Objective: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype–phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. Methods: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. Results: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. Conclusions: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.

Pompe disease is caused by an inborn defect of lysosomal acid α-glucosidase (GAA) and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD is still unclear. Here we generated induced pluripotent stem cells (iPSCs) from patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, which was dose-dependently rescued by rhGAA. We further demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in IOPD iPSC-derived myocytes. Comprehensive metabolomic and transcriptomic analyses suggested the disturbance of mTORC1-related signaling, including deteriorated energy status and suppressed mitochondrial oxidative function. In summary, we successfully established an in vitro skeletal muscle model of IOPD using patient-specific iPSCs. Disturbed mTORC1 signaling may contribute to the pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for Pompe disease.

Background: Recently, rehabilitation robots are expected to improve the gait of cerebral palsy (CP) children. However, only few previous studies have reported the kinematic and kinetic changes by using wearable exoskeleton robots. The aim of this study was to investigate the change in gait parameters in CP children by training with the wearable robot-assisted gait training.Methods: 10 spastic CP children with Gross Motor Function Classification Scale levels I-III completed a sham-controlled crossover randomized trial. Robot-assisted gait training (RAGT) and non-assisted gait training (NAGT) were performed on the treadmill with the Honda Walking Assist (HWA) in two different days. To examine the carry-over effect from treadmill walking to overground walking, participants also performed 5.5 m overground-walks without the HWA before and after treadmill training (pre- and post-trial). During treadmill walking, peak of both hip and knee angles were measured. Also, we calculated the limb symmetry of hip range of motion. In addition, gait speed and ground reaction force were measured in overground trials.Results: The maximum hip angle on the limb with fewer hip movements, which was defined as the affected limb, showed a significant interaction between ASSIST (RAGT and NAGT) and TIME (pre- and post-trial) (p < 0.05). Limb symmetry significantly improved after RAGT (p < 0.05), but not in NAGT. Furthermore, the affected limb showed a significant increase in the positive peak of the anterior-posterior ground reaction force during 70–100% of the gait cycle (p < 0.05). However, there was no change in gait speed.Conclusion: By assisting the both hip movements with the HWA, maximum hip flexion and extension angle of the affected limb improved. Also, limb symmetry and propulsion force of the affected limb improved. Our results suggest that assisting both hip movements with the HWA might be an effective method for improving gait in CP children.Trial registration: UMIN-CTR, UMIN000030667. Registered 3 January 2018,https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033737

N‐ethylmaleimide‐sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild‐type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy.