Cerebral arteriopathy in ACTA2 mutations: a spectrum of disease highlighted by a case of variable penetrance in two siblings

2021 ◽  
pp. 1-6
Author(s):  
Christine Tschoe ◽  
Teddy E. Kim ◽  
Kyle M. Fargen ◽  
Stacey Q. Wolfe
Keyword(s):  
Moyamoya Disease ◽  
De Novo ◽  
Early Recognition ◽  
Smooth Muscle Actin ◽  
Amino Acid Replacement ◽  
Single Mutation ◽  
Cerebral Arteriopathy ◽  
And Performance ◽  
Actin Protein ◽  
Revascularization Procedures

Until recently, cerebral arteriopathy due to heterozygous mutations of the ACTA2 gene was considered a variant of moyamoya disease. However, radiographic analysis of patients with these mutations reveals a distinctive angiographic appearance from that seen in moyamoya disease. Several heterozygous missense ACTA2 mutations have been implicated in the development of this distinct cerebrovascular entity; however, the penetrance and systemic manifestations of these mutations vary based on the location of the amino acid replacement within the α–smooth muscle actin protein. The severity of the phenotype may also differ among patients within a single mutation type. There is limited literature on the safety and efficacy of revascularization procedures for ACTA2 arteriopathy, which have been limited to those patients with known Arg179His mutations. The authors provide a review of the breadth of mutations within the ACTA2 literature and report a case of two siblings with de novo ACTA2 Arg258Cys mutations with differing clinical courses, highlighting the utility of indirect revascularization with 8-year follow-up data. This case highlights the importance of early recognition of the angiographic appearance of ACTA2 cerebral arteriopathy and performance of genetic testing, as the location of the mutation impacts clinical presentation and outcomes.

scholarly journals ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke

2018 ◽  
Vol 46 (3-4) ◽  
pp. 159-169 ◽  
Author(s):  
Joshua A. Cuoco ◽  
Christopher M. Busch ◽  
Brendan J. Klein ◽  
Michael J. Benko ◽  
Rachel Stein ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Moyamoya Disease ◽  
Literature Search ◽  
Case Reports ◽  
Smooth Muscle Actin ◽  
Muscle Dysfunction ◽  
Missense Mutations ◽  
Radiographic Findings ◽  
Cerebral Arteriopathy ◽  
Smooth Muscle Dysfunction

Background: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. Summary: We performed a literature search using PubMed with the key words “ACTA2 mutation,” “ACTA2 cerebral arteriopathy,” and “multisystemic smooth muscle dysfunction syndrome.” Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.

scholarly journals Whole-Genome Sequencing and Characterization of Buffalo Genetic Resources: Recent Advances and Future Challenges

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 904
Author(s):  
Saif ur Rehman ◽  
Faiz-ul Hassan ◽  
Xier Luo ◽  
Zhipeng Li ◽  
Qingyou Liu
Keyword(s):  
Selective Breeding ◽  
Reference Genome ◽  
De Novo ◽  
Phenotypic Diversity ◽  
Molecular Data ◽  
Genomic Diversity ◽  
Production Performance ◽  
Phylogeographic Structure ◽  
Economic Significance ◽  
And Performance

The buffalo was domesticated around 3000–6000 years ago and has substantial economic significance as a meat, dairy, and draught animal. The buffalo has remained underutilized in terms of the development of a well-annotated and assembled reference genome de novo. It is mandatory to explore the genetic architecture of a species to understand the biology that helps to manage its genetic variability, which is ultimately used for selective breeding and genomic selection. Morphological and molecular data have revealed that the swamp buffalo population has strong geographical genomic diversity with low gene flow but strong phenotypic consistency, while the river buffalo population has higher phenotypic diversity with a weak phylogeographic structure. The availability of recent high-quality reference genome and genotyping marker panels has invigorated many genome-based studies on evolutionary history, genetic diversity, functional elements, and performance traits. The increasing molecular knowledge syndicate with selective breeding should pave the way for genetic improvement in the climatic resilience, disease resistance, and production performance of water buffalo populations globally.

scholarly journals Extended haplotype-phasing of long-read de novo genome assemblies using Hi-C

