An overview of molecular mechanisms in fabry disease

Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is alpha-galactosidase A (alpha-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers

Contemporary lipid-lowering management and risk of cardiovascular events in homozygous familial hypercholesterolaemia: insights from the Italian LIPIGEN Registry

Aims: The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting. Methods and results: The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016). Conclusion: Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups &lt;0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and ResultsAn lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score &gt;= 1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups &lt;0.0001); however, subjects with FH/M- and lp(a) score &gt;= 1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level &gt;= 190 mg/dL (or from 68% to 50%, considering a more conservative formula). ConclusionsOur study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

MicroRNAs: From Junk RNA to Life Regulators and Their Role in Cardiovascular Disease

MicroRNAs (miRNAs) are single-stranded small non-coding RNA (18–25 nucleotides) that until a few years ago were considered junk RNA. In the last twenty years, they have acquired more importance thanks to the understanding of their influence on gene expression and their role as negative regulators at post-transcriptional level, influencing the stability of messenger RNA (mRNA). Approximately 5% of the genome encodes miRNAs which are responsible for regulating numerous signaling pathways, cellular processes and cell-to-cell communication. In the cardiovascular system, miRNAs control the functions of various cells, such as cardiomyocytes, endothelial cells, smooth muscle cells and fibroblasts, playing a role in physiological and pathological processes and seeming also related to variations in contractility and hereditary cardiomyopathies. They provide a new perspective on the pathophysiology of disorders such as hypertrophy, fibrosis, arrhythmia, inflammation and atherosclerosis. MiRNAs are differentially expressed in diseased tissue and can be released into the circulation and then detected. MiRNAs have become interesting for the development of new diagnostic and therapeutic tools for various diseases, including heart disease. In this review, the concept of miRNAs and their role in cardiomyopathies will be introduced, focusing on their potential as therapeutic and diagnostic targets (as biomarkers)

Altered CSF protein pattern in a case of mycosis fungoides with nervous system involvement

We report the clinical, neurophysiological and CSF study in a case of mycosis fungoides with nervous system involvement. The CSF contained an abnormal protein of molecular weight 22000 that was not in the patient's serum or in the CSF of control subjects and that disappeared after intrathecal immunosuppressive therapy. The nature of this protein is discussed in the light of hypothesis regarding the pathogenesis of the disease

An electromyographic evaluation of motor complications in thoracic herpes zoster

Motor complications in thoracic herpes zoster were evaluated in 52 patients by electromyographic examination of the paraspinal muscles. At the initial EMG examination, abnormal findings were observed in 18 patients (35%). In 8 patients the myomers involved coincided in location with affected dermatomes, while in 10 patients, in addition to the involvement of myomers corresponding to affected dermatomes, there also appeared an involvement of one or more contiguous myomers not corresponding to affected dermatomes. Our study demonstrated that motor involvement in thoracic HZ is much more common than previously suggested and its incidence (35%) appears to be greater than that reported in both cervical and lumbosacral HZ

ECG analysis in patients with acute coronary syndrome undergoing invasive management: rationale and design of the electrocardiography sub-study of the MATRIX trial.

BACKGROUND The twelve‑lead electrocardiogram (ECG) has become an essential tool for the diagnosis, risk stratification, and management of patients with acute coronary syndromes (ACS). However, several areas of residual controversies or gaps in evidence exist. Among them, P-wave abnormalities identifying atrial ischemia/infarction are largely neglected in clinical practice, and their diagnostic and prognostic implications remain elusive; the value of ECG to identify the culprit lesion has been investigated, but validated criteria indicating the presence of coronary occlusion in patients without ST-elevation are lacking; finally, which criteria among the multiple proposed, better define pathological Q-waves or success of revascularisation deserve further investigations. METHODS The Minimizing Adverse hemorrhagic events via TRansradial access site and systemic Implementation of AngioX (MATRIX) trial was designed to test the impact of bleeding avoidance strategies on ischemic and bleeding outcomes across the whole spectrum of patients with ACS receiving invasive management. The ECG-MATRIX is a pre-specified sub-study of the MATRIX programme which aims at analyzing the clinical value of ECG metrics in 4516 ACS patients (with and without ST-segment elevation in 2212 and 2304 cases, respectively) with matched pre and post-treatment ECGs. CONCLUSIONS This study represents a unique opportunity to further investigate the role of ECGs in the diagnosis and risk stratification of ACS patients with or without ST-segment deviation, as well as to assess whether the radial approach and bivalirudin may affect post-treatment ECG metrics and patterns in a large contemporary ACS population

Can apical ballooning cardiomyopathy and anterior STEMI be differentiated based on \u3b21 and \u3b22-adrenergic receptors polymorphisms?

Catecholamine excess along with an exaggerated sympathetic stimulation appears to play a major role in the pathophysiological mechanism of tako-tsubo cardiomyopathy (TTC), which mimics acute ST-elevation myocardial infarction (STEMI). The aim of the present study was to investigate differences in the distribution of allelic variants of \u3b21- and \u3b22-adrenoceptors between TTC and anterior STEMI patients compared to normal subjects