Association Between Epilepsy and Leigh Syndrome With MT-ND3 Mutation, Particularly the m.10191T>C Point Mutation

Background and Purpose: Recent advances in molecular genetic testing have led to a rapid increase in the understanding of the genetics of Leigh syndrome. Several studies have suggested that Leigh syndrome with MT-ND3 mutation is strongly associated with epilepsy. This study focused on the epilepsy-related characteristics of Leigh syndrome with MT-ND3 mutation identified in a single tertiary hospital in South Korea.Methods: We selected 31 patients with mitochondrial DNA (mtDNA) mutations who were genetically diagnosed with mtDNA-associated Leigh syndrome. Among them, seven patients with MT-ND3 mutations were detected. We reviewed various clinical findings such as laboratory findings, brain images, electroencephalography data, seizure types, seizure frequency, antiepileptic drug use history, and current seizure status.Results: The nucleotide changes in the seven patients with the Leigh syndrome with MT-ND3 mutation were divided into two groups: m.10191T>C and m.10158T>C. Six of the seven patients were found to have the m.10191T>C mutations. The median value of the mutant load was 82.5%, ranging from 57.9 to 93.6%. No particular tendency was observed for the first symptom or seizure onset or mutant load. The six patients with the m.10191T>C mutation were diagnosed with epilepsy. Three of these patients were diagnosed with Lennox–Gastaut syndrome (LGS).Conclusion: We reported a very strong association between epilepsy and MT-ND3 mutation in Leigh syndrome, particularly the m.10191T>C mutation. The possibility of an association between the epilepsy phenotype of the m.10191T>C mutation and LGS was noted.

Pediatric cystic nephroma: clinical and molecular genetic characteristics

Cystic nephroma (CN) is a rare renal tumor occurring in children which belongs to a group of neoplasms linked with the inherited DICER1 syndrome. Given the rarity of CNs, it is important to describe clinical, radiological, and molecular genetic characteristics of these tumors in children and adolescents as well as to analyze treatment outcomes. We present our experience in managing 8 patients with histologically verified CN who received treatment and consultations at the D. Rogachev NMRCPHOI over a period of 9 years (2012–2020). The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. The patients’ parents gave their consent to the use of their child’s data, including photographs, for research purposes and in publications. We performed a retrospective analysis of clinical presentation, radiological findings, the extent of treatment given to patients, treatment outcomes, and the results of molecular genetic testing. The study included patients aged between 8.6 and 197 months at diagnosis (the median age was 14.2 months). The analysis of initial complaints revealed that six patients (75%) had an increased abdominal girth and a palpable mass in the abdomen, one patient (12.5%) presented with arterial hypertension, and another patient (12.5%) had a mass detected by a routine abdominal ultrasound examination. On contrast-enhanced computed tomography scans, CNs appeared as multicystic masses with thin, contrast-enhancing septa; the CN volume ranged from 59.7 to 1293.1 cm3 (the median volume was 626.3 cm3 ). In all cases, the diagnosis of CN was verified histologically. Surgical treatment included nephrectomy (n = 6) or partial resection of the affected kidney (n = 2) with the removal of the tumor. Some patients (n = 5) included in our analysis received pre-operative chemotherapy at the discretion of their treating physicians. Molecular genetic testing was carried out for 7 children: 4 out of 7 patients (57.1%) were found to have somatic and germline mutations in the DICER1 gene. Carriers of pathogenic DICER1 variant were identified in the family of 1 patient. The median duration of follow-up was 17.6 months (range: 1.7 to 58.9 months). Currently, all patients are alive, no relapses have occurred. Cystic renal neoplasms detected by radiological investigations should be reviewed at the reference centers for pediatric oncological diseases and included CN in the differential diagnosis. Initial surgery is the first line of treatment for cystic nephroma. The final diagnosis is made on the basis of a histological examination of tumor tissue. All patients with confirmed CN should be referred for genetic counseling and molecular genetic testing for germline mutations in the DICER1 gene and should receive surveillance recommendations for the early detection of other metachronous DICER1-associated tumors.

Variant of the FLNC gene nucleotide sequence in a family with different phenotypic manifestations of left ventricular non-compaction

Left ventricular non-compaction is a heterogeneous heart disease with various phenotypic and clinical manifestations. The article presents the results of clinical, instrumental and molecular genetic investigations of a family with diagnosed left ventricular non-compaction (LVNC) with different clinical and phenotypic manifestations. As a result of a molecular genetic testing, all family members with the LVNC phenotype were found to have a likely pathogenic variant in the FLNC gene. Variants in this gene are associated with a number of cardiomyopathies: dilated, hypertrophic, and restrictive. In the international scientific literature, isolated clinical cases of LVNC development with variants of the FLNC gene nucleotide sequence are presented. In our work, we present a case report of LVNC with a variety of clinical manifestations within the same family.

Clinical Utility of the Addition of Molecular Genetic Testing to Newborn Screening for Sickle Cell Anemia

Sickle cell disease (SCD) is a group of related yet genetically complex hemoglobinopathies. Universal newborn screening (NBS) for SCD is performed in the United States and many other nations. Classical, protein-based laboratory methods are often adequate for the diagnosis of SCD but have specific limitations in the context of NBS. A particular challenge is the differentiation of sickle cell anemia (SCA) from the benign condition, compound heterozygosity for HbS and gene-deletion hereditary persistence of fetal hemoglobin (HbS/HPFH). We describe a sequential cohort of 44 newborns identified over 4.5 years who had molecular genetic testing incorporated into NBS for presumed SCA (an “FS” pattern). The final diagnosis was something other than SCA in six newborns (12%). Three (7%) had HbS/HPFH. All had a final, correct diagnosis at the time of their first scheduled clinic visit in our center (median 8 weeks of age). None received initial counseling for an incorrect diagnosis. In summary, genetic testing as a component of NBS for SCD is necessary to provide correct genetic counseling and education for all newborns' families at their first visit to a sickle cell center. Genetic testing also permits the use of early, pre-symptomatic hydroxyurea therapy by preventing infants with HbS/HPFH from receiving unnecessary therapy. We argue that genetic testing should be incorporated into contemporary NBS for SCD.

Real-World Patterns of Molecular Genetic Testing Among Patients with Acute Myeloid Leukemia in US Community Oncology Settings

