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Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c. 633delG and the other has c. 631delC. We also confirmed de novo germline (c. 631delC) and low-prevalence somatic (c. 633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10−28), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases. [ABSTRACT FROM AUTHOR]

Background and Objectives: Becker muscular dystrophy (BMD) is an allelic disorder of Duchenne muscular dystrophy (DMD) in which pathogenic variants in DMD cause progressive worsening of motor dysfunction, muscle weakness and atrophy, and death due to respiratory and cardiac failure. BMD often has in-frame deletions that preserve the amino acid reading frame, but there are some cases with microvariants or duplications. In recent years, the importance of therapeutic development and care for BMD has been emphasized. Therefore, the purpose of this study was to understand the clinical characteristics of BMD patients with microvariants or duplications and to determine the genotype-phenotype relationship., Methods: The study focused on patients with pathogenic microvariants or duplications in DMD who were ambulatory after 16 years of age or had specific muscle biopsy results between June 13, 2017, and March 31, 2023. Informed consent was obtained from the patients or their surrogates. Data concerning DMD variants, muscle biopsy findings, skeletal muscle, respiratory and cardiac function, and CNS involvement were collected and analyzed statistically., Results: Thirty-three patients with BMD had pathogenic microvariants (missense variants, nonsense variants, splice site variants, and other microvariants), and 16 patients had in-frame duplications in DMD . Many patients with microvariants had abnormal ECG findings. The effect of variant type on patient outcomes varied. Regardless of the type of microvariant, skeletal muscle and respiratory dysfunction was more severe in mutants of the cysteine-rich/C-terminal domain than in rod domain mutants. On the other hand, there was no significant difference in the complication rate of CNS disorders among the 3 domains of dystrophin., Discussion: Microvariant forms, in particular, tend to vary in clinical severity according to the site of the dystrophin protein mutation rather than the type of pathogenic variant. The results of this study may be useful for genetic counseling, care, and treatment of patients with BMD., Competing Interests: The authors report no conflicts of interest regarding this study. Dr. Madoka Mori-Yoshimura is deceased; to the best of our knowledge, the relevant disclosures are none. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Lissencephaly is a rare brain malformation characterized by abnormal neuronal migration during cortical development. In this study, we performed a comprehensive genetic analysis using next-generation sequencing in 12 unsolved Japanese lissencephaly patients, in whom PAFAH1B1, DCX, TUBA1A, and ARX variants were excluded using the Sanger method. Exome sequencing (ES) was conducted on these 12 patients, identifying pathogenic variants in CEP85L, DYNC1H1, LAMC3, and DCX in four patients. Next, we performed genome sequencing (GS) on eight unsolved patients, and structural variants in PAFAH1B1, including an inversion and microdeletions involving several exons, were detected in three patients. Notably, these microdeletions in PAFAH1B1 could not to be detected by copy number variation (CNV) detection tools based on the depth of coverage methods using ES data. The density of repeat sequences, including Alu sequences or segmental duplications, which increase the susceptibility to structural variations, is very high in some lissencephaly spectrum genes (PAFAH1B1, TUBA1A, DYNC1H1). These missing CNVs were due to the limitations of detecting repeat sequences in ES-based CNV detection tools. Our study suggests that a combined approach integrating ES with GS can contribute to a higher diagnostic yield and a better understanding of the genetic landscape of the lissencephaly spectrum., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Constipation is a very common medical issue among the general population worldwide. However, the association between exercise habits and constipation is still not fully understood. Additionally, no evidence regarding the association between exercise partners and constipation exists. This study aimed to evaluate this issue in a young Japanese population, taking the presence or absence of an exercise partner as an additional variable., Methods: The study subjects consisted of 12,497 Japanese university students. Information on constipation, exercise frequency, exercise intensity, and exercise partners was obtained through a self-administered questionnaire. Constipation was defined as present if a student answered "Yes" to the question, "Have you been constipated often recently?", Results: The prevalence of self-reported constipation was 6.5%. Frequency and intensity of exercise were independently inversely associated with constipation. After adjustment for age, body mass index, drinking, smoking, anemia, and sports injury, exercise with groups and friends was independently inversely associated with constipation (groups: adjusted odds ratio (OR) - 0.70 (95% confidence interval (CI): 0.53-0.90), friends: adjusted OR - 0.56 (95% CI: 0.42-0.74)). After further adjustment by adding intensity and frequency of exercise to confounding factors, only the association between exercise with friends and constipation was still significant (adjusted OR: 0.61 (95% CI: 0.39-0.96))., Conclusions: In this young Japanese population, the frequency and the intensity of exercise and the presence of exercise partners might be independently inversely associated with self-reported constipation. Exercising, especially exercising with others, may have a preventive effect on constipation, and opportunities to exercise with others should be provided., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Ethics Committee of the Ehime University Graduate School of Medicine issued approval 1610012. All subjects were provided an opt-out, and the study protocol was developed in accordance with the ethical guidelines of the Declaration of Helsinki. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Watanabe et al.)

