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To investigate short-term treatment outcomes of intravitreal brolucizumab (IVBr) for treatment-naïve neovascular age-related macular degeneration (AMD) in a Japanese multicenter study.Retrospective case control study METHODS: The subjects were 58 eyes of 57 patients with neovascular AMD (43 men and 14 women, mean age 74.6 years) of whom 43 eyes of 42 patients completed initial loading of 3 monthly IVBr injections and were followed for more than 3 months. Best-corrected visual acuity (BCVA) changes, anatomical outcomes, and complications were investigated.Of the 43 eyes that completed loading doses, the AMD subtype was type 1 and type 2 macular neovascularization (MNV) in 51%, polypoidal choroidal vasculopathy (PCV) in 42%, and type 3 MNV in 7%. At 3 months after initiating treatment, BCVA significantly improved (P = 0.002) and central retinal thickness significantly decreased (P 0.0001). At 3 months, complete retinal and subretinal fluid resolution was achieved in 91% of all eyes and complete regression of polypoidal lesions was achieved in 82% of PCV eyes. Iritis occurred in 8 eyes of 8 patients (14%), but resolved using topical or subtenon corticosteroid injection without visual loss in all cases.IVBr for treatment-naïve neovascular AMD was effective in the short-term, achieving significantly improved BCVA, good retinal fluid resolution, and a high rate of polypoidal lesion regression. However, iritis was noted in 14% of patients which may limit use of this drug.

Background Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. Case report A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. Conclusion The patient’s diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.

The pathologies of oculopharyngeal muscular dystrophy (OPMD) and oculopharyngodistal myopathy (OPDM) are indistinguishable. We found that p62-positive intra-nuclear inclusions (INIs) in myonuclei (myo-INIs) were significantly more frequent in OPMD (11.4 ± 4.1%, range 5.0– 17.5%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (1–2% on average, range 0.0–3.5%, p

In this review, we focus on congenital myopathies, which are a genetically heterogeneous group of hereditary muscle diseases with slow or minimal progression. They are mainly defined and classified according to pathological features, with the major subtypes being core myopathy (central core disease), nemaline myopathy, myotubular/centronuclear myopathy, and congenital fiber-type disproportion myopathy. Recent advances in molecular genetics, especially next-generation sequencing technology, have rapidly increased the number of known causative genes for congenital myopathies; however, most of the diseases related to the novel causative genes are extremely rare. There remains no cure for congenital myopathies. However, there have been recent promising findings that could inform the development of therapy for several types of congenital myopathies, including myotubular myopathy, which indicates the importance of prompt and correct diagnosis. This review discusses the major causative genes (NEB, ACTA1, ADSSL1, RYR1, SELENON, MTM1, DNM2, and TPM3) for each subtype of congenital myopathies and the relevant latest findings.

Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation. Our previously established DMD model rats (DMD rats) have a more severe disease phenotype than the broadly used mouse model. We aimed to investigate the role of senescence in DMD using DMD rats and patients. Senescence was induced in satellite cells and mesenchymal progenitor cells, owing to the increased expression of CDKN2A, p16- and p19-encoding gene. Genetic ablation of p16 in DMD rats dramatically restored body weight and muscle strength. Histological analysis showed a reduction of fibrotic and adipose tissues invading skeletal muscle, with increased muscle regeneration. Senolytic drug ABT263 prevented loss of body weight and muscle strength, and increased muscle regeneration in rats even at 8 months—the late stage of DMD. Moreover, senescence markers were highly expressed in the skeletal muscle of DMD patients. In situ hybridization of CDKN2A confirmed the expression of it in satellite cells and mesenchymal progenitor cells in patients with DMD. Collectively, these data provide new insights into the integral role of senescence in DMD progression.

