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Purpose To assess the effect of a preoperative virtual reality (VR) experience of 3-dimensional (3D) reconstructed magnetic resonance images (MRIs) on anxiety reduction in patients undergoing arthroscopic knee surgery. Methods Patients in the VR group watched a 3D model of their own MRI through a VR headset describing the anatomy of the knee as well as their own lesion of interest for an arthroscopic procedure. Patients in the non-VR (NR) group received standard preoperative information about their MRI. The primary outcome for analysis was the Amsterdam Preoperative Anxiety and Information Scale score to measure level of anxiety and the need for information in patients undergoing arthroscopic knee surgery. Secondary outcomes were rated with visual analog scale (VAS) scores measuring patient pain, preparedness, satisfaction, and stress. Results Regarding the Amsterdam Preoperative Anxiety and Information Scale score, the sum S (surgery-related anxiety) and sum C (combined anxiety component) subscales showed significantly better outcomes in the VR group (median [interquartile range] for sum S = 2.0 [2.0-4.0], median [quartile 1-quartile 3] sum C = 4.0 [4.0-8.5]) than in the NR group (median [interquartile range] for sum S = 4.9 [3.0-5.0], median [quartile 1-quartile 3] sum C = 8.0 [5.3-9.8]) (P = .014 and P = .005, respectively). Regarding VAS scores, preoperative measures showed significantly better outcomes in satisfaction among VR group patients (95 [90.0-100.0]) in comparison to NR group patients (85 [70.0-96.0]) (P = .010). For postoperative VAS measures, the VR group (satisfaction score = 95 [90.0-100.0], stress score = 15 [2.5-37.5]) showed significantly better outcomes in satisfaction and stress in comparison to the NR group (satisfaction score = 85 [70.0-97.5], stress score = 30 [30.0-50.0]). Conclusions Application of preoperative VR experience of 3D reconstructed knee MRIs in patients undergoing arthroscopic knee surgery reduces anxiety around surgical encounters. The VR patient group was more satisfied overall and less stressed postoperatively. However, perioperative pain and preparedness were not affected by VR exposure. Level of Evidence Level I, randomized controlled trial.

Objective Spinal muscular atrophy (SMA) is one of the most common severe hereditary diseases of infancy and early childhood in North America, Europe, and Asia. SMA is usually caused by deletions of the survival motor neuron 1 (SMN1) gene. A closely related gene, SMN2, modifies the disease severity. SMA carriers have only 1 copy of SMN1 and are relatively common (1 in 30–50) in populations of European and Asian descent. SMN copy numbers and SMA carrier frequencies have not been reliably estimated in Malians and other sub-Saharan Africans. Methods We used a quantitative polymerase chain reaction assay to determine SMN1 and SMN2 copy numbers in 628 Malians, 120 Nigerians, and 120 Kenyans. We also explored possible mechanisms for SMN1 and SMN2 copy number differences in Malians, and investigated their effects on SMN mRNA and protein levels. Results The SMA carrier frequency in Malians is 1 in 209, lower than in Eurasians. Malians and other sub-Saharan Africans are more likely to have ≥3 copies of SMN1 than Eurasians, and more likely to lack SMN2 than Europeans. There was no evidence of gene conversion, gene locus duplication, or natural selection from malaria resistance to account for the higher SMN1 copy numbers in Malians. High SMN1 copy numbers were not associated with increased SMN mRNA or protein levels in human cell lines. Interpretation SMA carrier frequencies are much lower in sub-Saharan Africans than in Eurasians. This finding is important to consider in SMA genetic counseling in individuals with black African ancestry. Ann Neurol 2014;75:525–532

