Autosomal Dominant Hypertrophic Cardiomyopathy Research Articles

Difficulties in Diagnosing Fabry Disease in Patients with Unexplained Left Ventricular Hypertrophy (LVH): Is the Novel GLA Gene Mutation a Pathogenic Mutation or Polymorphism?

Fabry disease (FD) is an X-linked, lysosomal glycosphingolipid storage disorder that occurs very rarely. Cardiac involvement may comprise of left ventricular hypertrophy (LVH), arrhythmias, conduction abnormalities, heart failure and valvular abnormalities. The goal of this study was to conduct gene analysis for FD in patients suffering from unexplained LVH. 120 patients over the age of 30 who were diagnosed by echocardiography with idiopathic LVH were included in the study. Patients with severe hypertension, intermediate valve disease such as moderate aortic stenosis, known FD, and a family history of autosomal dominant hypertrophic cardiomyopathy were excluded from the study. GLA gene mutations were studied by Sanger sequence analysis in all patients. Of the 120 total patients included in this study, 69 were female (58%) and 51 were male (42%). The mean age was 60.3 ± 15.7. GLA gene mutations were detected in three male patients. The detected mutations are as follows: NM_000169.2:IVS6-10G>A (c.1000-10G>A), NM_000169.2:c.937G>T (p.D313Y) (p.Asp313Tyr) and NM_000169.2:c.941A>T (p.K314M) (p.Lys314Met). Early diagnosis is of vital importance in FD, which can be treated with enzyme replacement. Genetic screening in patients diagnosed with idiopathic LVH by echocardiography is important in the early diagnosis and treatment of FD. Patients over 30 years of age with idiopathic LVH should be screened for FD. Various new polymorphisms can be detected in genetic screening. Identifying new polymorphisms is important for knowing the true mutations in FD.

The Involvement of ALPK3 in Hypertrophic Cardiomyopathy in East Asia.

ObjectiveALPK3 is associated with a recessive form of pediatric cardiomyopathy accompanied by musculoskeletal and craniofacial abnormalities. Heterozygous truncating variants in this gene (ALPK3tv) have recently been confirmed as a cause of autosomal dominant hypertrophic cardiomyopathy (HCM). Whether ALPK3 is also implicated in HCM in East Asia and the effect of missense variants in ALPK3 on HCM remains unresolved.MethodsWe compared the frequency of rare deleterious variants in ALPK3 in a study cohort comprised of 793 HCM cases of East Asian descent to that in the controls subset of Genome Aggregation Database (gnomAD). Gene burden test was used to assess this association. The involvement of these variants in HCM was further validated by independent cohort. The clinical characteristics and prognoses of these carriers were compared with sarcomere-positive and negative patients.ResultsRare deleterious variants in ALPK3 were significantly enriched in HCM compared with gnomAD controls (truncating: 4/793 vs. 4/4523, P = 0.02; missense: 25/793 vs. 46/4523, P = 2.56e-5). Replication in an independent cohort provided more supporting evidence. Further comparisons revealed that ALPK3 carriers displayed more severe hypertrophy in interventricular septum (IVS) and apex, as well as greater maximal left ventricular wall thickness, relative to sarcomere negatives.ConclusionHeterozygous rare variants in ALPK3, both missense and truncating variants, are associated with HCM in East Asians.

Covid-19 Associated Lymphocytic Myocarditis With Genetic Predisposition

IntroductionThere is a possible association between lymphocytic myocarditis and COVID-19 in patients genetically susceptible to cardiomyopathy.CaseA 50-year-old female with history of hypertension and a family history of sudden cardiac death in two siblings and COVID-19 related myocarditis in a brother presented with persistent shortness of breath at rest, orthopnea, exertional stabbing-type chest pain, and fatigue two weeks after diagnosis of COVID-19. Physical exam was notable for tachycardia, with no fever or signs of volume overload. Patient was found to have elevated troponin and erythrocyte sedimentation rate, with normal brain natriuretic peptide and c-reactive protein. Electrocardiogram showed sinus tachycardia. Computer tomography angiography of the chest was negative for pulmonary embolism, pneumonia, or interstitial lung disease. Echocardiogram revealed lateral wall hypokinesis with ejection fraction 50% and normal ventricular cavity size. Coronary angiogram revealed normal coronaries. Cardiac magnetic resonance revealed anterolateral wall hypokinesis and left ventricular ejection fraction 45% with no scar or edema and no evidence of myocardial or pericardial disease.The patient received treatment with NSAIDs, furosemide, carvedilol, and colchicine. Symptoms persisted over the next several months. Magnetic resonance FDG-PET revealed increased uptake in the lateral wall of the left ventricle. Subsequent biopsy of this region revealed lymphocytic myocarditis. The patient was started on prednisone 60 mg, with partial improvement of symptoms. Symptomatic treatment also required acetaminophen and aspirin, with continued use of colchicine. Genetic studies revealed a likely pathogenic variant in the MYBPC3 gene involving an altered consensus splice site associated with autosomal dominant hypertrophic cardiomyopathy and dilated cardiomyopathy. Symptoms recurred upon tapering of prednisone, requiring a longer course of treatment. The patient also developed symptoms of postural orthostatic tachycardia syndrome. With continued treatment, symptoms significantly improved.ConclusionOur case suggests that lymphocytic myocarditis could be a rare manifestation of coronavirus disease whose risk factors may include hereditary cardiomyopathies. It has potential to become a chronic condition with a challenging symptomatic management.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AimsThe aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.Methods and results In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.Conclusions Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

P.2.17 Hypertrophic cardiomyopathy in a patient with Duchenne muscular dystrophy

Dilated cardiomyopathy is observed in Duchenne muscular dystrophy (DMD). We report the case of a 28 year old DMD patient who exhibited a hypertrophic phenotype and preservation of cardiac function. On cardiac magnetic resonance imaging (CMR), the patient demonstrated severe asymmetric septal hypertrophy, raising the possibility of an underlying genetic cause distinct from DMD. Left ventricular systolic function was preserved with a normal ejection fraction. Additional CMR late gadolinium enhancement (LGE) imaging for myocardial fibrosis demonstrated an unusual LGE pattern. The sub-epicardial LGE in the left ventricular free wall was typical of those found in DMD patients. However, LGE was also present at the right and left ventricular insertion points typical of patients with hypertrophic cardiomyopathy. The patient has a commonly found DMD mutation, duplication in exons 3–4 of the dystrophin gene, predictive of the characteristic DMD dilated cardiomyopathy. Further genetic testing for genes known to cause hypertrophic cardiomyopathy identified two mutations: a heterozygous Glu542Gln mutation in the MYBPC3 gene and a heterozygous Glu195Lys mutation in the TNNT2 gene. Both mutations have been reported as disease causing in individuals with autosomal dominant hypertrophic cardiomyopathy. This case illustrates the co-occurrence of two relatively common genetic conditions: DMD and HCM. We postulate that these confounding gene mutations led to cardiac muscle hypertrophy, preventing the expected development of the typical dilated cardiomyopathy. The downstream pathways by which the cardiac hypertrophy and myocyte disarray resulting from MYBPC3 and TNNT2 mutations might abrogate cardiac dysfunction caused by dystrophinopathy are unknown but have important clinical implications. They may reveal a potential gene-based therapeutic strategy whereby insertion of a pro-hypertrophic gene variant may ameliorate or prevent dilated cardiomyopathy in DMD patient.

Prevalence of the MYBPC3-A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed

Objectives The MYBPC3-A31P mutation has been identified in the USA in a colony of Maine Coon cats with an autosomal dominant hypertrophic cardiomyopathy (HCM). The objectives of this prospective study were: 1) to evaluate the prevalence of this mutation in a large feline population from Europe; 2) to compare these data with the prevalence of HCM in the Maine Coon breed. Animals and methods 1) 3757 cats from different breeds including 2744 Maine Coon cats were screened for the mutation. 2) 164/2744 Maine Coon cats were subjected to echocardiography (Echo-Group, mean age = 2.6 years [0.3–11.5]). Results 1) In the whole study population, the mutation was only found in Maine Coon cats (prevalence = 41.5%), except for one British Longhair cat. 2) 55/164 (34%) cats from the Echo-Group carried the mutation while only 12/164 (7%; 5/48 heterozygous, 5/7 homozygous mutated, 2/109 homozygous wild-type cats) showed HCM. MYBPC3-A31P was associated with a significant increased risk of HCM (relative risk = 9.91). Conclusion The MYBPC3-A31P mutation is highly prevalent in Maine Coon cats in Europe and appears to be breed specific with potential marginal events. Young unaffected mutated cats and affected homozygous wild-type cats illustrate the phenotypic and etiological heterogeneity of feline HCM, as demonstrated in humans.

Abstract 1427: Pathogenesis of Hypertrophic Cardiomyopathy Caused by the Myozenin 2 Mutations Involves Calcineurin-Dependent and -Independent Mechanisms

Identification of myozenin-2 mutations (MYOZ2) has expanded the spectrum of causal mutations for hypertrophic cardiomyopathy (HCM) to include the Z disk proteins. The molecular mechanism(s) by which MYOZ2 mutations cause HCM are unknown. MYOZ2 is known to inhibit calcineurin phosphatase (PP2B). We posit mutant MYOZ2 lose their inhibitory effects on PP2B and hence, the ensuing cardiac phenotype results from enhanced activity of PP2B. To test this hypothesis, we generated lines of transgenic mice expressing either N-terminally flag-tagged wild type (MYOZ2-WT) or mutant MYOZ2-P48 or MYOZ2-M246 regulated by the α-myosin heavy chain promoter. Expression levels of the transgenic and endogenous MYOZ2 proteins were detected by immunoblotting using pan-specific anti-MYOZ2 and anti-Flag antibodies. The transgene proteins constituted 15 to 35% of the total MYOZ2 protein. The total MYOZ2 levels remained unchanged. Immunofluorescence staining showed both WT and mutant MYOZ2 proteins were incorporated into the Z disks. To determine the effects of the WT and mutant MYOZ2 proteins on PP2B activity, we measured PP2B phosphatase and Nuclear Factor of Activated T Cells (NFATc), a downstream target of PP2B, activities in myocardial protein extracts by ELISA-based assays. Expression of MYOZ2-WT reduced PP2B phosphatase and NFAT activities by ~90% and 20%, respectively while equal levels of expression of the mutant MYOZ2 reduced these activities by ~ 50% and 10%, respectively, i.e., a 2-fold reduction in inhibitory effect of the mutant as compared to WT. The mutant MYOZ2-P48 and MYOZ2-M246 showed increased mortality, cardiac hypertrophy, preserved cardiac systolic function, increased myocytes size and interstitial fibrosis. The MYOZ2-WT mice also exhibited cardiac hypertrophy and interstitial fibrosis. Thus, the mutation impart a loss of function effect on MYOZ2, suggesting a possible gain of function of PP2B in humans with with autosomal dominant HCM. However, excess inhibition of PP2B in the heart, as observed in the MYOZ2-WT mice, also led to cardiac hypertrophy and fibrosis. Thus both excess inhibition as well as relative enhancement of PP2B activity in the heart could cause cardiac hypertrophy and fibrosis.

M.I.1 New frontiers in glycogen storage diseases

Although the GSD have been investigated extensively over the years, this is far from a closed chapter. What follows is a brief account of recent developments. AMP-activated protein kinase (AMPK) is a crucial “cellular fuel gauge”, which is switched on by increases in the AMP/ATP ratio. AMPK is an αβγ heterotrimer, where α is the catalytic subunit and β and γ are regulatory subunits. Mutations in the gene encoding the γ2 subunit of AMPK (PRKAG2) have been found not only in adult patients with autosomal dominant hypertrophic cardiomyopathy and Wolff–Parkinson–White syndrome, but also in a few infants with de novo mutations in PRKAG2 and massive cardiac glycogenosis initially attributed to a defect of phosphorylase b kinase (PHK).

Novel Locus for an Inherited Cardiomyopathy Maps to Chromosome 7

Genetic mutations are the most common cause of hypertrophic cardiomyopathy (HCM) and an increasingly recognized cause of dilated cardiomyopathy. Autosomal dominant HCM is caused by mutations in sarcomere proteins; such mutations are not universally present, however, and fail to account for &40% of cases of phenotypic HCM. To add further complexity, other genetic origins can mimic the gross clinical phenotype of HCM, and mutations in sarcomere genes have been demonstrated to cause dilated cardiomyopathy. To explore novel genetic causes of inherited cardiomyopathies, genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death. Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM. Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified. Linkage was then established to a novel locus on chromosome 7 (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was obtained. Recombination events refine the disease interval between D7S506 and D7S3314, corresponding to a distance of 27.2 megabases. The discovery of a novel genetic locus in this family provides more evidence that molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere. Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling.

Fatal Congenital Heart Glycogenosis Caused by a Recurrent Activating R531Q Mutation in the γ2-Subunit of AMP-Activated Protein Kinase ( PRKAG2), Not by Phosphorylase Kinase Deficiency

Fatal congenital nonlysosomal cardiac glycogenosis has been attributed to a subtype of phosphorylase kinase deficiency, but the underlying genes and mutations have not been identified. Analyzing four sporadic, unrelated patients, we found no mutations either in the eight genes encoding phosphorylase kinase subunits or in the two genes encoding the muscle and brain isoforms of glycogen phosphorylase. However, in three of five patients, we identified identical heterozygous R531Q missense mutations of the PRKAG2 gene, which encodes the gamma 2-subunit of AMP-activated protein kinase, a key regulator of energy balance. Biochemical characterization of the recombinant R531Q mutant protein showed >100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity and increased phosphorylation of the alpha -subunit. Other PRKAG2 missense mutations were previously identified in patients with autosomal dominant hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome, characterized by juvenile-to-adult clinical onset, moderate cardiac glycogenosis, disturbed excitation conduction, risk of sudden cardiac death in midlife, and molecular perturbations that are similar to--but less severe than--those observed for the R531Q mutation. Thus, recurrent heterozygous R531Q missense mutations in PRKAG2 give rise to a massive nonlysosomal cardiac glycogenosis of fetal symptomatic onset and rapidly fatal course, constituting a genotypically and clinically distinct variant of hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome. R531Q and other PRKAG2 mutations enhance the basal activity and alpha -subunit phosphorylation of AMP-activated protein kinase, explaining the dominant nature of PRKAG2 disease mutations. Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal cardiac glycogenosis seems to be genetically heterogeneous. However, the existence of a heart-specific primary phosphorylase kinase deficiency is questionable, because no phosphorylase kinase mutations were found.

Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology.

Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism. Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.

Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy

Recent advances suggest that mutations in nuclear DNA are involved in the etiology of autosomal dominant hypertrophic cardiomyopathy. Mitochondria have their own DNA, and mutations in mitochondrial DNA have been shown to contribute to the genesis of various diseases. In this study, we developed rapid sequencing methods with the use of a fluorescence-based sequencing system and analyzed total mitochondrial DNA of seven patients with nonautosomal dominant hypertrophic cardiomyopathy. Multiple point mutations were observed in all patients with hypertrophic cardiomyopathy, although some of them were common among the subjects examined and the others are unique to each subject. Point mutations in transfer RNA genes were observed in five of the seven patients, and point mutations that replaced conserved amino acids were also observed. These mutations may result in the impairment of mitochondrial function. According to these results, mutations in mitochondrial DNA may contribute to the genesis of some cases of nonautosomal dominant hypertrophic cardiomyopathy, and our methods may be useful for the detection of point mutations in mitochondrial DNA.