Purpose To report the 2-year outcomes of intravitreal aflibercept injections (IAIs) in Japanese patients with neovascular age-related macular degeneration (AMD) using a 1-month adjusted treat-and-extend (TAE) regimen. Design Multicenter, prospective, nonrandomized, interventional study. Participants Ninety-seven eyes of 97 patients with treatment-naive AMD were studied at 3 tertiary ophthalmological institutions. Methods The patients were treated with 3 consecutive monthly IAIs followed by the TAE regimen with a 1-month adjustment for a maximum of 3 months. Our TAE regimen allowed us to shorten and extend the treatment intervals even after a 3-month or 1-month treatment interval, or both, were reached. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), and subfoveal choroidal thickness (SCT) were analyzed. Main Outcome Measures The mean changes in the BCVA, CRT, and SCT from the baseline to 2 years after initiating the treatment were determined. In addition, the number of injections also was determined. Results The mean BCVA significantly improved from 0.27 logarithm of the minimum angle of resolution (logMAR) units to 0.14 logMAR at 2 years (P Conclusions Intravitreal aflibercept injections with a 1-month adjusted TAE regimen significantly improved the BCVA and CRT with a reduced number of injections at 2 years. The treatment interval was adjusted to extend to 3 months in 60% and to shorten to 1 month in 20% of the eyes at 2 years.

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5′ UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

The NEXMIF (KIAA2022) gene is located in the X chromosome, and hemizygous mutations in NEXMIF cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in NEXMIF also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with NEXMIF mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in NEXMIF. The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with NEXMIF mutations.

Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_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.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_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2).The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy.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.

Core myopathies are clinically, pathologically, and genetically heterogeneous muscle diseases. Their onset and clinical severity are variable. Core myopathies are diagnosed by muscle biopsy showing focally reduced oxidative enzyme activity and can be pathologically divided into central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Although RYR1-related myopathy is the most common core myopathy, an increasing number of other causative genes have been reported, including SELENON, MYH2, MYH7, TTN, CCDC78, UNC45B, ACTN2, MEGF10, CFL2, KBTBD13, and TRIP4. Furthermore, the genes originally reported to cause nemaline myopathy, namely ACTA1, NEB, and TNNT1, have been recently associated with core-rod myopathy. Genetic analysis allows us to diagnose each core myopathy more accurately. In this review, we aim to provide up-to-date information about core myopathies.

This study evaluated the association of physical prefrailty with the prevalence of inadequate nutrients among community-dwelling Japanese elderly women.This cross-sectional study included 120 older women (age range, 65-79 years) at an elders college. Frailty was evaluated using the Japanese version of the Cardiovascular Health Study (J-CHS). Participants were classified as either prefrailty (1-2 deficits) or nonfrailty (0 deficits) based on set criteria. Both groups were compared in terms of physical function, exercise time, nutrient intake, and food group intake estimated by Food Frequency Questionnaire Based on Food Groups (FFQg), and estimated prevalence of inadequate nutrient intake, which was evaluated using each dietary reference value, set as the estimated average requirement (EAR) and dietary goal (DG), based on the Dietary Reference Intakes (DRIs) for Japanese, 2020.Of the participants, 45.0% exhibited physical prefrailty. Binary logistic regression analysis identified that vitamin C intake below EAR (OR, 7.12; 95% CI, 1.47-34.41, p=0.014) was the only factor associated with physical prefrailty.In addition to measuring physical function, dietary surveys and evaluation of nutritional adequacy by DRIs are expected to be useful for the early prevention of physical prefrailty by linking to nutrition education among community-dwelling Japanese elderly adults.

