Trends, safety, and efficacy of wearable male sexual devices.

INTRODUCTION: The prevalence of male sexual dysfunction (MSD) increases with age, with >50% of men aged >40 years reporting erectile dysfunction (ED). In recent years, wearable male sex devices (WMSDs) have been increasingly utilized by patients and recommended by sexual medicine clinicians. OBJECTIVES: This study seeks to investigate the safety and efficacy of products currently marketed for the treatment of MSD. METHODS: Available products for WMSDs were reviewed by analyzing product websites, forums, advertisements, and clinical recommendations. Qualitative comparisons were based on patient reviews, cost, and specific features. Investigatory evidence and Food and Drug Administration status were also reviewed. Additionally, Google Trends was used to determine the popularity of devices over time. RESULTS: Eight WMSDs for the treatment of MSD and enhancement of sexual pleasure were reviewed. Constriction bands, such as the Maintain Ring Loop, Eddie by Giddy, and Xialla, have shown significant benefits in clinical trials and were the most popular devices among patients. Smart devices can provide real-time feedback on erectile quality and/or sexual performance. Similar to the RigiScan, the Adam sensor provides feedback on erectile quality while monitoring changes in penile tumescence during sleep with additional analysis available through a mobile application. Neuromodulation devices such as the Morari Patch and vPatch/in2 Patch use electrical stimulation to delay ejaculation and improve sexual function. The FirmTech Performance Ring uses sensors to track the vital signs of erectile fitness with clinical trials ongoing. CONCLUSIONS: Overall, this review describes the available investigatory evidence for a range of WMSDs and highlights the potential benefits and limitations of these devices in treating MSD and enhancing sexual pleasure. Further research is needed to evaluate the effectiveness of these devices and to determine which ones may be the most suitable for individual patients.

Systematic reanalysis of copy number losses of uncertain clinical significance.

BACKGROUND: Reanalysis of exome/genome data improves diagnostic yield. However, the value of reanalysis of clinical array comparative genomic hybridisation (aCGH) data has never been investigated. Case-by-case reanalysis can be challenging in busy diagnostic laboratories. METHODS AND RESULTS: We harmonised historical postnatal clinical aCGH results from ~16 000 patients tested via our diagnostic laboratory over ~7 years with current clinical guidance. This led to identification of 37 009 copy number losses (CNLs) including 33 857 benign, 2173 of uncertain significance and 979 pathogenic. We found benign CNLs to be significantly less likely to encompass haploinsufficient genes compared with the pathogenic or CNLs of uncertain significance in our database. Based on this observation, we developed a reanalysis pipeline using up-to-date disease association data and haploinsufficiency scores and shortlisted 207 CNLs of uncertain significance encompassing at least one autosomal dominant disease-gene associated with haploinsufficiency or loss-of-function mechanism. Clinical scientist reviews led to reclassification of 15 CNLs of uncertain significance as pathogenic or likely pathogenic. This was ~0.7% of the starting cohort of 2173 CNLs of uncertain significance and 7.2% of 207 shortlisted CNLs. The reclassified CNLs included first cases of CNV-mediated disease for some genes where all previously described cases involved only point variants. Interestingly, some CNLs could not be reclassified because the phenotypes of patients with CNLs seemed distinct from the known clinical features resulting from point variants, thus raising questions about accepted underlying disease mechanisms. CONCLUSIONS: Reanalysis of clinical aCGH data increases diagnostic yield.

Does climate impact inflatable penile prosthesis infection (IPP) risk? Assessment of temperature and dew point on IPP infections.

BACKGROUND: Variations in climate have been associated with a greater risk of surgical site infections, urinary tract infections, and changes in the skin microbiome; however, limited data exist on the impact of climate on inflatable penile prosthesis (IPP) infections. AIM: We sought to evaluate the impact of climate on the risk of IPP infections in a large international, multicenter cohort. METHODS: We performed a multi-institutional, retrospective study of patients undergoing IPP surgery. We then evaluated whether the month or season, during which surgery was performed, affected device infections. Implant infections were defined as infections requiring device explantation. A univariate logistic regression analysis was undertaken. OUTCOMES: Our primary outcome was implant infection. RESULTS: A total of 5289 patients with a mean age of 62.2 ± 10.8 years received IPP placement. There was a fairly even distribution of implants performed in each season. A total of 103 (1.9%) infections were recorded. There were 32 (31.1%) IPP infections in patients who underwent surgery in the summer, followed by 28 (27.2%) in the winter, 26 (25.2%) in the spring, and 17 (16.5%) in the fall. No statistically significant differences were recorded in terms of season (P = .19) and month (P = .29). The mean daily temperature (P = .43), dew point (P = .43), and humidity (P = .92) at the time of IPP placement was not associated with infection. CLINICAL IMPLICATIONS: These findings provide reassurance to prosthetic urologists that infection reduction strategies do not need to be tailored to local climate. STRENGTHS AND LIMITATIONS: Climate data were not directly recorded for each hospital, but rather based on the monthly averages in the city where the surgery was performed. CONCLUSION: The climate at time of IPP placement and time of year of surgery is not associated with IPP infection risk.

