Very-long chain acyl-coA dehydrogenase deficiency: report of a Chinese pedigree and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the correlation between clinical classification and genotype and prognosis among Chinese children with Very-long chain acyl-CoA dehydrogenase deficiency (VLCADD).@*METHODS@#A Chinese pedigree affected with VLCADD admitted at the First People's Hospital of Yunnan Province in February 2019 was selected as the study subject. The characteristics of disease onset, diagnosis and treatment and prognosis were retrospectively analyzed. Relevant literature was also systematically searched and reviewed.@*RESULTS@#The proband, a 1-year-old boy, had the clinical manifestations of frequently vomiting, hypoglycemia, abnormal liver function and myocardial enzymes. Tandem mass spectrometry screening showed significantly elevated C14, C14:1, C16:1, C16:2, C18 and C14/C8. Genetic testing revealed that he has harbored compound heterozygous variants of the ACADVL gene, namely c.664G>A (p.G222R) and c.1345G>A (p.E449K), which were respectively derived from his father and mother. The child was diagnosed with VLCADD cardiomyopathy type and deceased 2 weeks later. Literature review has identified 60 Chinese children with VLCADD. The clinical classifications were mainly cardiomyopathy type and liver disease type, which accounted for 73.3% (43/60). The combination of ACADVL gene variants were correlated with the clinical classifications of VLCAD. Children with one or two loss-of-function (LOF) mutations showed more severe clinical manifestation and a higher mortality. Cardiomyopathy type had the poorest prognosis, with a mortality rate of 76.9% (20/26). C14:1 may be used as an indicator for the diagnosis of VLCADD, but cannot be used for clinical subtyping and prognosis evaluation. The c.1349G>A (p.R450H) variant had the highest frequency among the Chinese patients, accounting for 10.8% (13/120).@*CONCLUSION@#The clinical classifications of VLCADD are strongly correlated with the prognosis, and LOF mutations are more common in those with severe clinical manifestations. c.1349G>A (p.R450H) may be the most common variant among the Chinese patients, and early screening and diagnosis can greatly improve the prognosis of patients.

Miocardiopatia não compactada em crianças e adolescentes: do desafio do diagnóstico ecocardiográfico ao acompanhamento clínico / Non-compacted cardiomyopathy in children and adolescents: from the challenge of echocardiographic diagnosis to clinical follow-up

Fundamentos: Miocardiopatia não compactada (MCNC) caracteriza-se por hipertrabeculações e recessos profundos no ventrículo esquerdo, com apresentação clínica heterogênea, desde pacientes assintomáticos a insuficiência cardíaca (IC), eventos tromboembólicos arritmias com risco de morte súbita. Por ser rara e não apresentar critérios diagnósticos bem definidos, sua história natural na pediatria é pouco conhecida. Este estudo descreve a apresentação e evolução clínica de pacientes portadores de MCNC. Metodologia: Estudo observacional, longitudinal, prospectivo, de pacientes pediátricos atendidos em um centro de referência em cardiologia pediátrica provenientes da região metropolitana II do Estado do Rio de Janeiro, com fenótipo de MCNC ao ecocardiograma (ECO) no período de 2 anos de acompanhamento, provenientes do Registro ChARisMa. Resultados: Analisados seis pacientes com MCNC, de 4 a 14 anos de idade, média de idade de 7,5 anos (DP: 3,93), 3 do sexo masculino (50%). Apresentando-se com IC (n=2), sopro cardíaco (n=1), arritmia cardíaca (n=1), assintomático (n=1) ou em investigação de síndrome genética (n=1). Fenótipos ao ECO: MCNC/Miocardiopatia dilatada (n=1) e MCNC/Miocardiopatia restritiva (n=1), fenótipo isolado de MCNC (n=4). A ressonância magnética cardíaca foi realizada, confirmando o diagnóstico (n=4). Os desfechos observados foram tromboembolismo, indicação de transplante cardíaco e taquicardia ventricular sustentada. Conclusões: Esta série de casos proporciona dados relevantes da MCNC pediátrica, mostrando a heterogeneidade da apresentação clínica, bem como a ocorrência de complicações potencialmente fatais. São necessários mais estudos prospectivos para que seu diagnóstico seja corretamente realizado e sua evolução clínica, resposta terapêutica e prognóstico sejam mais bem conhecidos. (AU)

