povědomí o nemoci s cílem včasného stanovení diagnózy a zahájení terapie před rozvinutím ireverzibilního orgánového poškození. Identifikace vaskulárních abnormalit a vliv komorbidit na cerebrovaskulární fenotyp pacientů s FCh může pomoci rozšířit znalosti o patofyziologii cerebrovaskulárního postižení. Hlavními cíli studií, které jsou podkladem práce, bylo stanovit prevalenci FCh a zhodnotit relevanci diagnostiky FCh v rizikové skupině pacientů s akutním iktem, pomocí ultrazvuku analyzovat cerebrovaskulárního fenotyp pacientů s FCh a určit prediktory výraznějšího cerebrovaskulárního postižení. V práci jsme ukázali relativně vysokou prevalenci FCh u dospělých pacientů s akutní CMP, navrhli překlasifikování varianty G325S a identifikovali novou variantu R30K. Upozornili jsme, že spojení aseptické meningitidy s lakunárním iktem u mladého člověka by mělo vést k podezření na FCh. Dále jsme demonstrovali vícečetné rozdíly v neurosonologických parametrech mezi pacienty s FCh a skupinou subjektů bez FCh. Potvrdili jsme častější výskyt strukturálních změn cévní stěny velkých tepen a zjistili nižší...Neurological manifestations of Fabry disease Abstract The presented thesis deals with cerebrovascular manifestations of a rare X-linked disease, Fabry disease (FD). Screening programs can detect unrecognized disease and increase awareness of the disease with the goal of early diagnosis and initiation of therapy before developing an irreversible organ damage. Identifying vascular abnormalities and the influence of comorbidities on the cerebrovascular phenotype of FD patients may help to promote the knowledge of the pathophysiology of cerebrovascular involvement. The main objectives of the studies underlying this thesis were to determine the prevalence of FD and to evaluate the relevance of FD diagnosis in an at-risk group of patients with acute ischemic stroke, to analyse the cerebrovascular phenotype of patients with FD using ultrasound, and to identify predictors of significant cerebrovascular involvement. In this thesis we showed a relatively high prevalence of FD in adult patients with acute stroke, proposed to reclassify the G325S variant, and identified a novel R30K variant. We noted that the combination of aseptic meningitis with lacunar stroke in a young person should lead to suspicion of FD. We further demonstrated multiple differences in neurosonological parameters between patients with FD and a...Neurologická klinika 1. LF UK a VFNDepartment of Neurology First Faculty of Medicine Charles University and General University Hospital in Prague1. lékařská fakultaFirst Faculty of Medicin

Polimorfizam promotorske regije gena inhibitora aktivatora plazminogena-1 u bolesnika s moždanim udarom

Stroke (MU) is the leading cause of disability in modern society. In developed countries, the MU is in second place among the causes of mortality and in Croatia leading causes of death. Due to changing lifestyles and reducing risk factors, better management of patients with stroke, the incidence of stroke in developed countries declined, and mortality is reduced. Yet the treatment of stroke is far from satisfactory. In the last decade MU is finally recognized as emergency in medicine. Furthermore, treatment of stroke, primary and secondary prevention and rehabilitation in the specialized departments, have proven to be effective methods. In recent years several recommendations for the treatment of stroke were published. The goal of primary prevention is to reduce the risk of stroke in asymptomatic individuals. Lifestyle and certain diseases have been identified as a risk factor for stroke. The most common risk factors include inadequate diet, alcohol consumption, smoking, reduced physical activity, hypertension, diabetes, elevated cholesterol levels, myocardial infarction, atrial fibrillation and carotid stenosis. Stress, taking high amounts of oral contraceptives, polymorphism 4G/5G as a risk factor for lacunar stroke, while the incidence of 4G/4G mentioned as a protective factor in the elderly. Therefore, the gene polymorphism 4G/5G could be useful in identifying individuals at risk for developing cardiovascular disease, and dosing of patients fibrinolytic agents, like t-PA

Defining the Clinical Spectrum of Sickle Cell Disease in Tanzania: A Clinico-Epidemiological Study

