Inherited motor-sensory neuropathy with upper limb predominance associated with the tropomyosin-receptor kinase fused gene.

The Tropomyosin-receptor kinase fused gene (TFG) encodes TFG which is expressed in spinal motor neurons, dorsal root ganglia and cranial nerve nuclei, and plays a role in the dynamics of the endoplasmic reticulum. Two dominant missense TFG mutations have previously been reported in limited geographical areas (Far East, Iran, China) in association with hereditary motor sensory neuropathy with proximal involvement (HMSN-P) of the four limbs, or with Charcot-Marie-Tooth disease type 2 (CMT2). The 60-year-old female proband belonging to a three-generation Italian family presented with an atypical neuropathy characterized by diffuse painful cramps and prominent motor-sensory impairment of the distal upper limbs. Her sural nerve biopsy showed chronic axonal neuropathy without active degeneration or regeneration. Targeted next-generation sequencing of a panel with 98 genes associated with inherited peripheral neuropathies/neuromuscular disorders identified three candidate genes: TFG, DHTKD1 and DCTN2. In the family, the disease co-segregated with the TFG p.(Gly269Val) variant. TFG should be considered in genetic testing of patients with heterogeneous inherited neuropathy, independently of their ethnic origin.

Telomere length and LINE1 methylation is associated with chromosomal aberrations in peripheral blood.

The frequency of chromosomal aberrations in peripheral blood predicts a probable cancer risk. The individual telomere length and methylation of repetitive elements may be susceptibility factors for chromosomal aberrations. A cohort of healthy Norwegian men (N = 364) recruited during 1980-1999 were analyzed for chromosomal aberrations in phytohemagglutinin-stimulated lymphocytes from peripheral blood. Chromosome-type or chromatid-type aberrations were scored. DNA was extracted from slides cytogenetically analyzed and relative average telomere length and methylation of LINE1 repeats were determined by quantitative polymerase chain reaction and bisulfite pyrosequencing, respectively. Information about individuals with malignant tumors (N = 49) diagnosed after chromosomal aberrations testing until end of 2008 was obtained and two matched controls per case were used in a nested case-control analysis. Shorter relative telomere length and higher methylation of LINE1 were associated with higher frequency of total chromosomal aberrations (ß = -0.76, P = 0.022; and ß = 0.042, P = 0.048, respectively; age-adjusted ordinal regression). The telomere length was stronger associated with chromosome-type (ß = -1.00, P = 0.006) than with chromatid-type aberrations (ß = -0.49, P = 0.115). The LINE1 methylation was stronger associated with chromatid-type (ß = 0.062, P = 0.003) than with chromosome-type aberrations (ß = 0.018, P = 0.41). Telomere length [individuals with short telomeres odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.38-2.0], LINE1 (individuals with high methylation OR = 1.04, 95% CI 0.43-2.5) and chromosomal aberrations (individuals with high frequency OR = 1.6, 95% CI 0.63-3.9) at baseline did not predict cancer risk, but the conclusions were hampered by low statistical precision. The results suggest that shorter telomere length and higher LINE1 methylation in peripheral blood lymphocytes are predisposition factors for increased frequency of chromosomal aberrations.

Increased risk of ovarian hyperstimulation syndrome following controlled ovarian hyperstimulation in patients with vascular endothelial growth factor +405 cc genotype.

Ovarian hyperstimulation syndrome (OHSS) is a serious complication following controlled ovarian hyperstimulation (COH) for in vitro fertilization. OHSS has a range of clinical features from mild abdominal distention to severe thromboembolic events. Several clinical manifestations of OHSS such as ascites and hemoconcentration can be attributed to increased vascular permeability. Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 have been identified as an important signaling system in mediating this increase. There is considerable genetic variation in the VEGF/R2 signaling system. We present the first study to examine if single nucleotide polymorphisms (SNPs) in the genes encoding the VEGF/R2 signaling system are associated with OHSS following COH. Blood samples from 53 OHSS patients and 100 controls were analyzed for six SNPs of interest. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by a multivariate logistic regression model. We found an association between the VEGF +405cc genotype and OHSS (OR 3.4, 95% CI 1.01-11.7). This finding requires confirmation from other patient populations.

Genetic variability in BK Virus regulatory regions in urine and kidney biopsies from renal-transplant patients.

The human Polyomavirus BK (BKV) contains a hypervariable non-coding control region (NCCR), which regulates DNA replication and RNA transcription. The aim of this study was to characterize BKV NCCR-variants in kidney biopsies and urine samples from renal-transplant patients and to see whether there is any association between NCCR variability and BKV-nephropathy. Kidney biopsies and urine samples were examined from 11 patients with elevated serum creatinine and >5,000 genomic BKV copies per ml of urine. BKV-nephropathy was diagnosed in seven patients. Using PCR, BKV NCCR was amplified from urine from all BKV-nephropathy patients. The dominant NCCR corresponded to the archetype (WWT). In addition, a total of 14 non-archetype NCCR-variants were detected. Thirteen of these NCCR-variants were found in urine from one single BKV-nephropathy patient also suffering from hepatitis C. The NCCR of BKV was amplified from kidney biopsies of six BKV-nephropathy patients. Three patients demonstrated WWT NCCR, while three other patients harbored rearranged NCCR variants. The WWT NCCR was also detected in urine from control patients, except for one patient who harbored two non-archetypal NCCR variants. However, these variants were not resulting from complex rearrangements but instead had a linear NCCR anatomy with deletion(s) in the P-block. No BKV DNA was detected in biopsies from control patients. The results indicate that rearranged BKV NCCR is associated with BKV-nephropathy.