genetic disorder
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2022 ◽  
pp. 1-5
Christopher A. Chow ◽  
Katherine H. Campbell ◽  
Josephine C. Chou ◽  
Robert W. Elder

Abstract Background: Noonan syndrome is a genetic disorder with high prevalence of congenital heart defects, such as pulmonary stenosis, atrial septal defect and hypertrophic cardiomyopathy. Scarce data exists regarding the safety of pregnancy in patients with Noonan syndrome, particularly in the context of maternal cardiac disease. Study design: We performed a retrospective chart review of patients at Yale-New Haven Hospital from 2012 to 2020 with diagnoses of Noonan syndrome and pregnancy. We analysed medical records for pregnancy details and cardiac health, including echocardiograms to quantify maternal cardiac dysfunction through measurements of pulmonary valve peak gradient, structural heart defects and interventricular septal thickness. Results: We identified five women with Noonan syndrome (10 pregnancies). Three of five patients had pulmonary valve stenosis at the time of pregnancy, two of which had undergone cardiac procedures. 50% of pregnancies (5/10) resulted in pre-term birth. 80% (8/10) of all deliveries were converted to caesarean section after a trial of labour. One pregnancy resulted in intra-uterine fetal demise while nine pregnancies resulted in the birth of a living infant. 60% (6/10) of livebirths required care in the neonatal intensive care unit. One infant passed away at 5 weeks of age. Conclusions: The majority of mothers had pre-existing, though mild, heart disease. We found high rates of prematurity, conversion to caesarean section, and elevated level of care. No maternal complications resulted in long-term morbidity. Our study suggests that women with Noonan syndrome and low-risk cardiac lesions can become pregnant and deliver a healthy infant with counselling and risk evaluation.

2022 ◽  
Vol 16 (1) ◽  
Cempaka Thursina Srie Setyaningrum ◽  
Indra Sari Kusuma Harahap ◽  
Dian Kesumapramudya Nurputra ◽  
Irwan Taufiqur Rachman ◽  
Nur Imma Fatimah Harahap

Abstract Background Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia. Case presentation A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her clinical presentations, without any molecular genetic testing. She was married at the age of 25 years and was soon pregnant with her first child. At the gestational age of 32 weeks, her first pregnancy was ended by an emergency caesarean section because of premature rupture of the membranes. In this second pregnancy, she was referred early to the general hospital from the district hospital to receive multidisciplinary care. She and her first daughter underwent genetic testing for spinal muscular atrophy, which has been readily available in our institution since 2018, to confirm the diagnosis and prepare for genetic counseling. Conclusions Managing pregnancy in a patient with spinal muscular atrophy should be performed collaboratively. In this case, genetic testing of spinal muscular atrophy and the collaborative management of this patient allowed the clinical decision making and genetic counseling throughout her pregnancy and delivery.

2022 ◽  
Qianying Liu ◽  
Xiang Zhang ◽  
Hui Huang ◽  
Yuxin Chen ◽  
Fang Wang ◽  

Pendrin SLC26A4 is an anion exchanger expressed in apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder disease associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However, its molecular structure has remained unknown limiting our understanding. Here, we determined the structures of mouse pendrin with symmetric and characteristically asymmetric homodimer conformations by cryo-electron microscopy. The asymmetric homodimer consists of an inward-facing protomer and an intermediate-state protomer, representing the coincident uptake and secretion process, and exhibits the unique state of pendrin as an electroneutral exchanger. This previously unrevealed conformation, together with other conformations we captured, provides an inverted alternate-access mechanism for anion exchange. Furthermore, our structural and functional data disclosed the properties of anion exchange cleft and interpreted the important pathogenetic mutations. These investigations shed light on the pendrin exchange mechanism and extend our structure-guided understanding of pathogenetic mutations.

2022 ◽  
Vol 23 (2) ◽  
pp. 884
Sonja Djudjaj ◽  
Panagiotis Kavvadas ◽  
Niki Prakoura ◽  
Roman D. Bülow ◽  
Tiffany Migeon ◽  

Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.

2022 ◽  
Ramkumar Aishworiya ◽  
Tatiana Valica ◽  
Randi Hagerman ◽  
Bibiana Restrepo

AbstractWhile behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

2022 ◽  
Vol 12 ◽  
Abeer N. Alshukairi ◽  
Hazem Doar ◽  
Afaf Al-Sagheir ◽  
Mona A. Bahasan ◽  
Anas A. Sultan ◽  

