Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain / 神经科学通报·英文版

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Cerebrotendinous xanthomatosis： a family report and literature review / 中华神经科杂志

Objective:To summarize and review a Chinese family with cerebrotendinous xanthomatosis (CTX) so as to improve understanding of the disease.Methods:The proband was admitted to the Department of Neurology， the Second Hospital of Hebei Medical University on May 30, 2019. The medical history, neuro-imaging, pathology, CYP27A1 gene of the proband and CYP27A1 gene of her family were analyzed. Clinical features of similar cases from published literatures were retrieved and systematically summarized.Results:The proband was a 39-year-old female who was admitted to the Second Hospital of Hebei Medical University due to weakness of both lower limbs lasted for more than five years and aggravated for one year with speech slurred. The proband manifested with mental retardation, bilateral pyramidal tract impairment and cerebellar lesions, and had cholesterol crystal in xanthomas and compound heterozygous mutations of c.435G>A and c.1263+1G>A in CYP27A1 gene. The proband′s sister had the same mutation as the proband′s. The proband′s mother was the carrier of c.435G>A mutation, and father was the carrier of c.1263+1G>A mutation. Seventeen related cases concerning CTX with detailed clinical data were searched with major domestic databases. Combined with this case, clinical features with the frequency more than 50% were pyramidal sign, mental decline, ataxia, dysarthria, achilles tendon neoplasm, cataract, high arch foot.Conclusions:The onset of CTX is hidden, which can be diagnosed by its pathology and CYP27A1 gene detection. The possibility of CTX should be considered when there are unexplained clinical manifestations in common diseases such as pyramidal sign, mental decline, ataxia, dysarthria, achilles tendon neoplasm, cataract, high arch foot and so on.

Clinical features of Kennedy's disease without sensory nerve involvement: a report of 5 cases / 中国神经精神疾病杂志

Objective To analyze the clinical feature,serum examination,EMG of Kennedy'Disease to reduce misdiagnosis of Kennedy's Disease.Methods Five cases of Kennedy's disease were confirmed by genetic test.The clinical data was analyzed including clinical features,laboratory findings,EMG characteristics and determination of AR gene exon 1 CAG repeat sequence.Results These cases were male without an obvious positive family history.The average age of onset was 39.8 ±7.2 years old and the average duration from onset to diagnosis was 9 ±5.2 years.Onset symptoms included Lower limbs weakness in 3 cases,facial fasciculationin 1 cases and gynecomastia in 1 case.The most prominent clinical manifestations were tongue muscle atrophy,tongue muscle fibrillation and proximal limb muscle weakness.In addition,these 5 cases did not have clinical manifestation of sensation loss nor EMG evidence of abnormal sensation.Conclusion Kennedy's disease is a neurodegenerative disease characterized by lower motor neuron damage.The clinical features of these 5 cases are approximately the same as those reported in previous literatures.Although the patients have been reported to have abnormal sensation,the present study indicates that some patients with Kennedy's disease may not present with abnormal sensation and that the diagnosis of Kennedy's disease depends on the genetic test.

Clinical features of Kennedy's disease without sensory nerve involvement: a report of 5 cases / 中国神经精神疾病杂志

Objective To analyze the clinical feature,serum examination,EMG of Kennedy'Disease to reduce misdiagnosis of Kennedy's Disease.Methods Five cases of Kennedy's disease were confirmed by genetic test.The clinical data was analyzed including clinical features,laboratory findings,EMG characteristics and determination of AR gene exon 1 CAG repeat sequence.Results These cases were male without an obvious positive family history.The average age of onset was 39.8 ±7.2 years old and the average duration from onset to diagnosis was 9 ±5.2 years.Onset symptoms included Lower limbs weakness in 3 cases,facial fasciculationin 1 cases and gynecomastia in 1 case.The most prominent clinical manifestations were tongue muscle atrophy,tongue muscle fibrillation and proximal limb muscle weakness.In addition,these 5 cases did not have clinical manifestation of sensation loss nor EMG evidence of abnormal sensation.Conclusion Kennedy's disease is a neurodegenerative disease characterized by lower motor neuron damage.The clinical features of these 5 cases are approximately the same as those reported in previous literatures.Although the patients have been reported to have abnormal sensation,the present study indicates that some patients with Kennedy's disease may not present with abnormal sensation and that the diagnosis of Kennedy's disease depends on the genetic test.