Pathogenic variants of WD repeat domain 45 ( WDR45 ) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of WDR45 using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, WDR45 variants accounted for 12% (6/51) of the females with developmental delay, suggesting that WDR45 is a major gene in females with developmental delay. Pathogenic variants of WDR45 result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population., Methods: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking., Results: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype., Conclusion: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective and Rationale: To investigate the longitudinal incidence of kidney/urinary stones in patients with severe motor and intellectual disabilities and explore health burden events in patients with stone formation., Methods: This was a retrospective, observational study. We identified patients with severe motor and intellectual disabilities who had the following: 1) admission to our hospital wards for >10 years; 2) two or more assessments for stone formation by ultrasonography or computed tomography; and 3) absence of kidney/urinary stones in the first imaging study. The Kaplan-Meier method was used to analyze the cumulative incidence of kidney/urinary stones. Recurrent urinary tract infections, hydronephrosis, renal dysfunction, and death were identified as health burdens., Results: Among the 41 patients (19 men, 22 women; median age, 28 years; range, 8-50 years), stone formation was detected in 11 (27%) patients during the observation period. The cumulative incidence rate of stone formation was 9.8% (95% confidence interval, 3.8-23.9) and 18.7% (95% confidence interval, 9.2-35.7) at five and 10 years, respectively. Death was frequently observed in patients with stone formation; six (55%) of the 11 patients with stone formation died during the follow-up period; two (15%) died among the other 30 patients without stone formation. However, only one patient with stone formation died in a renal event; the causal relationship between the stone formation and the deaths was not clarified., Conclusion: The longitudinal incidence of kidney/urinary stones was higher in patients with severe motor and intellectual disabilities than in the general population. Considering the difficulty of patients with severe motor and intellectual disabilities in conveying their symptoms, regular assessment of the kidney using abdominal imaging may be recommended., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The National Center of Neurology and Psychiatry Ethics Committee issued approval 2021-422. This study was approved by the National Center of Neurology and Psychiatry ethics committee on July 7, 2021 and conformed to the provisions of the Declaration of Helsinki. Written informed consent was waived due to the retrospective nature of this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This study was partly supported by an Intramural Research Grant (3-6) for Neurological and Psychiatric Disorders from the National Center for Neurology and Psychiatry. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hashimoto et al.)

Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethical Review Board of the National Center of Neurology and Psychiatry issued approval A2022-094. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Eri Takeshita declare(s) a grant from National Center of Neurology and Psychiatry. This research is supported by the Intramural Research Grants in the writing of the report (5-5 to E.T. for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry (NCNP)). Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Aihara et al.)

Background The ABO blood type has been associated with several digestive diseases. Some evidence has shown an association between ABO blood type and clinical outcomes among Asian patients with Crohn's disease. However, there are no reports about the association between ABO blood type and clinical outcomes in ulcerative colitis (UC). In this study, we aimed to evaluate the association between ABO blood type and clinical characteristics among patients with UC. Methodology The study subjects consisted of 277 Japanese patients with UC. Information on clinical characteristics and ABO blood type data was collected using medical records and a self-reported questionnaire. The information on clinical remission was collected using medical records. The definition of mucosal healing (MH) and partial MH was Mayo endoscopic subscore of 0 or 0-1, respectively. Results Of the enrolled patients, 39.4% (109/277), 18.4% (51/277), 29.2% (81/277), and 13.0% (36/277) had blood types A, B, O, and AB, respectively. The mean current age, age at onset of UC, and body mass index were 51.3 years, 42.1 years, and 22.7 kg/m 2 , and the proportion of male patients was 59.2% (164/277). The proportion of patients with clinical remission, MH, partial MH, and prednisolone use were 58.1% (161/277), 25.6% (71/277), 63.2% (175/277), and 21.3% (59/277), respectively. Conclusions None of the blood types were associated with any of the variables in this study. Among Japanese patients with UC, ABO blood type might not be associated with clinical characteristics., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Yagi et al.)

