Clinical Outcomes of Patients with High-risk Metastatic Hormone-naïve Prostate Cancer: A 3-year Interim Analysis of the Observational J-ROCK Study.

BACKGROUND: Androgen deprivation therapy (ADT), administered alone, as combined androgen blockade (CAB) or as ADT plus androgen receptor signalling inhibitors (ARSIs) or ADT plus docetaxel, is the standard treatment for metastatic hormone-naïve prostate cancer (mHNPC) in Japanese real-world practice. OBJECTIVE: To investigate treatment patterns and clinical outcomes in LATITUDE criteria high-risk mHNPC. DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, multicentre, J-ROCK registry study enrolled patients initiating ADT in Japan after May 2019, and categorised them as cohort 1 (ADT or CAB) or cohort 2 (ADT plus ARSIs or docetaxel). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, progression-free survival (PFS), time to castrate-resistant prostate cancer (CRPC), overall survival (OS), and safety were evaluated. PFS, time to CRPC, and OS were estimated via the Kaplan-Meier method and between-cohort comparisons via multivariate Cox regression models. RESULTS AND LIMITATIONS: In total, 974 patients were included (cohort 1: 38.1%, cohort 2: 61.9%). CAB was preferred (67.4%) to ADT alone in cohort 1, and abiraterone acetate plus prednisolone was used most frequently in cohort 2 (59.4%). The proportion of patients with ≥50%/≥90% PSA decline or who achieved PSA ≤0.2/≤0.1 ng/ml tended to be higher in cohort 2. PFS (adjusted hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.55), time to CRPC (0.28; 95% CI 0.23-0.36), and OS (0.54; 95% CI 0.35-0.82) were longer in cohort 2. In cohorts 1 and 2, adverse drug reactions of special interest (ADRSIs) occurred in 1.3% and 15.1%, and fatal adverse events occurred in 1.9% and 1.7%, respectively. Limitations included nonrandomised design, varying time since marketing authorisation for ARSIs, and limited safety assessments. CONCLUSIONS: ADT plus ARSIs or docetaxel was used more frequently to treat high-risk mHNPC than standard ADT/CAB and was associated with more favourable clinical outcomes. Although ADRSIs were reported more in cohort 2, the safety profile was considered tolerable. PATIENT SUMMARY: Although many treatment options are available for high-risk metastatic prostate cancer, there are limited reports on real-world clinical experience with different therapies outside of the clinical trial setting. In this study, we compared clinical and safety outcomes with different treatment regimens, using a large series of patients with high-risk metastatic hormone-naïve prostate cancer across Japan. We found that androgen deprivation therapy in combination with newer androgen receptor signalling inhibitors resulted in improved response compared with androgen deprivation therapy alone or in combination with a first-generation antiandrogen.

Sex differences in symptom presentation and their impact on diagnostic accuracy in Werner syndrome.

AIM: Whether sex differences exist in hereditary progeroid syndromes remains unclear. In this study, we investigated sex differences in patients with Werner syndrome (WS), a model of human aging, using patient data at the time of diagnosis. METHODS: The presence of six cardinal signs in the diagnostic criteria was retrospectively evaluated. RESULTS: We found that the percentage of patients with all cardinal signs was higher in males than in females (54.2% vs. 21.2%). By the age of 40 years, 57.1% of male patients with WS presented with all the cardinal signs, whereas none of the female patients developed all of them. In particular, the frequency of having a high-pitched, hoarse voice, a characteristic of WS, was lower in female patients. The positive and negative predictive values for clinical diagnosis were 100% for males and females, indicating the helpfulness of diagnostic criteria regardless of sex. More female patients than male (86.7% vs. 64%) required genetic testing for their diagnosis because their clinical symptoms were insufficient, suggesting the importance of genetic testing for females even if they do not show typical symptoms of WS. Finally, the frequency of abnormal voice was lower in patients with WS harboring the c.3139-1G > C homozygous mutation. CONCLUSION: These results indicate, for the first time, that there are sex differences in the phenotypes of hereditary progeroid syndromes. The analysis of this mechanism in this human model of aging may lead to the elucidation of sex differences in the various symptoms of normal human aging. Geriatr Gerontol Int 2024; 24: 161-167.

Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.

Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.

Estimation of a Structural Equation Modeling of Quality of Life Mediated by Difficulty in Daily Life in Survivors of Breast Cancer.

BACKGROUND: The purpose of this study was to clarify the structural relationship of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experiences in daily activities, as health-related indicators. METHODS: Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences in daily activities). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from emotional distress (anxiety and depression) to QOL, and from SOC to emotional distress, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences in daily activities, and from negative experiences in daily activities to anxiety and depression were considered indirect effects on QOL. RESULTS: The participants comprised 73 survivors of breast cancer. The goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and the indirect effect was 0.164. CONCLUSIONS: An additional finding of this study is that coping with difficulty in daily life and negative experiences in daily activities related to QOL may improve QOL.

Relationship between Lower Extremity Peripheral Arterial Disease and Mild Cognitive Impairment in Hemodialysis Patients.

BACKGROUND: The link between arterial stiffness and mild cognitive impairment (MCI) in patients on hemodialysis (HD) has been receiving increased attention. The purpose of this study was to investigate the relationship between cognitive function and ankle brachial index (ABI) and toe brachial index (TBI) values in patients on hemodialysis. Of the 100 participants (mean age: 67.9 years; average history of hemodialysis: 7.3 years). Of these, 46.0% had MCI. The MoCA-J scores were significantly higher in the ABI ≥ 1.06 group. However, the MoCA-J scores divided into the two groups according to the TBI cutoff value were not significantly different. In a multiple regression model with the MoCA-J scores as the objective variable, the ABI was a significantly associated factor. This study indicates that a low ABI might be associated with MCI.

Occupational Dysfunction as a Mediator between Recovery Process and Difficulties in Daily Life in Severe and Persistent Mental Illness: A Bayesian Structural Equation Modeling Approach.

Background: This study is aimed at verifying a hypothetical model of the structural relationship between the recovery process and difficulties in daily life mediated by occupational dysfunction in severe and persistent mental illness (SPMI). Methods: Community-dwelling participants with SPMI were enrolled in this multicenter cross-sectional study. The Recovery Assessment Scale (RAS), the World Health Organization Disability Assessment Schedule second edition (WHODAS 2.0), and the Classification and Assessment of Occupational Dysfunction (CAOD) were used for assessment. Confirmatory factor analysis, multiple regression analysis, and Bayesian structural equation modelling (BSEM) were determined to analyze the hypothesized model. If the mediation model was significant, the path coefficient from difficulty in daily life to recovery and the multiplication of the path coefficients mediated by occupational dysfunction were considered as each the direct effect and the indirect effect. The goodness of fit in the model was determined by the posterior predictive P value (PPP). Each path coefficient was validated with median and 95% confidence interval (CI). Results: The participants comprised 98 individuals with SPMI. The factor structures of RAS, WHODAS 2.0, and CAOD were confirmed by confirmatory factor analysis to be similar to those of their original studies. Multiple regression analysis showed that the independent variables of RAS were WHODAS 2.0 and CAOD, and that of CAOD was WHODAS 2.0. The goodness of fit of the model in the BSEM was satisfactory with a PPP = 0.27. The standardized path coefficients were, respectively, significant at -0.372 (95% CI: -0.586, -0.141) from "difficulty in daily life" to "recovery" as the direct effect and at -0.322 (95% CI: -0.477, -0.171) mediated by "occupational dysfunction" as the indirect effect. Conclusions: An approach for reducing not only difficulty in daily life but also occupational dysfunction may be an additional strategy of person-centered, recovery-oriented practice in SPMI.

Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases.

BACKGROUND: Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by variants in WRN. The International Registry of Werner Syndrome has identified biallelic pathogenic variants in 179/188 cases of classical WS. In the remaining nine cases, only one heterozygous pathogenic variant has been identified. METHODS: Targeted long-read sequencing (T-LRS) on an Oxford Nanopore platform was used to search for a second pathogenic variant in WRN. Previously, T-LRS was successfully used to identify missing variants and analyse complex rearrangements. RESULTS: We identified a second pathogenic variant in eight of nine unsolved WS cases. In five cases, T-LRS identified intronic splice variants that were confirmed by either RT-PCR or exon trapping to affect splicing; in one case, T-LRS identified a 339 kbp deletion, and in two cases, pathogenic missense variants. Phasing of long reads predicted all newly identified variants were on a different haplotype than the previously known variant. Finally, in one case, RT-PCR previously identified skipping of exon 20; however, T-LRS did not detect a pathogenic DNA sequence variant. CONCLUSION: T-LRS is an effective method for identifying missing pathogenic variants. Although limitations with computational prediction algorithms can hinder the interpretation of variants, T-LRS is particularly effective in identifying intronic variants.

Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome.

Adult progeria Werner syndrome (WS), a rare autosomal recessive disorder, is characterized by accelerated aging symptoms after puberty. The causative gene, WRN, is a member of the RecQ DNA helicase family and is predominantly involved in DNA replication, repair, and telomere maintenance. Here, we report the generation of iPS cells from a patient with WS and correction of the WRN gene by the CRISPR/Cas9-mediated method. These iPSC lines would be a valuable resource for deciphering the pathogenesis of WS.

A novel podocyte protein, R3h domain containing-like, inhibits TGF-ß-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane.

Not only in kidney glomerular physiological function but also glomerular pathology especially in diabetic condition, glomerular podocytes play pivotal roles. Therefore, it is important to increase our knowledge about the genes and proteins expressed in podocytes. Recently, we have identified a novel podocyte-expressed gene, R3h domain containing-like (R3hdml) and analyzed its function in vivo as well as in vitro. Transforming growth factor-ß (TGF-ß) signaling regulated the expression of R3hdml. And R3hdml inhibited p38 mitogen-activated protein kinase phosphorylation, which was induced by TGF-ß, leading to the amelioration of podocyte apoptosis. Furthermore, a lack of R3hdml in mice significantly worsened glomerular function in streptozotocin (STZ)-induced diabetes, while overexpression of R3hdml ameliorated albuminuria in STZ-induced diabetes. Our results surmise that the functional analyses of R3hdml may lead to the development of novel therapeutic strategies for diabetic nephropathy in the future. KEY MESSAGES: • A novel podocyte expressed protein R3h domain containing-like was identified. • R3HDML inhibits podocyte apoptosis by inhibiting TGF-ß-mediated p38 MAPK signaling. • Overexpression of R3HDML ameliorates albuminuria in STZ-induced diabetes mice. • R3HDML may prove to be a novel therapeutic strategy for diabetic nephropathy.

Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome.

Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro. On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.

Development of a New Daily Activities Scale for the Affected Hand after Stroke.

OBJECTIVES: There are few scales that reflect the function of the stroke-affected arm as it relates to the performance of daily activities while also indicating the difficulty of scale items. In this study, we developed the Activities Specific Upper-extremity Hemiparesis Scale (ASUHS) to evaluate daily activities performable by the affected arm after stroke. We also clarified the validity, reliability, and item difficulty of the scale. METHODS: The participants were 145 patients with stroke who were consecutively admitted to a convalescent rehabilitation ward. The unidimensionality of ASUHS was assessed by principal component analysis. Analyses of item discrimination and content validity were conducted to assess the overall validity. Reliability was evaluated by assessing internal consistency and inter-rater reliability. Item difficulties were determined by Rasch analysis. RESULTS: Unidimensionality, high discrimination, and good content validity were shown for all items. ASUHS consists of a dominant hand scale and non-dominant hand scale. Both scales showed good internal consistency (Cronbach's α coefficient = 0.99) and substantial inter-rater reliability (Cohen's Kappa coefficient = 0.74 and 0.75, respectively). Item difficulty was determined as being in the range -8.71 to +5.18 logit. CONCLUSIONS: This study suggested good validity and reliability of ASUHS. Furthermore, because the item difficulties of daily activities performed by the affected arm were clarified, therapists can use ASUHS to identify the process that should be the next focus for training. Consequently, therapists may be able to train patients in daily activities that match the affected arm's ability step by step rather than determining training activities empirically.

Neurocognitive dysfunction and brain FDG-PET/CT findings in HIV-infected hemophilia patients and HIV-infected non-hemophilia patients.

This single-institution cross-sectional study aimed to grasp the prevalence and features of neurocognitive dysfunction in HIV-infected hemophilia patients in Japan. We conducted neuropsychological tests and medical examinations in 56 HIV-infected hemophilia patients who received outpatient treatment at the AIDS Clinical Center, National Center for Global Health and Medicine. A total of 388 HIV-infected non-hemophilia patients who received outpatient treatment at the same institution were included as a control group. To investigate sites responsible for neurocognitive dysfunction in HIV-infected hemophilia patients using brain FDG-PET/CT scans, the accumulation of FDG in each brain region was compared. Approximately 50% of HIV-infected hemophilia patients had neurocognitive dysfunction. The prevalence of asymptomatic neurocognitive impairment was high (34%). Neurocognitive dysfunction was associated with educational level in HIV-infected hemophilia patients. In the symptomatic group, hemophilic arthropathy and history of cerebrovascular disorders were associated with neurocognitive dysfunction. Left temporal lobe function was reduced in the symptomatic group.

R3hdml regulates satellite cell proliferation and differentiation.

In this study, we identified a previously uncharacterized skeletal satellite cell-secreted protein, R3h domain containing-like (R3hdml). Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice are lower compared to control mice. Expression levels of cell cycle-related markers, phosphorylation of Akt, and expression of insulin-like growth factor within the skeletal muscle are reduced in R3hdml KO mice compared to control mice. Expression of R3hdml increases during muscle regeneration in response to cardiotoxin (CTX)-induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml. Our results indicate that R3hdml is required for skeletal muscle development, regeneration, and, in particular, satellite cell proliferation and differentiation.

Emodin, as a mitochondrial uncoupler, induces strong decreases in adenosine triphosphate (ATP) levels and proliferation of B16F10 cells, owing to their poor glycolytic reserve.

Many types of cancer cells show a characteristic increase in glycolysis, which is called the "Warburg effect." By screening plant extracts, we identified one that decreases cellular adenosine triphosphate (ATP) levels and suppresses proliferation of malignant melanoma B16F10 cells, but not of noncancerous MEF cells. We showed that its active ingredient is emodin, which showed strong antiproliferative effects on B16F10 cells both in vitro and in vivo. Moreover, we also found that emodin can function as a mitochondrial uncoupler. Consistently, three known mitochondrial uncouplers also displayed potent antiproliferative effects and preferential cellular ATP reduction in B16F10 cells, but not in MEF cells. These uncouplers provoked comparable mitochondrial uncoupling in both cell types, but they manifested dramatically different cellular effects. Namely in MEF cells, these uncouplers induced three to fivefold increases in glycolysis from the basal state, and this compensatory activation appeared to be responsible for the maintenance of cellular ATP levels. In contrast, B16F10 cells treated with the uncouplers showed less than a twofold enhancement of glycolysis, which was not sufficient to compensate for the decrease of ATP production. Together, these results raise the possibility that uncouplers could be effective therapeutic agents specifically for cancer cells with prominent "Warburg effect."

Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C.

Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN gene (WRN). Most Japanese WS patients are born from a consanguineous marriage with homozygous WRN mutations. We herein report a rare WS patient born from non-consanguineous parents with compound heterozygous WRN mutations with a novel heterogeneous c.1720+1G>A substitution plus the most frequent heterogeneous c.3139-1G>C substitution among Japanese. Although the present case showed clinical characteristics common to previous Japanese WS patients, he had not developed any malignant tumors as of 43 years of age, suggesting that WS patients with this particular genetic mutation have a different phenotype than others.

Biallelic WRN Mutations in Newly Identified Japanese Werner Syndrome Patients.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by systemic accelerated aging. It is caused by pathogenic variants of the WRN gene that encodes a nuclear helicase. In this report, we describe 4 newly identified WS cases among those referred to the Japanese Werner Consortium, Chiba University, Japan. All 4 cases were compound heterozygotes of the Japanese founder mutation, c.3139-1G>C, and a novel null pathogenic variant, c.1587G>A, c.2448+1G>A, or c.3233+1G>T, or an amino acid substitution variant, c.1720G>A, p.Gly574Arg. These 3 null pathogenic variants were not previously described. The p. Gly574Arg was previously reported in a European patient, and the identification of the second p. Gly574Arg case, with classical WS features, further confirmed the pathogenic nature of this variant. For the case with c.3233+1G>T, we determined the phase of 2 disease-causing mutations and demonstrated that they are on different chromosomes. This assay would be particularly important for those cases with ambiguous clinical diagnosis.

Prediction of changes in functional ability of inpatients with schizophrenia using logarithmic and linear regression modelling.

BACKGROUND/OBJECTIVE: Few studies have addressed the type of time course regression that can predict changes in functional ability in inpatients with schizophrenia. This study investigated the possibility of predicting changes in functional ability by logarithmic and linear regression modelling when treating schizophrenia. METHODS: This longitudinal study included two analysis rounds. Analysis 1 comprised 40 inpatients (male/female: 16/24, mean age: 39.7 ± 13.5 years) for the identification of the time course of changes in functional ability based on the Activity Profile Scale for Patients with Psychiatric Disorders score from the group data. Analysis 2 comprised 17 inpatients (male/female: 9/8, mean age: 38.5 ± 9.4 years) to ensure correlation of the group data with the prediction of each individual's degree of functional ability. RESULTS: In Analysis 1, Activity Profile Scale for Patients with Psychiatric Disorders score was assessed at the initial occupational therapy visit, one week and one month thereafter, and at discharge; logarithmic modelling using the scores at the initial visit, one month later and at discharge was more suitable (R2 = .506, p < .001) than the logarithmic and linear regression models using other score combinations. In Analysis 2, the individual's predicted Activity Profile Scale for Patients with Psychiatric Disorders scores at discharge, as calculated by logarithmic modelling using scores from the initial visit and one month later, correlated moderately with actual Activity Profile Scale for Patients with Psychiatric Disorders scores (R2 = .574, p < .001; ICC = .747, p < .001). CONCLUSION: Logarithmic modelling based on Activity Profile Scale for Patients with Psychiatric Disorders score accurately predicted changes in the functional ability of inpatients with schizophrenia and is sufficiently uncomplicated to be adopted in daily clinical practice.

Association of age and time of disease with HIV-associated neurocognitive disorders: a Japanese nationwide multicenter study.

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome.

OBJECTIVES: To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. DESIGN: Retrospective cohort. SETTING: Longitudinal survey of WS and literature search for case reports. PARTICIPANTS: Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). MEASUREMENTS: A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. RESULTS: A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. CONCLUSION: The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future.

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.