Peyronie's disease response to intralesional collagenase clostridium histolyticum therapy is independent of baseline testosterone.

BACKGROUND: Testosterone plays an important role in collagen metabolism, transforming growth factor-ß1 expression, and wound healing, which are all critical factors in pathogenesis of Peyronie's disease. Some clinical studies have suggested an association between Peyronie's disease and hypogonadism. OBJECTIVE: We sought to investigate whether baseline total testosterone levels influence response to intralesional collagenase clostridium histolyticum in Peyronie's disease. METHODS: A retrospective review of patients receiving collagenase clostridium histolyticum injections with available total testosterone levels within 1 year of initial injection was conducted at a single institution. Baseline demographics, hypogonadal status, total testosterone, number of collagenase clostridium histolyticum cycles, and pre- and post-treatment degrees of curvature were collected. Hypogonadism was defined as total testosterone <300 ng/dL. RESULTS AND DISCUSSION: Thirty-six men were included with mean age of 58.2 years (SD 10.4) and mean body mass index 26.8 (SD 3.2). The mean total testosterone was 459.2 ng/dL (SD 144.0), and four (11.1%) were hypogonadal. Mean pre-treatment curvature was 47.6°, and mean post-treatment curvature was 27.8°, with mean improvement of 19.9° (40.1%). Hypogonadal status was not significantly associated with more severe curvature, 46.4° among hypogonadal men as to 57.5° among eugonadal men (p = 0.32). On linear regression analysis, total testosterone did not significantly predict improvement in degrees (ß = -0.02; R2 = 0.06; p = 0.14) or percent (ß = 0.0; R2 = 0.05; p = 0.18). Improvement in neither degrees nor percent differed significantly by hypogonadal status (p = 0.41 and 0.82, respectively). The cycle number did significantly predict greater improvement in curvature on both univariate and multivariate analyses (ß = 5.7; R2 = 0.34; p < 0.01). CONCLUSION: Neither total testosterone nor hypogonadism is associated with a degree of improvement after collagenase clostridium histolyticum treatment.

Penetrative anal intercourse may require high axial loading forces.

BACKGROUND: Despite increases in the lifetime prevalence of anal intercourse, little is known about the safety of inflatable penile prosthesis use during anal intercourse or the forces required for anal penetration. AIM: We sought to determine the force required for anal penetration. METHODS: A digital force gauge device was secured to a silicone phallus with a length and girth representative of the average male phallus in the United States and inserted into the anal canal of 6 male participants for a total of 5 measurements per participant. The maximum axial forces on insertion were recorded. Participants then completed a survey eliciting demographic information and past experience with receptive anal intercourse. OUTCOMES: The outcome measure was the force recorded during insertion of a force gauge device into the anal canal. RESULTS: The median maximal force recorded on anal penetration was 26.5 N (2.7 kg; range: 16.1-51.7 N or 1.64-5.27 kg). Participants who engaged in receptive anal intercourse more than once per month tended to use lesser median maximal forces (25.7 N or 2.62 kg) than participants who engaged less frequently in receptive anal intercourse (41.6 N or 4.24 kg). CLINICAL IMPLICATIONS: Compared with the forces required for vaginal penetration, anal penetration forces may cause additional mechanical stress to the phallus. STRENGTHS AND LIMITATIONS: While the study is limited primarily in its small sample size and in the use of a single device for anal penetration with a set size and rigidity, the resulting findings presented here are to our knowledge the first reported data pertaining the force required for anal penetration. CONCLUSION: As the forces required for anal penetration exceeded those for vaginal penetration, clinicians may need to carefully counsel patients on the safe use of an inflatable penile prosthesis for anal intercourse.

