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We report on a series of 1,4-naphthoquinone (NQ)-based photolabile molecules, including various functional compounds to be released under light irradiation. They were efficiently prepared from a common precursor for a photoremovable masking group, by attaching different functional compounds such as alcohols, amines, and acids by a concise synthetic method. Synthesis of the common precursor was optimized for two-step reactions and also for a one-pot reaction involving a 1,4-addition and successive aldol reaction from NQ. The functional compounds, such as alcohols, amines and carboxylic, phosphoric, and sulfonic acids, were masked with the NQ-based precursor and were successfully released by irradiation with UV light (λ = 360 nm) in high yields (>90%).

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot–Marie–Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

We analyzed the records of inpatients with amyotrophic lateral sclerosis (ALS) treated at 27 specialized institutions for muscular dystrophy in Japan from 1999 to 2013 registered in a database on October 1 of each year. The total number of ALS inpatients in 1999 was 29, then that showed rapid increases in 2006 and 2007, and reached 164 in 2013. Age regardless of year was predominantly greater than 50 years. In 1999, the respirator dependent rate was 68.9% and then increased to 92.7% in 2013, while the oral nutritional supply rate was 41.4% in 1999 and decreased to 10.4% in 2013. The number of deaths from 2000 to 2013 was 118. Cause of death was respiratory failure in 26 of 30 patients who maintained voluntary respiration at the time of death and in 5 of 6 with non-invasive ventilation. On the other hand, the main cause of death in patients with tracheostomy invasive ventilation was respiratory infection, which was noted in 26 of 82, while other causes varied. It is expected that the number of ALS patients admitted to specialized institutions with muscular dystrophy wards will continue to increase.

We analyzed the registration data of inpatients with facioscapulohumeral muscular dystrophy (FSHD) receiving care at 27 specialized institutions for muscular dystrophy in Japan from 1999 to 2013 using data from October 1 of each year. The number of inpatients of each year ranged from 63 to 72 (67.1 ± 3.3) throughout the study period. Those aged over 50 years gradually increased during the study period, while the oldest inpatient was 82.8 years old. Most could not walk. The rate of respirator dependency increased from 21.0% in 1999 to 71.0% in 2013, while the rate of patients receiving oral nutrition was 98.4% in 1999 and then reduced to 75.4% in 2013. There were 36 death cases reported in the database, including 15 patients with respiratory failure and 4 with heart failure. Our findings indicate that FSHD patients in a severe condition are impacted by respiratory and nutritional problems and their prognosis for survival is related to respiratory failure.

BackgroundMyotonic dystrophy type 1 involves cardiac conduction disorders. Cardiac conduction disease can cause fatal arrhythmias or sudden death in patients with myotonic dystrophy type 1.Methods and ResultsThis study enrolled 506 patients with myotonic dystrophy type 1 (aged ≥15 years; >50 cytosine‐thymine‐guanine repeats) and was treated in 9 Japanese hospitals for neuromuscular diseases from January 2006 to August 2016. We investigated genetic and clinical backgrounds including health care, activities of daily living, dietary intake, cardiac involvement, and respiratory involvement during follow‐up. The cause of death or the occurrence of composite cardiac events (ie, ventricular arrhythmias, advanced atrioventricular blocks, and device implantations) were evaluated as significant outcomes. During a median follow‐up period of 87 months (Q1–Q3, 37–138 months), 71 patients expired. In the univariate analysis, pacemaker implantations (hazard ratio [HR], 4.35; 95% CI, 1.22–15.50) were associated with sudden death. In contrast, PQ interval ≥240 ms, QRS duration ≥120 ms, nutrition, or respiratory failure were not associated with the incidence of sudden death. The multivariable analysis revealed that a PQ interval ≥240 ms (HR, 2.79; 95% CI, 1.9–7.19,PP< 0.01) were independent factors associated with a higher occurrence of cardiac events than those observed with a PQ interval ConclusionsCardiac conduction disorders are independent markers associated with cardiac events. Further investigation on the prediction of occurrence of sudden death is warranted.

