A Rare Cause of Juvenile Stroke: Extracranial Carotid Artery Aneurysm with Venous Complete Reconstruction of the Carotid Bifurcation.

Extracranial carotid artery aneurysms (ECAA) are a rare cause of embolic stroke. The underlying etiology is variable, with atherosclerosis being the most common entity in older subjects. Several treatments have been developed over the last 20 years, but the preferred method remains unknown. Notwithstanding the widespread use of endovascular techniques, surgical reconstruction by means of a bifurcated venous bypass graft should be applied in younger patients. In this way, it is possible to avoid major concerns about the development of long-term intrastent restenosis, and also to spare the external carotid artery which represents the main branch for the ipsilateral cerebral and facial perfusion. We propose ECAA resection and interposition of the inverted great saphenous vein to both the internal and external carotid artery by means the use of a tributary, i.e., the Giacomini vein.

Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events.

Classic Ehlers-Danlos syndrome (cEDS) is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring. Mutations in type V collagen, a regulator of type I collagen fibrillogenesis, underlie this type of EDS. In this article we report a genetic and clinical analysis of an Italian family that carried missense mutation c.934 C>T (p.R312C) in the COL1A1 gene. Literature review showed an association between this missense mutation and vascular complications. Genetic screening conducted on Italian family members, revealed that vascular events are absent. In conclusion, genetic and clinical data confirm the extreme heterogeneity of EDS. Nevertheless, vascular events could be a risk factor and periodical clinical evaluation could be relevant.

RETRACTED: Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events.

The article entitled "Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events" has been retracted because the description and characterization of the disease in a family may have been previously published. Upon publication of this article we were notified by an author of a study appearing in 2016 in another journal claiming that characteristics and symptoms of the family described closely matched their study, and that the two studies describe the same family. Whereas constituent family members appearing in both articles were not identical (differing by one member), symptoms and diagnoses of each family proband appeared to be consistent in both studies, leading to the editors' conclusion that it is likely that the same family was being described in two separate articles.The corresponding author of the article in Dermatology Online Journal was informed of this incident, and responded with the assertion that they were unaware of the study published in 2016, and provided no additional information. They further requested that their article be retracted. In light of the available information and author's request, the editors of Dermatology Online Journal have retracted this article.The original article was published on July15, 2018 and corrected on September 15, 2018.The original article was published on July15, 2018 and corrected on September 15, 2018.

Effects of particulate matter exposure on multiple sclerosis hospital admission in Lombardy region, Italy.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system, characterized by recurrent relapses of inflammation that cause mild to severe disability. Exposure to airborne particulate matter (PM) has been associated with acute increases in systemic inflammatory responses and neuroinflammation. In the present study, we hypothesize that exposure to PM<10µm in diameter (PM10) might increase the occurrence of MS-related hospitalizations. METHODS: We obtained daily concentrations of PM10 from 53 monitoring sites covering the study area and we identified 8287 MS-related hospitalization through hospital admission-discharge records of the Lombardy region, Italy, between 2001 and 2009. We used a Poisson regression analysis to investigate the association between exposure to PM10 and risk of hospitalization. RESULTS: A higher RR of hospital admission for MS relapse was associated with exposure to PM10 at different time intervals. The maximum effect of PM10 on MS hospitalization was found for exposure between days 0 and 7: Hospital admission for MS increased 42% (95%CI 1.39-1.45) on the days preceded by one week with PM10 levels in the highest quartile. The p-value for trend across quartiles was<0.001. CONCLUSIONS: These data support the hypothesis that air pollution may have a role in determining MS occurrence and relapses. Our findings could open new avenues for determining the pathogenic mechanisms of MS and potentially be applied to other autoimmune diseases.

Candidate gene analysis of semaphorins in patients with Alzheimer's disease.

Semaphorins of the SemaIV family are expressed in neurons and decreased in brains from patients with Alzheimer's disease (AD). Accumulation of an internalized form of Sema3A is associated with degeneration of neurons, making these molecules candidates for the development of AD. Single nucleotide polymorphisms (SNPs) rs36026860 and rs28469467 in Sema3A as well as rs13284404 and rs11526468 in Sema4D were analyzed in a population of 240 patients with AD compared with 222 age-matched controls. None of SNPs in Sema3A were present, either in patients or controls. The distribution of the Sema4D rs11526468 and rs13284404 SNPs was not significantly different between patients and controls, even stratifying for gender or age at onset. In silico analysis predicted that rs11526468 and rs28469467 are probably damaging. This high degree of conservation of Sema3A suggests a very important role for this protein. However, neither Sema3A nor Sema4D likely influence the susceptibility to AD.

MCP-1 A-2518G polymorphism: effect on susceptibility for frontotemporal lobar degeneration and on cerebrospinal fluid MCP-1 levels.

The distribution of the MCP-1 A-2518G single nucleotide polymorphisms (SNP) was analyzed in a population of 212 patients with frontotemporal lobar degeneration (FTLD) compared with 203 age-matched controls. A significantly decreased allelic frequency of the G allele in patients compared with controls was observed (21.1 versus 29.3%, P = 0.011, OR: 0.59, CI: 0.40-0.87). Stratifying according to gender, the association was maintained in male patients versus male controls (17.8 versus 29.4%, P = 0.016, OR = 0.46, 95% CI: 0.25-0.84), but not in female patients compared with female controls (23.5 versus 29.2%, P > 0.05). The frequency of apolipoprotein E epsilon4 carriers was increased in patients (26.4 versus 13.8%, P = 0.0015, OR: 2.24, 95% CI: 1.37-3.67). Apolipoprotein E status did not influence the distribution of the A-2518G SNP. Monocyte chemotactic protein (MCP)-1 levels were determined in cerebrospinal fluid (CSF) collected from 23 patients and 17 controls. MCP-1 CSF levels were increased in patients compared with controls (449.01 +/- 27.57 versus 364.19 +/- 23.75 pg/ml, P = 0.011). Stratifying patients according to the presence of the polymorphic allele, significantly increased CSF MCP-1 levels were observed in carriers of the G allele compared with non-carriers (502.21 +/- 44.57 versus 395.87 +/- 21.92 pg/ml, P = 0.045). The MCP-1 A-2518G SNP acts as protective factor for sporadic FTLD, possibly by influencing MCP-1 production.

Emerging roles of long non-coding RNAs in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and represents the most common form of senile dementia. The pathogenesis of AD is not yet completely understood and no curative treatment is currently available. With the recent advancement in transcriptome-wide profiling approach, several non-coding RNAs (ncRNAs) have been identified. Among them, long non-coding RNAs (lncRNAs), which are long transcripts without apparent protein-coding capacity, have received increasing interest for their involvement in a wide range of biological processes as regulatory molecules. Recent studies have suggested that lncRNAs play a role in AD pathogenesis, although their specific influences in the disorder remain to be largely unknown. Herein, we will summarize the biology and mechanisms of action of the best characterized dysregulated lncRNAs in AD, focusing the attention on their potential role in the disease pathogenesis. A deeper understanding of the molecular mechanisms and the complex network of interactions in which they are implicated should open the doors to new research considering lncRNAs as novel therapeutic targets and prognostic/diagnostic biomarkers.

Understanding the basis of Ehlers-Danlos syndrome in the era of the next-generation sequencing.

Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) defined by joint laxity, skin alterations, and joint hypermobility. The latest EDS classification recognized 13 subtypes in which the clinical and genetic phenotypes are often overlapping, making the diagnosis rather difficult and strengthening the importance of the molecular diagnostic confirmation. New genetic techniques such as next-generation sequencing (NGS) gave the opportunity to identify the genetic bases of unresolved EDS types and support clinical counseling. To date, the molecular defects have been identified in 19 genes, mainly in those encoding collagen, its modifying enzymes or other constituents of the extracellular matrix (ECM). In this review we summarize the contribution of NGS technologies to the current knowledge of the genetic background in different EDS subtypes.

Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer's disease and frontotemporal lobar degeneration.

