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2021 ◽  
Author(s):  
Maria Martinez de Lagran ◽  
Aleix Elizalde-Torrent ◽  
Roger Paredes ◽  
Bonaventura Clotet ◽  
Mara Dierssen

Abstract An elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases. Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and a genetic form of Alzheimer’s disease. For this reason, we hypothesized that treatment with reverse transcriptase inhibitors could ameliorate DS phenotypes. In this proof of concept study, we treated trisomic (Ts65Dn) mice, a model of DS, with lamivudine, a reverse transcriptase inhibitor. We detected a significant improvement of neurobehavioral phenotypes, and a complete rescue of the hippocampal-dependent recognition memory upon treatment with lamivudine. Despite clinical studies in patients with DS are warranted, this study lays the groundwork for a novel and actionable therapeutic approach.


2021 ◽  
Vol 14 (9) ◽  
pp. e243669
Author(s):  
Shayan Soomro ◽  
Kimia Ziahosseini ◽  
Poonam Sharma

Madelung’s disease is a rare disorder characterised by excessive and symmetrical deposits of adipose tissue, typically in the cervicofacial region. Alcohol is a known cause of the condition, however, there are reports that this condition is genetically inherited. Lipomatosis of the orbit has been described in the alcoholic Madelung’s disease, however, in our case report, we believe this is the first reported instance of proptosis caused by the genetic form of the condition. We present a 69-year-old woman, with a medical history of genetic Madelung’s disease, who presented with bilateral proptosis worse in her right eye. Her ocular examination was normal apart from exophthalmometry, showing bilateral proptosis. This was confirmed by an MRI, which further showed intraorbital fat deposition bilaterally. Due to the stability of her condition, no treatment was deemed necessary. We highlight the importance of monitoring for progressive optic nerve compromise and liposarcomatous malignant transformation.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huan Zou ◽  
Mingfeng Guan ◽  
Yundong Li ◽  
Fang Luo ◽  
Wenyuan Wang ◽  
...  

Abstract Background Achondroplasia (ACH) is the most common genetic form of dwarfism and belongs to dominant monogenic disorder caused by a gain-of-function point mutation in the transmembrane region of FGFR3. There are no effective treatments for ACH. Stem cells and gene-editing technology provide us with effective methods and ideas for ACH research and treatment. Methods We generated non-integrated iPSCs from an ACH girl’s skin and an ACH boy’s urine by Sendai virus. The mutation of ACH iPSCs was precisely corrected by CRISPR-Cas9. Results Chondrogenic differentiation ability of ACH iPSCs was confined compared with that of healthy iPSCs. Chondrogenic differentiation ability of corrected ACH iPSCs could be restored. These corrected iPSCs displayed pluripotency, maintained normal karyotype, and demonstrated none of off-target indels. Conclusions This study may provide an important theoretical and experimental basis for the ACH research and treatment.


F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 381
Author(s):  
Georgios Nikolakis ◽  
Katja Kreibich ◽  
Aristeidis Vaiopoulos ◽  
Katarzyna Kaleta ◽  
Joud Talas ◽  
...  

Syndromic hidradenitis suppurativa (HS) is a form of symptom constellations, which differs from the familial and genetic form and comprises predominantly osteoarticular manifestations. Many forms include pyoderma gangrenosum and acne (PASH), pyogenic arthritis (PAPASH), spondyloarthritis (PASS) and psoriatic arthritis (PsAPASH) and are categorized in the autoinflammatory syndromes. Anti-TNF-α and anti-IL-1a blockade are between the therapeutic approaches that improve skin symptoms and prevent permanent osteoarticular damage. This case report refers to the successful treatment of a mixed phenotype of the aforementioned symptoms using the IL-17A inhibitor secukinumab after initial treatment with adalimumab. The therapy improved both cutaneous and reported osteoarticular symptoms. Different approaches for these recalcitrant HS syndromes are essential in order to achieve long-term remission for those patients.


Author(s):  
James J. Fink ◽  
Jeremy D. Schreiner ◽  
Judy E. Bloom ◽  
Jadin James ◽  
Dylan S. Baker ◽  
...  

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 381
Author(s):  
Georgios Nikolakis ◽  
Katja Kreibich ◽  
Aristeidis Vaiopoulos ◽  
Katarzyna Kaleta ◽  
Joud Talas ◽  
...  

Syndromic hidradenitis suppurativa (HS) is a form of symptom constellations, which differs from the familial and genetic form and comprises predominantly osteoarticular manifestations. Many forms include pyoderma gangrenosum and acne (PASH), pyogenic arthritis (PAPASH), spondyloarthritis (PASS) and psoriatic arthritis (PsaPASH) and are categorized in the autoinflammatory syndromes. anti-TNF-α and anti-IL-1a blockade are between the therapeutic approaches that improve skin symptoms and prevent permanent osteoarticular damage. This case report refers to the successful treatment of a mixed phenotype of the aforementioned symptoms using the IL-17A inhibitor secukinumab after initial treatment with adalimumab. The therapy improved both cutaneous and reported osteoarticular symptoms. Different approaches for these recalcitrant HS syndromes are essential in order to achieve long-term remission for those patients.


Author(s):  
Margherita Migone De Amicis ◽  
Alessandro Rimondi ◽  
Luca Elli ◽  
Irene Motta

Anemia is a global health problem affecting one-third of the world population, and half of the cases are due to iron deficiency (ID). Iron de?ciency anemia (IDA) is the leading cause of disability in several countries. The causes of ID and IDA can be classified as i) insufficient iron intake for the body requirement, ii) reduced absorption, and iii) and blood losses, although multiple mechanisms may coexist. Oral iron represents the mainstay of IDA treatment. IDA is defined as "refractory" when the hematologic response after 4 to 6 weeks of treatment with oral iron (an increase of <1 g/dL of Hb) is absent. The cause of iron-refractory anemia is usually acquired and frequently related to gastrointestinal pathologies, although a rare genetic form called iron refractory iron deficiency anemia (IRIDA) exists. In some pathological circumstances, either genetic or acquired, hepcidin is increased, limiting the absorption in the gut, remobilization, and recycling of iron, thereby reducing iron plasma levels. Indeed, conditions with high hepcidin levels are often underrecognized as iron-refractory, leading to inappropriate and unsuccessful treatments. This review provides an overview of the conditions underlying iron-refractory anemia, from gastrointestinal pathologies to hepcidin dysregulation and iatrogenic or provoked conditions, and the specific diagnostic and treatment approach.


Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 435
Author(s):  
Dana Kosorinova ◽  
Girma Belay ◽  
Dana Zakova ◽  
Martin Stelzer ◽  
Eva Mitrova

The most frequent human prion disease is Creutzfeldt–Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10–15% of confirmed cases worldwide, in Slovakia as much as 65–75%. Focal accumulation of gCJD was confirmed in Orava region. The most common point mutation of the prion protein gene (PRNP) is E200K. CJD has a long asymptomatic phase and it is not known when the carriers of the mutation E200K become infectious. Precautions to prevent iCJD are focused especially on clinical CJD cases, but asymptomatic CJD-specific mutation carriers cannot be excluded, and represent a potential genetic CJD-risk group. The aim of this study was to determine the occurrence, frequency and geographic distribution of the E200K mutation among the newborns, comparing the areas of focal accumulation of gCJD with extra-focal ones, as well as distribution of the polymorphism M129V of the PRNP gene. A total of 2915 samples of dry blood spots from anonymous newborns were analyzed. We used RealTime PCR method to determine the presence of the E200K mutation and the M129V polymorphism. Genetic testing revealed 13 carriers of the E200K mutation. Investigation of the M129V polymorphism affirmed higher representation of methionine homozygotes (48% MM, 44% MV, 8% VV). Achieved results fully confirmed our previous observations concerning both the specific and nonspecific genetic CJD risk among the Slovak general population. The 48% of methionine homozygotes and 4 carriers of the E200K mutation among 1000 live-born children in Slovakia underline the benefits of genetic testing.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Daniel Beck ◽  
Millissia Ben Maamar ◽  
Michael K. Skinner

Abstract Background Environmentally induced epigenetic transgenerational inheritance of pathology and phenotypic variation has been demonstrated in all organisms investigated from plants to humans. This non-genetic form of inheritance is mediated through epigenetic alterations in the sperm and/or egg to subsequent generations. Although the combined regulation of differential DNA methylated regions (DMR), non-coding RNA (ncRNA), and differential histone retention (DHR) have been shown to occur, the integration of these different epigenetic processes remains to be elucidated. The current study was designed to examine the integration of the different epigenetic processes. Results A rat model of transiently exposed F0 generation gestating females to the agricultural fungicide vinclozolin or pesticide DDT (dichloro-diphenyl-trichloroethane) was used to acquire the sperm from adult males in the subsequent F1 generation offspring, F2 generation grand offspring, and F3 generation great-grand offspring. The F1 generation sperm ncRNA had substantial overlap with the F1, F2 and F3 generation DMRs, suggesting a potential role for RNA-directed DNA methylation. The DMRs also had significant overlap with the DHRs, suggesting potential DNA methylation-directed histone retention. In addition, a high percentage of DMRs induced in the F1 generation sperm were maintained in subsequent generations. Conclusions Many of the DMRs, ncRNA, and DHRs were colocalized to the same chromosomal location regions. Observations suggest an integration of DMRs, ncRNA, and DHRs in part involve RNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.


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