Aims: The aims of this study were to analyze the clinical characteristics, diagnostic features, and operative outcomes of patients with ovarian fibroma/fibrothecoma and to discuss appropriate management options. Methods: We performed a retrospective comparative analysis of 97 patients with ovarian fibroma/fibrothecoma who underwent laparoscopic and laparotomic procedures, including tumorectomy between January 2008 and December 2011. Results: The mean patient age was 42.5 ± 11.4 years. Seventy-three patients (75.3%) were premenopausal women. A preoperative diagnosis of benign ovarian tumor or fibroma was made in only 49 cases (50.5%). We found that 42.2% of cases were misdiagnosed as uterine myomas (n = 41) and 6.2% were misdiagnosed as malignant ovarian tumors (n = 6). The presence of ascites was associated with larger tumor size (p < 0.05) but not higher CA125 levels (p = 0.159). Twenty-nine patients (29.9%) underwent laparotomy, and 68 (70.1%), laparoscopic surgery. Laparoscopic surgery facilitated shorter operation times than laparotomy (p < 0.05). Tumorectomy was performed in 40 patients (43.5%), 36 (90%) of whom underwent laparoscopy with operative outcomes comparable to those of patients who underwent laparotomy. Conclusions: Ovarian fibromas/fibrothecomas are often misdiagnosed as uterine myomas and malignant ovarian tumors. Laparoscopic surgery including tumorectomy may be an effective surgical approach in patients with ovarian fibromas/fibrothecomas.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous and bi-functional inhibitor of angiogenesis. TIMP-2 is expressed in an insoluble form in Escherichia coli and secreted at a very low level from yeast. Here, we report on a high level of secretion of TIMP-2 fused with human serum albumin (HSA) from the yeast Saccharomyces cerevisiae. The secreted HSA–TIMP-2 fusion protein (87 kDa) was purified to greater than 95% homogeneity. The HSA–TIMP-2 protein inhibited approximately 81% of tube formation of human umbilical vein endothelial cells (HUVECs) when studied at a concentration of 187 μM. The systemic administration of HSA–TIMP-2 at 40 mg/kg to the C57B1/6 mouse inhibited the growth of B16BL6 tumors. Furthermore, a combination treatment of HSA–TIMP-2 with 5-fluorouracil (50 mg/kg) showed significant effects on tumor growth in this model. The high level of secretion of the biologically active angiogenesis inhibitor from S. cerevisiae should facilitate fundamental research and application studies of HSA–TIMP-2, as an attractive candidate for therapeutic agents treating angiogenesis-related diseases.

Essential tremor (ET) is the most prevalent adult-onset movement disorder showing evidence of non-random accumulation in some families. ET has previously been mapped to genetic loci on chromosomes 2p and 3q, but no causative genes identified. We conducted genomewide linkage screening with subsequent fine mapping in seven large North American families comprising a total of 325 genotyped individuals that included 65 patients diagnosed as definite ET. Linkage analysis was based on methodology implemented in SimWalk2 and LINKAGE programs. A multigenerational family revealed suggestive linkage to a locus on chromosome 6p23 with maximal nonparametric linkage (NPL) multipoint score 3.281 (P = 0.0005) and parametric multipoint log of the odds (LOD) score 2.983. A second family showed positive linkage to the same 6p23 region with a maximal NPL score 2.125 (P = 0.0075) and LOD score 1.265. Haplotype analysis led to the identification of a 600 kb interval shared by both families. Sequencing of coding regions of 15 genes located in the linked region detected numerous sequence variants, some of them predicting a change of the encoded amino acid, but each was also found in controls. Our findings provide evidence for linkage to a novel susceptibility locus on chromosome 6p23. Analysis of additional ET-affected families is needed to confirm linkage and identify the underlying gene.

Stuttering is a complex developmental speech disorder of unknown etiology. There is a substantial aggregation of stuttering in families, suggesting a genetic component to the disorder. However, the exact mode of transmission is still unknown. An earlier study of 56 multigenerational pedigrees ascertained through single adult probands (38 males and 18 females) found that biological relatives of persistent developmental stutterers have an approximately 10-fold higher risk than in the general population; risk is higher for male relatives, and proband's sex does not affect recurrence and relative risks. In the present paper we conduct a complex segregation analysis of the same data, using the logistic regression model of the SAGE software. Based on the comparisons of model likelihoods, the Mendelian model was selected over all other nongenetic models and the general transmission model. This model was further refined into the most parsimonious model, which shows an autosomal dominant major gene effect influenced by two covariates: sex and affection status of parents. With this model applied to 47 informative multiplex pedigrees, a power calculation based on linkage simulation produced an average lod score of 6.8 for 10-cM density genome scan markers. These results give impetus for a genomewide linkage analysis of susceptibility to persistent developmental stuttering.

We analyzed the prion protein gene (PRNP) region in patients with transmissible spongiform encephalopathy associated with the PRNP D178N mutation. The results suggest that the D178N chromosomes had independent origins in each affected pedigree or apparently sporadic case. A de novo spontaneous PRNP mutation was observed. We provide evidence that hereditary and apparently sporadic transmissible spongiform encephalopathy cases associated with the D178N mutation result from multiple recurrent mutational events.

Objectives To evaluate the recurrence rate of ovarian fibroma/fibrothecoma and reproductive outcomes following ovarian-sparing local mass excision in premenopausal women. Study design A retrospective cohort study was performed at two gynecologic surgery centers using data collected between January 2005 and December 2011. It included premenopausal patients treated with ovarian-sparing local mass excision and pathologically proven ovarian fibroma/fibrothecoma who were followed up for at least 6 months. The recurrence of fibroma/fibrothecoma and pregnancy outcomes in those who wanted to conceive after local mass excision were collected and analyzed. Results The mean age of the patients (n = 50) was 33.3 ± 6.9 years (range, 20–50 years), and the mean follow-up duration was 26.6 ± 19.2 months (range, 6–88 months). Fibroma was present in 40 patients, fibrothecoma in 7, and cellular fibroma in 3. Natural conception occurred in 11 of the 12 patients who became pregnant during the follow-up period. On follow-up ultrasonography, one patient experienced recurrent disease, 50 months after initial surgery, resulting in a crude overall recurrence rate of only 2%. Conclusion Given the 2% recurrence rate of ovarian fibroma/fibrothecoma following ovarian sparing local mass excision, local mass excision appears to be an effective surgical option in women of reproductive age.

Sixteen patients from nine Chinese families with spinocerebellar ataxia type 2 (SCA2) were heterozygous for a CAG repeat expansion in the SCA2 gene containing 37 to 56 repeats, whereas the normal alleles carried 14 to 28 repeats. One or two CAA triplets within the CAG tract were seen in normal, but not in the expanded alleles. A strong inverse correlation was established between the number of CAG repeats and the age of disease onset. SCA2 accounted for 12% of the known Chinese families with spinocerebellar ataxia.

Background Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown. Methods De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes. Results Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM). Conclusions The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.

Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRY A B, M YOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 M FM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in M YOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis. (C) 2011 Elsevier B.V. All rights reserved.

Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by disintegration of myofibrils. The inheritance pattern is commonly autosomal dominant, but there has been a striking absence of secondary cases noted in a BAG3-associated subtype. We studied three families with BAG3 p.Pro209Leu mutation showing a severe phenotype of myofibrillar myopathy and axonal neuropathy with giant axons. In one family, transmission to a pair of siblings has occurred from their asymptomatic father who showed somatic mosaicism. In two other families, neither of the parents was affected or showed detectable level of somatic mosaicism. These observations suggest that the BAG3 variant of myofibrillar myopathy may result from a spontaneous mutation at an early point of embryonic development and that transmission from a mosaic parent may occur more than once. The study underlines the importance of parental evaluation as it may have implications for genetic counseling.

Viliuisk encephalomyelitis (VE) is a unique disease occurring in the Yakut (Sakha) population of Eastern Siberia. VE is always fatal, with some patients dying during the acute encephalitic phase of illness; those surviving the acute phase develop progressive dementia, rigidity and spastic quadriparesis as part of a more prolonged pan-encephalitic syndrome. The disease is characterized neuropathologically by multiple widespread micronecrotic foci with marked inflammatory reactions and subsequent gliosis throughout the cerebral cortex, basal ganglia, cerebellum and brain stem. The acute febrile onset with cerebrospinal fluid pleocytosis and increased protein and neuropathology showing inflammatory reactions suggest that VE is an infectious disease, but the causative agent has not been identified. Initially detected in a small mixed Yakut-Evenk population of the mid-Viliui region, the disease subsequently spread south to densely populated areas around the capital city of Yakutsk. The occurrence of secondary VE cases in households and the introduction of the disease by migrants into new populations indicate that the disease is horizontally transmitted in a setting of a long intra-household contact. Although there has been a recent decline in the number of cases, increasing travel may result in further spread of this fatal disease to susceptible individuals in other regions of the world.

