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Objective: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early‐onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. Methods: Our research commenced with an in‐depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early‐onset ALS (onset age of <40 years). This involved whole‐exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early‐onset ALS and further included 440 patients with adult‐onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. Results: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early‐onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early‐onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. Interpretation: Our study revealed novel SPTLC2 variants in patients with early‐onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development. [ABSTRACT FROM AUTHOR]

Background Gait disturbance is a major problem for Parkinson's disease patients. Aim We examined the nature of parkinsonian gait using a triaxial accelerometer, and elucidated differences as compared with healthy adults. Methods A total of 16 patients with idiopathic Parkinson's disease, 14 healthy young adults and 10 healthy older adults took part in the study. The accelerometer was placed at the level of the L4 spinous process and the participants were instructed to walk along a 30-m horizontal walkway. Gait speed and acceleration were analyzed on the middle 10 m. Acceleration data were obtained by using the root mean square of acceleration in three directions as the mean acceleration value. Results Gait speed and mean acceleration had a high correlation in healthy young and older adults, but not in the Parkinson's disease patients. Gait speed in the Parkinson's disease patients was significantly slower than that in the healthy older adults ( P < 0.05). Evaluations of each component of acceleration showed that the mediolateral component in the patients was significantly high as compared with that in the healthy older adults ( P < 0.05), although the vertical and anteroposterior components were not different between the Parkinson's disease patients and healthy adults. Conclusions Gait speed in Parkinson's disease patients is significantly slower than that in healthy older adults. Furthermore, it is suggested that gait in Parkinson's disease patients swings in a more bilateral manner as compared with the gait in normal controls. [ABSTRACT FROM AUTHOR]

Recently, we have developed a new hybrid-rehabilitation combining 5 Hz repetitive transcranial magnetic stimulation and extensor motor training of the paretic upper-limb for stroke patients with flexor hypertonia. We previously showed that the extensor-specific plastic change in M1 was associated with beneficial effects of our protocol ( Koganemaru et al., 2010 ). Here, we investigated whether extensor-specific multiregional brain reorganization occurred after the hybrid-rehabilitation using functional magnetic resonance imaging. Eleven chronic stroke patients were scanned while performing upper-limb extensor movements. Untrained flexor movements were used as a control condition. The scanning and clinical assessments were done before, immediately and 2 weeks after the hybrid-rehabilitation. As a result, during the trained extensor movements, the imaging analysis showed a significant reduction of brain activity in the ipsilesional sensorimotor cortex, the contralesional cingulate motor cortex and the contralesional premotor cortex in association with functional improvements of the paretic hands. The activation change was not found for the control condition. Our results suggested that use-dependent plasticity induced by repetitive motor training with brain stimulation might be related to task-specific multi-regional brain reorganization. It provides a key to understand why repetitive training of the target action is one of the most powerful rehabilitation strategies to help patients. [ABSTRACT FROM AUTHOR]