Desmoplakin cardiomyopathy-an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury.

We present two female patients with recurrent episodes of myocardial injury, consisting of acute chest pain and elevated cardiac markers without coronary artery disease. Cardiovascular magnetic resonance imaging identified extensive late gadolinium enhancement suggestive of an inherited cardiomyopathy. Genetic testing showed heterozygous pathogenic variants in the desmoplakin (DSP) gene, the gene coding for the desmoplakin protein, a structural protein found in the cardiac desmosome. Pathogenic variants in the DSP gene are associated with dilated and arrhythmogenic cardiomyopathy. DSP cardiomyopathies may cause recurring myocardial injury mimicking an acute coronary syndrome or myocarditis. Cardiac magnetic resonance imaging is key in its diagnosis due to its specifying imaging features. Genetic testing is essential for the evaluation and confirmation of the diagnosis.

Five-year prognostic significance of global longitudinal strain in individuals with a hypertrophic cardiomyopathy gene mutation without hypertrophic changes.

BACKGROUND: Previous studies have reported that global longitudinal strain (GLS) is reduced in patients with hypertrophic cardiomyopathy (HCM) while left ventricular ejection fraction (LVEF) is normal. Our aim was to assess GLS in individuals with HCM mutations without hypertrophic changes and to determine its prognostic value for the development of HCM. METHODS AND RESULTS: This retrospective case-control and cohort study included 120 HCM mutation carriers and 110 controls. GLS and LVEF were assessed with Tomtec Imaging software. Age, gender, and body surface area were similar in mutation carriers and controls. Compared to controls, mutation carriers had a higher maximal wall thickness (9 ± 2 vs 8 ± 2 mm, p < 0.001), higher LVEF (60 ± 5 vs 58 ± 4%, p < 0.001) and higher GLS (-21.4 ± 2.3% vs -20.3 ± 2.2%, p < 0.001). The GLS difference was observed in the mid-left ventricle (-21.5 ± 2.5% vs -19.9 ± 2.5%, p < 0.001) and the apex (-24.1 ± 3.5% vs -22.1 ± 3.4%, p < 0.001), but not in the base of the left ventricle (-20.0 ± 3.3% vs -20.0 ± 2.6%, p = 0.9). Echocardiographic follow-up was performed in 80 mutation carriers. During 5.6 ± 2.9 years' follow-up, 13 (16%) mutation carriers developed HCM. Cox regression analysis showed age (hazard ratio (HR) 1.08, p = 0.01), pathological Q wave (HR 8.56; p = 0.01), and maximal wall thickness (HR 1.94; p = 0.01) to be independent predictors of the development of HCM. GLS was not predictive of the development of HCM (HR 0.78, p = 0.07). CONCLUSION: GLS is increased in HCM mutation carriers without hypertrophic changes. GLS was of no clear prognostic value for the development of HCM during follow-up, in contrast to age, pathological Q waves and maximal wall thickness.

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects.

BACKGROUND: Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects. METHODS: In this study, we describe a mutation in the MYH7 gene, c. 5754C > G; p. (Asn1918Lys), present in 15 probands and 65 family members. RESULTS: Of the 80 carriers (age range 0-88 years), 46 (57.5%) had cardiomyopathy (mainly dilated cardiomyopathy (DCM)) and seven (8.8%) had a congenital heart defect. Childhood onset of cardiomyopathy was present in almost 10% of carriers. However, in only a slight majority (53.7%) was the left ventricular ejection fraction reduced and almost no arrhythmias or conduction disorders were noted. Moreover, only one carrier required heart transplantation and nine (11.3%) an implantable cardioverter defibrillator. In addition, the standardised mortality ratio for MYH7 carriers was not significantly increased. Whole exome sequencing in several cases with paediatric onset of DCM and one with isolated congenital heart defects did not reveal additional known disease-causing variants. Haplotype analysis suggests that the MYH7 variant is a founder mutation, and is therefore the first Dutch founder mutation identified in the MYH7 gene. The mutation appears to have originated in the western region of the province of South Holland between 500 and 900 years ago. CONCLUSION: Clinically, the p. (Asn1918Lys) mutation is associated with congenital heart defects and/or cardiomyopathy at young age but with a relatively benign course.

Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin.

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Mutations to either the TSC1 or TSC2 gene are responsible for the disease. The TSC1 gene encodes hamartin, a 130-kDa protein without significant homology to other known mammalian proteins. Analysis of the amino acid sequence of tuberin, the 200-kDa product of the TSC2 gene, identified a region with limited homology to GTPase-activating proteins. Previously, we demonstrated direct binding between tuberin and hamartin. Here we investigate this interaction in more detail. We show that the complex is predominantly cytosolic and may contain additional, as yet uncharacterized components alongside tuberin and hamartin. Furthermore, because oligomerization of the hamartin carboxyl-terminal coiled coil domain was inhibited by the presence of tuberin, we propose that tuberin acts as a chaperone, preventing hamartin self-aggregation.

A gene from the Xp22.3 region shares homology with voltage-gated chloride channels.

In the framework of constructing a comprehensive transcript map of the human Xp22.3 region, we identified an evolutionary conserved CpG island and cloned the corresponding gene. The predicted 760 amino acid protein encoded by this gene contains 12 hydrophobic domains and shares significant sequence and structural similarities with all the previously isolated members of a recently identified family of voltage-gated chloride channels (the 'CIC family'). This gene, termed CICN4 (Chloride Channel 4), contains at least 10 exons spanning 60 to 80 kb on the X chromosome. In contrast to most genes isolated from the human Xp22.3 region, the CICN4 gene does not share homology with the Y chromosome and it is conserved in mouse and hamster. Expression studies revealed the presence of a 7.5 kb transcript which is particularly abundant in skeletal muscle and is also detectable in brain and heart. These data suggest that we have identified a new voltage-gated chloride channel which is encoded by a gene located in the distal short arm of the X chromosome.