Hereditary Connective Tissue Diseases in Young Adult Stroke: A Comprehensive Synthesis

Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis

A likely pathogenic variant in the SLC20A2 gene presenting with progressive myoclonus

A 60-year-old man is presented with progressive involuntary muscle movements and neuropsychiatric symptoms who developed a variety of additional complaints over 2 years. Brain imaging revealed bilateral basal ganglia calcifications suggesting primary familial brain calcification. Analysis of the SLC20A2 gene revealed a missense mutation (c.541C>T, p.(Arg181Trp)), in silico predicted to be deleterious and not found in available databases. Segregation analysis confirmed his asymptomatic father to harbor the same mutation, though on brain imaging basal ganglia calcifications were found. This report illustrates the intrafamilial variability of the phenotype and generalized myoclonus as the presenting symptom

The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders

The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to the ABCC6 gene. While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including nextgeneration sequencing, computational methods, and various "omics" technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement of ABCC6 in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases

Zebrafish models for ectopic mineralization disorders : practical issues from morpholino design to post-injection observations

Zebrafish (ZF, Danio rerio) has emerged as an important and popular model species to study different human diseases. Key regulators of skeletal development and calcium metabolism are highly conserved between mammals and ZF. The corresponding orthologs share significant sequence similarities and an overlap in expression patterns when compared to mammals, making ZF a potential model for the study of mineralization-related disorders and soft tissue mineralization. To characterize the function of early mineralization-related genes in ZF, these genes can be knocked down by injecting morpholinos into early stage embryos. Validation of the morpholino needs to be performed and the concern of aspecific effects can be addressed by applying one or more independent techniques to knock down the gene of interest. Post-injection assessment of early mineralization defects can be done using general light microscopy, calcein staining, Alizarin red staining, Alizarin red-Alcian blue double staining, and by the use of transgenic lines. Examination of general molecular defects can be done by performing protein and gene expression analysis, and more specific processes can be explored by investigating ectopic mineralization-related mechanisms such as apoptosis and mitochondrial dysfunction. In this paper, we will discuss all details about the aforementioned techniques; shared knowledge will be very useful for the future investigation of ZF models for ectopic mineralization disorders and to understand the underlying pathways involved in soft tissue calcification

Chikungunya outbreak in Bangladesh (2017) : clinical and hematological findings

Introduction: A massive outbreak of chikungunya virus (CHIKV) occurred in Bangladesh during the period of April-September 2017, and over two million people were at risk of getting infected by the virus. A prospective cohort of viremic patients was constituted and analyzed to define the clinical, hematological, and long-term aspects of this outbreak. Methods: A 35-day long comprehensive survey was conducted in two major, neighboring cities, Dhaka and Mymensingh. One-hundred and eighty-seven laboratory-confirmed CHIKV cases were enrolled in the cross-sectional cohort study. Additionally, a smaller group of 48 chikungunya patients was monitored for post-infection effects for 12 months. Results: Clinical data revealed that a combination of fever and arthralgia (oligoarthralgia and/or polyarthralgia) was the cardinal hallmark (97.9% of cases) of the infection. Hematological analysis showed that irrespective of age and sex groups, CHIKV patients had a decreased level of hemoglobin (n = 64, p < 0.01) and elevated erythrocyte sedimentation rate (n = 131, p < 0.01). Besides, a significant portion of the patients represented abnormal values for RBC (n = 38, p = 0.0005) and WBC (n = 63, p < 0.01) counts. The post-infection study revealed that children had an early recovery from the infection compared to the adults. Moreover, post-infection weakness, successive relapse of arthralgic pain, and memory problems were the most significant aftereffects, which had an impact on the daily activities of patients. Conclusions: This study represents a comprehensive overview of clinical and epidemiological features of the 2017 outbreak of CHIKV in Bangladesh as well as its chronic outcomes till the 12(th) month. It provides insights into the natural history of this disease, which may help to improve the management of CHIKV patients. Author summary: The clinical profile, epidemiology, and the economic impacts during the acute phase of chikungunya infection have been studied quite rigorously. However, studies regarding the hematological features and chronic consequences are infrequent. In this study, we analyzed the clinical and hematological features of 187 chikungunya patients in the acute phase of the infection. Also, we monitored a smaller group of 48 patients until 12 months to study its post-infection consequences. Clinical data revealed that a combination of fever and joint pain (arthralgia) was the cardinal hallmark in the acute phase of the infection. Hematological analysis showed that CHIKV infection features a significantly reduced hemoglobin and remarkably elevated erythrocyte sedimentation rate. Besides, RBC and WBC counts, especially in children and females, were beyond the reference values. The post-infection consequence study unveiled that children recovered better from the infection compared to the adults. Further, post-infection weakness, successive relapse of joint pain and memory problems were the most significant aftereffects. Overall, the infection had a moderate to severe impact on the daily activities of the respondents. This study provides insights into the clinical and hematological aspects of chikungunya infection during the acute phase as well as describes an account for its chronic outcomes, which puts forward to the knowledge for clinicians and epidemiologists regarding the infection diversity and to help improve patient management

