Despite some evidence of genetic and environmental factors on molar-incisor hypomineralization (MIH), its aetiology remains unclear. This family-based genetic association study aimed more comprehensively to investigate the genetic carriage potentially involved in MIH development. DNA was obtained from buccal cells of 391 individuals who were birth family members of 101 Brazilian nuclear families. Sixty-three single nucleotide polymorphisms (SNPs) were investigated in 21 candidate genes related to amelogenesis using the TaqMan™ OpenArray™ Genotyping platform. All SNPs were genotyped in 165 birth family members unaffected by MIH, 96 with unknown MIH status and 130 affected individuals (50.7% with severe MIH). Association analysis was performed by the transmission/disequilibrium test (TDT), and statistical results were corrected using the false discovery rate. Significant results were obtained for SNPs rs7821494 (FAM83H gene, OR = 3.7; 95% CI = 1.75-7.78), rs34367704 (AMBN gene, OR = 2.7; 95% CI = 1.16-6.58), rs3789334 (BMP2 gene, OR = 2.9; 95% CI = 1.34-6.35), rs6099486 (BMP7 gene, OR = 2.2; 95% CI = 1.14-4.38), rs762642 (BMP4 gene, OR = 2.3; 95% CI = 1.38-3.65), rs7664896 (ENAM gene, OR = 2.1; 95% CI = 1.19-3.51), rs1711399 (MMP20 gene, OR = 0.4; 95% CI = 0.20-0.72), rs1711423 (MMP20 gene, OR = 2.1; 95% CI = 1.18-3.61), rs2278163 (DLX3 gene, OR = 2.8; 95% CI = 1.26-6.41), rs6996321 (FGFR1 gene, OR = 2.7; 95% CI = 1.20-5.88), and rs5979395 (AMELX gene, OR = 11.7; 95% CI = 1.63-84.74). Through this family-based association study, we concluded that variations in genes related to amelogenesis were associated with the susceptibility to develop MIH. This result is in agreement with the multifactorial idea of the MIH aetiology, but further studies are necessary to investigate more thoroughly the factors that could influence MIH.

Altered glomerular metabolism of arachidonic acid (AA) has already been demonstrated in experimental nephrotoxic nephritis. The Isolated glomeruli from nephrotic rats studied 14 or 30 d after a single intravenous injection of adriamycin (7.5 mg/kg) when animals were heavily proteinuric generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. No significant changes were found in the other major AA metabolites formed through cyclooxygenase. Urinary excretion of immunoreactive TxB2 was also significantly higher in nephrotic than in normal animals. Administration of a selective Tx synthetase inhibitor, UK-38,485, from day 14 to day 18 after adriamycin resulted in a significant reduction of proteinuria compared with pretreatment values. Glomerular synthesis and urinary excretion of TxB2 were normal during the UK-38,485 treatment. Additional experiments showed that elevated glomerular synthesis and urinary excretion of TxB2 were not a consequence of increased substrate availability. Maximal stimulation of the renin-angiotensin axis with furosemide increased glomerular TxB2 synthesis in normal rats, which was significantly lower than in nephrotic animals. Finally, experiments using a unilateral model of adriamycin nephrosis indicated that the enhancement of glomerular TxB2This work was presented in part at the American Society of Nephrology Annual Meeting in Washington, DC, 1983. Received for publication 23 January 1984 and in revised form 23 July 1984.synthesis is not simply a consequence of the nephrotic syndrome.We conclude that: there is an abnormality of glomerular AA metabolism in nephrotic syndrome, which leads to increased TxA2 production; the increased Tx generation correlates with protein excretion and might be responsible for altering the glomerular basement membrane permeability to protein; and the alteration found in isolated glomeruli probably reflects a modification in vivo, in that urinary excretion of immunoreactive TxB2 is also consistently increased in adriamycin nephrosis.

Our objective was to estimate the frequency as well as to establish the clinical and neuroimaging profile of hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). HSP-TCC was recognized as a specific clinical subtype of HSP and mapped to chromosome (ch) 15q13-15 in Japanese families. It has been considered rare in western countries. We assessed 45 patients with autosomal recessive HSP from 20 different families in search of clinical and imaging criteria for the diagnosis of HSP-TCC. In addition, HSP-TCC patients underwent further neurological, imaging and genetic evaluation. MRI scans were performed in a 2T scanner and sagittal T1 weighted images used for semiautomated volumetric measurements of corpus callosum, cerebellum, and brain. In seven patients, a 2-year follow-up MRI scan was performed. We genotyped seven microsatellite markers flanking the 15q13-15 candidate region and calculated two-point and multipoint LOD scores (Z). We identified 13 patients from seven unrelated families with HSP-TCC. MRI showed significant corpus callosum, cerebral and cerebellar volumetric reductions (P<0.001, P=0.03, and P=0.01, respectively). In the prospective analysis, we found progressive corpus callosum atrophy (P=0.04). Two-point and multipoint LOD scores were significantly negative for markers genotyped on ch 15q. However, independent pedigree analysis did not yield significant results. HSP-TCC was found in 35% of families with autosomal recessive HSP. MRI volumetry showed cerebral and cerebellar atrophy in association with progressive corpus callosum thinning. Genetic studies did not show evidence for linkage to ch 15q.

Typical orofacial clefts (OFCs) comprise cleft lip, cleft palate and cleft lip and palate. The complex etiology has been postulated to involve chromosome rearrangements, gene mutations and environmental factors. A group of genes including IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, MSX1 and FGF has been implicated in the etiology of OFCs. Recently, the role of the copy number variations (CNVs) has been studied in genetic defects and diseases. CNVs act by modifying gene expression, disrupting gene sequence or altering gene dosage. The aims of this study were to screen the above-mentioned genes and to investigate CNVs in patients with OFCs. The sample was composed of 23 unrelated individuals who were grouped according to phenotype (associated with other anomalies or isolated) and familial recurrence. New sequence variants in GLI2, MSX1 and FGF8 were detected in patients, but not in their parents, as well as in 200 control chromosomes, indicating that these were rare variants. CNV screening identified new genes that can influence OFC pathogenesis, particularly highlighting TCEB3 and KIF7, that could be further analyzed. The findings of the present study suggest that the mechanism underlying CNV associated with sequence variants may play a role in the etiology of OFC.

Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms (SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in ABCB1, ABCC2, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner.