Homozygous plakophilin-2 (
) variants have been identified as a cause of a lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET) in three cases. We report three more cases from ...two families with homozygous pathogenic
variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function
variants cause a lethal, perinatal-onset cardiomyopathy.
Hypertrophic cardiomyopathy in children Moak, Jeffrey P; Kaski, Juan Pablo
Heart (British Cardiac Society),
07/2012, Letnik:
98, Številka:
14
Journal Article
Recenzirano
Hypertrophic cardiomyopathy (HCM) is the second commonest form of heart muscle disease affecting children and adolescents and is a leading cause of sudden death in young athletes. The aetiology of ...HCM is heterogeneous in the paediatric population, and includes inborn errors of metabolism, neuromuscular disorders and malformation syndromes. However, most cases of apparently idiopathic HCM in childhood are caused by mutations in cardiac sarcomere protein genes. Patients with metabolic or syndromic HCM usually present in infancy or early childhood, whereas those with neuromuscular disorders are more frequently diagnosed in adolescence. The diagnosis of HCM in infants is often made during evaluation for a heart murmur or congestive heart failure. Older children are usually referred for evaluation of symptoms, electrocardiographic abnormalities or heart murmur, or for family screening following the diagnosis of HCM in a relative. Risk stratification in the paediatric population remains a challenge. As most cases of HCM are familial, evaluation of first-degree relatives and other family members at risk of inheriting the disease should be a routine component of clinical management.
PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural ...history of the disease is poorly understood.
The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.
Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range IQR: 15 to 50 years) recruited from 27 centers were retrospectively studied.
At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.
PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
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Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal ...gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.
Patients with hypertrophic cardiomyopathy (HCM) exhibit a variable phenotype with ventricular hypertrophy as the cardinal manifestation and left ventricular (LV) outflow tract obstruction (LVOTO) as ...a key pathophysiologic determinant. Patients with severe LVOTO usually present with exertional dyspnea, exertional syncope, and heart failure symptoms, while successful relief of LVOTO by pharmacological or invasive interventions leads to a dramatic improvement in clinical status. Proper management of obstructive HCM remains challenging and poses numerous clinical dilemmas. Since the development of surgical myectomy over half a century ago, progress in the management of LVOTO in HCM has paralleled technological advances in genetic testing, cardiac imaging, arrhythmic prophylaxis, cardiac surgery and interventional cardiology. These changes have been incorporated in dedicated scientific guidelines on both sides of the Atlantic. However, either the 2011 American guidelines or the 2014 European guidelines remain largely based on expert consensus for lack of recommendations with level of evidence A regarding any of the treatment options commonly employed in HCM. Consequently, management of obstructive HCM patients remains largely subjective and dependent on clinical judgment, local expertise, and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, adequate evaluation and management of obstruction in HCM today requires a multidisciplinary team capable of optimizing referral, choosing the best available options, minimizing complications and ensuring state-of-the-art results. The concept of an HCM Heart Team is coming of age. This review aims to provide an update of available pharmacologic and invasive options for the management of LVOTO in HCM, either in adulthood or in childhood, highlighting areas for multidisciplinary integration and future development.
•LV outflow tract gradient is a key pathophysiologic determinant of HCM.•Treatment of obstructive HCM is challenging and poses numerous clinical dilemmas.•HCM is transitioning into an exciting phase of a pharmacologic discovery.•Extensive knowledge of HCM is needed to perform septal reduction treatments.•Management of obstruction in HCM today requires a multidisciplinary heart team.
The heart in RASopathies Delogu, Angelica Bibiana; Limongelli, Giuseppe; Versacci, Paolo ...
American journal of medical genetics. Part C, Seminars in medical genetics,
December 2022, 2022-12-00, 20221201, Letnik:
190, Številka:
4
Journal Article
The cardiovascular phenotype associated with RASopathies has expanded far beyond the original descriptions of pulmonary valve stenosis by Dr Jaqueline Noonan in 1968 and hypertrophic cardiomyopathy ...by Hirsch et al. in 1975. Because of the common underlying RAS/MAPK pathway dysregulation, RASopathy syndromes usually present with a typical spectrum of overlapping cardiovascular anomalies, although less common cardiac defects can occur. The identification of the causative genetic variants has enabled the recognition of specific correlations between genotype and cardiac phenotype. Characterization and understanding of genotype–phenotype associations is not only important for counseling a family of an infant with a new diagnosis of a RASopathy condition but is also critical for their clinical prognosis with respect to cardiac disease, neurodevelopment and other organ system involvement over the lifetime of the patient. This review will focus on the cardiac manifestations of the most common RASopathy syndromes, the relationship between cardiac defects and causal genetic variation, the contribution of cardiovascular abnormalities to morbidity and mortality and the most relevant follow‐up issues for patients affected by RAS/MAPK pathway diseases, with respect to cardiac clinical outcomes and management, in children and in the adult population.
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality in children. While the aetiology is heterogeneous, most cases are caused by variants in the genes encoding ...components of the cardiac sarcomere, which are inherited as an autosomal dominant trait. In recent years, there has been a paradigm shift in the role of clinical screening and predictive genetic testing in children with a first-degree relative with HCM, with the recognition that phenotypic expression can, and often does, manifest in young children and that familial disease in the paediatric age group may not be benign. The care of the child and family affected by HCM relies on a multidisciplinary team, with a key role for genomics. This review article summarises current evidence in clinical and genetic screening for hypertrophic cardiomyopathy in paediatric relatives and highlights aspects that remain to be resolved.
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