Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20–50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses.

Extracellular vesicles (EVs) are promising therapeutics for diseases associated with inflammation and tissue remodeling. However, a major limitation for th

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs. SPG15 is a rare form of autosomal recessive HSP due to mutations in ZFYVE26 gene, which encodes for spastizin, involved in autophagy and endocytosis ( 1 ). Here we describe the case of a 56 years old man who presented to our clinic in November 2020 referring a progressive motor clumsiness of both legs and walking instability during the last five years. No motor impairment at upper limb, no bulbar nor respiratory symptoms. These symptoms had a progressive evolution. In anamnesis only high blood pressure. No familiar history of neurodegenerative diseases. Neurological examination showed a spastic gait, a light hypotrophy and hyposthenia of the left leg, brisk reflexes at lower limb, no Hoffmann nor Babinski signs, no urinary nor intestinal problems. He underwent: blood examination (resulted normal, no HIV, HTLV infections), electroneurography/electromyography study (signs of chronic neurogenic muscle damage at lower limbs), brain MRI (normal), cervical MRI (normal medulla, small discal hernias without radicular or medulla compression), neuropsychological tests (executive and visuo-spatial impairments). On the basis of these examinations, we suspected a primary form of upper motor neuron disease. Therefore, we prescribed rehabilitation (with partial improvement of gait disturbances) and we executed a genetic examination in the suspect of a rare form of HSP. We observed a homozygous mutation in ZFYVE26 gene, which is the cause of a rare form of HSP (the SPG15). In detail, the mutation we found (c.195-1G>A) is a novel deletion in ZFYVE26 gene, never described in literature. This is a mutation in a splicing site and an in-silico evaluation demonstrated its pathogenic role. The clinical features of our patient are superimposable to other cases of SPG15. Background: Nicotinamide adenine dinucleotide (NAD+) is a central component for cell metabolism, and a vital factor for function of various groups of enzymes involved in pathways such as DNA repair, inflammation, genomic stability and stress resistance. NAD + is synthesised through three pathways; the Kynurenine, Preiss-Handler and salvage pathways. Conversely, NAD + is consumed to its reduced form nicotinamide adenine dinucleotide (NADH) via poly (ADP-ribose) polymerases (PARPs), sirtuins (SIRTs), ADP-ribosyl cyclases (CD38/CD157), and Sterile alpha and TIR motif containing 1 (SARM1). Reduced NAD + levels caused by impairment of enzymes involved in NAD + biosynthesis or up-regulation of enzymes that consume NAD + have been associated with aging and several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). While gene mutations are known to cause ALS, the genetics of ALS is highly complex, whereby only approximately 60–70% of familial and 10% of sporadic ALS cases have a known genetic cause. In additional to causal gene mutations, multiple gene variants may also act synergistically, with or without environmental influence, to cause or confer risk to the development of ALS. Objectives: We aimed to determine the genetic contribution of 36 genes involved in NAD + biosynthesis (focusing on Preiss handler and Salvage pathway, Kynurenine pathways), and NAD + consumption (PARPs, SIRTs, CD38/CD157, SARM1) by identification of novel gene variants and gene burden in a large cohort of Australian sporadic ALS cases. Methods: Whole-genome sequencing data from 609 Australian sporadic ALS cases was screened through the 36 genes. Novel variants absent in public control databases, and rare protein-altering variants (for gene burden analysis) were identified. For burden analysis, variants in genes involved in NAD + synthesis and each consumption pathway were grouped, and compared to two independent control databases. Results: Forty-two novel variants identified in 26/36 genes were identified. Burden analysis of rare variants performed on genes in combined Preiss-handler and Salvage pathway (NAD + synthesis), and genes belonging to the SIRT family (NAD + consumption) was statistically significant (p = 0.0014 and p = 0.006 respectively) when compared to Project MinE controls. Discussion: Some of these variants may represent ALS risk factors that disrupt NAD + biosynthesis or consumption, hence altering NAD + levels in ALS patients. Overall, our genetic findings suggest that rare genetic mutations in genes that alter NAD + levels may be associated with sporadic ALS in Australia. There is potential for therapeutic drugs that boost NAD + levels in ALS patients, and future studies can assess the specific pathogenic role of novel variants identified in patients to improve our understanding underlying the mechanisms of disease. SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which are capable of propagating throughout the genome and hence represent a source of genetic variation. We previously demonstrated that presence or absence of a human-specific SVA, termed SVA_67, correlated with both isoform- and tissue-specific expression of multiple genes at the MAPT locus, a locus associated with several neurodegenerative diseases including frontotemporal dementia and other tauopathies. A problem in defining regulatory associations is that this region is contained within a large genomic inversion termed H1/H2. We have identified that SVA _67 tags the H1 inversion and we are extending our analysis to distinguish the SVA specific regulation from that associated with the inversion. In the current study we show that SVA_67 is not only a retrotransposon insertion polymorphism (RIP), but also variable in the size of its variable number tandem repeat (VNTR) domain. Four different alleles of the SVA_67 VNTR were identified which demonstrated differential properties of a regulatory domain in a reporter gene assay. We expanded these findings by...