Non-genetic Causes Research Articles

Update on Mayer-Rokitansky-Küster-Hauser syndrome.

This review presents an update of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome on its etiologic, clinical, diagnostic, psychological, therapeutic, and reproductive aspects. The etiology of MRKH syndrome remains unclear due to its intrinsic heterogeneity. Nongenetic and genetic causes that may interact during the embryonic development have been proposed with no definitive etiopathogenesis identified. The proportion of concomitant extragenital malformations varies in different studies, and the discrepancies may be explained by ethnic differences. In addition to physical examination and pelvic ultrasound, the performance of pelvic magnetic resonance imaging is crucial in detecting the presence of rudimentary uterine endometrium. MRKH syndrome has long-lasting psychological effects on patients, resulting in low esteem, poor coping strategies, depression, and anxiety symptoms. Providing psychological counseling and peer support to diagnosed patients is recommended. Proper and timely psychological intervention could significantly improve a patient's outcome. Various nonsurgical and surgical methods have been suggested for treatment of MRKH syndrome. Due to the high success rate and minimal risk of complications, vaginal dilation has been proven to be the first-line therapy. Vaginoplasty is the second-line option for patients experiencing dilation failure. Uterine transplantation and gestational surrogacy are options for women with MRKH syndrome to achieve biological motherhood.

Hereditary spastic paraplegia in Mali: epidemiological and clinical features.

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases divided into pure and complex forms, with spasticity in lower limbs only, or associated with other neurologic and non-neurologic manifestations, respectively. Although widely reported in other populations, very little data exist in sub-Saharan Africa. Patients with neurodegenerative features were evaluated over a 19-month period at the Department of Neurology, Teaching Hospital of Point "G", Bamako, Mali. The diagnosis of HSP was considered based on family history and the absence of other known non-genetic causes. Genetic analysis including candidate gene and whole exome sequencing was performed and variant pathogenicity was tested using prediction tools and ACMG guidelines. Of the 170 families with hereditary neurological disorders enrolled, 16 had features consistent with HSP, a frequency of 9%. The average age of onset was 14.7years with 46% starting before age 6. The male/female ratio was 2.6:1. Complex forms were seen in 75% of cases, and pure forms in 25%. Pyramidal findings were present in all patients. Associated features included mental retardation, peripheral neuropathy, epilepsy, oculomotor impairment and urinary urgency. Most patients were treated with a muscle relaxant and physical therapy, and restorative surgery was done in one. Genetic testing identified novel variants in three families (19%). This study confirms the clinical variability of HSPs and adds African data to the current literature.

How do alterations in epigenetic mechanisms cause intellectual disability?

Intellectual disability is associated with many syndromes, its main symptom includes low IQ. There are a variety of genetic and non-genetic causes of ID including environmental factors, chromosomal aberrations and single gene mutations. One example of ID that have been explored have to do with the enzyme ATRX which enhances transcription and remodels chromatin. Due to its involvement in chromatin remodeling ATRX can affect the expression of genes, through turning genes on. ATRX assists learning and memory hence leading to ID when organisms are ATRX-null. Chromatin remodeling enzymes can also cause ID by affecting neural progenitor generation, neural circuits and neural migration. These syndromes assist in comprehending the logistics in the KAT5 syndrome. The KAT5 syndrome comprises variants in the KAT5 enzyme and causes detrimental effects on neurodevelopment, leading to ID. TIP60-CB and acetyl-coA binding domains are 2 key domains in the lysine acetyltransferase enzyme (KAT5), mutations in these domains have been studied and have proven to cause ID. This data suggests that reduced acetyl of chromatin in neural cells, may lead to an impairment in cognition and memory (ID). Keywords: Intellectual disability, neurodevelopment, chromosome, DNA, ATRX, Epigenetic, Chromatin remodeling, KAT5, histone, TIP60-CB, Acetyl-coA and DNA acetylation. DOI: 10.7176/JMPB/72-08 Publication date: November 30 th 2022

Kadın İnfertilitesinin Genetik Nedenlerine Güncel Yaklaşım ve Genetik Danışmanlık

