SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.

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.

Task-specific brain reorganization in motor recovery induced by a hybrid-rehabilitation combining training with brain stimulation after stroke.

Recently, we have developed a new hybrid-rehabilitation combining 5Hz 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.

Recovery of upper-limb function due to enhanced use-dependent plasticity in chronic stroke patients.

Patients with chronic stroke often show increased flexor hypertonia in their affected upper limbs. Although an intervention strategy targeting the extensors of the affected upper limb might thus be expected to have benefits for functional recovery, conventional repetitive motor training has limited clinical utility. Recent studies have shown that repetitive transcranial magnetic stimulation could induce motor recovery. The present study tested whether 5 Hz repetitive transcranial magnetic stimulation of the upper-limb area of the primary motor cortex, combined with extensor motor training, had a greater effect on motor recovery than either intervention alone in stroke hemiparesis. Nine patients with chronic subcortical stroke and nine age-matched healthy subjects completed the crossover study. In separate sessions, we examined the single intervention effect of repetitive wrist and finger extension exercises aided by neuromuscular stimulation, the single intervention effect of 5 Hz repetitive transcranial magnetic stimulation and the combined effect of the two interventions. The motor functions were evaluated behaviourally in patients (Experiment 1) and electrophysiologically in healthy subjects (Experiment 2), both before and after the intervention. In addition, we tested the long-term effect by repeating the combined interventions 12 times in patients (Experiment 3). The motor functions were measured again 2 weeks after the end of the repetitive intervention period. In Experiment 1, the combined intervention, but neither of the single interventions, resulted in an improvement of extensor movement (P < 0.0001) and grip power (P < 0.05), along with a reduction of flexor hypertonia (P < 0.01), in their paretic upper limbs. In Experiment 2, only the combined intervention resulted in selective plastic changes of cortico-spinal excitability (P < 0.01), motor threshold (P < 0.001) and silent period (P < 0.01) for the extensors. In Experiment 3, we also confirmed long-term beneficial effects of the combined intervention in patients. These findings indicate that combining motor training with repetitive transcranial magnetic stimulation can facilitate use-dependent plasticity and achieve functional recovery of motor impairments that cannot be attained by either intervention alone. This method could be a powerful rehabilitative approach for patients with hemiparetic stroke.