Irene M. van Langen

Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands.

BACKGROUNDnIn sudden unexplained death (SUD) in the young (age 1-50 years), cardiologic and genetic examination in surviving relatives may unmask the cause of death in a significant proportion. The causes of aborted cardiac arrest (ACA) in this age group likely are similar to those in sudden cardiac death. However, there is a paucity of recent data on this topic.nnnOBJECTIVEnThe purpose of this study was to gain insight into the yield of current diagnostic strategies used in relatives of SUD victims and in ACA victims aged 1-50 years in our dedicated tertiary referral center.nnnMETHODSnWe studied (1) all consecutive families who presented to the cardiology department for examination because of ≥1 first-degree related SUD victim aged 1-50 years and (2) all consecutive ACA victims aged 1-50 years who presented to the cardiology department from 1996 to 2009. Comprehensive cardiologic and genetic examination was performed in both populations.nnnRESULTSnA certain or probable diagnosis was made in 47 (33%) of 140 SUD families, including 45 (96%) cases of inherited cardiac diseases. Long QT syndrome (19%) was the most prevalent diagnosis. In 42 (61%) of 69 ACA victims, the cause of the event was determined (inherited in 31 [74%]). Hypertrophic cardiomyopathy was most prevalent (17%).nnnCONCLUSIONnThe yield of the current diagnostic workup in relatives of young SUD victims is 33% and is almost twice as high in young ACA victims. Inherited cardiac diseases are predominantly causative in both groups.

Incidence, Causes, and Outcomes of Out-of-Hospital Cardiac Arrest in Children: A Comprehensive, Prospective, Population-Based Study in the Netherlands

OBJECTIVESnThis study sought to determine comprehensively the incidence of pediatric out-of-hospital cardiac arrest (OHCA) and its contribution to total pediatric mortality, the causes of pediatric OHCA, and the outcome of resuscitation of pediatric OHCA patients.nnnBACKGROUNDnThere is a paucity of complete studies on incidence, causes, and outcomes of pediatric OHCA.nnnMETHODSnIn this prospective, population-based study, OHCA victims younger than age 21 years in 1 province of the Netherlands were registered through both emergency medical services and coroners over a period of 4.3 years. Death certificate data on total pediatric mortality, survival status, and neurological outcome at hospital discharge also were obtained.nnnRESULTSnWith a total mortality of 923 during the study period and 233 victims of OHCA (including 221 who died and 12 who survived), OHCA caused 24% (221 of 923) of total pediatric mortality. Natural causes of OHCA amounted to 115 (49%) cases, with cardiac causes being most prevalent (n = 90, 39%). The incidence of pediatric OHCA was 9.0 per 100,000 pediatric person-years (95% confidence interval: 7.8 to 10.3), whereas the incidence of pediatric OHCA from cardiac causes was 3.2 (95% confidence interval: 2.5 to 3.9). Of 51 resuscitated patients, 12 (24%) survived; among survivors, 10 (83%) had a neurologically intact outcome.nnnCONCLUSIONSnOut-of-hospital cardiac arrest accounts for a significant proportion of pediatric mortality, and cardiac causes are the most prevalent causes of OHCA. The vast majority of OHCA survivors have a neurologically intact outcome.

Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy : overview of 10 years' experience

With more than 40 dilated cardiomyopathy (DCM)‐related genes known, genetic analysis of patients with idiopathic DCM is costly and time‐consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort.

Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks

BACKGROUNDnMutations in the gene encoding desmin (DES), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients.nnnOBJECTIVEnTo determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate right ventricular involvement in DES mutation carriers, and to establish the role of DES mutations in ARVC(-like) phenotypes.nnnMETHODSnWe evaluated the clinical phenotype in two families carrying two different DES mutations. One family was diagnosed with DRM, with an ARVC(-like) phenotype in one patient, while the other family presented with a severe biventricular cardiomyopathy. Additional immunohistochemistry of desmosomal proteins was performed in myocardial tissue from two patients of the last family. The DES gene was screened for mutations in 50 ARVC(-like) patients.nnnRESULTSnExcept for two different DES mutations (p.N342D and p.R454W) in two families with DRM and severe biventricular cardiomyopathy, respectively, we did not find additional DES mutations in ARVC(-like) patients. In addition to desmin aggregates, immunohistochemistry demonstrated a decreased amount of desmoplakin and plakophilin-2 at the intercalated disk in p.R454W mutation carriers.nnnCONCLUSIONSnWe confirmed that either an ARVC-like phenotype or a severe cardiomyopathy with right ventricular involvement are possible, yet infrequent, cardiac phenotypes in DRM. Moreover, we demonstrated that the DES mutation p.R454W affects the localization of desmoplakin and plakophilin-2 at the intercalated disk, suggesting a link between desmosomal cardiomyopathies (mainly affecting the right ventricle) and cardiomyopathies caused by DES mutations.

Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy

AIMnPeripartum cardiomyopathy (PPCM) can be an initial manifestation of familial dilated cardiomyopathy (DCM). We aimed to identify mutations in families that could underlie their PPCM and DCM.nnnMETHODS AND RESULTSnWe collected 18 families with PPCM and DCM cases from various countries. We studied the clinical characteristics of the PPCM patients and affected relatives, and applied a targeted next-generation sequencing (NGS) approach to detect mutations in 48 genes known to be involved in inherited cardiomyopathies. We identified 4 pathogenic mutations in 4 of 18 families (22%): 3 in TTN and 1 in BAG3. In addition, we identified 6 variants of unknown clinical significance that may be pathogenic in 6 other families (33%): 4 in TTN, 1 in TNNC1, and 1 in MYH7. Measurements of passive force in single cardiomyocytes and titin isoform composition potentially support an upgrade of one of the variants of unknown clinical significance in TTN to a pathogenic mutation. Only 2 of 20 PPCM cases in these families showed the recovery of left ventricular function.nnnCONCLUSIONnTargeted NGS shows that potentially causal mutations in cardiomyopathy-related genes are common in families with both PPCM and DCM. This supports the earlier finding that PPCM can be part of familial DCM. Our cohort is particularly characterized by a high proportion of TTN mutations and a low recovery rate in PPCM cases.

A case of catecholaminergic polymorphic ventricular tachycardia caused by two calsequestrin 2 mutations

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon heritable disease presenting with syncope or sudden cardiac death. Two genes involved in calcium homeostasis, the ryanodine receptor gene and the calsequestrin 2 (CASQ2) gene, have been implicated in this disease. We describe a young man presenting with exercise‐induced syncope, clinically diagnosed as CPVT. Genetic analysis revealed two mutations, p.Y55C (c.164A>G) and p.P308L (c.923C>T), in the CASQ2 gene. Subsequent familial analysis indicates a compound heterozygous form of inheritance.

Genetic testing and common disorders in a public health framework: how to assess relevance and possibilities

Genetic testing and common disorders in a public health framework: how to assess relevance and possibilities

Trial by Dutch laboratories for evaluation of non-invasive prenatal testing. Part II—women's perspectives†

To evaluate preferences and decision‐making among high‐risk pregnant women offered a choice between Non‐Invasive Prenatal Testing (NIPT), invasive testing or no further testing.

Mortality risk of untreated myosin-binding protein C-related hypertrophic cardiomyopathy: insight into the natural history

OBJECTIVESnThe goal of this study was to assess the mortality of hypertrophic cardiomyopathy (HCM), partly in times when the disease was not elucidated and patients were untreated.nnnBACKGROUNDnHCM is feared for the risk of sudden cardiac death (SCD). Insight in the natural history of the disorder is needed to design proper screening strategies for families with HCM.nnnMETHODSnIn 6 large, 200-year multigenerational pedigrees (identified by using genealogical searches) and in 140 small (contemporary) pedigrees (first-degree relatives of the proband) with HCM caused by a truncating mutation in the myosin-binding protein C gene (n = 1,118), we determined all-cause mortality using the family tree mortality ratio method. The studys main outcome measure was the standardized mortality ratio (SMR).nnnRESULTSnIn the large pedigrees, overall mortality was not increased (SMR 0.86 [95% confidence interval (CI): 0.72 to 1.03]), but significant excess mortality occurred between 10 and 19 years (SMR 2.7 [95% CI: 1.2 to 5.2]). In the small families, the SMR was increased (SMR 1.5 [95% CI: 1.3 to 1.6]) [corrected] and excess mortality was observed between 10 and 39 years (SMR 3.2 [95% CI: 2.3 to 4.3]) and 50 and 59 years (SMR 1.9 [95% CI: 1.4 to 2.5]).nnnCONCLUSIONSnWe identified specific age categories with increased mortality risks in HCM families. The small, referred pedigrees had higher mortality risks than the large 200-year multigenerational pedigrees. Our findings support the strategy of starting cardiological and genetic screening in the first-degree relatives of a proband from 10 years onward and including persons in the screening at least until the age of 60 years. Screening of more distant relatives is probably most efficient between 10 and 19 years.

Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young: a population-based approach

AIMSnTo investigate the yield of cardiogenetic screening of relatives of young sudden cardiac death (SCD) and sudden unexplained death (SUD) victims in a population-based setting.nnnMETHODS AND RESULTSnA population-based study was carried out between 2000 and 2006. Records of the hospital, death declaration certificates, and resuscitation records were reviewed for SCD and SUD cases (1-40 years). Information on autopsy results and cardiogenetic screening of the victims first-degree relatives was collected. Relatives were invited for additional cardiogenetic screening when this had not yet been performed. The search led to 16 cases of SCD/SUD and 4 cases of aborted SCD/SUD. Causes of SCD/SUD were myocardial infarction (n = 3), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 2), long-QT syndrome (n = 1), hypertrophic cardiomyopathy (n = 2), left ventricular hypertrophy due to aortic stenosis (n = 1), and unknown cause of death (n = 7). Causes of aborted SCD/SUD were myocardial infarction (n = 2), idiopatic ventricular fibrillation (n = 1), and the Brugada syndrome (n = 1). The cardiogenetic screening of 37 relatives of 12 victims led to a diagnosis of Brugada syndrome in 3 relatives and the suspicion of ARVC in 2 relatives. The yield of screening of these relatives was 14% (95% confidence interval: 3-25%).nnnCONCLUSIONnIn the usual care, relatives of (aborted) SCD and SUD victims are often not referred for cardiogenetic screening. Screening is often not performed according to a systematic approach, and the detection rate of inherited diseases in relatives of (aborted) SCD and SUD victims in a population-based setting, although substantial, is lower than expected based on previous studies.