Single Dilation in Primary Inflatable Penile Prosthesis Placement Is Associated With Fewer Corporal Complications Than Sequential Dilation.

OBJECTIVE: To assess the difference in outcomes between single dilation (SingD) and sequential dilation (SeqD) in primary penile implantation, hypothesizing that patients who undergo SeqD had higher rates of noninfectious complications. METHODS: We performed a multicenter, retrospective study of men undergoing primary inflatable penile prosthesis placement. Intraoperative complications and postoperative noninfectious outcomes were assessed between the two groups. Multivariable analysis was performed to identify predictors of complications. RESULTS: A total of 3293 patients met inclusion criteria. After matching, there were 379 patients who underwent SingD and 379 patients who underwent SeqD. There was no significant difference in intraoperative complications between patients who underwent SingD vs SeqD, nor was there any difference in cylinder length (20 cm with interquartile range [IQR] 18-21 cm vs 20 cm with IQR 18-20 cm respectively, P = .4). On multivariable analysis, SeqD (OR 5.23 with IQR 2.74-10, P < .001) and older age (OR 1.04 with IQR 1.01-1.06, P = .007) were predictive of postoperative noninfectious complications. There was no significant difference in intraoperative complications between patients who underwent SingD vs SeqD, nor was there any difference in cylinder length. SeqD and older age were predictive of postoperative noninfectious complications. CONCLUSION: During inflatable penile prosthesis placement in the uncomplicated patient without fibrosis, SingD is a safe technique to utilize during implantation that will minimize postoperative adverse events, and promote device longevity without loss of cylinder length.

Testosterone replacement therapy is associated with high satisfaction rates: results of a survey study.

Despite a well-documented increase in both the prevalence of Testosterone Deficiency (TD) and prescription of testosterone replacement therapy (TRT), few studies have investigated the preferences of patients receiving TRT and factors associated with increased treatment satisfaction. To investigate the preferences of patients receiving TRT and factors associated with improved treatment satisfaction, an open survey was completed by 140 men receiving TRT at a single institution. Survey questions investigated demographics, symptom burden of TD, TRT regimen, treatment preferences, and treatment satisfaction. 62.7% of patients were satisfied with their current TRT regimen. Those using auto-injectors (91.7%, odds ration [OR] = 9.3), subcutaneous pellets (90.0%, OR = 15.2), and intramuscular injections (67.5%, OR = 5.7), were with significantly increased satisfaction rates (p < 0.05). The majority of patients indicated that they would prefer to receive TRT injections when self-administered or administered at home. While patients noted that treatment efficacy was a significant driving factor when evaluating a TRT regimen, few patients felt that cost was the most significant factor.

Does Medicaid cover artificial urinary sphincter and male urethral sling surgery?-a state-by-state analysis.

Background: Information regarding the Medicaid coverage of artificial urinary sphincter (AUS) and male suburethral slings (MS) placement in the United States (US) is not readily available. In this manuscript, we seek to elucidate the state-by-state Medicaid coverage of these two procedures in the US. Methods: State Medicaid websites were utilized to access publicly available physician fee schedules for the calendar year 2020. Fee schedules were searched for current procedural terminology (CPT) codes. CPT codes representing insertion of tandem cuff, insertion of AUS, removal of AUS, removal and replacement AUS, sling operation for correction of male stress urinary incontinence (SUI), and removal or revision of sling for male SUI were utilized. Data were recorded by the procedure for each device, including the coverage status and physician fees. Results: Of the 50 US states analyzed, 49 publish publicly accessible physician fee schedules. All 49 of these states reported coverage for removal with and without revision of the AUS, and 48 states reported coverage for insertion of an AUS, and insertion of a tandem cuff. The median reimbursement for each AUS related procedure was $624.00 ($181.84-$10,960.90) for tandem cuff, $665.54 ($199.89-$11,949.86) for AUS insertion, $528.03 ($146.90-$1,893.12) for AUS removal, and $630.29 ($208.55-$11,586.74) for AUS revision. All 49 states reported coverage for placement of MS, and 48 states reported coverage for removal or revision of MS. The median reimbursement was $652.57 ($198.00-$5,237.35) for MS placement and $554.47 ($104.27-$2,288.93) for MS revision. Conclusions: AUS and MS procedures in the Medicaid population are covered by nearly all states. Therefore, surgical treatment of SUI may be offered to Medicaid patients in most states without reimbursement concerns.

Oral testosterone therapy: past, present, and future.