Infertility is a disease of the male or female reproductive system and is defined as the inability to achieve pregnancy after 12 months or more of regular and unprotected sexual intercourse. Data shows that more than 186 million people worldwide are infertile. About 10% of the women of reproductive age are unable to conceive or maintain a pregnancy. In this study, the causes of female infertility were reviewed under several headings and the importance of genetic counseling in infertility was also mentioned. There are many different causes of female infertility, including both genetic and non-genetic causes. In this review, current developments and approaches in the genetic etiology of female infertility were reviewed under six main headings, chromosomal abnormalities, female genital system disorders, hypogonadotropic hypogonadism, primary ovarian failure, polycystic ovary syndrome, and gonadal dysgenesis. Also, the role of genetic counseling in these diseases was discussed. The aim of genetic counseling is to inform people with a hereditary disease or at high risk of carrying it about the course of the disease and treatment methods, and also to guide future generations and family members about their risks. After all tests and examinations, genetic counseling has a very important place in reproductive health.

Congenital cytomegalovirus infection: features of the clinical course and catamnesis according to own observations

Congenital cytomegalovirus infection is the most common congenital infection, occurs in 0.6-5% of newborns worldwide, and is considered the leading non-genetic cause of sensorineural hearing loss in children. Most newborns with a manifest form of the disease develop psychomotor and cognitive disorders, and about half of them develop visual impairment.The purpose of publication: to present a clinical case of severe congenital cytomegalovirus infection in the manifest period with multisystem manifestations (hemorrhagic syndrome, encephalitis, myocarditis, hepatitis, splenomegaly) and follow-up data at the age of 1 year.Conclusion. this clinical example demonstrates diagnostic and therapeutic difficulties in the acute period of the disease and a significant list of diseases resulting from infection. Based on the information presented, the importance and necessity of close attention to the results of a serological study of pregnant women during the entire gestation period with an assessment of the antibody titer to cytomegalovirus infection in dynamics are updated. Specific antiviral therapy, prescribed on the basis of a life-threatening course of a severe manifest form of the disease, made it possible to achieve positive dynamics in the acute period, eradicate the virus and prevent severe outcomes, including death.

Congenital Infections: Priorities and Possibilities for Resource-limited Settings.

Congenital Infections: Priorities and Possibilities for Resource-limited Settings.

Sociodemographic and hearing profile of a population with sensorineural hearing loss in Chile

Background. Evidence-based information on genetic sensorineural hearing loss in Latin America is limited, hindering the advancement of related clinical practice and the development of relevant healthcare policies in the field. This study describes sociodemographic and clinical characteristics of a group of Chilean participants with congenital, childhood, progressive or late-onset sensorineural hearing loss of unknown etiology; all non-genetic causes of hearing loss were excluded. Methods. A quantitative study, with a non-experimental, observational, cross-sectional design and a descriptive scope. From 978 patients diagnosed with SNHL, 286 subjects fulfilled the inclusion criteria, and 138 patients accepted to participate. Results. The most frequent audiological-profile was symmetrical-bilateral-profound-SNHL with a sloping pattern. The median age at audiological diagnosis was 24.5 months (IQR:12-53) and at first-time Hearing-Assistive-Device-use (HAD-use) was 30 months (IQR:13-69). 71% of HAD were financed by public resources. Conclusion. The age at audiological diagnosis in SNHL of suspected genetic causes is still far from international standards. These results are valuable for public health research and policy development, not only for the Chilean population, but also for other Hispanic communities and other middle-high income countries.

Congenital cytomegalovirus infection diagnostics and management.

Congenital cytomegalovirus infection (cCMV) is the most frequent congenital infection and a leading nongenetic cause of sensorineural hearing loss (SNHL) and brain disease. The purpose of this review is to highlight recent developments in the diagnosis and management of children with cCMV. Progress is being made in the efforts to identify more infants with cCMV, especially those with asymptomatic infection. Largely due to efforts by various advocacy/parent groups, a number of states in the United States and many hospital systems have implemented hearing targeted CMV screening and mandated education of pregnant women about CMV. cCMV is an important cause of SNHL and neurologic morbidity worldwide. Early identification of infected children is critical to improve outcomes by providing timely interventions and guidance for long-term follow up. The fact that most infants with cCMV have no abnormal clinical findings, and the need to obtain samples for diagnosis within the first 2-3 weeks of life, makes it challenging to identify a majority of infants with cCMV without universal newborn CMV screening.