Background: Non-compacted cardiomyopathy (NCCM) is characterized by hypertrabeculations and deep recesses in the left ventricle, with a heterogeneous clinical presentation, ranging from asymptomatic patients to those with heart failure (HF), thromboembolic events and arrhythmias with risk of sudden death. As it is rare and does not have well-defined diagnostic criteria, its natural history in pediatrics is poorly understood. This study describes the clinical presentation and clinical course of patients with NCCM. Methodology: Observational, longitudinal, prospective study of pediatric patients seen at a pediatric cardiology referral center from metropolitan region II in the state of Rio de Janeiro, with NCCM phenotype on echocardiogram (ECHO) during a 2-year follow-up, from the ChARisMa registry. Results: 6 patients aged 4 to 14, with NCCM, were analyzed. Mean age 7.5 years (SD: 3.93), 3 males (50%). The patients presented HF (n=2), cardiac murmur (n=1), cardiac arrhythmia (n=1), were asymptomatic (n=1) or were under investigation for a genetic syndrome (n=1). Phenotypes on ECHO: NCCM/dilated cardiomyopathy (n=1) and NCCM/restrictive cardiomyopathy (n=1), isolated phenotype of NCCM (n=4). Cardiac magnetic resonance imaging was performed and confirmed the diagnosis (n=4). The outcomes observed were thromboembolism, indication for heart transplantation, and sustained ventricular tachycardia. Conclusions:This case series provides relevant data for pediatric NCCM as it shows its heterogeneous clinical presentation and potentially fatal complications. More prospective studies are needed for an accurate diagnosis and to allow its clinical course, therapeutic response and prognosis to be better known. (AU)

Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy / 中华医学杂志(英文版)

Desmoplakin (DSP), encoded by the DSP gene, is the main desmosome component and is abundant in the myocardial tissue. There are three DSP isoforms that assume the role of supporting structural stability through intercellular adhesion. It has been found that DSP regulates the transcription of adipogenic and fibrogenic genes, and maintains appropriate electrical conductivity by regulating gap junctions and ion channels. DSP is essential for normal myocardial development and the maintenance of its structural functions. Studies have suggested that DSP gene mutations are associated with a variety of hereditary cardiomyopathy, such as arrhythmia cardiomyopathy, dilated cardiomyopathy (DCM), left ventricular noncompaction, and is also closely associated with the Carvajal syndrome, Naxos disease, and erythro-keratodermia-cardiomyopathy syndrome with skin and heart damage. The structure and function of DSP, as well as the clinical manifestations of DSP-related cardiomyopathy were reviewed in this article.

Identification of the difference in the pathogenesis in heart failure arising from different etiologies using a microarray dataset

OBJECTIVES: Clinically, patients with chronic heart failure arising from different etiologies receive the same treatment. However, the prognoses of these patients differ. The purpose of this study was to elucidate whether the pathogenesis of heart failure arising from different etiologies differs. METHODS: Heart failure-related dataset GSE1145 was obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using R. A protein-protein interaction network of the differentially expressed genes was constructed using Search Tool for the Retrieval of Interacting Genes. The modules in each network were analyzed by Molecular Complex Detection of Cytoscape. The Database for Annotation, Visualization and Integrated Discovery was used to obtain the functions of the modules. RESULTS: Samples contained in GSE1145 were myocardial tissues from patients with dilated cardiomyopathy, familial cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, and post-partum cardiomyopathy. The differentially expressed genes, modules, and functions of the modules associated with different etiologies varied. Abnormal formation of extracellular matrix was overlapping among five etiologies. The change in cytoskeleton organization was specifically detected in dilated cardiomyopathy. The activation of the Wnt receptor signaling pathway was limited to hypertrophic cardiomyopathy. The change in nucleosome and chromatin assembly was associated with only familial cardiomyopathy. Germ cell migration and disrupted cellular calcium ion homeostasis were solely detected in ischemic cardiomyopathy. The change in the metabolic process of glucose and triglyceride was detected in only post-partum cardiomyopathy. CONCLUSION: These results indicate that the pathogenesis of heart failure arising from different etiologies varies, which may provide molecular evidence supporting etiology-based treatment for heart failure patients.