Chikungunya outbreak in Bangladesh (2017) : clinical and hematological findings

A massive outbreak of Chikungunya occurred in Bangladesh during the period of April-September, 2017 and over two million people were at risk of getting infected by the virus. A prospective cohort of viremic patients was constituted and analyzed to define the clinical, hematological and long-term aspects of this outbreak. A 35-day long comprehensive survey was conducted in two major, neighboring cities, Dhaka and Mymensingh. One-hundred and eighty-seven clinically proven Chikungunya cases were enrolled in the cross-sectional cohort study. Additionally, a smaller group of 48 Chikungunya patients was monitored for post-infection effects for 12 months. Clinical data revealed that a combination of fever and arthralgia (oligoarthralgia and/or polyarthralgia) was the cardinal hallmark (97.9% of cases) of the infection. Hematological analysis showed that, irrespective of age groups, hemoglobin level significantly decreased and erythrocyte sedimentation rate remarkably increased in Chikungunya confirmed patients. However, the majority of the patients had a normal range of whole WBC and platelet counts; RBC counts for mid aged (40 – 60 years) and senior (61+ years) patients (especially in the females) were beyond the reference values. The post-infection study revealed that children had an early recovery from the infection compared to the adults. Moreover, post-infection weakness, successive relapse of arthralgic pain and memory problems were the most significant aftereffects, which had an impact on daily activities of patients. This study represents a comprehensive overview of clinical and epidemiological features of the 2017 outbreak of Chikungunya in Bangladesh as well as its chronic outcomes till the 12th month. It provides insights into the natural history of this disease which may help to improve management of the Chikungunya patients.Author summeryThe clinical profile, epidemiology and the economic impacts during the acute phase of Chikungunya infection has been studied quite rigorously. However, studies regarding the hematological features and chronic consequences are very limited. In this study, a dataset of 187 clinically proven chikungunya patients were analyzed for the clinical and hematological features at acute phase of the infection. Additionally, the long-term consequences till month 12 after the infection were studied for a smaller group of 48 patients. Clinical data revealed that a combination of fever and joint pain (arthralgia) was the cardinal hallmark in the acute phase of the infection. Hematological analysis showed that, hemoglobin levels of the patients were significantly reduced and erythrocyte sedimentation rate increased remarkably. Also, RBC counts for mid-aged and older patients were beyond the reference values. The post-infection consequence study unveiled that children recovered better from the infection compared to the adults. Further, post-infection weakness, successive relapse of joint pain and memory problems were the most significant aftereffects. Overall, the infection had moderate to severe impact on daily activities of the respondents. This study provides insights into the clinical and hematological aspects of Chikungunya infection during the acute phase as well as describes an account for its chronic outcomes which puts forward to the knowledge for clinicians and epidemiologists regarding the infection diversity and to help improved patient management

Acral Acquired Cutis Laxa Associated with IgA Multiple Myeloma, Joint Hyper laxity and Urticarial Neutrophilic Dermatosis

Peer reviewe

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals

ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G&gt;A (p.Val787Ile) and c.1171A&gt;G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A&gt;G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling

Nonlinear optical microscopy is a novel tool for the analysis of cutaneous alterations in pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet

The physicochemical deposition of calcium-phosphate in the arterial wall is prevented by calcification inhibitors. Studies in cohorts of patients with rare genetic diseases have shed light on the consequences of loss-of-function mutations for different calcification inhibitors, and genetic targeting of these pathways in mice have generated a clearer picture on the mechanisms involved. For example, generalized arterial calcification of infancy (GACI) is caused by mutations in the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (eNPP1), preventing the hydrolysis of ATP into pyrophosphate (PPi). The importance of PPi for inhibiting arterial calcification has been reinforced by the protective effects of PPi in various mouse models displaying ectopic calcifications. Besides PPi, Matrix Gla Protein (MGP) has been shown to be another potent calcification inhibitor as Keutel patients carrying a mutation in the encoding gene or Mgp-deficient mice develop spontaneous calcification of the arterial media. Whereas PPi and MGP represent locally produced calcification inhibitors, also systemic factors contribute to protection against arterial calcification. One such example is Fetuin-A, which is mainly produced in the liver and which forms calciprotein particles (CPPs), inhibiting growth of calcium-phosphate crystals in the blood and thereby preventing their soft tissue deposition. Other calcification inhibitors with potential importance for arterial calcification include osteoprotegerin, osteopontin, and klotho. The aim of the present review is to outline the latest insights into how different calcification inhibitors prevent arterial calcification both under physiological conditions and in the case of disturbed calcium-phosphate balance, and to provide a consensus statement on their potential therapeutic role for arterial calcification