The Xiluodu Reservoir, situated on the lower Jinsha River, is fourth-largest hydropower in the world. The dam lies in the central part of the Leibo–Yongshan block, bounded by the Ebian–Jinyang, Lianfeng, and Mabian–Yanjin faults. Following the impoundment of the Xiluodu Reservoir in May 2013, seismic activity in the surrounding area increased markedly, and the Yongshan MS5.1 and MS5.2 earthquakes occurred on April 5 and August 17, 2014, respectively. In this study, we collected a high-resolution seismic catalog for the Xiluodu Reservoir region from 2010 to 2019. Using statistical parameters including the coefficient of variation (CV), b-value, Epidemic-Type Aftershock Sequence (ETAS) model, and nearest-neighbor distance, we analyzed the spatiotemporal characteristics of post-impoundment seismicity and explored its classification. The rapid rise in the b-value during the early filling stage suggests that reservoir loading disturbed the local stress field, triggering a surge in microseismic events. The high consistency between the ETAS model and NND results demonstrates that reservoir-induced earthquakes in the Xiluodu Reservoir area predominantly follow the background mode and exhibit an almost unipolar distribution in spatiotemporal density plots. This phenomenon reflects the distinctive nature of the driving mechanisms underlying seismic activity in the reservoir area. The area near the dam shows a very high seismic attenuation rate and a denser background pattern, while a small proportion of earthquake events in the MS5.1 and MS5.2 source regions show a clustered distribution, indicating the existence of a seismic triggering mechanism here.

BACKGROUND:Sex differences are increasingly recognized as important modifiers of neuroimmune processes in neurodegenerative disorders. However, the sex-associated clinical phenotypes and underlying neuroinflammatory mechanisms in amyotrophic lateral sclerosis (ALS) remain poorly understood. This study integrated multimodal clinical assessments, cerebrospinal fluid (CSF) neuroimmune biomarkers, neuroimaging-based glymphatic metrics, and complementary animal analyses to characterize shared and sex-associated alterations in male and female ALS patients. METHODS:Two independent cohorts including 158 newly diagnosed ALS patients and 112 healthy controls (HCs) underwent evaluations of motor function, cognition, sleep disturbances, and emotional symptoms. Glymphatic function was assessed using choroid plexus volume (CPV), diffusion-derived analysis along the perivascular space (ALPS) index, and white-matter free-water (FW) fraction. In the original cohort, 12 CSF biomarkers spanning astrocytic activation, neuroinflammation, TDP-43 pathology, synaptic dysfunction, and axonal injury were quantified, and glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were further examined in an independent verification cohort. Complementary neuroimmune alterations were further examined in TDP-43 N390D knock-in mice using ELISA and immunofluorescence. RESULTS:Male ALS patients showed markedly elevated CSF GFAP, IL-6, and IL-18 compared with female ALS patients and HCs after false discovery rate correction (q < 0.05). Female ALS patients exhibited increased CSF IL-6 versus HCs, whereas GFAP and IL-18 levels were unchanged. Female ALS patients also demonstrated more severe depressive symptoms and post-traumatic stress disorder than male ALS patients and HCs (p < 0.05). Both sexes displayed glymphatic impairment characterized by increased CPV and FW and reduced ALPS index, as well as pronounced sleep disturbances relative to HCs (all p < 0.05), with no clear sex-related differences. Complementary animal data showed that, at a fixed chronological age, male TDP-43 N390D mice exhibited more severe motor impairment accompanied by higher brain levels of GFAP, IL-6, and IL-18 and more prominent astrocyte-associated IL-6 and IL-18 signals than female mutant mice. Although microglial activation was also observed in TDP-43 N390D mice, no clear sex-related difference was detected at the sampled age. CONCLUSIONS:This multimodal clinical-translational study reveals sex-associated neuroinflammatory heterogeneity in ALS. Male patients exhibit a more pronounced GFAP-, IL-6-, and IL-18-related inflammatory profile, whereas female patients display more prominent affective disturbances. Glymphatic dysfunction and sleep impairment emerge as common pathological pathways across sexes. These findings highlight sex as a crucial biological variable shaping ALS heterogeneity and underscore the importance of incorporating sex-stratified analyses in future ALS neuroimmune research and clinical trials.

This case report describes generalized dystonia and dopaminergic system involvement in a woman with methylmalonic acidemia.