Ablação e mapeamento eletroanatômico na displasia arritmogênica ventricular / Ablation and electroanatomical mapping in arrhythmogenic right ventricular dysplasia

Alterações estruturais provenientes da displasia arritmogênica ventricular direita criam um importantesubstrato para focos de taquicardias ventriculares por reentrada. Pacientes com alto risco de desenvolverem essasarritmias são submetidos a tratamento farmacológico associado ao uso de cardiodesfibriladores implantáveis.Porém, em casos mais complexos e refratários, nos quais as terapias adequadas pelo cardiodesfibrilador implantávelsão frequentes, uma nova estratégia se fez necessária, visando à diminuição da morbidade desse subgrupo de pacientes.Estudos recentes demonstram que o mapeamento eletroanatômico associado a ablações por radiofrequênciaendocárdica e epicárdica foi eficaz nesse tratamento adjuvante, diminuindo o número de recorrências dastaquicardias ventriculares.

The structural abnormalities caused by arrhythmogenic right ventricular dysplasia create an importantsubstrate for ventricular tachycardia due to anatomic reentry. Patients at high risk of presenting arrhythmias aresubmitted to drug treatment in combination with the use of implantable cardioverter-defibrillators. However, incomplex and refractory cases, in which appropriate implantable cardioverter-defibrillator therapies are frequent,a new strategy is required to decrease the morbidity of this subgroup of patients. Recent studies demonstrate thatelectroanatomical mapping in combination with endocardial and epicardial radiofrequency catheter ablation is aneffective adjuvant therapy and decreases the rate of ventricular tachycardia recurrence.

Canalopatías arritmogénicas como causa de muerte súbita en pediatría / Arrhythmic canal diseases causing sudden death in children

La muerte súbita cardíaca de niños con corazón estructuralmente sano está estrechamente relacionada con las canalopatías arritmogénicas. Se presenta una revisión actualizada sobre las canalopatías y la relación de éstas con la muerte súbita. Se analiza especialmente la aplicación del método clínico y la importancia del trazado electrocardiográfico como herramientas indispensables para el certero diagnóstico de estas entidades.

Cardiac sudden death in children with a heart structurally healthy is closely related to arrhythmic canal diseases. An update review on canal diseases and its relation to the sudden death is presented. The application of clinical method is analyzed, as well as the significance of electrocardiographic recordings like essential tools for an accuracy diagnosis of these entities.

Chronic eosinophilic leukemia with a unique translocation.

We report a case of chronic eosinophilic leukemia in a 9 year old girl who presented with anemia, thrombocytopenia, leucocytosis (mostly dysplastic eosinophils), lymphadenopathy and hepatosplenomegaly. There was no increase in blasts but myelofibrosis was seen in the bone marrow. A previously unreported translocation 46,XX,t(1;4)(q24;q35), was found on cytogenetic analysis and involvement of the myocardium was also present. Shortly after commencing steroids, the family abandoned therapy.

Left ventriular noncompaction

LVNC is a genetic cardiac disease of emerging importance with a distinct clinical and pathophysiological presentation. The diagnosis of LVNC, however, is often missed, most often as a consequence of ignorance of the condition. Echocardiography is considered the reference standard for the diagnosis of LVNC. Prognosis remains poor for patients with impaired systolic left ventricular function, as treatment options are very limited. Because of the familial association of LVNC, first-degree relatives should be screened by Echocardiography

Naxos disease: a rare occurrence of cardiomyopathy with woolly hair and palmoplantar keratoderma.