GENOMIC POLITICS AND EQUALITY

GENOMIC POLITICS AND EQUALITY

Urinary tract infection in patients with diabetes mellitus and the role of parental genetics in the emergence of the disease.

This study aimed to assess the role of paternal genetics in the development of diabetic mellitus (DM) and determine the impact of DM on the urinary system by investigating the percentage of patients with urinary tract infection (UTI). The study included 100 people with DM; their ages ranged from 5 to 83 years. The DM and blood sugar levels were diagnosed clinically and at a laboratory in Al-Zahra Teaching Hospital and the outpatient clinics. The age, gender, and causes of DM and the family history of diabetes were reported. Isolation and identification of bacterial species were made depending on culture media and biochemical tests. The average age of patients was 47.7±5.5, and most of them were female (67%). The incidence of DM increased with age, and the main cause of DM was likely to be a genetic predisposition (family history), where 32% of patients appeared to have a positive family history and the presence of DM in both parents or only the mother had a significant role in increasing the genetic predisposition of developing DM. Among the non-genetic causes of DM, the most common was exposure to sudden psychological or nervous shock (41%). Obesity also had an important role in the development of diabetes, and also pregnancy and smoking. Moreover, 66% of patients with type 2 DM and all with type 1 DM suffered from UTIs. The main causative agents were E. coli (60%) and Proteus spp. (13%). The majority of patients suffering from UTIs (73%) were females. In conclusion, type 2 DM is the most common, especially in females, and increases with age. The main cause of DM was family genetic predisposition and sudden shocks. The current study also showed that most diabetic patients suffered from UTIs, especially females, and the main causes of UTI inflammation are E. coli isolates.

Congenital cytomegalovirus infection: Advocating for screening and education

Cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital neurosensory hearing loss in children, accounting for 21% of cases of hearing loss at birth and 25% of deafness at age 4 years.1 It can also give rise to other serious sequelae such as cerebral palsy, cognitive impairment, seizures and visual impairment.2 CMV infection in

#62 Resolution of thrombocytopenia during treatment for symptomatic congenital cytomegalovirus disease

Abstract Background Congenital cytomegalovirus (cCMV) is the most common congenital viral infection in the United States (4.5 per 1000 live births) and is the leading non-genetic cause of sensorineural hearing loss and developmental disabilities in children worldwide. However, reliable estimates of time to resolution for manifestations of cCMV disease have not been fully elucidated. A better understanding of the resolution of laboratory abnormalities for cCMV is needed to guide decisions about frequency of platelet assessments following diagnosis and potentially optimize antiviral therapy. Method Data from 243 infants with symptomatic cCMV were retrospectively analyzed from four studies conducted by the NIH-funded Collaborative Antiviral Study Group over the years 1989-2011. Individuals were compared based on baseline platelet value, utilizing Division of AIDS Toxicity Scale categorization, and treatment received. Kinetics of the trend in platelets over time were compared between groups using Kaplan-Meier plots and binomial assessments of abnormal vs. normal. All analyses were conducted over the 6-week (45 day) time period. Results Predicted curves showed that the interaction between antiviral therapy and platelet value over time was found to be significant (p=0.0106) for individuals with normal baseline platelet counts (Grade 0, defined as ≥ 125,000). For individuals with Grades 1-4 thrombocytopenia at baseline, probability curves showed that both baseline grade (p=0.0006) and time (p<.0001) correlated with rate of resolution of thrombocytopenia, but antiviral treatment did not (p=0.1964). Kaplan-Meier plots of time to platelet count of ≥ 125,000 demonstrated that baseline platelet grade was significantly (p=0.0003) correlated with time to resolution of thrombocytopenia. Kaplan-Meier plots of time to platelet count of ≥ 100,000 demonstrated that baseline platelet grade was significantly (p=0.0056) correlated with time to Grade 1 thrombocytopenia. Conclusion For neonates with baseline thrombocytopenia from cCMV, antiviral therapy does not hasten time to resolution of thrombocytopenia. For neonates with normal baseline platelet values, antiviral therapy correlated with increasing platelet counts. Degree of baseline thrombocytopenia correlated with time to normalization of platelet count. Further understanding of the kinetics of resolution of laboratory abnormalities for symptomatic cCMV is needed to directly inform patient management decisions.