Socioeconomic status is a risk factor for poor disease prognosis. No studies of patients with ulcerative colitis (UC) have investigated the association between socioeconomic status and erectile dysfunction (ED), although UC is independently positively associated with ED. Therefore, the purpose of this survey to evaluate this issue in Japanese patients with UC. The study enrolled 165 patients with UC. Education status (low, middle, high) and household income (low, middle, high) were classified in three groups using self-administered surveys. The information regarding the Sexual Health Inventory for Men (SHIM) was obtained using self-administered questionnaires. The definition of mild to moderate or severe ED and severe ED was SHIM score <17 and SHIM score <8, respectively. The prevalence of mild to moderate or severe ED and severe ED was 64.9% and 47.9%, respectively. In crude analysis, household income was inversely associated with mild to moderate or severe ED and severe ED. After adjustment for age, current drinking, current smoking, exercise habit, body mass index, mucosal healing, and duration of UC, high household income was independently and inversely associated with mild to moderate or severe ED (adjusted odds ratio [OR] 0.23, 95% confidence interval [CI] [0.05, 0.93], p for trend = .038) and severe ED (adjusted OR 0.26, 95% CI [0.07, 0.85], p for trend = .024). In contrast, no association between education status and ED was found. In conclusion, household income was independently and inversely associated with ED in Japanese UC patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/aims: Although certain allergic diseases have been reported to be associated with the prevalence of functional dyspepsia (FD) and irritable bowel syndrome (IBS), it is unclear whether the presence of multiple allergic diseases further increases the prevalence of FD and IBS. The aim of this study is to determine this issue in young people., Methods: A cohort of 8923 Japanese university students was enrolled and diagnoses of FD and IBS were confirmed using Rome III criteria. Allergic disorders diagnosed at medical institutions were obtained by means of a self-administered questionnaire., Results: The prevalence of FD, IBS, and their overlap was found to be 1.9%, 6.5%, and 1.1%, respectively. Pollen allergy was independently positively correlated with FD, IBS, and overlap of FD and IBS. Allergic rhinitis was positively linked to IBS. Drug allergy was positively associated with FD. The presence of multiple allergic diseases was positively correlated with FD and IBS (FD: adjusted OR for 2 allergic diseases: 1.95 [95% CI, 1.24-2.98], P for trend = 0.003; and IBS: adjusted OR for 1 allergic disease: 1.40 [95% CI, 1.15-1.69], 2 allergic diseases 1.47 [95% CI, 1.12-1.91], and 3 or more allergic diseases: 2.22 [95% CI, 1.45-3.28], P for trend = 0.001). Additionally, the concomitant existence of multiple allergic diseases was also demonstrated to have a trend that correlated with the overlap of FD and IBS ( P for trend = 0.018)., Conclusion: Allergic disease multimorbidity is positively correlated with the prevalence of FD and IBS in a young population.

Objectives: Some upper-limb function assessments can evaluate treatments in the non-ambulatory stage of Duchenne muscular dystrophy (DMD). The Functional Classification of the Upper Extremities (FCUE) was developed for DMD in Japan. The FCUE is easier to use than the Performance of Upper Limb (PUL) and is more detailed than the Brooke Upper Extremity Scale. This study aimed to determine the concurrent validity of FCUE with other methods of assessment for DMD., Methods: This retrospective study reviewed the medical records of 39 boys with DMD from the National Center of Neurology and Psychiatry to evaluate the concurrent validity of the FCUE and PUL using non-parametric Spearman rank correlation (ρ). We also determined the concurrent validity of the Brooke Upper Extremity Scale and PUL for comparison., Results: The ρ value between the FCUE and PUL was -0.914 (P<0.001). The FCUE showed robust concurrent validity with the PUL. That correlation between the FCUE and Brooke Upper Extremity Scale gave a ρ value of -0.854 (P<0.001)., Conclusions: The FCUE had a higher concurrent validity with the PUL than with the Brooke Upper Extremity Scale. The FCUE is considered a valid assessment tool of upper-limb function in boys with DMD. Selecting the best assessment method depends on the severity of the patient's condition and a balance between assessment accuracy and evaluation time., Competing Interests: CONFLICTS OF INTEREST: KM has received annual payments from the General Insurance Association of Japan. HK has received research grants from Chugai Pharmaceutical and Taiho Pharmaceutical. ET has received research grants from Daiichi Sankyo, Nippon Shinyaku, Taiho Pharmaceutical, and Takeda Pharmaceutical. HK has received lecture fees from Chugai Pharmaceutical, Nippon Shinyaku, Biogen Japan, Novartis, and Pfizer. The remaining authors declare no conflict of interest., (2024 The Japanese Association of Rehabilitation Medicine.)

