Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant.

Background and Objectives: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy. Methods: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. Results: All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene. Discussion: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

MYH2-related Myopathy: Expanding the Clinical Spectrum of Chronic Progressive External Ophthalmoplegia (CPEO).

Chronic progressive external ophthalmoplegia (CPEO) is symptom complex with progressive ptosis and restricted ocular motility without diplopia. MYH2 myopathy is rare disorder presenting with CPEO and muscle weakness. We report two Indian patients of MYH2 myopathy with unique features. Patient-1 presented with early adult-onset esophageal reflux followed by, proximal lower limb weakness, proptosis, CPEO without ptosis. He had elevated creatine kinase along with characteristic muscle MRI findings of prominent semitendinosus and medial gastrocnemius involvement. Patient -2 presented with early adult onset CPEO without limb weakness. His creatine kinase was normal. Both the patients had novel MYH2 mutations: a homozygous 5'splice variation in intron 4 (c.348 + 2dup) in patient 1 and homozygous single base pair deletion in exon 32 (p. Ala1480ProfsTer11) in patient 2. Unique features noted include adult onset, isolated CPEO, proptosis, esophageal reflux disease and absence of skeletal abnormalities. MYH2 myopathy has to be considered in adult patients with CPEO.

Cardioprotective Role of Estrogen in Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a rare, reversible cause of left ventricular wall motion abnormality (LVWMA) that mimics the presentation of acute myocardial infarction (AMI). TC is usually preceded by an emotional or physical stressor and appears to be more common in postmenopausal women. Various pathophysiological hypotheses of TC have been proposed, but the exact mechanism of action remains elusive. Elevated levels of catecholamines leading to cardiac dysfunction are the most prevalent hypothesis. The protective role of estrogen in the development of cardiomyopathies has been studied extensively. International Takotsubo Diagnostic Criteria (InterTAK) and Mayo clinic diagnostic criteria both have the stipulation stating prevalence of TC is higher in postmenopausal women which hints towards the protective role of estrogen in the development of TC. To review the protective role of estrogen in the mechanism of this novel pathology, we searched Pubmed and Google scholar for the relevant articles by using keywords such as: "takotsubo cardiomyopathy", "apical ballooning", "broken heart syndrome", "stress cardiomyopathy", "left ventricle wall motion abnormality", "estrogen", "estradiol" and "sex hormones". Our research revealed that although the prevalence of TC is greater in postmenopausal women as compared to men, the prognosis is worse in men. It also revealed the involvement of multiple cellular pathways under the influence of estrogen that could explain the cardioprotective effect of estrogen. Most of the articles found were based on animal studies, thus, there is an emphasis on future human studies. However, we strongly suggest evaluating estrogen levels as part of the initial workup for any patient presenting with signs and symptoms of cardiac pathology.

Effect of Catechol-O-Methyltransferase Genotype Polymorphism on Neurological and Psychiatric Disorders: Progressing Towards Personalized Medicine.

Different polymorphisms of the catechol-O-methyltransferase (COMT) gene affect the COMT enzyme activity. The COMT enzyme plays a major role in the pathophysiology of various neurological and psychiatric disorders. This review article aims to discuss what recent research has discovered about the association of COMT genotype polymorphism with neurological and psychiatric disorders and the scope for the knowledge to be applied for advancement in therapeutics. We searched PubMed and Google Scholar databases and found 1656 articles. We included observational studies, clinical trials, and meta-analyses in the English language published between 2019 and 2021. We screened the articles based on the title and the abstract and found 26 relevant articles. Diseases or conditions studied primarily were schizophrenia, Parkinson's disease, Alzheimer's disease, substance use, and depression. This article highlights how genetics influences the susceptibility of an individual to neurological and psychiatric diseases and the variations in the specific symptoms of those diseases. The review showed that the variability in individual response to therapeutic interventions stems from the gene level. This knowledge can contribute towards the dawn of a new era of personalized medicine.

Oxidative Stress in Polycystic Ovarian Syndrome and the Effect of Antioxidant N-Acetylcysteine on Ovulation and Pregnancy Rate.

Polycystic ovarian syndrome (PCOS) is an endocrinological condition that leads to infertility in many females. N-acetylcysteine (NAC), a novel antioxidant, is being used as an adjuvant to treat infertility in females suffering from PCOS. This review aims to evaluate oxidative stress in females suffering from PCOS and assess whether the anti-oxidizing properties of NAC are beneficial in enhancing the rate of ovulation and pregnancy in infertile PCOS females. A literature search was conducted manually on PubMed and Google Scholar databases using the following keywords: "N-Acetylcysteine," "PCOS," "Oxidative stress," "Antioxidants," and "infertility" alone and/or in combination for data collection. The studies were manually screened and, after applying inclusion-exclusion criteria, 32 studies consisting of 2466 females of the reproductive age group are included in this review. Our review revealed that females suffering from PCOS tend to show elevated levels of inflammatory markers and a decrease in antioxidant capacity. When used in combination with clomiphene citrate or letrozole, NAC increases ovulation and pregnancy rate in infertile females suffering from PCOS and positively affects the quality of oocytes and number of follicles ≥18mm. Moreover, its side effect profile is low. It also results in a mild increase in endometrial thickness in some females. Future studies on a large sample size using NAC alone are highly recommended to evaluate its role as a single-drug therapy for treating infertility in females suffering from PCOS.

Stress Urinary Incontinence Among Young Nulliparous Female Athletes.

Urinary incontinence (UI) is described as unintentional voiding of urine that is usually seen in post-partum and post-menopausal women due to the weakening of pelvic floor muscles (PFM). Recent studies have shown an increase in the prevalence of stress urinary incontinence (SUI) among young nulliparous female athletes. The association between UI and high-impact physical activity is due to increased intra-abdominal pressure during high-impact sports exceeding intra-urethral pressure. Usually, the levator ani muscle (LAM) helps in urethral closure. However, weakening or injury of LAM can reduce the pelvic support and cause UI in young female athletes. This study aims to assess the prevalence of SUI among young nulliparous athletes and also explore the association between SUI and athletic sports in young females. We searched PubMed and Google Scholar as databases to find specific articles about the topic. After the inclusion and exclusion criteria were applied, 52 articles were selected for this review. It is found that there is an increased UI prevalence, mainly SUI, among young nulliparous female athletes, especially in volleyball players and long-distance runners. Nulliparous athletes involved in high-impact exercises were found to have an increased cross-sectional area of LAM and puborectalis muscle width. SUI is usually under-reported and underdiagnosed due to lack of knowledge and unawareness, which can negatively affect the personal and social life of young females. PFM training is considered the first line of therapy among nulliparous athletes. However, it is unclear whether the high-impact effects of sports cause UI through PFM fatigue or PFM damage. More research is needed to better understand this effect.

An Exploration of the Effects of Radiofrequency Radiation Emitted by Mobile Phones and Extremely Low Frequency Radiation on Thyroid Hormones and Thyroid Gland Histopathology.

The use of mobile phones has widely increased over the last two decades. Mobile phones produce a radiofrequency electromagnetic field (RF-EMF), a form of non-ionizing radiation. In contrast to the ionizing radiation proven to cause DNA damage, the harmful effects of non-ionizing radiation on the human body have not been discovered yet. The thyroid gland is among the most susceptible organs to mobile phone radiation due to its location in the anterior neck. Our purpose in this literature review is to explore the effects of the electromagnetic field (EMF), especially radiofrequency emitted from mobile phones, on thyroid hormones and thyroid gland histopathology. We searched PubMed and Google Scholar databases for relevant studies published after the year 2000, using the following keywords: 'cell phones', 'mobile phones', 'telephones', 'electromagnetic fields', 'radiofrequency radiation', 'microwaves', 'thyroid gland', 'thyroid hormones', and 'thyroid cancer'. Our review revealed that mobile phone radiofrequency radiation (RFR) might be associated with thyroid gland insufficiency and alterations in serum thyroid hormone levels, with a possible disruption in the hypothalamic-pituitary-thyroid axis. The review also showed histopathological changes in the thyroid gland follicles after exposure of rats to non-ionizing radiation. The results were directly related to the amount and duration of exposure to EMF radiation. Further human studies exploring thyroid gland hormones, microscopic morphology, and thyroid cancer are highly recommended for future researches.

Endoscopic Surveillance in Idiopathic Achalasia.

Idiopathic achalasia is a rare esophageal dysmotility disorder of unknown etiology with only palliative treatment available. Many studies have established a significantly increased risk of esophageal cancer in patients with achalasia. However, current guidelines advise against routine surveillance due to low absolute risk and a paucity of high-quality evidence and cost-effectiveness assessments. This review aims to assess the need for routine endoscopic surveillance in achalasia based on a growing body of literature calling in support of it, mainly due to the increased risk of esophageal cancer. We searched PubMed and Google Scholar electronic databases for articles within the last 10 years using the keywords 'achalasia', 'cancer,' 'neoplasms,' 'screening,' and 'surveillance.' After excluding pseudoachalasia/secondary achalasia, other esophageal dysmotility disorders, and associations with malignancies outside the esophagus, we selected 31 articles for this review. Through these articles, we identified areas of focus for ongoing and future research that may result in significant risk reduction of complications, including esophageal cancer and beyond.

Role of Gut Microbiota Dysbiosis in Breast Cancer and Novel Approaches in Prevention, Diagnosis, and Treatment.

Breast cancer is the most common cause of cancer-related deaths in women. Breast cancer is still a major cause of morbidity and mortality among women despite all the available diagnostic and treatment modalities. The gut microbiota has drawn keen interest as an additional environmental risk factor in breast cancer, especially in sporadic cases. This article explores factors that disrupt the normal gut microbial composition and the role of gut microbial dysbiosis in the development of breast cancer. We finalized 40 relevant articles after searching Pubmed and Google Scholar using regular keywords and the Medical Subject Headings (MeSH) strategy. Gut microbiota dysbiosis has been shown to play a role in the development of breast cancer via estrogen-dependent mechanisms and non-estrogen-dependent mechanisms involving the production of microbial-derived metabolites, immune regulation, and effects on DNA. The gut microbiota influence estrogen metabolism hence estrogen levels. The metabolites that have demonstrated anticancer properties include lithocholic acid, butyrate, and cadaverine. New approaches targeting the gut microbiota have come up and may yield new advances in the prevention, diagnosis, and treatment of breast cancer. They include the use of prebiotics, probiotics, and hormone supplements to restore normobiosis in the prevention and treatment of breast cancer.