Congenital Cytomegalovirus

Congenital Cytomegalovirus

Cytomegalovirus variation among newborns treated with valganciclovir

Congenital cytomegalovirus (cCMV) infection is the leading non-genetic cause of long-term neurological and sensory sequelae, the most common being sensorineural hearing loss (SNHL). Standard therapy for infants with symptomatic cCMV is valganciclovir for six months. However, little is known about the effects of antiviral therapy on CMV diversity while patients are on treatment. In this study, CMV variation was analyzed from urine specimens isolated from two patients with cCMV shortly after birth and at seven months. One was treated with valganciclovir for six weeks and the other for six months. In order to track these variants a novel bioinformatic approach was employed to analyze changes in low frequency variants over time. In the infant receiving antivirals for only six weeks, there was a fourfold increase in variation in UL97 from the seven month specimen. Furthermore, an eightfold increase in variation was seen in UL83 (pp65) with seven potential escape mutations occurring, and a twofold increase in UL73 (gN). In contrast variation did not increase or was reduced in these coding regions in the infant receiving valganciclovir for six months. However, there were increases in other CMV regions in samples isolated from both patients indicating further longitudinal studies are warranted to better understand the interplay between CMV diversity, antiviral therapy and patient outcome.

Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and – possibly – also stress-related symptoms of major mental illnesses.

Precision psychiatry: The complexity of personalizing antipsychotic dosing

Recently, Salagre and Vieta commented on the complexity of implementing precision medicine in psychiatry. For 25 years, this author has focused on a circumscribed type of precision medicine: personalized dosing using pharmacokinetic mechanisms to stratified patients. This short communication focuses on personalized dosing of three oral antipsychotics (clozapine, risperidone and paliperidone) and presents their maintenance dosing in a table which provides dose-correction factors generated by pharmacokinetic studies. Inhibitors need dose-correction factors < 1 and inducers need correction factors >1. Clozapine maintenance dosing is based on the dose needed to reach 350 ng/ml (the minimum plasma therapeutic concentration in treatment-resistant schizophrenia). Clozapine maintenance dosing is influenced by 3 levels of complexity: 1) ancestry groups (Asians/Native Americans; Europeans and Blacks), 2) sex-smoking subgroups (lowest dose in female non-smokers and highest in male smokers) and 3) presence/absence of poor metabolizer status (due to genetic and non-genetic causes including co-prescription of inhibitors, obesity or inflammation). Risperidone and paliperidone maintenance dosing are based on the dose needed to reach plasma concentrations of 20–60 ng/ml. Risperidone PMs need approximately half the dose, which can be explained by genetics (CYP2D6 PMs) or co-prescription of CYP2D6 inhibitors. Fluoxetine co-prescription may require one fourth the risperidone maintenance dose. Carbamazepine co-prescription may require twice the risperidone maintenance dose. Although not well studied, two groups may need higher doses of oral paliperidone: Koreans may need 1.5 times higher doses while those taking carbamazepine may need 3 times higher paliperidone maintenance doses. Precision dosing in psychiatry requires using blood levels of individuals.

EP465: Role of next-generation sequencing in the evaluation of families with non-immune fetal hydrops

Fetal hydrops, which refers to the pathological accumulation of fluid in the fetal soft tissues and serous cavities, is an important cause of prenatal and perinatal morbidity and mortality. Non-immune fetal hydrops (NIFH) is an etiologically heterogeneous condition, which can occur due to genetic as well as non-genetic causes. Genetic causes for NIFH include numerical and structural chromosomal anomalies, and many different monogenic conditions including inborn errors of metabolism (IEMs), lethal skeletal dysplasias, hematological disorders, multiple malformation syndromes, etc.

Familial Mortality Risks in Patients With Ischemic Stroke: A Swedish Sibling Study.