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930_Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930_Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930_Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM.

Kuru reached epidemic proportions by the mid-twentieth century among the Fore people of New Guinea and disappeared after the abolition of cannibalistic rituals. To determine susceptibility to kuru and its role in the spread and elimination of the epidemic, we analyzed the PRNP gene coding sequences in 5 kuru patients; no germline mutations were found. Analysis of the PRNP 129 methionine (M)/valine (V) polymorphism in 80 patients and 95 unaffected controls demonstrated that the kuru epidemic preferentially affected individuals with the M/M genotype. A higher representation of M/M carriers was observed among the affected young Fore males entering the age of risk, whereas a lower frequency of M/M homozygotes was found among the survivors. M/V and V/V genotypes predisposed to a lower risk of disease development and longer incubation times. These findings are relevant to the current outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom, because all vCJD patients tested thus far have been M/M carriers.

Myofibrillar myopathies, often referred to as desmin-related myopathies, are a heterogeneous group of inherited or sporadic distal-onset skeletal myopathies associated with cardiomyopathy. Among the myofibrillar proteins that characteristically accumulate within the muscle fibers of affected patients, the one found most consistently is desmin, a muscle-specific intermediate-filament protein responsible for the structural integrity of the myofibrils. Skeletal and cardiac myopathy develops in mice that lack desmin, suggesting that mutations in the desmin gene may be pathogenic.We examined 22 patients from 8 families with dominantly inherited myofibrillar or desmin-related myopathy and 2 patients with sporadic disease and analyzed the desmin gene for mutations, using complementary DNA (cDNA) amplified from muscle-biopsy specimens and genomic DNA extracted from blood lymphocytes. Restriction-enzyme analysis was used to confirm the mutations. Expression vectors containing normal or mutant desmin cDNA were introduced into cultured cells to determine whether the mutant desmin formed intermediate filaments.Six missense mutations in the coding region of the desmin gene that cause the substitution of an amino acid were identified in 11 patients (10 members of 4 families and 1 patient with sporadic disease); a splicing defect that resulted in the deletion of exon 3 was identified in the other patient with sporadic disease. Mutations were clustered in the carboxy-terminal part of the rod domain, which is critical for filament assembly. In transfected cells, the mutant desmin was unable to form a filamentous network. Seven of the 12 patients with mutations in the desmin gene had cardiomyopathy.Mutations in the desmin gene affecting intermediate filaments cause a distinct myopathy that is often associated with cardiomyopathy and is termed "desmin myopathy." The mutant desmin interferes with the normal assembly of intermediate filaments, resulting in fragility of the myofibrils and severe dysfunction of skeletal and cardiac muscles.

Two separate disorders, autosomal dominant distal spinal muscular atrophy type V (dSMA-V) characterized by marked bilateral weakness in the hands and atrophy of thenar eminence and the first interosseous muscle, and Charcot-Marie-Tooth disease type 2D (CMT2D) characterized by sensory deficits in addition to the upper limb weakness and wasting, have been independently linked to chromosome 7p. We identified a multigenerational Mongolian kindred with 17 members affected with either dSMA-V or CMT2D and mapped both syndromes to the same region on chromosome 7p15. A maximum two-point lod score of 4.74 at recombination fraction zero was obtained with marker D7S474. Tight linkage without recombination was also detected with markers D7S526 and D7S632. A multipoint lod score of 6.07 suggested that the gene is located between markers D7S526 and D7S474. A single conserved haplotype was associated with dSMA-V and CMT2D. Based on informative recombination events, the disease locus was placed between markers D7S516 and D7S1514 within the 7p15 band. Data obtained from this study suggest that a single gene is responsible for both syndromes, dSMA-V and CMT2D, and extend our knowledge of the candidate region.

The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt–Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future “epidemic curve” of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD “epidemic.” The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation.

Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells1,2,3,4. The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy5. We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy.