Afirst-of-its-kind clinical study from India has found the specific phenotypic expression and clinical outcome of non-sarcomeric protein—PRKAG2-linked HCM in South Asia. The study, which was aimed at analyzing the inheritance pattern of the genetic mutation linked to hypertrophic cardiomyopathy (HCM), was conducted in a large number of multigenerational affected members from three unrelated families for a period of seven years.
HCM affects the health of the heart muscle. Though the genetic causes of about 40 to 50% of HCM cases are not yet known, it was believed that the mutations responsible for HCM were often localised to genes encoding sarcomeric proteins.
In the new Indian study published in Nature Scientific Reports, scientists from genetics research firm MedGenome, Bangalore, and Amrita Institute of Medical Science and Research, Cochin, reported a rare form of HCM where the mutation is identified in a non-sarcomeric protein PRKAG2 or Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2. The genetic data obtained in the study helped refine the clinical diagnosis providing a template for personalised treatment applying genomics in the clinic. The families in the study were followed longitudinally for over 7 years to understand the natural history and clinical outcomes of the affected individuals, adding to our knowledge of the disease and interventions needed.
HCM is the most common genetic cause of cardiomyopathy worldwide and a genetic origin for this heterogenous group of diseases is found in about 40–60% of patients, usually with an autosomal dominant mode of inheritance. The disease is characterised by a hypertrophied, non-dilated left ventricle — without evidence of any other cardiac or systemic disease — which then leads to heart failure and sudden cardiac death (SCD).
The mutations responsible for HCM are often localized to genes encoding for sarcomeric proteins. There are several other genetic cardiomyopathies which are not caused by cardiac sarcomere mutations and yet they share many of the phenotypic manifestations of HCM, such as evidence of left ventricular hypertrophy on the electrocardiogram and echocardiogram. These HCM phenocopies include lysosomal storage disorders, glycogen storage disorders, mitochondrial cytopathies, fatty acid metabolism disorders and cardiac amyloidosis.
Authors of the new study report say that PRKAG2 cardiomyopathy, an important HCM phenocopy, is a rare autosomal dominant, non-lysosomal glycogen storage disease characterized by ventricular pre-excitation, supra-ventricular arrhythmias and cardiac hypertrophy. The clinical phenotypes of PRKAG2 cardiomyopathies often overlap with HCM due to sarcomere protein mutations and often lead to misdiagnosis.
According to the report, PRKAG2 cardiomyopathy was earlier found to be caused by mutations in the gene encoding ɣ2 regulatory subunit of the 5′ AMP-activated protein kinase (AMPK). AMPK is a highly conserved, ubiquitously expressed serine/threonine-protein kinase responsible for cellular energetic homeostasis control. γ2 regulatory subunit of AMPK (PRKAG2) binds AMP, enhancing the activation of the catalytic α-subunit. PRKAG2 mutations are suspected to modify the three-dimensional structure of AMPK, altering its affinity for AMP and modifying the enzyme activity which alters the myocyte glucidic uptake and metabolism causing the deposition of glycogen. These glycogen-filled myocytes interfere with the normal atrio-ventricular septation and leads to the observed cardiac phenotype.
Overall, about 24 pathogenic PRKAG2 mutations have been identified, showing clear genotype/phenotype correlations in PRKAG2 cardiomyopathies. The actual prevalence of PRKAG2 cardiomyopathies has not been properly investigated and only about 200 cases have been reported worldwide so far. Different studies in the US and Europe on large populations have given different estimates. There are no studies published on PRKAG2 cardiomyopathies from the South Asian region.
But in the new study, the authors have reported the morphological expression and clinical course of a cohort of 22 PRKAG2 cardiomyopathy patients belonging to three unrelated families, identified at the Amrita HCM centre. The quantum of literature on PRKAG2 cardiomyopathy and its outcomes have been limited and hence, this 7.0 ± 1.5 year follow-up data aims to throw light on the distinctive clinical features, natural history and outcomes of this disease.
“Genetic testing for HCM diagnosis and screening for risk can now be used routinely for overall disease management,” says Dr. Sameer Phalke, the study co-author and Senior Scientist at MedGenome, Bangalore, India.
“The unique population structure of India makes studies such as this possible. Familial disease studies in India will create a wealth of knowledge and opportunity to understand many diseases beyond HCM,” Dr Phalke added.
“As far as inherited cardiovascular disease is concerned, it is quite clear that we are now in the era of leveraging the potential of cardiovascular genetic testing for the prompt recognition of potentially life-threatening disease as well as choosing an appropriate management strategy to achieve optimum outcomes in our patients,” said Dr Hisham Ahmed, the lead clinical scientist and senior study co-author.
According to Dr Ahmed, Clinical Associate Professor of Cardiology at Amrita Institute of Medical Sciences and Research, Kochi, the judicious use of genetic testing in this study accurately characterised the specific type of cardiomyopathy in each patient and thus led to the rapid identification of a large number of family members who inherited the same disease.
“This timely recognition led to the systematic risk stratification of the patients and their family members, which allowed them to receive advanced therapy which would protect them from the risk of a potential sudden cardiac death,” Dr Ahmed added.