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The main clinical features in patients with Duchenne muscular dystrophy (DMD) are (1) progressive muscle atrophy and weakness, (2) cardiac dysfunction, and (3) intellectual disability. However, there are few reports about natural history of patients with DMD develop renal dysfunction with age. Previous studies have shown that as skeletal muscle mass decreases, serum creatinine levels are less likely to reflect renal functions. In this study, we retrospectively examined how blood urea nitrogen (BUN) levels change over time. Patients clinically or genetically diagnosed with DMD were included in this study. The study period was from April 1st, 2012 to August 31st, 2023. The eligible patients underwent BUN levels' measurement at least twice. High BUN was defined as 30mg/dl or higher. Two or more consecutive increases in BUN are counted as one time. A total of 52 patients were included in the study, and their mean duration of observation was 7.7 years. Those with a BUN level ≤30 mg/dl obtained during the study period were considered to have renal dysfunction, accounting to 15 patients. High BUN was initially detected at 28.7 years of age (±8.0) and mean peak BUN level was 116.5 mg/dl. Their mean total duration of rising periods was 108 days, respectively. And these periods occurred 2.33 times/person on average. Two patients died from renal failure, according to the attending clinician. However, renal function improved in the remaining patients. No patients died of heart failure in the study period. The results for the remaining 37 patients showed that the mean age at the time of the first measurement was 14.8 years old (±6.1) and the mean observation period was 7.03 years. The average number of BUN tests was 20.5/7.03 y. (1 test /4.1month). The average maximum BUN value was 16.0 mg/dL (±5.6), the average minimum BUN value was 5.8 (±3.0), and the average value was 10.2. Although increase in BUN levels can be found in conditions other than renal dysfunction, BUN levels changed in 30% of patients with DMD. Since renal dysfunction is an inhibitory factor of treatment with morpholino-based drugs and affects survival, a future prospective study is required for elderly patients with DMD, renal function tests are recommended once every 3 to 4 months, and shorter follow-up is recommended if abnormalities are detected. 30% of patients with elderly DMD may have renal dysfunctions. About 10% in these patients may die by renal dysfunction, although in 90% of these patients' recovery can be expected within 3 months of natural course. [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.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. The etiology of sporadic ALS (sALS) has not yet been clarified. An increasing body of evidence suggests the involvement of viral infections and interferons (IFNs). Human myxovirus resistance protein A (MxA) is an IFN-induced dynamin-like GTPase that acts as a potent antiviral factor. This study examined MxA expression in ALS patient spinal cords using immunohistochemistry. Thirty-two cases of sALS (pathologically proven ALS-TDP), 10 non-ALS, other neurological disease control cases were examined. In most ALS cases, MxA cytoplasmic condensates were observed in the remaining spinal anterior horn neurons. The ALS group had a significantly higher rate of MxA-highly expressing neurons than the non-ALS group. Colocalization of MxA cytoplasmic condensate and transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusions was rarely observed. Because MxA has antiviral activity induced by IFNs, our results suggest that IFNs are involved in the pathogenesis of ALS in spinal cord anterior horn neurons. Our study also suggests that monitoring viral infections and IFN activation in patients with ALS may be critically important., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

FUS mutations are one of the major mutations in familial amyotrophic lateral sclerosis (ALS). The pathological hallmark is FUS-positive neuronal cytoplasmic inclusions (FUS-NCI), known as FUS proteinopathy. Human myxovirus resistance protein 1 (MxA) is an IFN-induced dynamin-like GTPase that acts as antiviral factor. In this study, we examined the expression of MxA in neurons bearing FUS-NCI. We performed immunohistochemistry for FUS and MxA to examine the expression of MxA in two autopsy cases with different FUS gene mutations localized at the nuclear localization signal site (Case 1, H517P; Case 2, R521C). MxA. Most neurons bearing FUS-NCI have increased cytoplasmic MxA expression. Increased cytoplasmic MxA showed several distribution patterns in relation to FUS-NCIs such as the following: colocalization with NCI, distribution more widely than NCI, and different distribution peaks from NCI. Our results suggested that antiviral signaling IFNs are involved upstream in the formation of FUS-NCI in ALS-FUS patients., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

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.)