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zev N. Kronenberg ◽  
Arang Rhie ◽  
Sergey Koren ◽  
Gregory T. Concepcion ◽  
Paul Peluso ◽  
...  
Keyword(s):  
Zebra Finch ◽  
Cultured Cells ◽  
De Novo ◽  
Single Cells ◽  
Variant Calling ◽  
Chromatin Interaction ◽  
Extended Haplotype ◽  
Benchmark Datasets ◽  
And Performance ◽  
Genome Assemblies

AbstractHaplotype-resolved genome assemblies are important for understanding how combinations of variants impact phenotypes. To date, these assemblies have been best created with complex protocols, such as cultured cells that contain a single-haplotype (haploid) genome, single cells where haplotypes are separated, or co-sequencing of parental genomes in a trio-based approach. These approaches are impractical in most situations. To address this issue, we present FALCON-Phase, a phasing tool that uses ultra-long-range Hi-C chromatin interaction data to extend phase blocks of partially-phased diploid assembles to chromosome or scaffold scale. FALCON-Phase uses the inherent phasing information in Hi-C reads, skipping variant calling, and reduces the computational complexity of phasing. Our method is validated on three benchmark datasets generated as part of the Vertebrate Genomes Project (VGP), including human, cow, and zebra finch, for which high-quality, fully haplotype-resolved assemblies are available using the trio-based approach. FALCON-Phase is accurate without having parental data and performance is better in samples with higher heterozygosity. For cow and zebra finch the accuracy is 97% compared to 80–91% for human. FALCON-Phase is applicable to any draft assembly that contains long primary contigs and phased associate contigs.

scholarly journals Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants

2020 ◽  
Vol 6 (6) ◽  
pp. e528
Author(s):  
Federica Malerba ◽  
Giulio Alberini ◽  
Ganna Balagura ◽  
Francesca Marchese ◽  
Elisabetta Amadori ◽  
...  
Keyword(s):  
De Novo ◽  
Cognitive Outcome ◽  
Single Mutation ◽  
Genetic Modifiers ◽  
Seizure Onset ◽  
Pathogenic Variants ◽  
Intellectual Outcome ◽  
The Mean ◽  
Patients With Epilepsy ◽  
The Impact

ObjectiveEarly identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations.MethodsPatients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.ResultsWe included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.ConclusionsWe highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

scholarly journals P007: A comparative analysis of qSOFA, SIRS and Early Warning Scores Criteria to identify sepsis in the prehospital setting

CJEM ◽  
2017 ◽  
Vol 19 (S1) ◽  
pp. S79-S80 ◽  
Author(s):  
S. AlQahtani ◽  
P. Menzies ◽  
B. Bigham ◽  
M. Welsford
Keyword(s):  
Severe Sepsis ◽  
Screening Tool ◽  
Early Recognition ◽  
Capture Rate ◽  
Data Capture ◽  
Prehospital Setting ◽  
Life Saving ◽  
Data Points ◽  
And Performance ◽  
Definition Of

Introduction: Early recognition of sepsis is key in delivering timely life-saving interventions. The role of paramedics in recognition of these patients is understudied. It is not known if the usual prehospital information gathered is sufficient for severe sepsis recognition. We sought to: 1) evaluate the paramedic medical records (PMRs) of severe sepsis patients to describe epidemiologic characteristics; 2) determine which severe sepsis recognition and prediction scores are routinely captured by paramedics; and 3) determine how these scores perform in the prehospital setting. Methods: We performed a retrospective review of patients ≥18 years who met the definition of severe sepsis in one of two urban Emergency Departments (ED) and had arrived by ambulance over an eighteen-month period. PMRs were evaluated for demographic, physiologic and clinical variables. The information was entered into a database, which auto-filled a tool that determined SIRS criteria, shock index, prehospital critical illness score, NEWS, MEWS, HEWS, MEDS and qSOFA. Descriptive statistics were calculated. Results: We enrolled 298 eligible sepsis patients: male 50.3%, mean age 73 years, and mean prehospital transportation time 30 minutes. Hospital mortality was 37.5%. PMRs captured initial: respiratory rate 88.6%, heart rate 90%, systolic blood pressure 83.2%, oxygen saturation 59%, temperature 18.7%, and Glasgow Coma Scale 89%. Although complete MEWS and HEWS data capture rate was <17%, 98% and 68% patients met the cut-point defining “critically-unwell” (MEWS ≥3) and “trigger score” (HEWS ≥5), respectively. The qSOFA criteria were completely captured in 82% of patients; however, it was positive in only 36%. It performed similarly to SIRS, which was positive in only 34% of patients. The other scores were interim in having complete data captured and performance for sepsis recognition. Conclusion: Patients transported by ambulance with severe sepsis have high mortality. Despite the variable rate of data capture, PMRs include sufficient data points to recognize prehospital severe sepsis. A validated screening tool that can be applied by paramedics is still lacking. qSOFA does not appear to be sensitive enough to be used as a prehospital screening tool for deadly sepsis, however, MEWS or HEWS may be appropriate to evaluate in a large prospective study.