Cerebrospinal fluid (CSF) levels of interleukin (IL)-6, IL-11 and leukaemia inhibitory factor (LIF) were evaluated in 43 patients with Alzheimer's disease (AD) and 24 patients with frontotemporal lobar degeneration (FTLD) as compared with 30 agematched controls (CON), and correlated with clinical and demographic data and with CSF biomarkers amyloid beta (A beta)42, total tau and tau phosphorylated at position 181 (P-tau). CSF IL-11 mean levels were significantly increased in AD and FTLD as compared with CON (6.5 +/- 4.6 and 6.6 +/- 5.1 versus 3.1 +/- 3.3 pg/ml, P = 0.009). IL-6 mean levels did not differ between patients and CON (P > 0.05),whereas LIF levels were not detectable in patients or in CON. In AD patients, a significantly positive correlation between MMSE scores and IL-11 CSF concentration was observed (r = 0.344, P = 0.028). No correlations with CSF A beta 42, total tau and P-tau were found. IL-11, but not IL-6 levels are increased in AD and FTLD, and the highest peaks were observed in patients with a less severe degree of cognitive deterioration, therefore suggesting a role of this cytokine in early phases of neurodegeneration.

Gender-specific influence of the chromosome 16 chemokine gene cluster on the susceptibility to Multiple Sclerosis.

Macrophage-derived chemokine (MDC/CCL22) plays a role in Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis (MS). MDC/CCL22 gene is part of a chemokine cluster, which includes also thymus and Activation-Regulated Chemokine (TARC/CCL17). The frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL22 as well as the C/T SNP in the promoter of CCL17 were determined in 370 patients with Multiple Sclerosis (MS) compared with 380 controls. A trend towards a decreased allelic frequency of the A allele of the CCL22 C/A SNP as well as of the T allele of the CCL17 C/T SNP was found in patients compared with controls. The frequency of the AT haplotype was significantly decreased in MS patients (P=0.017, OR: 0.49, CI: 0.28-0.87). Stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P=0.004, OR=0.18, 95% CI: 0.06-0.50), whereas no significant differences were observed in females. Therefore, the presence of the AT haplotype in chromosome 16 chemokine cluster is likely to confer a decreased risk of developing MS, particularly in males.

Ehlers-Danlos syndromes and epilepsy: An updated review.

The Ehlers-Danlos syndromes (EDS) comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs), characterised by joint hypermobility, hyperextensibility of the skin and tissue fragility that can induce symptoms from multiple organ systems. The latest EDS nosology distinguished thirteen subtypes with an overlap of phenotypic features, making the clinical diagnosis rather difficult and highlighting the importance of molecular diagnostic confirmation. Although the nervous system is not considered a primary target of the underlying molecular defect, recently, increasing attention has been focused on neurological manifestations of EDS. Among them, epilepsy represents a frequent cause of morbidity in these syndromes and can influence the long-term evolution of these patients, but the mechanisms are needed to be clarified. The aim of this review is to give a comprehensive overview and to analyze a possible association between EDS and epilepsy, focusing on the various brain anomalies and the types of epilepsy reported in patients affected by EDS.

Epileptic seizures in autosomal dominant forms of Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and represents the most common form of dementia in the elderly. Mutations in genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) are responsible for early-onset familial AD (EOFAD). Several pieces of evidence report that patients with rare autosomal dominant forms of AD carry a significant risk to develop seizures. However, the molecular mechanisms linking epilepsy and AD are needed to be clarified: the pathophysiology of seizures in AD may be related to an increased production of amyloid-ß (Aß) peptide or structural alterations in neurons probably due to cerebrovascular changes, neurotransmitter or cytoskeletal dysfunctions. Seizures have traditionally been related to neuronal loss in the late stages of AD as a consequence of neurodegeneration, however, recent studies indicated that seizures may contribute to the emergence of AD symptoms in early stages of the disease, mainly in familial AD. So, a better understanding of possible common neural mechanisms might help to improve the clinical management of both conditions. This review aims to give a comprehensive overview and to analyze the association between epilepsy and EOFAD, focusing on possible overlapping pathological mechanisms.

PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline.

Epigenetic mechanisms might be involved in Alzheimer's disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change - 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.

Usefulness of JAK2V617F mutation in distinguishing idiopathic erythrocytosis from polycythemia vera.

Idiopathic erythrocytosis (IE) is a primary erythrocytosis not fulfilling the criteria for polycythemia vera (PV) diagnosis. In order to verify the relationship between IE and PV, we screened JAK2V617F mutation in a consecutive series of 11 IE and, for comparison, in 15 PV. JAK2V617F mutation was screened by both cDNA sequencing and mutation specific PCR in both peripheral blood and bone marrow samples. All 11 IE tested negative for JAK2V617F mutation, which, conversely, occurred in 11/15 (73.3%) PV. Our results demonstrate that JAK2V617F is absent in IE and may represent a useful molecular marker for distinguishing IE from PV.

