autosomal dominant disorder
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2022 ◽  
Vol 11 (2) ◽  
pp. 444
Author(s):  
Angelos Kaspiris ◽  
Olga D. Savvidou ◽  
Elias S. Vasiliadis ◽  
Argyris C. Hadjimichael ◽  
Dimitra Melissaridou ◽  
...  

Neurofibromatosis type 1 (NF1), which is the most common phacomatoses, is an autosomal dominant disorder characterized by clinical presentations in various tissues and organs, such as the skin, eyes and nervous and skeletal systems. The musculoskeletal implications of NF1 include a variety of deformities, including scoliosis, kyphoscoliosis, spondylolistheses, congenital bony bowing, pseudarthrosis and bone dysplasia. Scoliosis is the most common skeletal problem, affecting 10–30% of NF1 patients. Although the pathophysiology of spinal deformities has not been elucidated yet, defects in bone metabolism have been implicated in the progression of scoliotic curves. Measurements of Bone Mineral Density (BMD) in the lumbar spine by using dual energy absorptiometry (DXA) and quantitative computer tomography (QCT) have demonstrated a marked reduction in Z-score and osteoporosis. Additionally, serum bone metabolic markers, such as vitamin D, calcium, phosphorus, osteocalcin and alkaline phosphatase, have been found to be abnormal. Intraoperative and histological vertebral analysis confirmed that alterations of the trabecular microarchitecture are associated with inadequate bone turnover, indicating generalized bone metabolic defects. At the molecular level, loss of function of neurofibromin dysregulates Ras and Transforming Growth factor-β1 (TGF-β1) signaling and leads to altered osteoclastic proliferation, osteoblastic activity and collagen production. Correlation between clinical characteristics and molecular pathways may provide targets for novel therapeutic approaches in NF1.


Author(s):  
Yun-Sic Bang ◽  
Jaeho Cho ◽  
Chunghyun Park

Background: Hereditary angioedema (HAE) is an autosomal dominant disorder. The characteristic of HAE is recurrent angioedema episodes due to low C1 esterase inhibitor (C1-INH) level. HAE symptoms, especially those affecting oropharynx or larynx may develop respiratory distress syndrome due to impaired airway, which can be potentially fatal. Case: We report a clinical case of a 57 year-old woman, with type I HAE, scheduled for total laparoscopic hysterectomy under general endotracheal anesthesia, which was done successfully without inducing airway edema. Danazol, which increases liver synthesis of C1-INH, was administered and fresh frozen plasma (FFP), which contained C1-INH, was transfused after induction.Conclusions: For HAE patients, the greatest concern is that general anesthesia can induces upper airway edema by direct mucosal irritation by the endotracheal tube. The perioperative management should include both prophylactic increase of C1-INH production and on-demand administration of C1-INH or FFP.


2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Troels Hvelplund ◽  
Bibi Lange ◽  
Susanne Djernes Bird ◽  
Malene Korsholm ◽  
Anette Drøhse Kjeldsen

Abstract Background Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by several clinical symptoms including epistaxis, arteriovenous malformations (AVM), and telangiectasia. In 2018, European Reference Network for Rare Vascular Diseases (VASCERN) recommended five outcome measures for HHT-patients to guide health care providers, some with limited experience in treating HHT, and thereby maximizing the number of HHT-patients receiving good care. The outcome measures cover the following aspects: (1) 90% of the patients should receive a pulmonary AVM (PAVM) screening; (2) 90% of the patients should receive written advice on nosebleed; (3) 70% should be assessed for iron deficiency; (4) 100% of the patients should receive written advice on antibiotic (AB) prophylaxis prior to dental and surgical procedures, and (5) 100% of relevant patients should receive written advice on pregnancy. We have introduced the outcome measures as Benchmarks in our HHT-centre and wanted to evaluate the extend of implementation we have achieved. We constantly struggle to secure the best possible treatment of our HHT-patients. Methods The study was a non-interventional retrospective study. Data was collected manually from patient records and from the Danish HHT-database. Results A total of 180 HHT-patients were included, all diagnosed in the period from January 1st, 2016, to December 31st, 2020. All patients were screened for PAVM. We could confirm that 66% of patients who had epistaxis received thoroughly advice. Assessment for iron deficiency was performed in 80% of the adult patients. Thoroughly advice on AB prophylaxis was documented in 75%. Thoroughly advice on pregnancy was documented in 80% of female patients 15–45 years of age. There were no significant differences over time for any of the outcome measures. Conclusions The Danish HHT-centre reached the target threshold for outcome measures 1 and 3. It could not be documented that the target thresholds for outcome measures 2, 4, and 5 were achieved. As information and education are a very important part of HHT care, focus on and documentation that all patients receive the relevant advice must be a priority in order to ensure best care.