Surgery for Moyamoya Disease in Children

2019 ◽  
Vol 34 (9) ◽  
pp. 517-529 ◽  
Author(s):  
Ramana Appireddy ◽  
Manish Ranjan ◽  
Bryce A. Durafourt ◽  
Jay Riva-Cambrin ◽  
Walter J. Hader ◽  
...  
Keyword(s):  
Moyamoya Disease ◽  
Hemorrhagic Stroke ◽  
Pediatric Population ◽  
Surgical Revascularization ◽  
Surgical Options ◽  
Revascularization Procedures ◽  
Cerebrovascular Occlusive Disease ◽  
The Brain ◽  
Internal Carotid Arteries ◽  
Selection Of

Moyamoya disease is a chronic progressive cerebrovascular occlusive disease of the terminal portion of the internal carotid arteries associated with an acquired abnormal vascular network at the base of the brain, often leading to ischemic or hemorrhagic stroke. Moyamoya disease is a relatively common cause of pediatric stroke with a specific racial and well-identified clinical and imaging phenotype. Moyamoya disease is more prevalent in East Asian countries compared with other geographic regions with a higher incidence of familial cases and clinically more aggressive form. Moyamoya disease is one of the few causes of stroke that is amenable to effective surgical revascularization treatment. There are various surgical options available for revascularization, including the direct, indirect, or combined bypass techniques, each with variable responses. However, due to the heterogeneity of the diseases, different clinical course, geographical variables associated with the disease, and availability of a wide variety of surgical revascularization procedures, optimal selection of a surgical candidate and the surgical technique becomes challenging, particularly in the pediatric population. This brief review presents pertinent literature of clinical options for the diagnosis and surgical treatment of moyamoya disease in children.

scholarly journals Clinical features and long-term outcomes of moyamoya disease: a single-center experience with 528 cases in China

2015 ◽  
Vol 122 (2) ◽  
pp. 392-399 ◽  
Author(s):  
Xing-ju Liu ◽  
Dong Zhang ◽  
Shuo Wang ◽  
Yuan-li Zhao ◽  
Mario Teo ◽  
...  
Keyword(s):  
Clinical Features ◽  
Moyamoya Disease ◽  
Positive Impact ◽  
Chinese Patients ◽  
Single Center ◽  
Long Term Outcomes ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Revascularization Procedures

OBJECT The aim of this study was to describe the baseline clinical features and long-term outcomes of patients with moyamoya disease (MMD) based on a 25-year period at a single center in China. METHODS  Data obtained in 528 consecutive patients with MMD treated at the authors' hospital from 1984 to 2010 were reviewed retrospectively. Events of transient ischemic attack, new infarction, and hemorrhage were included. The Kaplan-Meier risk of stroke was calculated. RESULTS  The mean (± SD) patient age was 26 ± 13 years (range 2–67 years), and the female/male ratio was 0.9:1. There were 332 cases of ischemia and 196 hemorrhages. Adults had a higher rate of bleeding than children (50.7% vs 14.0%, respectively; p < 0.001). One hundred twenty-two patients were treated conservatively, and 406 patients underwent revascularization procedures. Of 528 patients, 331 (62.7%) had at least 1 year of follow-up (median 39.5 months) and data from these patients were analyzed. Rebleeding and mortality rates in patients with hemorrhagic MMD (n = 104) were higher than in those with ischemic MMD (n = 227) (26.9% vs 2.2% [p < 0.001] and 4.8% vs 0.4% [p < 0.05], respectively). Twenty-five of 60 (41.7%) conservatively treated patients and 8 of 271 (2.9%) surgically treated patients experienced rebleeding events, a difference that was significant in the Kaplan-Meier curve of rebleeding (p < 0.01). An improvement in perfusion was found in 164 of 224 (73.2%) surgically treated patients 1 month after discharge. However, there was no significant difference in the rate of ischemic events in the surgical and conservative groups (18.8% and 28.3%, respectively; p = 0.09). Among the 104 hemorrhagic cases, rebleeding attacks were observed in 25 patients in the nonsurgical group (n = 60) and 3 patients in the surgical group (n = 44) (41.7% and 6.8%, respectively; OR 9.7 [95% CI 2.7–35.0]; p < 0.01). CONCLUSIONS  There was no difference in the sex distribution of Chinese patients with MMD. Patients with hemorrhagic MMD had a much higher rate of rebleeding and poorer prognosis than those with the ischemic type. Surgical revascularization procedures can improve cerebral perfusion and have a positive impact in preventing rebleeding in patients with hemorrhagic MMD.