Observation of choroidal thickness after anti-vascular endothelial growth factor (VEGF) therapy may be important for the ideal management of neovascular age-related macular degeneration (AMD). This study investigated changes in subfoveal choroidal thickness (SCT) during loading doses of intravitreal injections of brolucizumab in eyes with neovascular AMD.This study included 73 eyes of 72 patients with neovascular AMD at five university hospitals in Japan. All 73 eyes underwent three monthly 6.0 mg intravitreal injections of brolucizumab at baseline, 1 month, and 2 months. The SCT at 3 months was evaluated using optical coherence tomography.The 73 eyes were classified into the treatment-naïve group (43 eyes) and the switched group (30 eyes) that were switched from other anti-VEGF treatments. After three intravitreal injections of brolucizumab, SCT significantly decreased from 236.5 ± 98.8 µm at baseline to 200.4 ± 98.3 µm at 3 months (percent of baseline 84.7%, P 0.001) in the treatment-naïve group. In the switched group, SCT also significantly decreased from 229.0 ± 113.2 μm at baseline to 216.9 ± 110.2 μm at 3 months (percent of baseline 94.7%, P = 0.039), although the decrease was not as marked compared to that of the treatment-naïve group.Intravitreal injections of brolucizumab for neovascular AMD significantly reduced the SCT in both the treatment-naïve and switched groups. Brolucizumab may cause significant anatomic changes in the choroid, particularly in treatment-naïve AMD eyes, possibly more than that previously reported for other anti-VEGF agents.

Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets. To address this gap, we developed an algorithm based on deep convolutional neural networks (CNNs) and collected 4041 microscopic images of 1400 hematoxylin-and-eosin-stained pathology slides stored in the National Center of Neurology and Psychiatry for training CNNs. Our trained algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) with an area under the curve (AUC) of 0.996 and achieved better sensitivity and specificity than the diagnoses done by nine physicians under limited diseases and conditions. Furthermore, it successfully and accurately classified four subtypes of the idiopathic inflammatory myopathies with an average AUC of 0.958 and classified seven subtypes of hereditary muscle disease with an average AUC of 0.936. We also established a method to validate the similarity between the predictions made by the algorithm and the seven physicians using visualization technology and clarified the validity of the predictions. These results support the reliability of the algorithm and suggest that our algorithm has the potential to be used straightforwardly in a clinical setting. The authors developed a deep convolutional neural network-based algorithm to support pathological muscle diagnosis. The algorithm differentiated idiopathic inflammatory myopathies and outperformed nine human physicians under limited diseases and conditions. These results suggest that the algorithm has the potential to be used directly in clinical settings.

Histopathologic evaluation is essential for categorizing and studying neuromuscular disorders. However, experienced specialists and pathologists are limited, especially in underserved areas. Although new technologies, such as artificial intelligence, are expected to improve medical reach, their use in rare diseases is challenging because of the limited availability of training datasets. To address this knowledge gap, we developed an algorithm based on deep convolutional neural networks that used data from microscopic images of hematoxylin-and-eosin-stained pathology slides. Our algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) and achieved better sensitivity and specificity than real physicians' diagnoses. Furthermore, it successfully and accurately classified four subtypes of the abovementioned muscular conditions. These results suggest that our algorithm can be safely used in a clinical setting. We established the similarity between the algorithm's and physicians' predictions using visualization technology, and clarified the validity of the predictions.

Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Note that 211 patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of identified patients with OPDM_NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM_NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

Typical central core disease (CCD) is characterized pathologically by the presence of a core and is accompanied by type 1 fiber uniformity. Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is characterized pathologically by the presence of type 1 fiber uniformity but without the abnormal structural changes in muscle fibers. Interestingly, typical CCD and 40% of CNMDU1 cases are caused by the same mutations in RYR1, and thus CNMDU1 has been considered an early precursor to CCD. To better understand the nature of CNMDU1, we re-evaluated muscle biopsies from 16 patients with CNMDU1 using immunohistochemistry to RYR1, triadin and TOM20, and compared this to muscle biopsies from 36 typical CCD patients. In CCD, RYR1, and triadin were present in the core regions, while TOM20 was absent in the core regions. Interestingly, in 5 CNMDU1 cases with the RYR1 mutation, RYR1, and triadin were similarly present in core-like areas, while TOM20 was absent in the subsarcolemmal region. Furthermore, there was a correlation between the core position and the disease duration or progression-the older patients in more advanced stages had more centralized cores. Our results indicate that CNMDU1 due to RYR1 mutation is a de facto core myopathy.

BackgroundOculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC.ObjectivesTo identify and to clinicopathologically characterize OPDM patients who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC).MethodsTwo hundred eleven patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of the identified OPDM_NOTCH2NLC patients were re-reviewed. Intra-myonuclear inclusions were further evaluated by immunohistochemistry and electron microscopy.ResultsSeven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically had ptosis, ophthalmoplegia, dysarthria, and muscle weakness, and myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which are diagnostic of NIID typically on skin biopsy, in addition to rimmed vacuoles. Sample for electron microscopy was available only from one patient, which showed intranuclear inclusions of 12.6 ± 1.6 nm in diameter.ConclusionsWe identified seven OPDM_NOTCH2NLC patients. Our patients had various additional central and/or peripheral nervous system involvement, albeit all being clinicopathologically compatible; thus, diagnosed as having OPDM, expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

Background To evaluate the three-year outcome after intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration (nAMD). Methods Forty-nine treatment-naïve nAMD patients (50 eyes) were enrolled in this prospective study. The eyes received IAI at two-month intervals in the first year. The treatment regimen was changed to IAI based on a treat-and-extend approach in the second and third years. Results Twenty-nine eyes of 28 patients were successfully followed up over 36 months. The nAMD subtypes included 15 eyes with typical AMD and 14 eyes with polypoidal choroidal vasculopathy. The number of IAIs performed over the 3 years was 17.2 ± 3.1 (mean ± standard deviation). The mean logMAR, which was 0.42 at baseline, improved to 0.19 (P = 0.001) at 12 months, and 0.26 (P = 0.049) at 36 months. The central retinal thickness (CRT) was 329 ± 120 μm at baseline, 151 ± 38 μm (P P P P Conclusion Long-term aflibercept injection can achieve visual improvement and reduce the thickness of the retina and choroid in nAMD. Morphological improvement of these tissues may not be sufficient to sustain earlier visual improvement over the long-term.

Importance Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, setting, and participants This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main outcomes and measures Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and relevance This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

An experiment was conducted to quantify the non-volatile key taste compounds, including free amino acids (FAAs), nucleotides, inorganic ions, organic acids, and bases of dried herring (Clupea pallassi) fillet (DHF). A taste recombinant was also prepared using those key taste compounds to compare the taste profiles with water soluble extracts (WSE) by sensory perception. The total FAA of DHF muscle was 12.25 mg/g on dry matter basis. The most dominant FAAs were alanine, glycine, lysine, and histidine. The nucleotides were identified as 5´-adenosine monophosphate (AMP) (1.74 mg/100 g) and 5´-inosine monophosphate (IMP) (5.28 mg/100 g). Potassium, phosphate, and chloride were the major inorganic ions while trimethylamine oxide, creatine, and lactic acid were the major organic bases. Sensory evaluation showed that WSE markedly increased the intensities of umami, mouthfulness, thickness, and taste continuity of Japanese noodle soup (JNS). However, addition of taste recombinant to the JNS did not bring any changes in the taste intensities of saltiness, umami, mouthfulness, taste continuity, and thickness of the soup. Results of this study indicated that the taste recombinant was lacking of some important key taste compounds that might be formed during drying of herring fillet.

To report the 2-year outcomes of intravitreal aflibercept injections (IAIs) in Japanese patients with neovascular age-related macular degeneration (AMD) using a 1-month adjusted treat-and-extend (TAE) regimen.Multicenter, prospective, nonrandomized, interventional study.Ninety-seven eyes of 97 patients with treatment-naive AMD were studied at 3 tertiary ophthalmological institutions.The patients were treated with 3 consecutive monthly IAIs followed by the TAE regimen with a 1-month adjustment for a maximum of 3 months. Our TAE regimen allowed us to shorten and extend the treatment intervals even after a 3-month or 1-month treatment interval, or both, were reached. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), and subfoveal choroidal thickness (SCT) were analyzed.The mean changes in the BCVA, CRT, and SCT from the baseline to 2 years after initiating the treatment were determined. In addition, the number of injections also was determined.The mean BCVA significantly improved from 0.27 logarithm of the minimum angle of resolution (logMAR) units to 0.14 logMAR at 2 years (P0.01). The mean CRT decreased significantly from 307±132 μm to 202±76 μm at 2 years (P0.01). The mean SCT decreased significantly from 247±106 μm to 203±96 μm at 2 years (P0.01). Seventy eyes (72.2%) showed a dry macula at 2 years. The treatment interval at 2 years was 1 month in 20 eyes (20.6%), 2 months in 18 eyes (18.6%), and 3 months in 59 eyes (60.8%). In 49 (50.5%) eyes with a 3-month treatment interval immediately after the loading phase, no fluid was seen in 25 eyes (51.0%) for the duration of this study. The rest had switched to a more frequent scheme. The mean number of injections during the 2-year period was 13.0±3.9.Intravitreal aflibercept injections with a 1-month adjusted TAE regimen significantly improved the BCVA and CRT with a reduced number of injections at 2 years. The treatment interval was adjusted to extend to 3 months in 60% and to shorten to 1 month in 20% of the eyes at 2 years.

