Cascade testing using DNA-mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty-five probands from six UK centres were tested for 18 low-density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct-sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty-one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty-eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.

The cutoffs developed here are designed to give the greatest overall accuracy when testing relatives of FH patients in the absence of a genetic diagnosis. They have a more balanced specificity and sensitivity than the MEDPED cutoffs that are designed to achieve higher specificity, which is more appropriate for cascade testing purposes. The data suggest that country-specific LDL-C cutoffs may lead to greater accuracy for identifying FH patients, but should be used with caution and only when a genetic diagnosis (DNA) is not available.

We present a comparison of patient-reported outcomes (PROMs) in relation to patient age, in patients who had received a total (TKR) or unicompartmental knee replacement (UKR). The outcome was evaluated using the Oxford knee score (OKS), EuroQol (EQ-5D) and satisfaction scores. Patients aged 65 to 84 years demonstrated better pre-operative function scores than those aged < 65 years (OKS, p = 0.03; EQ-5D, p = 0.048) and those aged ≥ 85 years (OKS, p = 0.03). Post-operative scores were comparable across age groups, but a linear trend for greater post-operative improvement in OKS and EQ-5D was seen with decreasing age (p < 0.033). The overall mean satisfaction score at six months was 84.9, but those aged < 55 years exhibited a lower mean level of satisfaction (78.3) compared with all other age groups (all p < 0.031). The cumulative overall two-year revision rate was 1.3%. This study demonstrates that good early outcomes, as measured by the OKS and EQ-5D, can be anticipated following knee replacement regardless of the patient's age, although younger patients gain greater improvement. However, the lower satisfaction in those aged < 55 years is a concern, and suggests that outcome is not fully encapsulated by the OKS and EQ-5D evaluation, and raises the question whether the OKS alone is an appropriate measure of pain and function in younger, more active individuals.