A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies.

BACKGROUND: Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes - 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities. OBJECTIVES: Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them. METHOD: For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India. RESULTS: Our study revealed a total of 10 variations - 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls. CONCLUSIONS: MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians.

Atherogenesis in Psoriasis: Evaluation of the Serum Activities of Non-high-density Lipoprotein Cholesterol and Other Lipids Among Newly Diagnosed Psoriasis Patients.

Introduction  Psoriasis is a chronic inflammatory skin disorder which commonly affects people aged between 15-25 years with a 2-3 % prevalence rate throughout the world. Psoriasis is a systemic inflammatory disease associated with severe co-morbidities that include cardiovascular risk. Although changes in the atherogenic lipids among psoriasis patients is already documented, very little is known about their role in atherogenesis among the new onset cases of psoriasis. Hence, this study is undertaken to assess the activities of non-high-density lipoprotein cholesterol (non-HDL-C) and other lipids among newly diagnosed psoriasis patients. Methods The study included 25 new onset cases of psoriasis patients aged between 20-60 years (mean age 38.2 years) attending the Dermatology outpatient department (OPD) of the Chalmeda Anandrao Institute of Medical Sciences (CAIMS), Karimnagar, Telangana, India, a tertiary care teaching hospital. An equal number of healthy individuals were included as controls. Blood was collected from all the subjects included in the study and was analyzed for various lipid parameters that included total cholesterol (TC), HDL-C, and triglycerides. The non-HDL-C and low-density lipoprotein cholesterol (LDL-C) were later calculated manually by using the standard formulae. The data were tabulated using Microsoft Excel and was analyzed for their statistical significance using the Student t-test. Results The results demonstrated a statistically significant difference in the lipid parameters between the cases and controls. Among the parameters measured, the pro-atherogenic lipids including the LDL-C and non-HDL-C activities among the cases (LDL-C 171.46±17.13, p=0.0002; non-HDL-C 213.27±20.17, p ≤ 0.0001) and controls (LDL-C 91.04±11.41, p=0.0002; Non-HDL-C 119.0± 12.28, p ≤ 0.0001) were found to be statistically significant. The ratios of non-HDL-C to HDL-C and total cholesterol to HDL-C both among the cases (7.10±0.1, 8.13±1.2) and control groups (3.05±0.30, 4.03±0.42) were also showing a statistically significant difference. Conclusion The results clearly demonstrate the significance of the evaluation of lipids among newly diagnosed cases of psoriasis patients. The activities of different lipoproteins including the non-HDL-C and LDL-C revealed an increase among the psoriasis patients. The ratios of non-HDL-C to HDL-C and TC to HDL-C also showed significant variability. Further, to establish their clinical utility in the development of cardiovascular disease (CVD), and to manage appropriately, a regular follow-up of such parameters both before and after initiation of treatment is required.

Concurrent Presentation of Therapy Related Acute Myeloid Leukemia in a Case of Neuroblastoma.

Therapy related Acute Myeloid Leukemia/Myelodysplastic syndrome (t-AML/MDS) occur due to the direct mutational events of the chemotherapeutic agents and radiotherapy. The disease latency, mutational events and prognosis vary with the type of chemotherapeutic agent. Therapy related Acute Myeloid Leukemia occurring with DNA topoisomerase II inhibitors have a shorter latency period and poor prognosis than anthracyclin based regimens. We report a case of a 9 year old boy who developed t-AML with mixed-lineage-leukemia gene translocation within a year of high dose chemotherapy for stage 4 neuroblastoma. He had residual mass of neuroblastoma in the abdomen and bone marrow. The patient expired within 2 weeks of induction chemotherapy.

Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM.

Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases-patient #1, aged 44, and patient #2, aged 65-and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. Interestingly, two novel thick filaments, D896N (homozygous) and I524K (heterozygous) mutations, in the MYH7 gene were identified exclusively in patient #1 and his family members. Thus, we strongly suggest that the coexistence of these digenic mutations is rare, but leads to severe hypertrophy in a South Indian familial hypertrophic cardiomyopathy (FHCM).