The complication of anarthria in hereditary spastic paraplegia (HSP) patients has been reported to result from mutations in either ALS2 or FA2H. Here, we present a case of a 12-year-old boy with hereditary spastic paralysis and anarthria associated with a SPAST mutation. Initial presentation was at 14 months of age, when the patient experienced leg stiffness. At 3 years of age, he could speak well using sentences. At 9 years of age, he was found to have dysarthria and had difficulty writing. At 12 years of age, the ability to speak was lost. The patient could not vocalize any words, despite contraction of his neck and respiratory muscles during attempted vocalization. Additionally, the patient has never walked independently in his life. Considering these symptoms, we diagnosed him as having infantile onset ascending hereditary spastic paralysis (IAHSP) complicated with anarthria. By whole-exome sequencing, we discovered a heterozygous SPAST mutation c.1496G > A (p.Arg499His), which was not found in the parents and is probably de novo. This mutation was already repeatedly described with similar phenotype. Our results suggest that the p.Arg499His mutation in SPAST should be considered as a differential diagnosis in IAHSP.

To evaluate the development and rate of growth in macular atrophy after intravitreal injections of aflibercept (IVAs) for neovascular age-related macular degeneration (AMD) over a 2-year period. Retrospective, interventional, consecutive case series. This study included 94 eyes of 92 patients with treatment-naive AMD involving the foveal center treated with IVAs at 3 university hospitals in Japan. The patients underwent IVAs bimonthly after 3 initial monthly doses in the first year. The protocol was converted to a treat-and-extend regimen in the second year. The incidence and growth rate of macular atrophy were quantified based on hypoautofluorescence detected by fundus autofluorescence images. Additionally, possible background factors related to the development and rate of growth of macular atrophy were investigated. Of 94 eyes, 39 (41.5%) had typical AMD and 55 (58.5%) had polypoidal choroidal vasculopathy. Ten eyes (10.6%) had macular atrophy at the baseline. Of the remaining 84 eyes, 14 (16.7%) had developed new macular atrophy at 2 years, the square root of the growth rate of atrophy was 0.52 mm/year. In multivariate analyses, a poorer best-corrected visual acuity (P = 0.01) and the presence of intraretinal fluid (P = 0.04) at baseline were found to be the independent predictors for the development of macular atrophy. No factors were found that were significantly related to the growth rate of the macular atrophy. Our study determined the incidence and rate of growth of macular atrophy after IVAs for neovascular AMD in clinical settings. Eyes with vision reduction and intraretinal fluid at the baseline develop macular atrophy more frequently after IVAs for neovascular AMD.

