The weight of obesity in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is one of the most frequently diagnosed primary conditions of the heart muscle. It is considered to be inherited, caused by genetic mutations encoding for sarcomere proteins. The marked heterogeneity in clinical manifestations and natural course of the disease, even among family members sharing the same genetic mutation, has raised the question of non-genetic environmental factors contributing to the phenotype. Obesity has been associated with worse cardiovascular outcomes in the general population. Its prevalence is increased in hypertrophic cardiomyopathy, and the two conditions share some similar pathophysiological and clinical characteristics. In this review, we aim to summarise the effects of obesity in the cardiac phenotype, the symptoms and management in patients with hypertrophic cardiomyopathy.

Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of PKD1 Hypomorphic Alleles.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic PKD1 variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including PKHD1, HNF1B and PKD1 allowed the identification of biallelic PKD1 variants. Furthermore, we review the medical literature in order to report likely PKD1 hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare PKD1 missense variants, especially if previously unreported, remain challenging.

Corrigendum: Do common infections trigger disease-onset or -severity in CTLA-4 insufficiency?

[This corrects the article DOI: 10.3389/fimmu.2022.1011646.].

Do common infections trigger disease-onset or -severity in CTLA-4 insufficiency?

Purpose: Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. Methods: To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers. Results: The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. Conclusions: Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.

Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers.

Chronic heart failure (HF) is rare in the young and common in the elderly in the Western world. HF in the young is usually due to specific causes, predominantly or exclusively affecting the heart (adult congenital heart disease, different types of cardiomyopathies, myocarditis, or cardiotoxicity). In contrast, the mechanisms underlying HF development in the elderly have not been completely delineated. We propose that in most elderly patients, HF, regardless of the left ventricular ejection fraction (LVEF), is the consequence of the acceleration of cardiovascular aging by specific risk factors (usually hypertension, obesity, type 2 diabetes mellitus [T2DM], coronary artery disease [CAD], and valvular heart disease [VHD]), most affecting both the heart and the vasculature. These risk factors act individually or more commonly in groups, directly or indirectly (hypertension, obesity, and T2DM may lead to HF through an intervening myocardial infarction). The eventual HF phenotype and outcomes in the elderly are additionally dependent on the presence and/or development of comorbidities (atrial fibrillation, anemia, depression, kidney disease, pulmonary disease, sleep disordered breathing, other) and disease modifiers (race, sex, genes, other). The clinical implications of this paradigm are that aggressive treatment of hypertension, obesity, T2DM (preferably with metformin and sodium-glucose cotransporter-2 inhibitors), CAD, and VHD on top of measures that retard cardiovascular aging are the steadfast underpinning for HF prevention in the elderly, which represent the vast majority of HF patients.

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis.

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.

The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1RC/RC mouse model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD), primarily due to PKD1 or PKD2 mutations, causes progressive kidney cyst development and kidney failure. There is significant intrafamilial variability likely due to the genetic background and environmental/lifestyle factors; variability that can be modeled in PKD mice. Here, we characterized mice homozygous for the PKD1 hypomorphic allele, p.Arg3277Cys (Pkd1RC/RC), inbred into the BALB/cJ (BC) or the 129S6/SvEvTac (129) strains, plus F1 progeny bred with the previously characterized C57BL/6J (B6) model; F1(BC/B6) or F1(129/B6). By one-month cystic disease in both the BC and 129 Pkd1RC/RC mice was more severe than in B6 and continued with more rapid progression to six to nine months. Thereafter, the expansive disease stage plateaued/declined, coinciding with increased fibrosis and a clear decline in kidney function. Greater severity correlated with more inter-animal and inter-kidney disease variability, especially in the 129-line. Both F1 combinations had intermediate disease severity, more similar to B6 but progressive from one-month of age. Mild biliary dysgenesis, and an early switch from proximal tubule to collecting duct cysts, was seen in all backgrounds. Preclinical testing with a positive control, tolvaptan, employed the F1(129/B6)-Pkd1RC/RC line, which has moderately progressive disease and limited isogenic variability. Magnetic resonance imaging was utilized to randomize animals and provide total kidney volume endpoints; complementing more traditional data. Thus, we show how genetic background can tailor the Pkd1RC/RC model to address different aspects of pathogenesis and disease modification, and describe a possible standardized protocol for preclinical testing.

DNA Repair in Huntington's Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses.

The use of genome wide association studies (GWAS) in Huntington's disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS).

BACKGROUND: Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS. MAIN BODY: The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications. CONCLUSION: Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.

Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity-Related Cardiac Defects as a Major Disease Modifier.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype-phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity-induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity-related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation-induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment.

Spinal muscular atrophy (SMA) is currently classified into five different subtypes, from the most severe (type 0) to the mildest (type 4) depending on age at onset, best motor function achieved, and copy number of the SMN2 gene. The two recent approved treatments for SMA patients revolutionized their life quality and perspectives. However, upon treatment with Nusinersen, the most widely administered therapy up to date, a high degree of variability in therapeutic response was observed in adult SMA patients. These data, together with the lack of natural history information and the wide spectrum of disease phenotypes, suggest that further efforts are needed to develop precision medicine approaches for all SMA patients. Here, we compile the current methods for functional evaluation of adult SMA patients treated with Nusinersen. We also present an overview of the known molecular changes underpinning disease heterogeneity. We finally highlight the need for novel techniques, i.e., -omics approaches, to capture phenotypic differences and to understand the biological signature in order to revise the disease classification and device personalized treatments.

Phenotype-genotype relations in facioscapulohumeral muscular dystrophy type 1.

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by large variability in disease severity, that is only partly explained by (epi)genetic factors. Clinical observations and recent in vitro work suggest a protective effect of estrogens in FSHD. The aims of this study were to assess whether the lifetime endogenous estrogen exposure contributes to the variability in disease severity in female patients, and whether female patients experience changes in disease progression during periods of hormonal changes. We calculated the lifetime endogenous estrogen exposure by subtracting periods with high progesterone levels (in which estrogens are counteracted) from the reproductive life span. Multiple linear regression in 85 patients did not show a contribution of the lifetime endogenous estrogen exposure to disease severity (B = 0.063, P-value = 0.517, ΔR2 = 0.003). The majority of women reported an unchanged rate of disease progression through periods of hormonal changes, like menarche, pregnancy or menopause. Women that noticed differences reported accelerations as well as decelerations. These results indicate that differences in estrogen exposure do not have a clinically relevant modifying effect on disease severity. However, a clinically relevant protective effect of greater differences in estrogen levels, or a protective effect caused by a more complex interplay with other reproductive hormones, cannot be ruled out.

Staufen1s role as a splicing factor and a disease modifier in Myotonic Dystrophy Type I.

In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1. Here, we discuss our major findings and speculate on the details of the mechanisms by which Staufen1 could regulate alternative splicing, in both normal and DM1 conditions. Finally, we highlight the importance of disease modifiers, such as Staufen1, in the DM1 pathology in order to understand the complex disease phenotype and for future development of new therapeutic strategies.

Alpha-linolenic acid given as enteral or parenteral nutritional intervention against sensorimotor and cognitive deficits in a mouse model of ischemic stroke.

Stroke is a leading cause of disability and death worldwide. Numerous therapeutics applied acutely after stroke have failed to improve long-term clinical outcomes. An emerging direction is nutritional intervention with omega-3 polyunsaturated fatty acids acting as disease-modifying factors and targeting post-stroke disabilities. Our previous studies demonstrated that the omega-3 precursor, alpha-linolenic acid (ALA) administrated by injections or dietary supplementation reduces stroke damage by direct neuroprotection, and triggering brain artery vasodilatation and neuroplasticity. Successful translation of putative therapies will depend on demonstration of robust efficacy on common deficits resulting from stroke like loss of motor control and memory/learning. This study evaluated the value of ALA as adjunctive therapy for stroke recovery by comparing whether oral or intravenous supplementation of ALA best support recovery from ischemia. Motor and cognitive deficits were assessed using rotarod, pole and Morris water maze tests. ALA supplementation in diet was better than intravenous treatment in improving motor coordination, but this improvement was not due to a neuroprotective effect since infarct size was not reduced. Both types of ALA supplementation improved spatial learning and memory after stroke. This cognitive improvement correlated with higher survival of hippocampal neurons. These results support clinical investigation establishing therapeutic plans using ALA supplementation.

Large-Scale Functional RNAi Screen in C. elegans Identifies TGF-ß and Notch Signaling Pathways as Modifiers of CACNA1A.

Variants in CACNA1A that encodes the pore-forming α1-subunit of human voltage-gated Cav2.1 (P/Q-type) Ca(2+)channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6. To identify modifiers of incoordination in movement disorders, we performed a large-scale functional RNAi screen, using the Caenorhabditis elegansstrain CB55, which carries a truncating mutation in the unc-2gene, the worm ortholog for the human CACNA1A The screen was carried out by the feeding method in 96-well liquid culture format, using the ORFeome v1.1 feeding library, and time-lapse imaging of worms in liquid culture was used to assess changes in thrashing behavior. We looked for genes that, when silenced, either ameliorated the slow and uncoordinated phenotype of unc-2, or interacted to produce a more severe phenotype. Of the 350 putative hits from the primary screen, 37 genes consistently showed reproducible results. At least 75% of these are specifically expressed in the C. elegansneurons. Functional network analysis and gene ontology revealed overrepresentation of genes involved in development, growth, locomotion, signal transduction, and vesicle-mediated transport. We have expanded the functional network of genes involved in neurodegeneration leading to cerebellar ataxia related to unc-2/CACNA1A, further confirming the involvement of the transforming growth factor ß pathway and adding a novel signaling cascade, the Notch pathway.

New concepts in nutraceuticals as alternative for pharmaceuticals.

Nutraceuticals are products, which other than nutrition are also used as medicine. A nutraceutical product may be defined as a substance, which has physiological benefit or provides protection against chronic disease. Nutraceuticals may be used to improve health, delay the aging process, prevent chronic diseases, increase life expectancy, or support the structure or function of the body. Nowadays, nutraceuticals have received considerable interest due to potential nutritional, safety and therapeutic effects. Recent studies have shown promising results for these compounds in various complications. In the present review much effort has been devoted to present new concepts about nutraceuticals based on their diseases modifying indications. Emphasis has been made to present herbal nutraceuticals effective on hard curative disorders related to oxidative stress including allergy, alzheimer, cardiovascular, cancer, diabetes, eye, immune, inflammatory and Parkinson's diseases as well as obesity. The recently published papers about different aspects of nutraceuticals as alternative for pharmaceuticals were searched using scientific sites such as Medline, PubMed, and Google Scholar. The used terms included nutraceutical and allergy, alzheimer, cardiovascular, cancer, diabetes, eye, immune, inflammatory or Parkinson.