2022 ◽  
Vol 9 ◽  
Author(s):  
Poomiporn Katanyuwong ◽  
Arthaporn Khongkraparn ◽  
Duangrurdee Wattanasirichaigoon

Left ventricular non-compaction (LVNC) is a rare and genetically heterogeneous cardiomyopathy. The disorder vastly affects infants and young children. Severe neonatal LVNC is relatively rare. The prevalence of genetic defects underlying pediatric and adult-onset LVNC is about 17–40%. Mutations of MYH7 and MYBPC3 sarcomeric genes are found in the vast majority of the positive pediatric cases. PKP2 encodes plakophilin-2, a non-sarcomeric desmosomal protein, which has multiple roles in cardiac myocytes including cell–cell adhesion, tightening gap junction, and transcriptional factor. Most of the reported PKP2 mutations are heterozygous missense and truncating variants, and they are associated with an adult-onset autosomal dominant disorder, namely arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Homozygous PKP2 mutations have been rarely described. Herein, we present a rare case of an infant with neonatal onset of congestive heart failure owing to severe LVNC and multiple muscular VSD. Medical treatments failed to control the heart failure and the patient died at 11 months of age. Whole-exome sequencing identified a novel homozygous PKP2 variant, c.1511-1G>C, in the patient. An mRNA analysis revealed aberrant transcript lacking exon 7, which was predicted to cause a frameshift and truncated peptide (p.Gly460GlufsTer2). The heterozygous parents had normal cardiac structures and functions as demonstrated by electrocardiogram and echocardiography. Pathogenic variants of sarcomeric genes analyzed were not found in the patient. We conducted a literature review and identified eight families with biallelic PKP2 mutations. We observed that three families (our included) with null variants were linked to lethal phenotypes, while homozygous missense mutations resulted in less severe manifestations: adolescent-onset ARVD/C and childhood-onset DCM. Our data support a previous notion that severe neonatal LVNC might represent a unique entity and had distinct genetic spectrum. In conclusion, the present study has extended the phenotypes and genotypes of PKP2-related disorders and lethal LVNC.


2022 ◽  
Vol 12 ◽  
Author(s):  
Takuya Takeichi ◽  
John Y. W. Lee ◽  
Yusuke Okuno ◽  
Yuki Miyasaka ◽  
Yuya Murase ◽  
...  

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.


Author(s):  
Zakoun M ◽  
◽  
Belghmaidi S ◽  

Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant disorder that has both systemic and ocular anterior segment dysgenesis. The ocular manifestations include posterior embryotoxon, iris and anterior angle abnomalies with a high risk of glaucoma and blindness. The systemic manifestations can include craniofacial abnomalies such as maxillary hypoplasia, hypodontia, oligodontia and microdont.


Author(s):  
Hoang Thi Yen ◽  
Vu Duc Anh ◽  
Le Thi Yen ◽  
Dang Thi Ngoc Dung

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism characterized by high levels of LDL-cholesterol (LDL-C) in the blood. Studies identified more than 1,000 mutations of the LDLR gene in FH patients with incidence rates between 1: 500 and 1: 300. The mutation that occurs primarily in: LDLR, apoB, PCSK9, LDLRAP1 genes, 80% of which were detected the LDLR gene mutation. Nowaday, FH disease has not been paid much attention, leading to a delay in treatment.  Objectives: identify mutations in other family members of the patient FH.  Subjects and Methods: 14 family members of FH patients were gene analyzed, identified mutations on exons 4, 9 LDLR genes. Results: 11/15 family members carrying heterozygous mutations on exon 4 and exon 9 of LDLR gene. Patient and 1 family member detected and treated late, leading to complications of myocardial infarction. Conclusion: Therefore, Cascade screening of patient's family members has an important role in early detection, genetic counseling and treatment, even in cases where pedigree members do not have xanthomas and no increase or slight increase in blood lipids. This is the basis for early counseling and treatment for members with mutations, reducing the risk of coronary artery diseases in the future.


Author(s):  
Myrthe R Naber ◽  
Saya Ahmad ◽  
Annemarie A Verrijn Stuart ◽  
Rachel H Giles ◽  
Gerlof D Valk ◽  
...  

Abstract Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess what their clinical relevance in diagnosing panNENs in VHL patients is. We searched the databases of Pubmed/Medline, Embase and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.


2021 ◽  
Vol 12 ◽  
Author(s):  
Haochang Hu ◽  
Tian Shu ◽  
Jun Ma ◽  
Ruoyu Chen ◽  
Jian Wang ◽  
...  

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.


2021 ◽  
Vol 33 (4) ◽  
pp. 311-318
Author(s):  
Lorenz Peters ◽  
Christel Depienne ◽  
Stephan Klebe

Abstract Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by myoclonus and seizures. The genetic variant underlying FAME is an intronic repeat expansion composed of two different pentamers: an expanded TTTTA, which is the motif originally present at the locus, and an insertion of TTTCA repeats, which is usually located at the 3′ end and likely corresponds to the pathogenic part of the expansion. This repeat expansion has been identified so far in six genes located on different chromosomes, which remarkably encode proteins with distinct cellular localizations and functions. Although the exact pathophysiological mechanisms remain to be clarified, it is likely that FAME repeat expansions lead to disease independently of the gene where they occur. We herein review the clinical and molecular characteristics of this singular genetic disorder, which interestingly shares clinical features with other more common neurological disorders whose etiology remains mainly unsolved.


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