The influence of familial factors on the prognosis of ischemic stroke (IS) is unknown. This nationwide follow-up study evaluated familial mortality risks of IS among Swedish sibling pairs hospitalized for IS. We linked Swedish nationwide registers for the identification of 1380 Swedish born sibling pairs (2760 cases), where both siblings were hospitalized for first-time IS between 1991 and 2010. Median age was 62 years (range, 26-78 years). Sibling pairs with cancer were excluded. Familial hazard ratios (FHRs) for mortality after first IS hospitalization were determined with Cox regression. The influence of proband survival after IS was categorized as short sibling survival (<1, 2, 3, 4, or 5 years) or long sibling survival (≥1, 2, 3, 4, or 5 years) after IS. FHRs were adjusted for age at onset, sex, education, county, year of diagnosis, days of hospitalization, and comorbidities. Short sibling survival (ie, <3 or <4 years) after IS was associated with an adjusted FHR of 1.29 (95% CI, 1.05-1.58) and 1.24 (95% CI, 1.02-1.51), respectively, for overall mortality after IS. Stratified analysis showed that short sibling survival (ie, <2-<5 years) was stronger and significant only among younger individuals (<62 years) and males. Highest FHR for short sibling survival (ie, <4 years) was 1.42 (95% CI, 1.08-1.88) for younger individuals and 1.50 (95% CI, 1.21-1.87) for males. For young male subjects, FHR was 1.80 (95% CI, 1.33-2.46). In the adjusted model, mortality was also associated with sex, education, age at onset, year of diagnosis, days of hospitalization, coronary heart disease, diabetes, dementia, heart failure, obesity, alcoholism, and hyperlipidemia. Our results suggest that family history of short survival in siblings after IS is associated with mortality after IS for younger male subjects. Additional studies are needed to characterize possible genetic and nongenetic familial environmental causes of this association.

Clinical and Echocardiographic Assessment of Patients with Dilated Cardiomyopathy

Introduction: Cardiomyopathy is the disorder of the heart muscles which can be dilated, hypertrophic or restrictive type. Dilated cardiomyopathy is caused by genetic and non-genetic causes but many of the causes are still not known. Echocardiography is an important imaging technique to diagnose and manage dilated cardiomyopathy.&#x0D; Aims: This study aims to assess the clinical and echocardiographic findings among patients with dilated cardiomyopathy.&#x0D; Methods: This is a cross-sectional, observational study conducted in Nepalgunj Medical College from January 2021 to June 2021. A total of 61 patients with dilated Cardiomyopathy were enrolled after obtaining written informed consent. Clinical examination and echocardiographic findings were recorded and data analysis was done using Statistical Package for Social Sciences.&#x0D; Results: The participants included 31 men and 30 women with dilated cardiomyopathy. The mean age of the participants was 58.49 + 15.46 years. The most common complaint was shortness of breath 84.5% and the most common clinical presentation was bilateral basal crepitation 98.4%. The patients mostly had diastolic left ventricle internal diameter of 5.5-6 cm and ejection fraction of 21-30%. Mitral regurgitation was observed among most 58(95.1%) of the patients.&#x0D; Conclusion: This study concludes that shortness of breath and bilateral basal crepitation are the most common presentation. Left ventricle dilation, reduced ejection fraction and mitral regurgitation are seen among majority of the patients.

The Clinical Diagnostic Utility of Array CGH in Children with Syndromic Microcephaly.

A prospective study using array CGH in children with Syndromic microcephaly from a tertiary pediatric healthcare centre in India. To identify the copy number variations causative of microcephaly detected through chromosomal array CGH. Of the 60 patients, 33 (55%) males and 27 (45%) females who consulted the Rare Disease Clinic at Department of Pediatrics, SMS Medical College, Jaipur, with developmental delay/facial dysmorphism/congenital anomalies in combination with microcephaly were included. Children with acquired or non-genetic causes of microcephaly, craniosynostosis, metabolic diseases, known chromosomal aneuploidy such as trisomy 21, 13, and 18 and abnormal karyotype were excluded. The cohort was analyzed by array CGH in order to identify potentially pathogenic copy number variants (CNVs). Clinically relevant pathogenic or likely pathogenic copy number variations (CNVs) were identified in 20/60 (33.3%) patients, variant of uncertain significance (VOUS) in 4/60 (6.6%) cases and benign CNVs in 3/60 (5%) of total cases. Out of 20 cases with pathogenic CNVs, 12 (60%) patients detected with a deletion, five (25%) patients with duplication and three (15%) patients resulted with a complex chromosomal rearrangement. Twelve cases present CNVs containing genes known to be implicated in microcephaly etiology. This research highlights the contribution of submicroscopic chromosomal changes in the etiology of microcephaly in combination with developmental delay/facial dysmorphism/congenital anomalies (syndromic microcephaly). Our studies provide more insights into the benefits derived by using array CGH analysis in patients with syndromic microcephaly.