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Revista de Neurologia Apr 2024Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted... (Observational Study)
Observational Study
INTRODUCTION
Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM.
PATIENTS AND METHODS
An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant.
RESULTS
Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.
CONCLUSIONS
RYR1-RM in our series exhibited phenotypic and involvement variability, with an incidence in our area of around 1 in 10,000 live births. Most cases were male, with dominant missense variants. We contribute five previously undescribed genetic variants.
Topics: Humans; Male; Child; Adolescent; Female; Ryanodine Receptor Calcium Release Channel; Cross-Sectional Studies; Incidence; Muscular Diseases; Genetic Association Studies; Phenotype; Genotype
PubMed: 38502166
DOI: 10.33588/rn.7807.2023348 -
BioRxiv : the Preprint Server For... Mar 2024Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug...
BACKGROUND AND AIMS
Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca2+ dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca2+-driven instabilities compared to male cardiomyocytes. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs females and establish their responses to Ca2+-targeted interventions.
METHODS AND RESULTS
We incorporated known sex differences and AF-associated changes in the expression and phosphorylation of key Ca2+-handling proteins and in ultrastructural properties and dimensions of atrial cardiomyocytes into our recently developed 3D atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca2+-handling processes. Our simulations of quiescent cardiomyocytes show increased incidence of Ca2+ sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca2+ releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca2+ transients compared with the male model. Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation in female AF cardiomyocytes emerged as the major SCR contributor, while reduced L-type Ca2+ current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulations of tentative Ca2+-targeted interventions identified potential strategies to attenuate Ca2+-driven arrhythmogenic events in female atria (e.g., t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), and revealed enhanced efficacy when applied in combination.
CONCLUSIONS
Our sex-specific computational models of human atrial cardiomyocytes uncover increased propensity to Ca2+-driven arrhythmogenic events in female compared to male atrial cardiomyocytes in AF, and point to combined Ca2+-targeted interventions as promising approaches to treat AF in female patients. Our study establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms.
PubMed: 38496584
DOI: 10.1101/2024.03.04.583217 -
Journal of Neuromuscular Diseases 2024Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological...
Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism.
Topics: Humans; Genetic Association Studies; Mosaicism; Myotonia Congenita; Phenotype; Ryanodine Receptor Calcium Release Channel; Male; Child, Preschool
PubMed: 38489196
DOI: 10.3233/JND-230216 -
Molecular Metabolism Apr 2024The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise...
OBJECTIVE
The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated.
METHODS
To determine the effects of maternal exercise on offspring cardiovascular health, female mice were fed a chow (C; 21% kcal from fat) or high-fat (H; 60% kcal from fat) diet and further subdivided into sedentary (CS, HS) or wheel exercised (CW, HW) prior to pregnancy and throughout gestation. Offspring were maintained in a sedentary state and chow-fed throughout 52 weeks of age and subjected to serial echocardiography and cardiomyocyte isolation for functional and mechanistic studies.
RESULTS
High-fat fed sedentary dams (HS) produced female offspring with reduced ejection fraction (EF) compared to offspring from chow-fed dams (CS), but EF was preserved in offspring from high-fat fed exercised dams (HW) throughout 52 weeks of age. Cardiomyocytes from HW female offspring had increased kinetics, calcium cycling, and respiration compared to CS and HS offspring. HS offspring had increased oxidation of the RyR2 in cardiomyocytes coupled with increased baseline sarcomere length, resulting in RyR2 overactivity, which was negated in female HW offspring.
CONCLUSIONS
These data suggest a role for maternal exercise to protect against the detrimental effects of a maternal high-fat diet on female offspring cardiac health. Maternal exercise improved female offspring cardiomyocyte contraction, calcium cycling, respiration, RyR2 oxidation, and RyR2 activity. These data present an important, translatable role for maternal exercise to preserve cardiac health of female offspring and provide insight on mechanisms to prevent the transmission of cardiovascular diseases to subsequent generations.
Topics: Pregnancy; Mice; Female; Animals; Ryanodine Receptor Calcium Release Channel; Calcium; Obesity; Diet, High-Fat; Oxidative Stress
PubMed: 38479548
DOI: 10.1016/j.molmet.2024.101914 -
International Journal of Molecular... Feb 2024Caffeine is one of the most widely consumed psychoactive drugs in the world. It easily crosses the blood-brain barrier, and caffeine-interacting adenosine and ryanodine...
Caffeine is one of the most widely consumed psychoactive drugs in the world. It easily crosses the blood-brain barrier, and caffeine-interacting adenosine and ryanodine receptors are distributed in various areas of the brain, including the hypothalamus and pituitary. Caffeine intake may have an impact on reproductive and immune function. Therefore, in the present study performed on the ewe model, we decided to investigate the effect of peripheral administration of caffeine (30 mg/kg) on the secretory activity of the hypothalamic-pituitary unit which regulates the reproductive function in females during both a physiological state and an immune/inflammatory challenge induced by lipopolysaccharide (LPS; 400 ng/kg) injection. It was found that caffeine stimulated ( < 0.01) the biosynthesis of gonadotropin-releasing hormone (GnRH) in the hypothalamus of ewe under both physiological and inflammatory conditions. Caffeine also increased ( < 0.05) luteinizing hormone (LH) secretion in ewes in a physiological state; however, a single administration of caffeine failed to completely release the LH secretion from the inhibitory influence of inflammation. This could result from the decreased expression of GnRHR in the pituitary and it may also be associated with the changes in the concentration of neurotransmitters in the median eminence (ME) where GnRH neuron terminals are located. Caffeine and LPS increased ( < 0.05) dopamine in the ME which may explain the inhibition of GnRH release. Caffeine treatment also increased ( < 0.01) cortisol release, and this stimulatory effect was particularly evident in sheep under immunological stress. Our studies suggest that caffeine affects the secretory activity of the hypothalamic-pituitary unit, although its effect appears to be partially dependent on the animal's immune status.