INTRODUCTION: Testosterone replacement therapy (TRT) remains a commonly utilized treatment for men with testosterone deficiency (TD). Despite the recent FDA approval of new oral TRT medications, concerns remain regarding their efficacy and safety, and prescription rates for these medications have decreased compared to those for TD medications with other routes of administration. OBJECTIVE: In this study we sought to investigate the efficacy and safety of oral testosterone undecanoate (oTU), a new oral TRT medication. METHODS: A comprehensive review of the literature was performed using the Medline, EMBASE, and Cochrane Library databases; 1269 articles were identified, with 44 articles included in the final review and 12 used to perform meta-analyses to investigate the change in serum total testosterone (TT) and risk of adverse effects following oral testosterone undecanoate (oTU) use. Articles were also reviewed to investigate the reported effects of oTU on body composition, liver function, hematologic assays, lipid profiles, hormone assays, prostate growth, hypertension, and symptoms of TD. RESULTS: Across placebo-controlled randomized trials, there was no significant increase in TT for those receiving oTU vs placebo (mean difference, -0.26 [95% CI, -1.26 to 0.73]). On subanalysis, when eugonadal participants received oTU, a significant decrease in TT was demonstrated (mean difference -0.86 [95% CI, -1.28 to 0.43]). When participants who were hypogonadal at baseline received oTU, a significant increase in TT compared to placebo was seen (mean difference 1.25 [95% CI, 0.22-2.29]). There was no significant risk of adverse effects (RR, -0.03 [95% CI, -0.08 to 0.03]) or serious adverse effects (RR, 0.15 [95% CI, -0.66 to 0.96]) in the oTU groups compared to placebo. CONCLUSION: oTU was found to be well tolerated in hypogonadal patients, resulting in improved testosterone levels, height velocity, and sexual symptoms, without significant hepatotoxicity, prostatic enlargement, or worsening hypertension. There was no consensus regarding the effect of oTU on lean and fat mass percentages, hematologic assays, lipid profiles, mood, and general well-being.

AUA-recommended Antibiotic Prophylaxis for Primary Penile Implantation Results in a Higher, Not Lower, Risk for Postoperative Infection: A Multicenter Analysis.

PURPOSE: Our aim was to determine if the AUA-recommended prophylaxis (vancomycin + gentamicin alone) for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard regimens. MATERIALS AND METHODS: We performed a multicenter, retrospective study of patients undergoing primary inflatable penile prosthesis surgery. Patients were divided into those receiving vancomycin + gentamicin alone and those receiving any other regimen. A Cox proportional-hazards model was constructed adjusted for major predictors. A subgroup analysis to identify the appropriate dosage of gentamicin was also performed. RESULTS: A total of 4,161 patients underwent primary inflatable penile prosthesis placement (2,411 received vancomycin + gentamicin alone and 1,750 received other regimens). The infection rate was similar between groups, 1% vs 1.2% for standard vs nonstandard prophylaxis. In the multivariable analysis, vancomycin + gentamicin (HR: 2.7, 95% CI: 1.4 to 5.4, P = .004) and diabetes (HR: 1.9, 95% CI: 1.03 to 3.4, P = .04) were significantly associated with a higher risk of infection. Antifungals (HR: 0.08, 95% CI: 0.03 to 0.19, P < .001) were associated with lower risk of infection. There was no statistically significant difference in infection rate between weight-based gentamicin compared to 80 mg gentamicin (HR: 2.9, 95% CI: 0.83 to 10, P = .1). CONCLUSIONS: Vancomycin + gentamicin alone for antibiotic prophylaxis for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard antibiotic regimens while antifungal use is associated with lower infection risk. A critical review of the recommended antimicrobial prophylactic regimens is needed. Prospective research is needed to further elucidate best practices in inflatable penile prosthesis antimicrobial prophylaxis.

Satisfaction rates of inflatable penile prosthesis in men who have sex with men are high.

Men with erectile dysfunction (ED) have high patient satisfaction after placement of inflatable penile prostheses (IPP). The impact on satisfaction and quality of life has never been studied in men who have sex with men (MSM). This study sought to assess the satisfaction rates and quality of life of MSM after placement of IPP for ED. This study was a multi-institutional, retrospective study that enrolled adult men who self-identified as MSM and underwent IPP placement. Two questionnaires were administered at one time point post-operatively, the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), and the Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) questionnaire. Results of these questionnaires were analyzed with descriptive statistics. Forty-nine MSM were assessed retrospectively with median age of 62 years with average follow-up of 15.2 months. Median EDITS score was 93.2/100 (range, 70.5-100). Median overall QoLSPP score was 72/80 (58-79), with median scores of 22/25 (16-25), 19/20 (13-20), 18/20 (12-20), and 14/15 (9-15), for the functional, personal, relational, and social domains respectively. Overall, MSM report high satisfaction rates and quality of life after IPP placement. A better understanding of the needs and demands of this patient population may lead to improved patient satisfaction and quality of life.