In this study, we used LOC-FLOW to process continuous waveforms recorded by 55 stations near the Baihetan Reservoir in China, which is the second-largest reservoir in the world with installed capacity, from January 2021 to July 2022. We identified 53,838 seismic events with relative location errors within tens of meters, representing a fourfold increase compared to the manual catalog, and recalling approximately 99.0 % of the events listed therein. Our location results indicate that the seismicity after the impoundment of the Baihetan Reservoir is mainly controlled by the regional geological structure, mostly distributed on the sub-structures or fractures near the main fault. Moreover, there are significant differences in seismicity on both sides of the Jinsha River, which is attributed to the different lithology. In some areas, the seismicity gradually migrates away from the reservoir inundation zone. Some clusters exhibit significantly different migration speeds, which may be related to the mechanisms or underground structure. In addition, some events migrate along the depth which is attributed to the earthquake causing rock fractures to allow groundwater infiltration. Below the area submerged by the reservoir water, there are not only notable differences in the b-values, but also distinct correlations between water depths and earthquake rates at those different depths. This may be due to the influence of both water load and pore pressure on rocks in shallow areas, facilitating rapid stress release through microearthquakes. Conversely, in the deeper, stress accumulation results in larger-magnitude earthquakes with weak pore pressure increasing. Our results show that high-resolution earthquake catalogs can reveal the dynamic response of earthquakes to reservoirs and help understand the factors that control their distribution and magnitude. This is of great significance for future earthquake tracking in reservoir areas and for the study of other reservoirs around the world.

The Anninghe–Zemuhe Fault and the Xiaojiang Fault are critical active faults along the middle-eastern boundary of the South Chuan–Dian Block. Many researchers have identified these faults as potential strong-earthquake risk zones. In this study, we leveraged a dense seismic array to investigate the high-resolution shallow crust shear wave velocity (Vs) structure beneath the junction of the Zemuhe Fault Zone and the Xiaojiang Fault Zone, one of the most complex parts of the eastern boundary of the South Chuan–Dian Block. We analyzed the distribution of microseismic events detected between November 2022 and February 2023 based on the fine-scale Vs model obtained. The microseismicity in the study region was clustered into three groups, all spatially related to major faults in this region. These microseismic events indicate near-vertical fault planes, consistent with the fault geometry revealed by other researchers. Moreover, these microseismic events are influenced by the impoundment of the downstream Baihetan Reservoir and the complex tectonic stress near the junction of the Zemuhe Fault Zone and the Xiaojiang Fault Zone. The depths of these microseismic events are shallower in the junction zone, whereas moving south along the Xiaojiang Fault Zone, the microseismic events become deeper. Additionally, we compared our fine-scale local Vs model with velocity models obtained by other researchers and found that our model offers greater detail in characterizing subsurface heterogeneity while demonstrating improved reliability in delineating fault systems.

Background Evidence for the efficacy of risdiplam in adolescents and adults with 5q spinal muscular atrophy (SMA) has been demonstrated in clinical trials, but its sustained effectiveness and safety in real-world settings, particularly in Chinese populations, remains to be demonstrated. We evaluated the efficacy and safety of risdiplam in this population in a real-world setting. Methods This prospective observational study included adolescent and adult patients with genetically confirmed 5q SMA under standard clinical care (January 2023 to December 2024). Patients received risdiplam monotherapy (5 mg daily), with dosing adjusted based on clinical condition and tolerability. Primary outcomes were changes in Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) scores, and 6-min walk test (6MWT). Results Fifteen patients (8 male, 7 female) were included, with a mean (SD) efficacy assessment time of 1.45 (0.38) years. The mean (SD) RULM score significantly improved from 17.60 (10.87) at baseline to 19.33 (11.11) at final follow-up (P = 0.043). The mean (SD) HFMSE score showed a non-significant increase (13.00 (16.21) to 13.60 (16.26), P = 0.159). The 6-minute walk test remained stable, with improvement observed in two patients. The mean (SD) ALSFRS-R scores were unchanged (31.47 (7.61) vs. 31.80 (7.59), P = 0.936). No adverse events were reported, indicating good tolerability. Conclusions Our real-world findings provide evidence supporting the sustained efficacy and safety of risdiplam in managing SMA in adolescent and adult patients. Longer-term and larger-scale studies remain warranted to further characterize its clinical sustainability.