Topics: Female; Sheep; Animals; Gonadotropin-Releasing Hormone; Caffeine; Luteinizing Hormone; Lipopolysaccharides; Hypothalamus
PubMed: 38473910
DOI: 10.3390/ijms25052663 -
Translational Pediatrics Feb 2024Ryanodine receptor 2 () gene mutation causing catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the identified causes of sudden death in adults and...
BACKGROUND
Ryanodine receptor 2 () gene mutation causing catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the identified causes of sudden death in adults and children.
CASE DESCRIPTION
We report a case of gene mutation presented with cardiac arrest and recurrent syncopal attack with accidental finding of cardiac tumour. For the systematic review, we used four databases (Scopus, PubMed, Ovid and Google Scholar) to search articles with the terms " gene mutation" and "catecholaminergic polymorphic ventricular tachycardia (CPVT)". Fourteen studies were chosen and reviewed together with our reported patient. Most of the patients presented initially with syncopal attack and developed cardiac arrest later. Some of them presented with both syncopal attack and seizures precipitated by exercise or stress. We found that 43.8% of patients shared similar variants or coding effects in gene mutation. Demographically, the mean age at presentation is 11 years old with 53% of reported cases were male.
CONCLUSIONS
Refractory arrhythmias cardiac arrest not responding to adrenaline should raise the suspicion towards gene mutations. Recognition of this condition is important as it affects the outcome of resuscitation. Untimely diagnosis of gene mutations with appropriate use of pharmacological agents during resuscitation is important to ensure a better outcome.
PubMed: 38455755
DOI: 10.21037/tp-23-255 -
Proceedings of the National Academy of... Mar 2024PD1 blockade therapy, harnessing the cytotoxic potential of CD8 T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited...
PD1 blockade therapy, harnessing the cytotoxic potential of CD8 T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8 T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8 T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8 T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8 T cells, revealed that CD38-expressing CD8 T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8 T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8 T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8 T cells elevated intracellular Ca levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8 T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Ryanodine Receptor Calcium Release Channel; Proto-Oncogene Proteins c-akt; Neoplasms; T-Lymphocyte Subsets
PubMed: 38451948
DOI: 10.1073/pnas.2315989121 -
The Journal of General Physiology Apr 2024JGP study (Asghari et al. 2024. J. Gen. Physiol.https://doi.org/10.1085/jgp.202213108) indicates that β-adrenergic signaling enlarges dyads and reorganizes RyR2...
JGP study (Asghari et al. 2024. J. Gen. Physiol.https://doi.org/10.1085/jgp.202213108) indicates that β-adrenergic signaling enlarges dyads and reorganizes RyR2 tetramers in cardiomyocytes.
Topics: Myocytes, Cardiac; Phosphorylation; Ryanodine Receptor Calcium Release Channel; Signal Transduction
PubMed: 38451203
DOI: 10.1085/jgp.202413569 -
Frontiers in Endocrinology 2024Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes...
Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor ( gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with mutations. RyR2-mediated Ca release contributes to glucose-mediated insulin secretion and pathogenic mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the gene that co-segregates with diabetes in the absence of overt CPVT.
Topics: Adult; Animals; Humans; Mice; Diabetes Mellitus, Type 2; Exome Sequencing; Genome-Wide Association Study; Glucose; Glucose Intolerance; Mutation, Missense; Ryanodine Receptor Calcium Release Channel
PubMed: 38444585
DOI: 10.3389/fendo.2024.1258982 -
Degenerative Neurological and... 2024Myasthenia gravis (MG) is an autoimmune disease which can impact pregnancy. We describe a transient neonatal myasthenia gravis (TNMG) born to an asymptomatic mother aged...
Myasthenia gravis (MG) is an autoimmune disease which can impact pregnancy. We describe a transient neonatal myasthenia gravis (TNMG) born to an asymptomatic mother aged 26. The newborn presented cyanosis and generalized muscular weakness quickly after birth. Nasal continuous positive airway pressure (nCPAP) ventilation was performed immediately. On day 3, detailed family history showed that the neonate's 50-year-old maternal grandmother was diagnosed as ocular MG at the age of 40. Ryanodine receptor calcium release channel antibody (RyR-Ab) and acetylcholine receptor antibody (AChR-Ab) tested on day 5 were positive. However, neostigmine tests were negative for the neonate. Intravenous immunoglobulin (IVIG) and oral pyridostigmine were administered. The infant was weaned from the ventilator on day 7. On day 10, the neonate's asymptomatic mother was confirmed to have positive AChR-Ab either. The neonate regained the capability of bottle feeding on day 17 and discharged on day 26. Asymptomatic pregnant women with MG family history can also deliver infants who develop TNMG. Testing AChR antibodies in pregnant women with a family history of MG should be necessary as TNMG was a life-threatening disease. With timely diagnosis and accurate treatment, TNMG can be effectively relieved.
PubMed: 38444566
DOI: 10.2147/DNND.S451611