Comparing Risk Factors for Adverse Outcomes in Virgin Inflatable Penile Prosthesis Implantations and Revisions: A Retrospective Cohort Study.

INTRODUCTION: Recent studies place the risk of infection following inflatable penile prosthesis (IPP) implantation at 1-2%. This risk may be underestimated due to the exclusion of high-risk patients, such as patients undergoing multiple revisions or revision following IPP infection, from data. AIM: To calculate the rate of postoperative complications for all patients undergoing IPP implantation and revision, and to determine the risk factors predictive of complications following virgin implantation and revision independently. METHODS: The charts of 280 patients undergoing 331 IPP implantations performed over the last 20 years at a large academic medical center were reviewed for postoperative complications and suspected preoperative and operative risk factors. MAIN OUTCOME MEASURE: This included the prevalence of adverse operative outcomes including postoperative infection and device malfunction. RESULTS: 63 (20.7%) surgeries resulted in postoperative complications: 38 (12.5%) resulting in device malfunction and 25 (8.20%) resulting in infection. Smoking (odds ratio [OR] = 4.14, P = .00) was associated with overall postoperative complications. Within subgroups, concomitant procedures (OR = 4.77, P = .03) were associated with infection for those undergoing virgin implantation, but not those undergoing revision procedures. Alternatively, diabetes mellitus (DM) (OR = 28.3, P = .02) was associated with postoperative infection for those undergoing revision procedures, but not those undergoing virgin implantation. CONCLUSION: The rate of postoperative infection for all patients undergoing IPP was found to be 8.20%, a higher estimate than historically recorded. To varying degrees, smoking, concomitant procedures, and DM were associated with adverse operative outcomes. Subset analyses revealed significant associations between postoperative infections and either concomitant procedures or DM in those undergoing virgin implantations or revision surgeries, respectively. Miller JA, Bennett NE. Comparing Risk Factors for Adverse Outcomes in Virgin Inflatable Penile Prosthesis Implantations and Revisions: A Retrospective Cohort Study. J Sex Med 2020;8:388-395.

First presentation of a scrotal glomus tumor in an adolescent male: A case report.

Glomus tumor of the scrotal skin is an extremely rare diagnosis in adult men with only five previous cases reported in the literature. We report the case of a 19-year-old man who was diagnosed with a glomus tumor following the surgical removal of a painful scrotal lesion, and further discuss the diagnosis and treatment of scrotal glomus tumors.

Tumor-to-Nipple Distance as a Predictor of Nipple Involvement: Expanding the Inclusion Criteria for Nipple-Sparing Mastectomy.

BACKGROUND: A tumor-to-nipple distance of greater than 2 cm has traditionally been considered a criterion for nipple-sparing mastectomy. This study evaluates whether magnetic resonance imaging and sonographic measurements of tumor-to-nipple distance accurately reflect the risk of nipple involvement by disease. METHODS: All nipple-sparing mastectomy cases with implant-based reconstruction performed by the senior author between July 2006 and December 2014 were retrospectively reviewed. Therapeutic cases with preoperative magnetic resonance imaging or sonography were included. RESULTS: One hundred ninety-five cases were included. Preoperative imaging consisted of sonography (n = 169), magnetic resonance imaging (n = 152), or both (n = 126). With sonography, nipple involvement did not differ between nipple-sparing mastectomy candidates and noncandidates using a tumor-to-nipple distance cutoff of 2 cm (10.7 percent versus 10.6 percent; p = 0.988) or 1 cm (9.3 percent versus 15.0 percent; p = 0.307). With magnetic resonance imaging, nipple involvement did not differ between candidates and noncandidates using a cutoff of 2 cm (11.6 percent versus 12.5 percent; p = 0.881) or 1 cm (11.4 percent versus 13.8 percent; p = 0.718). When sonography and magnetic resonance imaging findings were both available and concordant, nipple involvement still did not differ between candidates and noncandidates using a cutoff of 2 cm (8.8 percent versus 11.8 percent; p = 0.711) or 1 cm (7.6 percent versus 14.3 percent; p = 0.535). CONCLUSION: A tumor-to-nipple distance as small as 1 cm, as measured by sonography or magnetic resonance imaging, should not be considered a contraindication to nipple-sparing mastectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL.

