RESUMEN
Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein-2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.
Asunto(s)
Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Desmogleína 2/genética , Mutación , Proteínas de Dominio T Box/genética , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Adulto , Células Cultivadas , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad , Pruebas de Función Cardíaca , Humanos , Imagen por Resonancia Magnética/métodos , Linaje , Evaluación de SíntomasRESUMEN
Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. RESULTS: Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health ("National Pediatric Center") aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16-17 from refractory heart failure and two underwent heart transplantation. All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. CONCLUSION: The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo.
Asunto(s)
Cardiomiopatías , Enfermedad por Depósito de Glucógeno de Tipo IIb , Adolescente , Femenino , Humanos , Niño , Anciano , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico , Enfermedad por Depósito de Glucógeno de Tipo IIb/genética , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Arritmias Cardíacas , Hipertrofia Ventricular Izquierda/patología , Diagnóstico PrecozRESUMEN
Background: Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). Methods: All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. Results: A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Conclusion: Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.
RESUMEN
OBJECTIVES: The objective of this work was to develop technology to create 'soft' patient-specific models of semilunar heart valves, the aortic valve in particular, suitable for training and simulation of surgical and endovascular interventions. METHODS: Data obtained during routine cardiac contrast-enhanced multislice computed tomography were used to create 3-dimensional models of the aortic root. Three-dimensional models were used to create soft silicone models of the aortic root made by casting silicone into a negative mould printed with stereolithography. A comparison between the constructed models and the size of the aortic root was performed. We quantified how much time was needed for production of each model. RESULTS: Four patient-specific soft models of the aortic root were produced. Data from patients of different ages and body surface areas were used as prototypes. All models had minimum size errors. During development of this technology, production time per model was reduced from 63 to 39 h. CONCLUSIONS: We have demonstrated the feasibility of making soft patient-specific 3-dimensional aortic root models using currently available technology. These models can be used both for training physicians in a variety of open surgical and endovascular interventions and for the study of complex aortic root geometry.