Purpose To investigate the characteristics of complement activation products and angiogenic cytokines in the aqueous humor in eyes with pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD). Methods This was a prospective, comparative, observational study. All patients with choroidal neovascularization were classified as PNV without polyps, PNV with polyps (polypoidal choroidal vasculopathy [PCV]), or drusen-associated nAMD according to the presence or absence of pachychoroid features and soft drusen. This study included a total of 105 eyes. Aqueous humor samples were collected from 25 eyes with PNV without polyps, 23 eyes with PCV, and 24 eyes with drusen-associated nAMD before intravitreal anti-vascular endothelial growth factor (VEGF) injection and cataract surgery in 33 control eyes. Clinical samples were measured for complement component 3a (C3a), C4a, C5a, VEGF, and macrophage chemoattractant protein 1 (MCP-1) using a bead-based immunoassay. Results C3a and MCP-1 levels were significantly higher in PCV (P = 0.032 and P = 0.039, respectively) and drusen-associated nAMD (P = 0.01 for both comparisons) than in controls, and no difference was seen in C3a and MCP-1 levels between PNV and controls (P = 0.747 and P = 0.294, respectively). VEGF levels were significantly higher in PNV (P = 0.016), PCV (P = 0.009), and drusen-associated nAMD (P = 0.043) than in controls. In PNV, the VEGF levels elevated without elevated C3a and MCP-1. Conclusions PNV, PCV, and drusen-associated nAMD had significantly distinct profiles of complement activation products and cytokines in the aqueous humor.

The complement system may be activated in the posterior segment of the eye with chorioretinal disease, which may be reflected to the concentration of anaphylatoxins in the aqueous humor. Little is known about the distribution of anaphylatoxins in the aqueous and vitreous humor. The aim of the present study was to investigate the distribution of anaphylatoxin concentration in the aqueous and vitreous humor of the eyes with idiopathic epiretinal membrane or idiopathic macular hole. This was an experimental, observational case series. This study included 43 eyes from 43 patients; 29 eyes with idiopathic epiretinal membrane, and 14 eyes with idiopathic macular hole. All 43 eyes underwent cataract surgery and vitrectomy. The aqueous and vitreous humor were collected at the surgery. The anaphylatoxin concentrations were measured by using a cytometric beads array, and the respective C3a, C4a, and C5a concentrations were 2.003 ± 0.679 (mean ± standard deviation) ng/ml, 1.389 ± 0.419 ng/ml, and 0.003 ± 0.004 ng/ml in the aqueous humor, and 1.236 ± 0.642 ng/ml, 1.250 ± 0.542 ng/ml, and 0.048 ± 0.069 ng/ml in the vitreous humor. The mean C3a concentration in the aqueous humor was significantly higher than in the vitreous humor in 43 eyes of iMH and iERM (P 0.001). The mean C4a concentration showed no significant difference between the aqueous humor and vitreous humor (P = 0.282), and the mean C5a in the aqueous humor was significantly lower than in the vitreous humor overall (P 0.001). The C3a concentration in the aqueous humor strongly correlated with that in the vitreous humor (R = 0.510, P 0.001). The concentrations of C4a and C5a in the aqueous humor moderately correlated with those in the vitreous humor (C4a; R = 0.356, P = 0.019, C5a; R = 0.464, P = 0.022). In conclusion, the anaphylatoxin concentrations measured by cytometric beads array in the aqueous humor may be associated with those measured in the vitreous humor.

Introduction Chilaiditi syndrome is a rare pathophysiology in which the colon or other organs are interposed between the diaphragm and liver, and respiratory or digestive symptoms sometimes manifest. Although there have been some cases of Chilaiditi syndrome complicating neuromuscular disorders, none have described resulting respiratory or digestive symptoms. Case presentation Our patient was a 20-year-old man with DMD who had been receiving noninvasive positive-pressure ventilation during the night. He experienced respiratory distress when changing from a supine to sitting position. Ventilator adjustment did not relieve the respiratory distress. Abdominal computed tomography revealed marked constipation and interposition of the transverse colon between the diaphragm and liver, indicating Chilaiditi syndrome. The right side of the diaphragm was elevated by the interposed transverse colon when the respiratory distress was present on chest radiograph, but not when symptoms were absent. The patient was diagnosed with platypnea-orthodeoxia attributed to Chilaiditi syndrome. The respiratory distress was improved by the relief of constipation, in addition to the usage of the ventilator throughout the day. Conclusion The rare symptoms and pathophysiology of DMD complicated by Chilaiditi syndrome are reported and discussed herein.