About 10% of inherited diseases are caused by nonsense mutations [Trends Mol Med 18 (2012) 688], and nonsense suppression drug therapy promoting translation through premature stop codons is an emerging therapeutic approach. Infantile neuronal ceroid lipofuscinosis (INCL), a childhood neurodegenerative disease, results from mutations in the CLN1 gene encoding the lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1) [Biochim Biophys Acta 1832 (2013) 1806, Hum Mutat (2012) 63, Biochim Biophys Acta 1832 (2013) 1881]. The nonsense mutation p.R151X is the most common disease-causing CLN1 mutation Hum Mutat (2012) 63. In the novel Cln1(R151X) mouse model of INCL, we found large, tissue-specific variations in Cln1(R151X) mRNA level and PPT1 residual enzyme activity. These tissue-specific differences strongly influenced the read-through efficiency of ataluren (PTC124), a well-known nonsense suppression drug. A two-day treatment with ataluren (10 mg/kg) increased PPT1 enzyme activity in the liver and muscle, but not in any other tissue examined. Our study identifies a new challenge/hurdle for read-through drug therapy: variable efficiency of read-through therapy in the different tissues/organs because of tissue-specific variations in nonsense mutant transcript levels.

State-of-the-art equipment for sterilization and biocontainment since 1925.

Tuttnauer is a worldwide leader in the market for sterilization and infection control. An expansive global presence has aided Tuttnauer's growth over the past four decades. Tuttnauer's products are marketed through seven subsidiaries with local dealers in over 120 countries. The company also holds offices in the United States, Netherlands, India, China, and Vietnam. Facing the most challenging and complex projects worldwide, Tuttnauer has become a driving force in advancing technology in this market to a new standard.

The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy.

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive neurodegenerative disorders in children characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. Patients with mutations in CLN1 primarily manifest with infantile NCL (INCL or Haltia-Santavuori disease), which is second only to congenital NCL for its age of onset and devastating progression. CLN1 encodes a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1). Nonsense mutations in CLN1 account for 52.3% of all disease causing alleles in infantile NCL, the most common of which worldwide is the p.R151X mutation. Previously, we have shown how nonsense-mediated decay is involved in the degradation of CLN1 mRNA transcripts containing the p.R151X mutation in human lymphoblast cell lines. We have also shown how the read-through drugs gentamicin and ataluren (PTC124) increase CLN1 (PPT1) enzyme activity. Here, we provide the initial characterization of the novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis that we have generated. This nonsense mutation model recapitulates the molecular, histological and behavioral phenotypes of the human disease. Cln1(R151X) mice showed a significant decrease in Cln1 mRNA level and PPT1 enzyme activity, accumulation of autofluorescent storage material, astrocytosis and microglial activation in the brain. Behavioral characterization of Cln1(R151X) mice at 3 and 5 months of age revealed significant motor deficits as measured by the vertical pole and rotarod tests. We also show how the read-through compound ataluren (PTC124) increases PPT1 enzyme activity and protein level in Cln1(R151X) mice in a proof-of-principle study.

Nonsense-mediated decay in genetic disease: friend or foe?

Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.

A novel c.1135_1138delCTGT mutation in CLN3 leads to juvenile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis is the most common childhood neurodegenerative disorder in the world, with an incidence of 1 in 100,000 live births. More than 400 mutations in at least 14 different genes are linked to multiple clinical variants. These progressive genetic disorders primarily manifest in the central nervous system due to an extensive loss of neurons, primarily in the cerebral and cerebellar cortices. Juvenile neuronal ceroid lipofuscinosis is the most common form and is primarily due to mutations in CLN3, which encodes a protein of unknown function. The most common such mutation in CLN3 is a 1.02-kb deletion that results in a frameshift and subsequent premature termination codon. Here we describe a patient with juvenile neuronal ceroid lipofuscinosis who has a novel c.1135_1138delCTGT mutation in CLN3. This deletion induces a frameshift and premature termination codon in CLN3 messenger ribonucleic acid that is likely recognized by nonsense-mediated decay and degraded, subsequently leading to decreased CLN3 protein abundance.