Mitochondrial DNA Copy Number as a Biomarker of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS). In its early stages, it results in inflammation, demyelination, and axonal loss. Egypt has the highest rates in the Middle East region. The pathogenicity of MS involves mitochondrial function. Damage to mitochondrial DNA (mtDNA) can produce variation in the copy number (CN) and decline in mitochondrial function. Our goal was to determine the potential of mtDNA-CN as a biomarker of MS and the progression of the disease. The study included 25 patients with relapsing remitting MS (RRMS) and 25 age and sex matched apparently healthy control. Two peripheral blood samples were collected from each patient, one during the remission phase and the other during the phase of relapse. A quantitative real-time polymerase chain reaction (qPCR) was performed to assess CN of mitochondrial DNA. There was a statistically significant decline in the number of mtDNA copies during the remission phase as compared to controls (p < 0.01), yet no difference was seen between mtDNA-CN in relapsing subjects versus controls. Moreover, the copy number of mtDNA during the relapse phase was significantly higher than the remission phase suggesting the ability of mtDNA to differentiate between remission and relapse phases (p < 0.05). Our study observed that mtDNA-CN at a cut off (0.75), can differentiate between RRMS patients in the remission phase and controls with a sensitivity of 56%, specificity 84%, positive predictive value (PPV) 65.6% and negative predictive value (NPV) 77.8%, and at a cut off (1), mtDNA-CN can differentiate between remission and relapse MS patients with a sensitivity 72%, specificity 56%, PPV 62.1% and NPV 66.7%. In conclusion, mtDNA-CN can be proposed as a biomarker of MS.

Metabolism and memory: α-synuclein level in children with obesity and children with type 1 diabetes; relation to glucotoxicity, lipotoxicity and executive functions.

BACKGROUND/OBJECTIVES: Children with obesity and those with type 1diabetes (T1D) exhibit subtle neurocognitive deficits, the mechanism of which remains unknown. α-synuclein plays a fundamental role in neurodegeneration. Moreover, its role in glucose and lipids metabolism is emerging. This study aims to assess whether α-synuclein is correlated with the degree of neurodegeneration in children with obesity and those with T1D in comparison to healthy controls and correlate it to various neurocognitive and metabolic parameters. SUBJECTS/METHODS: Forty children with obesity, 40 children with T1D and 40 matched-healthy controls were assessed for anthropometric measurements and blood-pressure. Cognitive evaluation was performed using Stanford-Binet scale and Barkley Deficits in Executive Functioning (EF) Scale-Children and Adolescents. α-synuclein, fasting lipids and glucose were measured with calculation of the homeostatic model of insulin-resistance and estimated-glucose disposal rate. RESULTS: Children with obesity and those with T1D had significantly higher α-synuclein (p < 0.001) and total EF percentile (p = 0.001) than controls. α-synuclein was negatively correlated to total IQ (p < 0.001 and p = 0.001), and positively correlated with total EF percentile (p = 0.009 and p = 0.001) and EF symptom count percentile (p = 0.005 and p < 0.001) in children with T1D and obesity, respectively. Multivariate-regression revealed that α-synuclein was independently related to age (p = 0.028), diabetes-duration (p = 0.006), HbA1C% (p = 0.034), total IQ (p = 0.013) and EF symptom count percentile (p = 0.003) among children with T1D, and to diastolic blood-pressure percentile (p = 0.013), waist/hip ratio SDS (p = 0.007), total EF percentile (P = 0.033) and EF symptom count percentile (p < 0.001) in children with obesity. CONCLUSION: α-synuclein could have a mechanistic role in neurocognitive deficit among children with obesity and T1D.

DNMT3A and TET2; Potential Estimates of Generic DNA Methylation in Children and Adolescents with Obesity; Relation to Metabolic Dysregulation.

INTRODUCTION: The role of DNA methylation in metabolic dysregulation is emerging. However, the functional role of methylation in obesity and metabolic dysregulation is poorly understood. AIM: The aim of this study was to compare DNA methyltransferase-3A (DNMT3A) and ten-eleven translocase-2 (TET2) levels in children and adolescents with obesity to normal-weighed children and adolescents and to correlate them to various metabolic parameters. METHODS: Fifty children and adolescents with obesity were compared to 50 matched normal-weighed children and adolescents. Participants underwent assessment for anthropometric measurements, Tanner staging, acanthosis nigricans, and mean blood pressure percentile on three different occasions. TET2, DNMT3A, fasting lipids, and insulin were measured with calculation of the homeostatic model assessment insulin resistance (HOMA-IR). RESULTS: The median BMI SDS of the studied children and adolescents with obesity was 3.40, their mean TET2 was 178.40 ng/mL, and their mean DNMT3A was 2.18 ng/mL. TET2 is significantly lower (p = 0.009), while DNMT3A is significantly higher (p < 0.001) in children and adolescents with obesity than controls. Children and adolescents with obesity and insulin resistance have significantly lower TET2 (p = 0.012) and significantly higher DNMT3A (p = 0.013) than those without insulin resistance. Diastolic blood pressure percentile and HOMA-IR are positively correlated to DNMT3A (p < 0.001) and negatively correlated to TET-2 (p < 0.001). Multivariate logistic regression analysis revealed that TET2 and DNMT3A are independently associated with diastolic blood pressure percentile (p = 0.03 and p = 0.014, respectively) and HOMA-IR (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Children and adolescents with obesity have significantly higher DNMT3A and significantly lower TET2 than controls. This is more evident in those having insulin resistance than those without. DNMT3A and TET2 are independently associated with systemic hypertension and insulin resistance in children with obesity.