Objective: To evaluate the swallowing function in the advanced stages of progressive supranuclear palsy (PSP) and clarify the factors that lead to adjustment of food consistency and discontinuation of oral intake., Methods: A total of 56 patients with PSP were recruited. Based on medical records, information about the basic attributes, clinical features (including axial rigidity and dementia), food intake, the results of a videofluoroscopic swallowing study (VFSS), and the timing of nasogastric tube transition and gastrostomy were extracted. From the VFSS images, the presence or absence of aspiration and retrocollis were assessed., Results: The average age at the onset, diagnosis, and the final follow-up examination were 67.6 ± 6.4 years, 71.6 ± 5.8 years, and 75.4 ± 5.6 years, respectively. The average duration of illness was 64.6 ± 42.8 months. Twenty-four individuals (42.9%) were continuing oral intake, while 32 were tube-fed, among whom 16 (50.0%) underwent gastrostomy tube placement. There were significant differences in the duration from the disease onset to tube feeding between the patients with and without cognitive decline at the time of the diagnosis ( p  < 0.01) and in the duration from the initial VFSS to tube feeding between the patients with and without aspiration on the initial VFSS ( p  < 0.01). There were significant differences in the duration from the diagnosis to tube feeding and from the initial VFSS to tube feeding between patients with and without axial rigidity at the time of the diagnosis ( p  < 0.05 and p  < 0.05, respectively). Additionally, there was a significant association between axial rigidity and retrocollis ( p  < 0.01)., Conclusion: Cognitive decline, axial rigidity and retrocollis, which are associated with the deterioration of dysphagia in PSP, are the highest risk factors for the discontinuation of oral intake. The early identification of these factors associated with the progression of dysphagia can contribute to the improvement of patient care and management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Iwashita, Umemoto, Fujioka, Arahata, Dotsu, Oike and Tsuboi.)

Fused in sarcoma (FUS), coded by FUS, is a heterogeneous nuclear ribonucleoprotein (hnRNP). FUS mutations are among the major mutations in familial amyotrophic lateral sclerosis (ALS-FUS: ALS6). The pathological hallmarks of ALS-FUS are FUS-positive neuronal cytoplasmic inclusions (NCI). We examined various hnRNPs in FUS NCIs in the hippocampus in ALS-FUS cases with different FUS mutations (Case 1, H517P; Case 2, R521C). We also examined TDP43-positive NCIs in sporadic ALS hippocampi. Immunohistochemistry was performed using primary antibodies against FUS, p-TDP43, TDP43, hnRNPA1, hnRNPD, PCBP1, PCBP2, and p62. Numerous FUS inclusions were found in the hippocampal granule and pyramidal cell layers. Double immunofluorescence revealed colocalization of FUS and p-TDP43, and FUS and PCBP2 (p-TDP43/FUS: 64.3%, PCBP2/FUS: 23.9%). Colocalization of FUS and PCBP1, however, was rare (PCBP1/FUS: 7.6%). In the hippocampi of patients with sporadic ALS, no colocalization was observed between TDP43-positive inclusions and other hnRNPs. This is the first study to show that FUS inclusions colocalize with other hnRNPs, such as TDP43, PCBP2, and PCBP1. These findings suggest that in ALS-FUS, FUS inclusions are the initiators, followed by alterations of multiple other hnRNPs, resulting in impaired RNA metabolism., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Myotonic dystrophy type 1 (DM1) is an inherited autosomal-dominant condition that induces altered splicing of transcripts, including MAPT, leading to a distinctive abnormal deposition of tau protein in the CNS. We characterized the tau isoforms of abnormal depositions in the brains of 4 patients with classic DM1 by immunohistochemistry using isoform-specific antibodies. All patients, including those of presenile age, showed numerous neurofibrillary tangles (NFTs) of both 3-repeat and 4-repeat tau in the limbic area and mild involvement in the cerebral cortex. Amyloid-β deposition was only seen in 1 senile case while cortical tauopathy in all other cases was consistent with primary age-related tauopathy (PART). In the putamen and globus pallidus, only a few tau deposits were observed. Tau deposits in the brainstem frequently showed a DM1-specific pattern with 3-repeat tau dominant NFTs. Additionally, tau-positive astrocytes morphologically similar to tufted astrocytes and astrocytic plaques were occasionally observed in the brainstem; however, they were predominantly composed of 3-repeat tau. Thus, the classic DM1 showed both early onset of PART-like pathology in the limbic areas as a progeroid syndrome of DM1 and an abnormal splicing event in the brainstem leading to 3-repeat tau dominant accumulation with both neuronal and astrocytic involvement., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM&#95;NOTCH2NLC) GIPC1 (OPDM&#95;GIPC1), or LRP12 (OPDM&#95;LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy., Methods: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM&#95;NOTCH2NLC [n = 2], OPDM&#95;GIPC1 [n = 6] and OPDM&#95;LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2)., Results: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM&#95;NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM&#95;GIPC1, and all in three cell types in one of the three patients with OPDM&#95;LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy., Conclusion: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes., (© 2021 British Neuropathological Society.)