Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

The relative roles of aggressive wound care versus revascularization in salvage of the threatened lower extremity in the renal failure diabetic patient

Current literature indicates poor survival and limb salvage rates in renal failure diabetic patients who present with ulcerated or gangrenous lower extremities. Even in those limbs that were successfully revascularized, the amputation rate was as high as 37 percent. This has led some to advocate immediate amputation when treating the threatened limb of a renal failure diabetic patient. The authors reviewed all renal failure diabetic patients in their wound registry to determine whether such pessimism was warranted. The authors then analyzed the relative roles of revascularization and aggressive wound care on long-term limb salvage. Forty-five consecutive renal failure diabetic patients with 71 wounds in 54 limbs were identified. Twenty-seven patients had chronic renal insufficiency, 15 patients had end-stage renal disease, and three patients received kidney transplants. The revascularization procedures (46 percent of all limbs) included angioplasty, femoral-popliteal, femoral-distal, and popliteal-distal bypasses. Forty-three amputations in combination with 67 soft-tissue repairs (delayed primary wound closure, skin grafts, local flaps, pedicled flaps, and free flaps) were necessary to close the defects. After a mean follow-up of over 3 years, the data indicate that 79 percent of wounds healed, 89 percent of all limbs were salvaged, and 49 percent of patients survived. Revascularization improved the threatened limb\u27s salvage rate from negligible to a level similar to that of the adequately vascularized limb. Fifteen out of 71 wounds did not heal because of the patient\u27s early postoperative death, ischemia not amenable to revascularization, or noncompliance. Six below-knee amputations were performed (one despite a patent bypass and five in adequately vascularized patients). The average time for wounds to heal in the revascularized patients was 79 days versus 71 days in adequately vascularized patients. There was an overall 43 percent complication rate. Of the patients who were alive after the 3-year follow-up, 73 percent were independently ambulating, whereas 27 percent were bound to wheelchair or bed. Eighty-two percent of patients were very satisfied with the salvage attempt, 18 percent were moderately satisfied, and all patients said they would go through the process again. The authors believe that salvaging the threatened extremity in the renal failure diabetic patient is justified whether or not the limb requires revascularization. Revascularization improved the limb salvage rate, patient survival, and days for wounds to heal to a level comparable to that of the adequately vascularized limb. The key to subsequently achieving high salvage rates is the quality of perioperative wound care (e.g., serial debridements, antibiotics, dressings) and the timing and selection of appropriate soft-tissue coverage