Evaluation of Professional Ballet Dancers Body Posture During Barre Movements

2020 ◽  
Vol 142 (3) ◽  
Author(s):  
R. M. Patterson ◽  
N. Hershberger ◽  
E. Balyakina ◽  
W. Capell ◽  
A. Mirochnitchenko ◽  
...  
Keyword(s):  
Early Recognition ◽  
Movement Patterns ◽  
Ballet Dancers ◽  
Leg Extension ◽  
Proper Form ◽  
Flexion Extension ◽  
Left And Right ◽  
Mechanical Overload ◽  
And Performance ◽  
Different Levels

Abstract Ballet dancers have finite careers due to the demands placed upon their bodies throughout years of training, study, and performance. The average age a dancer retires is 34 due to persistent stress on their joints and injuries due to mechanical overload or overuse. Proper form is crucial to prevent injury. The aim of this study was to establish benchmarks for normal movement patterns among professional dancers. Ten professional ballerinas were studied. Reflective markers were placed on the pelvis, left and right anterior superior iliac spine (ASIS), and posterior iliac spine (PSIS) to evaluate motion during Barre movements: plié, grand battement, and développé. Pelvis flexion/extension, mediolateral rotation, and torsion were analyzed. These motions test different skills. The plié is a controlled coordinated motion using both legs. The grand battement and développé both require leg extension, one with a quick motion that creates momentum and one using controlled motion that requires strength. Each requires core and pelvis stability to perform accurately and with less injury. Dancers' motions were consistent. Maximum pelvis range of motion for the plié, grand battement, and développé were 8.0, 42, and 50 deg, respectively. This represents usable benchmarks with which other dancers may be compared, for example, those who are at different levels of training, injured, predisposed to injury, or recovering from injury. Early recognition of pathologic movement patterns could benefit professional and amateur dancers by helping to prevent injuries, and potentially improve the quality and length of their careers.

scholarly journals A Rare and Fatal Complication of a Self-Limiting Infection: A Case Report on Dengue Associated Hemophagocytic Lymphohistiocytosis

2019 ◽  
Vol 30 (2) ◽  
pp. 93-95
Author(s):  
Alvin Oliver Payus ◽  
Cheong Lei Wah ◽  
Syahrul Sazliyana Shaharir
Keyword(s):  
Case Report ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
De Novo ◽  
Medical Condition ◽  
Early Recognition ◽  
Genetic Disorder ◽  
Intravenous Methylprednisolone ◽  
Appropriate Treatment ◽  
Life Threatening

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that driven by excessive cytokines production which resulted in cellular destructions. It can arise de novo as a result of an autosomal recessive genetic disorder, or in the background of an infection, malignancy or autoimmune disease. Dengue fever is one of the uncommon causes of infection related secondary HLH. Here, we present a case of a Dengue associated HLH which was successfully treated with intravenous methylprednisolone and immunoglobulin G. In conclusion, the purpose of this case report is to illustrate the importance of early recognition and prompt initiation of the appropriate treatment for HLH suspected patient whom otherwise has high mortality rate. Bangladesh J Medicine July 2019; 30(2) : 93-95

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