Females with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) mutations rarely exhibit clinical symptoms from childhood, although potential mechanisms for symptoms associated with DMD and BMD in females have been reported. We report the case of a female DMD patient with a clinical course indistinguishable from that of a male DMD patient, and who possessed compound heterozygous contiguous exon deletions in the dystrophin gene. She exhibited Gowers' sign, calf muscle hypertrophy, and a high serum creatine kinase level at 2 years. Her muscle pathology showed most of the fibers were negative for dystrophin immunohistochemical staining. She lost ambulation at 11 years. Multiplex ligation-dependent probe amplification analysis of this gene detected one copy of exons 48-53; she was found to be a BMD carrier with an in-frame deletion. Messenger RNA from her muscle demonstrated out-of-frame deletions of exons 48-50 and 51-53 occurring on separate alleles. Genomic DNA from her lymphocytes demonstrated the accurate deletion region on each allele. To our knowledge, this is the first report on a female patient possessing compound heterozygous contiguous exon deletions in the dystrophin gene, leading to DMD.

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with anoctamin 5 (ANO5) gene mutation, mainly reported from Northern and Central Europe. We report the case of a Japanese male patient with a novel homozygous mutation of c.2394dup, p.Arg799Thrfs in ANO5 gene, the second patient in the Asian population. He had had marked elevation of creatine kinase (CK) level for more than 10 years with minimal muscular symptoms consisting of muscle stiffness and occasional cramps, preceding the onset of proximal limb weakness. Calf hypertrophy and selective fatty replacement of the adductor magnus and gastrocnemius muscles were prominent clinical and muscle imaging features. This case suggests that LGMD2L may affect a broader population than has been previously thought, physicians should consider the possibility of ANO5 mutation even in patients showing elevated CK level with no apparent muscle weakness but muscle stiffness or cramps.

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

Purpose The goal of the present study was to clarify the clinical characteristics and laboratory results of parkinsonian symptoms among patients with and without camptocormia. Methods Seventy-eight Parkinson's disease (PD) patients with camptocormia and 78 PD patients without camptocormia underwent a neurological examination, a blood test, and spinal magnetic resonance imaging (MRI). PD with camptocormia group and PD with non-camptocormia group were matched on age, age at PD onset, and sex. Principal results Camptocormia group had significantly higher prevalence of compression fractures, more severe parkinsonian symptoms, and a greater incidence of dementia than those without camptocormia. Serum creatine kinase levels in camptocormia group significantly elevated compared with non-camptocormia group. There were higher prevalence of abnormal findings in spine MRI including compression fractures and paravertebral muscle changes in camptocormia group compared with non-camptocormia group. Major conclusions Camptocormia is associated with a greater prevalence of compression fractures and associated with greater UPDRS part II, part III score, axial score, and lower MMSE in this cross-sectional study. Thus, it can be concluded that camptocormia in PD is predominantly myopathic.

Objective This study investigated the relationship between mental retardation and lifetime events in patients with Duchenne muscular dystrophy (DMD). Methods The data on mental retardation and ages of lifetime events (first walking, loss of ambulation, introductions of ventilator support and tube nutrition and death) were collected retrospectively, and the relationships between the factors were analyzed. Patients Among 194 DMD patients admitted to our hospital between 1995 and 2007, 74 patients underwent evaluation of their intelligence quotient (IQ). Results Twenty-eight patients (38%) demonstrated mental retardation (IQ

Objective To investigate the relationship between heart rate variability and hypercapnia. Patients and Methods We measured the coefficient of variation of R-R interval (CVrr) and arterial blood gas pressures in 73 patients with Duchenne muscular dystrophy. Results CVrr was negatively correlated with arterial partial pressure of carbon dioxide (PaCO2). In patients whose CVrr was larger than 5%, 84% of them had no hypercapnia while the other 16% had hypercapnia (PaCO2 >45 mmHg). In contrast, 27% of those with CVrr smaller than 3% had no hypercapnia, 73% had hypercapnia and 47% had severe hypercapnia (PaCO2 >50 mmHg). Conclusion We first showed that CVrr was negatively correlated with PaCO2, and propose that abnormally low CVrr indicates respiratory insufficiency in patients with Duchenne muscular dystrophy.

We report the beneficial and adverse effects of modafinil for daytime sleepiness in a 62-year-old female patient with myotonic dystrophy. Although it was effective for excessive daytime sleepiness, orolingual dyskinesia appeared the day following administration of modafinil (100 mg/day), and dyskinesia disturbed her daily life including dental treatment. When modafinil was stopped, dyskinesia was improved. However, excessive daytime sleepiness deteriorated gradually; re-treatment with smaller dosage (50 mg every other day) resulted in partial improvement but aggravation of both dyskinesia and diabetes mellitus. Modafinil should be administered carefully when the patient is older or has complications such as glucose intolerance.

