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BackgroundThe causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions.MethodsWe gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies.ResultsWe identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases.ConclusionWe initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group ( p  = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group ( p  = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens ( p  = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns ( p  = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

Background and aimsMutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot–Marie–Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3′ untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan.MethodsWe analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot–Marie–Tooth (CMT) disease and spinal muscular atrophy (SMA).ResultsWe identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect.InterpretationThis is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

Background The design process of a removable partial denture (RPD) consists of rests, major connectors, minor connectors, denture base, and retainer. The abutment tooth contour determines the location of the retention portion of the clasp at the retention areas. The load capacity of the clasp depends on various factors such as type, the position of a clasp, tooth position, clasp length, and pullout location. As a general rule, the amount of retention required to dislodge the RPD from the supporting structure should always be the minimum necessary to resist reasonable dislodging forces. Excessive force from the clasps may cause many problems. Although there are many reports on the retentive force of cast clasps using large devices, it has not been possible to measure it using simple devices until now. Method The purpose of the present study is to develop a small-sized retentive force measurement device that can easily measure the retentive force of a clasp used for an RPD. It is to examine inter-rater and intra-rater reliability. A small-sized retentive force measurement device that can be easily measured in the laboratory has been developed. Using commercially available hard plaster cast, a skilled dental technician has made 10 types of cast clasps used in clinical practice using conventional techniques. Three assessors measured the retentive force of 10 types of cast clasps. To confirm the reliability, the intra-class correlation coefficients ICC (1,1) and ICC (1,3) of the 3 assessors were calculated, and the reliability within the assessor was examined. The inter-class correlation coefficients ICC (3,1) and ICC (3,3) were calculated, and the reliability of the assessors was examined. Result The intra-class correlation coefficients of 3 assessors are as follows: assessor 1 has ICC (1,1) = 0.971, ICC (1,3) = 0.990, assessor 2 has ICC (1,1) = 0.967, ICC (1,3) = 0.989, assessor 3 has ICC (1,1) = 0.962, ICC (1,3) = 0.987. The inter-class correlation coefficients of 3 assessors are as follows: ICC (3,1) = 0.993, ICC (3,3) = 0.998. From the evaluation standard of the intraclass correlation coefficients of reliability value by ICC, it was evaluated as almost perfect and high reproducibility was confirmed. Conclusion The developed small-sized retentive force measurement device has reproducibility within and between the assessors.

Background and Objectives The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late‐onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. Methods We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat‐primed PCR, and long‐read sequencing. Results Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow‐up study conducted after a mean period of 6 years did not reveal any significant progression. Discussion This study highlights the importance of FGF14 GAA repeat analysis in patients with late‐onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA‐FGF14‐related diseases.

Histopathologic examinations of primary central nervous system lymphoma (PCNSL) reveal concentric accumulation of lymphocytes in the perivascular area with fibrosis. However, the nature of this fibrosis in “stiff” PCNSL remains unclear. We have encountered some PCNSLs with hard masses as surgical findings. This study investigated the dense fibrous status and tumor microenvironment of PCNSLs with or without stiffness. We evaluated by silver-impregnation nine PCNSLs with stiffness and 26 PCNSLs without stiffness. Six of the nine stiff PCNSLs showed pathological features of prominent fibrosis characterized by aggregation of reticulin fibers, and collagen accumulations. Alpha-smooth muscle actin (αSMA)-positive spindle cells as a cancer-associated fibroblast, the populations of T lymphocytes, and macrophages were compared between fibrous and control PCNSLs. Fibrous PCNSLs included abundant αSMA-positive cells in both intra- and extra-tumor environments (5/6, 87% and 3/6, 50%, respectively). Conversely, only one out of the seven control PCNSL contained αSMA-positive cells in the intra-tumoral area. Furthermore, the presence of extra-tumoral αSMA-positive cells was associated with infiltration of T lymphocytes and macrophages. In conclusion, recognizing the presence of dense fibrosis in PCNSL can provide insights into the tumor microenvironment. These results may help stratify patients with PCNSL and improve immunotherapies for these patients.

Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

Background Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. Methods We performed whole‐exome sequencing (WES) of DNA samples from 804 Charcot–Marie–Tooth (CMT) cases that could not be genetically diagnosed by DNA‐targeted resequencing microarray using next‐generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. Results We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early‐onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. Conclusion Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT‐related gene panel for comprehensive genetic screening, particularly for patients with early‐onset demyelinating CMT.