Double-stranded RNA-activated protein kinase R (PKR) is highly expressed in colorectal cancer (CRC). However, the role of PKR in CRC remains unclear. The aim of this study was to clarify whether C16 (a PKR inhibitor) exhibits antitumor effects and to identify its target pathway in CRC. We evaluated the effects of C16 on CRC cell lines using the MTS assay. Enrichment analysis was performed to identify the target pathway of C16. The cell cycle was analyzed using flow cytometry. Finally, we used immunohistochemistry to examine human CRC specimens. C16 suppressed the proliferation of CRC cells. Gene Ontology (GO) analysis revealed that the cell cycle-related GO category was substantially enriched in CRC cells treated with C16. C16 treatment resulted in G1 arrest and increased p21 protein and mRNA expression. Moreover, p21 expression was associated with CRC development as observed using immunohistochemical analysis of human CRC tissues. C16 upregulates p21 expression in CRC cells to regulate cell cycle and suppress tumor growth. Thus, PKR inhibitors may serve as a new treatment option for patients with CRC., (© 2024. The Author(s).)

Background: Constipation is a common gastrointestinal symptom in patients with ulcerative colitis (UC). Several studies on the general population have demonstrated a link between allergic diseases and constipation. However, evidence regarding the association between allergic diseases and constipation in UC is limited. This study aims to evaluate this issue in Japanese patients with UC., Methods: This cross-sectional study recruited consecutive 387 patients with UC. We used a self-administered questionnaire to estimate the prevalence of physician-diagnosed allergic diseases. The definition of constipation was based on Rome I criteria and/or medication for constipation., Results: The prevalence of constipation was 12.5%. The prevalence rates of asthma, atopic dermatitis, pollen allergy, food allergy, and drug allergy were 11.8%, 9.0%, 36.3%, 6.2%, and 8.3%, respectively. Allergic diseases were not associated with constipation (adjusted odds ratio [OR] with asthma (adjusted OR 0.98 [95% confidence interval [CI] 0.27-2.80]), atopic dermatitis (adjusted OR 0.67 [95% CI 0.10-2.56]), pollen allergy (adjusted OR 0.92 [95% CI 0.41-1.97]), food allergy (adjusted OR 0.76 [95% CI 0.11-2.95]), and drug allergy (adjusted OR 1.06 [95% CI 0.28-3.24]). Additionally, the number of allergic diseases was not associated with the prevalence of constipation., Conclusions: In Japanese UC patients, no association between allergic diseases and constipation was found., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Yagi et al.)

Objective: Becker muscular dystrophy (BMD) is a milder variant of Duchenne muscular dystrophy (DMD), a lethal X-linked muscular disorder. Here, we aim to investigat the clinical involvement of skeletal, respiratory, cardiac, and central nervous systems in patients with BMD, as well as genotype-phenotype relationships., Methods: This nationwide cohort study investigated the clinical manifestations and genotype-phenotype relationships in 225 patients with BMD having in-frame deletion from 22 medical centers. The primary outcome was to elucidate the association of genotype with skeletal muscle, respiratory, cardiac, and central nervous system disorders. Descriptive statistics were used to analyze the data., Results: The average age of the subjects was 31.5 (range, 1-81) years. Initial symptoms of BMD were muscular (60%), followed by asymptomatic hypercreatine kinasemia (32.4%) and central nervous system disorders (5.3%). Gait disturbance was observed in 53.8% of patients and the average age at wheelchair introduction was 36.5 years. The ventilator introduction rate was 6.7% at an average age of 36.6 years. More than 30% of patients had an abnormal electrocardiogram and approximately 15% had heart failure symptoms. Cardiac function on echocardiography varied significantly among the patients. The frequencies of seizures and intellectual/developmental disability were 8.0% and 16.9%, respectively. Exon 45-47deletion (del) was the most common (22.6%), followed by exon 45-48del (13.1%). Patients with exon 45-49del patients demonstrated severe skeletal muscle damage. Patients with exon 45-47del and exon 45-55del patients did not require ventilator use., Interpretation: The study provides important prognostic information for patients and clinicians to establish therapy plans and to implement preventative medicine., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)