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.

We investigated the relationship between nasal flaring and SpO2 in 19 patients with Duchenne muscular dystrophy (DMD) and 26 patients with myotonic dystrophy (DM1). In DMD patients, nasal flaring was observed when SpO2 was lower than 96%, while it was not seen even at 82% of SpO2 in DM1. None of the DM1 patients could perform voluntary nasal flaring. Nasal flaring is a useful indicator of hypoxemia in DMD but not in DM1. It remains to be elucidated whether the lack of nasal flaring in DM1 patients is due to abnormal respiratory central mechanism or nasal muscle weakness.

We investigated a progression of brain atrophy and somatosensory system dysfunction in multiple system atrophy (MSA). Subjects were 21 MSA patients [12 MSA-C (cerebellar type) and 9 MSA-P (parkinsonism type)]. The relative volumes of cerebrum, brainstem and cerebellum to the intracranial volume were obtained from three-dimensional computed tomography (3D-CT) of the brain. The median nerve somatosensory evoked potentials (SEPs) were recorded, and the latencies and amplitudes of N9, N11, P13/14, N20 and P25 components were measured. We studied correlations between brain volumes, SEP and clinical features. The brainstem and cerebellar atrophies were aggravated with progression of the disease. The central sensory conduction time (CSCT) was progressively prolonged in parallel with the disease duration irrespective of the actual age of the patients. In MSA patients, the volume reductions of cerebellum and brainstem could be one of structural markers of disease progression, and the sensory pathway is progressively involved with the progression of disease processes.

We report an 18-year-old man with elevation of the creatine kinase (CK) level to 11,068 IU/L. There was no muscle atrophy or fat replacement on CT while muscles in the posterior compartment of lower legs showed high T2 signal intensity on MRI. We performed muscle biopsy from the gastrocnemius muscle. Immunohistochemical analysis demonstrated an absence of dysferlin leading to a diagnosis of preclinical dysferlinopathy. Typical distribution of muscle involvement was demonstrated not by CT but by MRI which may have contributed to facilitating diagnosing the earliest stage of preclinical dysferlinopathy, presenting with asymptomatic elevation of serum creatine kinase.

There is an enormous amount of information available on past accidents in the form of incident reports available as documents and managed by databases. Engineers who perform safety analysis can benefit from this information. However, incident reports and accident databases are written the form of textual natural language descriptions. This paper presents a knowledge-based approach to extract knowledge directly from such sources while reducing the number of mismatches.

We conducted spinal MR imaging on a 35-year-old man with Lhermitte's sign that had manifested over the previous 4 years. He had consumed more than 500 ml of whisky daily for at least 10 years. However, he did not show any evidence of severe liver disease with hepato-systemic blood shunting. Neurologic examination revealed markedly depressed sense of vibration in the feet and mild spasticity in the lower limbs, together with Lhermitte's sign. MR imaging revealed abnormal signal intensity in the posterior column spanning the whole length of the upper cervical cord, which is consistent with Lhermitte's sign.

Myotonic dystrophy (DM) is an autosomal dominant disorder with dysfunction of multiple systems. Concurrent features of skeletal muscles, myotonia and weakness, do not make difficulties with DM patients in early and mild stage, and progress slowly. Consequently, the diagnosis of DM in the early stage is difficult and tends to delay. We analyzed main symptoms at onset and chief complaints at the first visit to clinic from the medical records of 67 our patients with DM (41 males, 26 females). Mean age of their onset was 27.2 ± 14.1. The main symptoms at onset were; weakness, 40; myotonia, 17; mental retardation, 8; dysarthria, 1; lumbago, 1. Mean interval from onset to their first visit to neurological clinics about DM was 11.6 ± 9.9 years. The chief complaints at the first visit to clinics were; weakness, 44; myotonia, 7; dysarthria, 2; lumbago, 2; genetic counseling, 2; apathy, 1; syncope, 1; no complaint, 8. Among 17 patients onset with myotonia, only 7 were with also myotonia as the chief complaint at the first visit to clinic. Among 40 patients onset with weakness, 33 were with weakness as the chief complaint at the first visit to clinic. Myotonia is a characteristic and important sign for DM, which provides early diagnosis. In contrast, myotonia is less likely to be a reason for consultation to medical doctor, suggesting that patients with DM are suffering more with weakness than with myotonia.