Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family

Hereditary hearing impairment affects about 1 in 1000 newborns. In most cases hearing loss is non-syndromic with no other clinical features, while in other families deafness is associated with specific clinical abnormalities. Analysis of large families with non-syndromic and syndromic deafness have been used to identify genes or gene locations that cause hearing impairment. The present report describes a large Norwegian family with autosomal dominant non-syndromic, progressive high tone hearing loss with linkage to 1q21-q23. A maximum LOD score of 7.65 (theta = 0.00) was obtained with the microsatellite marker D1S196. Analysis of recombinant individuals maps the deafness gene (DFNA7) to a 22 cM region between D1S104 and D1S466. The region contains several attractive candidate genes. This report supports the idea of extensive genetic heterogeneity in hereditary hearing impairment and represents the first localization of a deafness gene in a Norwegian family.      

Mononucleosis syndrome and coincidental human herpesvirus-7 and Epstein-Barr virus infection

Two girls (a 5 year old and a 21 month old) experiencing mononucleosis syndrome with coincidental human herpesvirus (HHV)-7 and Epstein-Barr virus (EBV) infections are described. One patient had primary HHV-7 infection and reactivated EBV infection. The other had primary HHV-7 and EBV infections. These cases indicated that HHV-7 is capable of inducing infectious mononucleosis-like illness. Multiple herpesvirus infection in one of the patients also suggests that interaction among herpesviruses can occur in vivo. The consequence of this interaction may have clinical implications.     

Peroneal artery-only runoff following endovascular revascularizations is effective for limb salvage in patients with tissue loss

OBJECTIVE: Peroneal artery bypass is effective for limb salvage (LS), however, the efficacy of peroneal artery-only runoff (PAOR) following endovascular (EV) interventions is unknown. The goal of our article was to compare the efficacy of EV interventions with PAOR to those with other runoff vessels for LS in patients presenting with tissue loss. METHODS: A retrospective review of 111 consecutive patients who underwent infrainguinal EV revascularizations for nonhealing ulcers/gangrene between June 2001 and December 2006 was performed. Patients with PAOR (n = 33) were compared with those with other vessel runoff (OTHER, n = 78). Fisher exact test and chi2 test were used for comparing variables, Kaplan-Meier analyses for patency, LS, and Cox regression multivariate analysis was used for identifying factors associated with limb loss. RESULTS: The patients in PAOR were older, but other morbidities were similar between groups. The most distal level of intervention was infrapopliteal (tibioperoneal or peroneal artery) in 42% in PAOR group whereas this was 24% in OTHER group (P = .071). Preoperative ankle-brachial index (ABI) was similar (0.49 +/- 0.23 vs 0.50 +/- 0.23), however, postprocedure ABI was significantly less for patients with PAOR (0.76 +/- 0.21 vs 0.92 +/- 0.13, P = .001). The primary patency, assisted primary patency, secondary patency and LS were not significantly different between groups. There was also no difference in time-to healing between groups (PAOR vs OTHER, 2.9 +/- 2.1 mo vs 3.7 +/- 3.6 mo, P = .319). We found the presence of gangrene (odds ratio [OR]: 3.5, 95% confidence interval [CI], 1.1-10.8, P = .028) and dialysis-dependence (OR: 2.9, 95% CI, 1.0-8.2, P = .046) to be associated with limb loss, when adjusted for diabetes, hypertension, hyperlipidemia, smoking, location of wound, and PAOR. CONCLUSION: Endovascular revascularization with PAOR results in acceptable patency and limb salvage rates in patients presenting with tissue loss, and is equivalent to other vessel runoff for patency, limb salvage and wound healing rates.     

The management of ischemic heel ulcers and gangrene in the endovascular era

BACKGROUND: The objective of this study was to compare the outcome of patients presenting with heel ulcers or gangrene (HEEL group) with those having lesions in other parts of the foot (non-HEEL group). METHODS: Treatment and outcomes of all HEEL and non-HEEL patients between June 2001 and October 2006 were compared. RESULTS: Three hundred eight patients were treated (71 HEEL and 237 non-HEEL). The HEEL group was more frequently nonambulatory, had lower albumin levels, and had gangrene. The primary amputation rate (11% vs 3%, P < .001) was higher in HEEL patients, and more endovascular interventions were also performed in the HEEL group (75% vs 55%, P = .015). The 24-month limb salvage and patency rates were similar; but survival was worse in HEEL patients. Serum albumin <3 g/dL, dialysis dependence, and gangrene were associated with limb loss in the HEEL group. Mean time to healing was 4.3 +/- 3.4 months. CONCLUSIONS: Patients with ischemic heel ulcers or gangrene were more likely to undergo primary amputation; however, limb salvage rates were similar to those of non-HEEL patients after attempted salvage. Endovascular interventions currently play a significant role in the management of these patients. Gangrene, serum albumin <3 g/dL, and dialysis dependence resulted in increased limb loss in patients with ischemic heel lesions.     

The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.     

Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP)

The gene for the most frequent from of X-linked retinitis pigmentosa (XLRP), RP3, has been assigned by genetic and physical mapping to a segment of less than 1000 kbp, which is flanked by the marker DXS1110 and the ornithine transcarbamylase (OTC) gene. In search of microdeletions, we have screened the DNA of 30 unrelated patients with XLRP by employing a representative set of YAC-derived DNA fragments that were generated by restriction enzyme digestion and PCR amplification. In one of these patients, a 6.4 kbp microdeletion was detected which was not present in the DNA of 444 male controls. A cosmid contig spanning the deletion was constructed and used to isolate cDNAs from retina-specific libraries. Exons corresponding to these expressed sequences as well as other putative exons were identified by sequencing more than 30 kbp of the critical region. So far, no point mutations in these putative exon sequences have been identified.      

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.