BackgroundAlthough genetic diseases are rare, children with such conditions who get infected with COVID-19 tend to have a severe illness requiring hospitalization. Osteogenesis imperfecta (OI) is a rare genetic disorder of collagen resulting in fractures and skeletal deformities. Kyphoscoliosis, restrictive lung disease, and pneumonia worsen the prognosis of patients with OI. The use of bisphosphonate improves bone mineral density (BMD) and reduces fractures in OI. There is no literature describing the impact of COVID-19 in patients with OI.MethodologyA retrospective multi-center study was performed in three hospitals in Jeddah and Riyadh, Saudi Arabia, from March 1st, 2020, until August 31st, 2021, aiming to evaluate the outcome of COVID-19 in patients with OI. Demographics, vaccination status, underlying kyphoscoliosis, functional status, use of bisphosphonate, BMD, and COVID-19 severity, and course were recorded for all patients.ResultsTwelve cases of confirmed COVID-19 were identified among 146 patients with OI. 9 (75%) of patients were less than 18 years, 6 (50%) were male, 5 (41%) had kyphoscoliosis, and 5 (41%) were wheelchair-bound. 6 (50%) received bisphosphonate, and 7(58%) had normal BMD. All patients had mild disease and did not require hospitalization. None of OI the patients with COVID-19 were fully vaccinated before the infection, and some were ineligible for vaccination.ConclusionPatients with OI and COVID-19 in our study recovered without complications, unlike patients with other genetic diseases. Young age and mild illness contributed to the favorable outcome. Half of the patients received bisphosphonate and had normal BMD.

2022 ◽  
Vol 9 ◽  
Yu-Ming Chang ◽  
Chih-Chia Chen ◽  
Ni-Chung Lee ◽  
Junne-Ming Sung ◽  
Yen-Yin Chou ◽  

Paired box 2 (PAX2)-related disorder is an autosomal dominant genetic disorder associated with kidney and eye abnormalities and can result in end stage renal disease (ESRD). Despite reported low prevalence of PAX2 mutations, the prevalence of PAX2 related disorders may have been underestimated in past studies. With improved genetic sequencing techniques, more genetic abnormalities are being detected than ever before. Here, we report three patients from two families with PAX2 mutations identified within 1 year. Two patients were adults with chronic kidney disease and were followed for decades without correct diagnoses, including one with ESRD who had even undergone kidney transplant. The third patient was a neonate in whom PAX2-related disorder manifested as oligohydramnios, coloboma, and renal failure that progressed to ESRD within 1 year after birth. The phenotypes of PAX2 gene mutation were shown to be highly variable, even within the same family. Early detection promoted genetic counseling and guided clinical management. The appropriate time point for genetic study is an important issue. Clinicians must be more alert for PAX2 mutation when facing patients with congenital kidney and urinary tract anomalies, chronic kidney disease of unknown etiology, involvement of multiple systems, and/or a family history of renal disease.

2022 ◽  
Jinfen Yu ◽  
Wang Linsheng ◽  
Tian Jing ◽  
Yu Xuewen ◽  
Lixin Sun

Objective: Juvenile hyaline fibromatosis (JHF) is an autosomal recessive condition caused by a mutation in capillary morphogenesis gene 2 (CMG2) on chromosome 4q21. JHF is an extremely rare genetic disorder, and fewer than a hundred cases have been reported worldwide. In this case report, the clinical features, histopathological features and imaging manifestations of a case of JHF are presented. We present imaging manifestations of one case of JHF to deepen the radiologist’s understanding of this condition. The histopathological feature of JHF is hyaline degeneration involving skeletal muscle. Therefore, the lesion has a slightly high density on CT imaging, iso- or hypointense signal on T1WI and hypointense signal on T2WI. The boundary between the lesion and skeletal muscle is unclear. Methods: An 8-year-old male (case 1) was examined in our department with a complaint of multiple masses on the head, neck and back in 2021. The boy was the only child of his parents and was delivered at 40 weeks gestation by caesarean section. His parents were nonconsanguineous. Results : JHF displays multiple slowly or rapidly growing subcutaneous nodules. The imaging manifestations can reflect histopathological components, including nodular connective tissue and amorphous, partially calcified hyaline material.

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 140
Roberto Ravazzolo

The Special Issue on “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches” has published interesting and useful review articles and original experimental articles on fibrodysplasia ossificans progressiva (FOP), a very rare genetic disorder for which much effort is being devoted to search for a cure. In this editorial, I briefly cite the essential content of all the published articles.

2022 ◽  
Vol 14 ◽  
Alice C. Borges ◽  
Kerensa Broersen ◽  
Paula Leandro ◽  
Tiago G. Fernandes

Phenylketonuria is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function leads to the accumulation of neurotoxic phenylalanine levels in the brain. Severe cognitive and neuronal impairment are observed in untreated/late-diagnosed patients, and even early treated ones are not safe from life-long sequelae. Despite the wealth of knowledge acquired from available disease models, the chronic effect of Phenylketonuria in the brain is still poorly understood and the consequences to the aging brain remain an open question. Thus, there is the need for better predictive models, able to recapitulate specific mechanisms of this disease. Human induced pluripotent stem cells (hiPSCs), with their ability to differentiate and self-organize in multiple tissues, might provide a new exciting in vitro platform to model specific PKU-derived neuronal impairment. In this review, we gather what is known about the impact of phenylalanine in the brain of patients and highlight where hiPSC-derived organoids could contribute to the understanding of this disease.

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