Introduction: Molecular genetic testing is essential to inform disease diagnosis, prognosis, and treatment selection for patients with acute myeloid leukemia (AML). The standard treatment is induction chemotherapy followed by post-remission consolidation therapy including chemotherapy and allogeneic hematopoietic stem cell transplantation. Since May 2017, targeted therapies such as midostaurin, ivosidenib, enasidenib, and gemtuzumab ozogamicin were introduced for the treatment of AML. The use of targeted therapies is driven in part by the results of molecular genetic testing. The aim of this study was to determine molecular genetic testing utilization among patients with AML before and after the introduction of targeted therapies in May 2017 within community oncology clinics. Methods: A retrospective observational cohort study was conducted using de-identified data from The US Oncology Network iKnowMed electronic health record database and chart review. The iKnowMed is an oncology-specific system that captures outpatient practice encounter history for patients under care, including (but not limited to) laboratory tests, diagnosis, therapy administration, line of therapy, staging, and performance status information. These structured data were supplemented by targeted chart review to capture unstructured data. All patients aged 18 years or older with newly diagnosed or relapsed/refractory AML who received treatment in The US Oncology Network from January 2014 through February 2019 were included in the study cohort. Patients enrolled in clinical trials were excluded. Patients were classified into two groups: those who received treatment prior to May 2017 and those who received it after May 2017. Molecular genetic testing included IDH1, IDH2, FLT3-ITD, FLT3-TDK and CD33 genes. We assessed the proportion of newly diagnosed or relapsed/refractory AML patients who received molecular genetic testing in the inpatient setting, outpatient setting and prior to treatment initiation before and after May 2017. Results: The study population consisted of 434 patients diagnosed with AML, of whom 313 had newly diagnosed and 121 had relapsed/refractory AML. The median age of the study cohort was 73 (interquartile range: 63.0, 79.0) years. Most of the study cohort were male (57.6%, n=250) and Caucasian (77.0%, n=334). Approximately 75% (235/313) of newly diagnosed patients (75.1%; 235/313) and 81.0% (98/121) of patients with relapsed/refractory AML had molecular genetic testing. The proportion of patients who had molecular genetic testing before and after May 2017 were similar for newly diagnosed AML patients (72.2% vs. 78.1%; p=0.2260) and relapsed/refractory AML patients (80.0% vs. 83.9%; p=0.6357). The proportion of newly diagnosed AML patients who received molecular genetic testing in the inpatient setting (18.5% vs. 23.8%; p=0.3403) and outpatient setting (49.4% vs. 51.0%; p=0.4223) did not change before and after May 2017. Likewise, among patients with relapsed/refractory AML, the proportion of molecular genetic testing in the inpatient setting (31.1% vs. 35.5%; p=0.8523) and outpatient setting (44.4% vs. 51.6%; p=0.7749) were similar before and after May 2017. In addition, the proportion of newly diagnosed AML patients (55.6% vs. 62.9%; p=0.3835) and relapsed/refractory AML patients (45.6% vs. 61.3%; p=0.3063) who received molecular genetic testing prior to AML treatment initiation did not change before and after May 2017. Time from test order date to test result availability was not significantly different before [mean (SD) =9.3 days (16.8)] and after May 2017 [mean (SD)=9.0 days (9.9)]. Conclusion: Introduction of targeted therapies for AML did not increase molecular genetic testing rates nor improve the turnaround time for test result availability in newly diagnosed and relapsed refractory AML patients by February 2019. Two out of 5 patients did not have molecular genetic testing performed prior to initiation of AML therapy after May 2017 when targeted therapies became available. Patients age, comorbidities and drug access issues may have contributed to under-utilization of molecular genetic testing. Further research is needed to identify barriers to molecular genetic testing in patients with AML. Disclosures Sura: McKesson Life Sciences: Current Employment. Annavarapu: McKesson Life Sciences: Current Employment. Kwong: Daiichi Sankyo, Inc: Current Employment. Fliss: Daiichi Sankyo, Inc: Current Employment.

Prognostic possibilities of molecular genetic testing for assessing the risk of recurrence of papillary thyroid cancer in children

The assessment of aggressiveness and risk of death in papillary thyroid cancer in children is currently based on clinical criteria. To ensure a more accurate risk stratification, new criteria and various molecular genetic markers are constantly being sought. The article studied the dependence of the clinical and pathological manifestations of papillary thyroid cancer in children on the level of expression of various microRNAs and the presence of the BRAF mutation. It was found that the BRAF mutation was present in 20.4% of cases, while the dependence of the clinical behavior of cancer on the BRAF mutation was not established. Of the 14 microRNAs studied, statistical differences were obtained for oncogenic miR-146b, -221, -31, and oncosuppressive miR-144, which correlated with signs such as extrathyroid tumor growth, multi-focus, and metastasis to the neck lymph nodes.

National clinical recommendations for the diagnosis and treatment of mastocytosis

Introduction. Recommendations cover the current state of diagnosis and treatment of mastocytosis.Aim — а consolidation of the Russian experts’ opinion on treatment for adult mastocytosis.Main findings. The recommendations have been developed taking into account foreign literature, national experience and world clinical evidence on therapy for systemic and cutaneous mastocytoses, mast cell leukaemia and other mastocytosis forms. The significance of bone marrow and peripheral blood molecular genetic testing for the presence of KITD816V gene variants is demonstrated. The treatment regimens described are based on midostaurin, imatinib, cladribine, hydroxycarbamide, interferon alfa and haematopoietic stem cell transplantation. Prognosis in different forms of mastocytosis is provided.