Naxos disease is a rare genodermatosis with woolly hair, keratoderma of palms and soles and cardiomyopathy. A seven-year-old boy presented with woolly hair and hyperkeratotic lesions on the palms and soles since birth. His cardiac status was evaluated and echocardiography revealed early cardiomyopathy. Scalp biopsy revealed hair shaft in an angulated outline suggestive of woolly hair. So the diagnosis of Naxos disease was made. Since he was asymptomatic no treatment was offered but a regular follow-up of the patient and treatment of emergent symptoms should prevent sudden death.

Hipertrofia miocárdica: bases moleculares, modulación e implicancias clínicas / Myocardial hypertrophy: molecular bases, clinical modulation and implications

El corazón es una bomba contráctil regulada por estímulos mecánicos y neurohumorales encargado de mantener un flujo sanguíneo acorde con las demandas metabólicas de nuestro organismo. Los cardiomiocitos y sus sarcómeros son las unidades básicas responsables del proceso de contracción miocárdica. Dado que los cardiomiocitos no proliferan después del nacimiento, estas células experimentan hipertrofia, aumentando la cantidad de sarcómeros, con objeto de aumentar el trabajo cardíaco en situaciones de estrés. En este trabajo se hace una revisión crítica de las señales y mecanismos de transducción responsables del desarrollo de la hipertrofia cardíaca fisiológica y patológica. Además se abordan las implicancias clínicas y bases genéticas asociadas a la cardiomiopatía hipertrófica. El conocimiento de estas vías transduccionales permite comprender las bases biológicas de esta patología y proyectar futuras intervenciones terapéuticas.

Calcium cycling proteins in heartfailure, cardiomyopathy and arrhythmias

A growing body of evidence, including studies using genetically engineered mouse models, has shown that Ca2+ cycling and Ca2+ -dependent signaling pathways play a pivotal role in cardiac hypertrophy and heart failure. In addition, recent studies identified that mutations of the genes encoding sarcoplasmic reticulum (SR) proteins cause human cardiomyopathies and lethal ventricular arrhythmias. The regulation of Ca2+ homeostasis via the SR proteins may have potential therapeutic value for heart diseases such as cardiomyopathy, heart failure and arrhythmias.

Miocardiopatias / Cardiomiopathies

O grupo-tarefa constituído pela Organização Mundial da Saúde/Federação e Sociedade Internacional de Cardiologia (OMS/SIFC) define miocardiopatia (ou cardiomiopatia), como doença miocárdica associada à disfunção cadíaca. Esta definição, excessivamente genérica, encerra o inconveniente de ampliar em demasia o campo de estudo, de sorte que, no presente capítulo, o termo será empregado em sentido mais restrito, englobando apenas as afecções miocárdicas associadas à disfunção cardíaca não decorrentes de aterosclerose coronária significativa, disfunção valvar ou obstáculo fixo à ejeção das câmaras ventriculares, shunts dentro ou fora do coração e de hipertensão arterial sistêmica ou pulmonar passada ou presente...

Miocardiopatía hipertrófica familiar: arritmias por electrocardiografía ambulatoria / Familial hypertrophic myocardiopathy: arrythmias by ambulatory electrocardiography

Se estudian las arritmias en la miocardiopatía hipertrófica familiar y la relación entre su severidad y la anormalidad ecocardiográfica. Se investigan 16 pacientes de una misma familia, con miocardiopatía hipertrófica, seguida por 18 años. Se les realiza estudio electrocardiográfico ambulatorio de larga duración (Holter) de 24 horas, 13 fueron anormales por aparición de arritmias (frente a 9 en los trazados convencionales); 11 de los 13 ecocardiogramas resultaron anormales. Las arritmias fueron: bloqueo fascicular anterior izquierdo, extrasístoles y taquicardia supraventriculares y ventriculares, trastornos intraventriculares inespecíficos y otras. Predominaron los trastornos de la conducción a distintos niveles. Hubo congruencia entre ambos estudios en cuanto a la severidad de las arritmias y las alteraciones ecocardiográficas. Las arritmias en estos pacientes son frecuentes, complejas y en ocasiones de mal pronóstico. Mediante Holter se puede determinar su cantidad, calidad y complejidad, detectar las evanescentes, hacer una evaluación pronóstica aproximada y los posibles "candidatos" a muerte súbita