1.
Primary creatine deficiency syndrome as a potential missed diagnosis in children with psychomotor delay and seizure: case presentation with two novel variants and literature review.
Rostami, P, Hosseinpour, S, Ashrafi, MR, Alizadeh, H, Garshasbi, M, Tavasoli, AR
Acta neurologica Belgica. 2020;(3):511-516
Abstract
Creatine is the main source of energy for the brain. Primary creatine deficiency syndromes (PCDSs) are inborn error of metabolism of creatine synthesis. Symptoms of central nervous system involvement are the most common clinical manifestations in these disorders. We reviewed medical records of all genetically confirmed patients diagnosed by whole exome sequencing who were referred to Myelin and Neurodegenerative Disorders Clinic, Children's Medical Center, Tehran, Iran, from May 2016 to Dec 2018. A literature review was conducted on clinical and genomic variability of PCDS to compare our patients with previously reported cases. We report two patients with creatine deficiency among a cohort of 550 registered cases out of which 200 patients had a genetically confirmed neurodegenerative disorder diagnosis. The main complain in the first patient with creatine transporter (CRTR) deficiency was seizure and genetic study in this patient identified a novel hemizygote variant of "c.92 > T; p.Pro31Leu" in the first exon of SLC6A8 gene. The second patient with guanidinoacetate methyltransferase (GAMT) deficiency had an unknown motor and speech delay as the striking manifestation and molecular assay revealed a novel homozygote variant of "c.134G > A; p.Trp45*" in the first exon of GAMT gene. PCDSs usually are associated with nonspecific neurologic symptoms. The first presented case had a mean delayed diagnosis of 5 years. Therefore, in children with unexplained neurologic features including developmental delay and/or regression, mental disability and repeated seizures without any significant findings in metabolic studies, PCDSs can be considered as a differential diagnosis and molecular analysis can be helpful for the precise diagnosis and treatment.
2.
Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.
Haydar, S, Grigorescu, F, Vintilă, M, Cogne, Y, Lautier, C, Tutuncu, Y, Brun, JF, Robine, JM, Pugeat, M, Normand, C, et al
PloS one. 2019;(3):e0214122
Abstract
Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.
3.
Saxagliptin Upregulates Nesfatin-1 Secretion and Ameliorates Insulin Resistance and Metabolic Profiles in Type 2 Diabetes Mellitus.
Chen, K, Zhuo, T, Wang, J, Mei, Q
Metabolic syndrome and related disorders. 2018;(7):336-341
Abstract
BACKGROUND AND AIMS Saxagliptin as one of dipeptidyl peptidase-4 (DPP-4) inhibitors can effectively improve glycaemic control in type 2 diabetes mellitus, and nesfatin-1 is regarded as a very important factor in regulating feeding behavior and energy homeostasis. In this trial, we observed the effect of saxagliptin on regulating nesfatin-1 secretion and ameliorating insulin resistance and metabolic profiles in type 2 diabetes mellitus. METHODS One hundred two type 2 diabetes participants (M/F = 48/54) were investigated. Fifty-one (M/F = 24/27) of them as the treatment group were treated with oral glucose-lowering agents including saxagliptin, the other 51 (M/F = 24/27) as the control group were treated with oral glucose-lowering agents excluding any DPP-4 inhibitors. The parameters of serum nesfatin-1, C-peptide, homeostasis model assessment-β (HOMA-β) function, HOMA insulin resistance (HOMA-IR), glycosylated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), and blood pressure (BP) at baseline, month 3, 6, and 12 were observed and compared respectively. RESULTS Saxagliptin significantly upregulated nesfatin-1 secretion (P < 0.001 at 3-, 6-, and 12-months vs. baseline), increased serum C-peptide (P < 0.05, 0.001, and 0.001 at 3-, 6-, and 12-months vs. baseline), improved HOMA-IR and function of HOMA-β (P < 0.001 at 3-, 6-, and 12-months vs. baseline) and metabolic profiles (P < 0.001 with HbA1c at 3-, 6- and 12-months; P < 0.001 with LDL-C at 6- and 12-months; P < 0.001 and 0.01 with HDL-C at 6- and 12-months vs. baseline), declined BMI (P < 0.05 at 6- and 12-months vs. baseline) and BP (P < 0.001 with systolic BP (SBP), and mean BP at 6- and 12-months, P < 0.01 with diastolic BP at 6- and 12-months vs. baseline). CONCLUSIONS Saxagliptin could upregulate nesfatin-1 secretion and ameliorate insulin resistance and metabolic profiles in type 2 diabetes mellitus. Saxagliptin had the potential to play fundamental by upregulating nesfatin-1 secretion besides lowering glucose by inhibiting the degradation of glucagon-like peptide-1.