Introduction: The burden of Sickle Cell Disease (SCD) in Africa is high; having over 75% of annual global births and mortality reaching 95% in childhood. Introduction of interventions, which could prevent 70% of deaths, have been limited because of lack of local evidence. This study described the clinical spectrum of SCD in Tanzania as the first step in providing evidence to guide targeted interventions. Methods: SCD patients attending Muhimbili Hospital in Dar-es-Salaam, Tanzania were recruited between 2004 and 2009. Prospective surveillance of clinical and laboratory information was done at outpatient clinic and during hospitalisation. Specific investigations included blood cultures on all hospitalised SCD patients, Transcranial Doppler (TCD) ultrasonography to measure cerebral blood flow velocity (CBFv) and HPLC to measure levels of foetal haemoglobin (HbF). The outcomes of interest were death, hospitalisation, malaria, bacteraemia and stroke. Results: 1,725 SCD patients [mean age 9.7 (SD 7.9) years; 10% below 2 years] were enrolled with information recorded from 14,000 visits during the study period. 12% of enrolled SCD patients were lost to follow up and 23% of 86 deaths occurred at the hospital. The mortality was 2 deaths/100 person years of observation (PYO); highest under 5 years and independently associated with low haemoglobin (Hazard ratio 0.7 95%CI 0.6-0.8; p0.01). 504 (29%) of the SCD cohort were hospitalised with pain, fever and anaemia as the commonest cause of hospitalisation. SCD patients had less malaria than non-SCD patients at clinic (OR, 0.46; 95% CI, 0.25-0.94; P = .01) and during hospitalisation (OR, 0.53; 95% CI, 0.32-0.86; P = .008). In SCD patients, prevalence of malaria was higher during hospitalisation and associated with severe anaemia and death. 43 out of 890 hospitalisations had bacteraemia (4.8%) with Staphylococcus aureus (28%), non-typhii Salmonella (21%) and Streptococcus pneumoniae (7%) as the most common organisms. The mean CBFv in 372 patients (2 - 16 years) was 132 cm/sec with CBFv > 200cm/sec occurring in 40 (10%) patients. The incidence of stroke was 0.3 per 100PYO; associated with sickle haemoglobin and reticulocyte count but not with CBFv. The mean HbF level in 1,669 SCD patients was 6.3 (SD 4.7) % with no association with mortality and hospitalisation. Conclusion: This study has highlighted the burden of disease to individuals and health system. The findings have important implications for policies to improve healthcare as well as identifying areas for further research

Novel Genetic Causes of Cerebral and Systemic Vasculopathies

Vasculopathies are a varied group of disorders that affect the vascular tree resulting in arterial stenosis or dilatation causing multi-organ ischaemia and significant cardiac and cerebral circulation complications. Commonly, vasculopathies present in infancy and segregate within families so a genetic cause is often suspected but not always identified by the current routinely available genetic tests in the UK National Health Service (NHS). Due to the overlapping phenotypes of these disorders genetic sequencing is required for accurate diagnosis and appropriate clinical intervention. In this thesis, a cohort of children with cerebral and systemic vasculopathies was subject to next-generation genetic sequencing. Several discoveries were made and various families are discussed herein. Firstly, a novel heterozygous mutation in MYH11, a gene affecting smooth muscle myosin heavy chain, was identified in a child with a moyamoya-like cerebrovascular disease and renal artery stenosis. This expanded the vasculopathic phenotype associated with MYH11, which previously was associated with familial aortopathy. Secondly, multiple members of three families diagnosed with a moyamoya arteriopathy were studied and were all found to have heterozygous mutations in c-CBL, an E3 ubiquitin ligase that down regulates various receptor tyrosine kinases. Detailed in vitro functional expression studies were undertaken in the patients with mutations in c-CBL showing impaired CBL-mediated degradation of cell-surface receptors in a dominant negative fashion. These results were compatible with dysregulated intracellular signaling through RAS. Lastly, three families with systemic vasculopathies associated with heterozygous mutations in RNF213 were also studied. This protein possesses both ubiquitin ligase and ATPase activity and adversely affects endothelial cell function. For the first time I showed that heterozygous mutations in RNF213 cause a vasculopathy that is not confined to the cerebral circulation