Candidate gene analysis of SPARCL1 gene in patients with multiple sclerosis.

Recently, proteomic analysis in cerebrospinal fluid (CSF) from patients with MS identified four proteins which are present in MS but not in normal human CSF, including SPARCL1, an extracellular matrix-associated protein member of the SPARC family. One hundred eighty-six patients with MS and 185 age-matched controls were genotyped for A/G single nucleotide polymorphism (SNP) in exon 1 (rs1049539), C/G SNP in exon 4 (rs1049544), resulting in a substitution of an aspartate with an histidine, and A/G substitution in the exon 5 (rs1130643), leading to the substitution of alanine with threonine. No significant differences in either allelic or genotypic frequency of the three SNPs were found (P>0.05), even in stratifying MS patients according to the course of the disease. Stratifying according to gender, a trend towards a decreased frequency of the C/C genotype of the rs1049544 was observed in male patients as compared with male controls (30.2% versus 44.0%; P=0.217). Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. However, the frequency of the C/C genotype of rs1049544 was decreased in male patients, possibly conferring a lower risk of developing MS in male population. Further studies are needed to clarify this issue.

A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type With Different Phenotypes in the Same Family.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain ( COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance.

Next-generation sequencing and a novel COL3A1 mutation associated with vascular Ehlers-Danlos syndrome with severe intestinal involvement: a case report.

BACKGROUND: The vascular type of Ehlers-Danlos syndrome is an autosomal dominant connective tissue disorder caused by a mutation in the COL3A1 gene encoding pro-alpha1 chain of type III collagen. The vascular type of Ehlers-Danlos syndrome causes severe fragility of connective tissues with arterial and intestinal ruptures and complications in surgical and radiological treatments. CASE PRESENTATION: We present a case of a 38-year-old Italian woman who was diagnosed as having the vascular type of Ehlers-Danlos syndrome. Genetic testing, conducted by Target Enrichment approach (Agilent Technologies), identified a new mutation c.1493G>A, p.G498D in exon 21 of COL3A1 gene (heterozygous state). This mutation disrupts the normal glycine-X-Y repetitions of type III procollagen by converting glycine to aspartic acid. CONCLUSIONS: We report a new genetic mutation associated with the vascular type of Ehlers-Danlos syndrome. We also describe clinical and genetic findings that are important to understand the genotype/phenotype correlation in patients with the vascular type of Ehlers-Danlos syndrome.

Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia.

Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls.A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR:0.63, 95%CI:0.49-0.80), rs4792938 (30.7 versus 39.7%, P = 0.005, OR: 0.70, 95%CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P = 0.007, OR: 0.71, 95%CI: 0.56-0.91). Mean±SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69±3.97 and 116.14±5.80 ng/ml, respectively, versus 180.81±18.39 ng/ml P<0.001) and were not correlated with age.In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results.

Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII.

The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.

Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred.

The Asp22fs(g.63_64insC) mutation in progranulin gene (GRN) has been so far reported in one patient who developed frontotemporal dementia (FTD) at the age of 65. Here, we describe the clinical heterogeneity associated with the GRN Asp22fs mutation in a large Italian family. Clinical and instrumental workup of two symptomatic carriers in two generations has been carried out, together with genetic analysis of probands and of nine asymptomatic family members. The first proband was a 47-year old male clinically diagnosed with FTD. Family history was positive and suggestive of an autosomal dominant pattern of inheritance. Evaluation of plasma GRN levels was consistent with the presence of a mutation in its encoding gene, that was demonstrated by sequencing [Asp22fs(g.63_64insC)]. Brain MRI showed multiple T2 and FLAIR hyperintense areas in the frontal lobe white matter and right hemisphere cortical atrophy. The second proband was his 79 year old uncle, presenting with mild cognitive impairment. Brain MRI showed small T2 hyperintense lesions and widespread cortical atrophy. Cerebrospinal fluid amyloid-ß, tau, and phosphotau protein levels were in both cases in the range of normality. Additional nine asymptomatic family members were studied. This family's description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by GRN mutations, suggesting that the diagnosis could be missed in some individuals with an atypical presentation, and points up the importance of GRN plasma level evaluation.