The source parameters of earthquakes (stress drop, corner frequency, seismic moment, source size, radiant energy, etc.) provide important information about the source features, the state of stress, and the mechanism of earthquake rupture dynamics. Using the digital observation data obtained from a high-density seismic monitoring network deployed in the Baihetan reservoir area of the lower Jinsha River, we obtained Brune source parameters of the 459 earthquakes ranging in magnitude ML 1.50~4.70. The results revealed seismic moments M0 within the range of 2.03 × 1012~1.45 × 1016 N·m, corner frequencies fc between 2.00 and 10.00 Hz, and source dimensions varying from 130.00 to 480.00 m, with stress drops spanning from 0.12 to 61.24 MPa. It is noteworthy that the majority of the earthquakes had stress drops less than 10.00 MPa, with as much as 73.30% of these events having stress drops within the range of 0.10 to 2.00 MPa. We found that stress drop, corner frequency, and source size in the study area exhibited positive correlations with earthquake magnitude. Earthquakes occurring at shallower depths for the same magnitude tended to have smaller stress drops and corner frequencies, but larger rupture scales. During the first 2 years of impoundment with significant water level fluctuation, earthquakes beneath or near the reservoir released higher stress drops relative to pre-reservoir conditions, with average stress drops significantly elevated from 5.52 to 13.562 Mpa for events above ML3 since the impoundment. The radiated energy released by earthquakes with magnitudes below ML3.0 are significantly more than before impoundment, indicating that earthquakes of similar magnitudes in the reservoir area may produce greater intensity and perceptibility following the impoundment. According to our result, the triggered seismicity will continue to be active under annual regulation changes in the water level of the Baihetan Dam at high elevations in future years.

Areas of active tectonics host many active faults and frequently experience moderate to large earthquakes. The possibility of devastating earthquakes makes the development of major infrastructure projects in these areas risky. World-class large-scale step hydroelectric projects have been built along the Jinsha River, such as the Xiangjiaba, Xiluodu, Baihetan and Wudongde reservoirs in the Daliang Mountains of the southeastern Tibetan Plateau. Using the SKUA-GoCAD modelling platform, we created a thorough 3D model of the active faults. Regional geological information, historical strong earthquake catalogues, small earthquakes with fine displacement and 3D seismic tomography are all integrated in this model. The Mabian–Yanjin fault belt consists of a number of discontinuous faults that are either exposed on the surface or concealed, according to the 3D fault model. Some destructive earthquakes, including two enormous M s 7 and many moderate earthquakes, have occurred along this fault belt. Some pre-existing thrust faults, together with numerous immature faults in specific areas, may have been reactivated and changed into strike-slip faults. The Jinsha River basin's seismic and geological concerns must be carefully considered given the existence of such intricate fault networks and seismic activity. Supplementary material: A video of the 3D fault model is available at https://doi.org/10.6084/m9.figshare.c.6949201

The eastern boundary of the Sichuan-Yunnan rhombic block (EB-SYRB) has complex structures and strong seismicity. Although multiple 3D high-resolution velocity models have been constructed for this region, its seismogenic environment has been controversial. Seismic wave attenuation (inversely proportional to Q) describes the anelastic properties of the Earth's medium, and is more sensitive to changes in subsurface fluid and temperature than seismic wave velocity. Based on the data of a long-term dense array in downstream of the Jinsha River, this article uses local earthquake tomography to obtain 3D Q(P) and Q(S) models of the middle EB-SYRB with the highest resolution to date, improving the lateral resolution of the Q model from 100 km to 5-10 km and the depth resolution from 10 to 2 km. Combined with the existing high-resolution velocity and resistivity models and geochemical observation results, we can comprehensively understand the medium structure and the seismogenesis in the study area. The results show that the high-attenuation characteristics in the shallow layer of the Xiaojiang fault zone and the Zemuhe fault zone (within a depth of similar to 5 km) are consistent with the topographic relief and the distribution of hot springs, which reveals the Quaternary sedimentary characteristics of the basins and the presence of shallow fluids in the fault zone. The columnar high-attenuation anomaly beneath Huize reveals the fluid channel created by deep melting. The Ludian earthquake sequence occurred in a prominent lowattenuation area, which is favorable for stress accumulation and has a seismogenic environment for strong earthquakes. The high attenuation near the southwest end of the Huize fault is closely related to the Huize earthquake cluster, which is driven by fluids in the upper crust.

The Xiluodu Reservoir (XLD), the third hydropower station developed downstream of the Jinsha River, is currently the fourth largest hydropower station worldwide. The reservoir has been impounded for 10 years, and numerous earthquakes have occurred, thus indicating an increased seismic risk. In existing studies, the deep tectonics and fine-scale structure in the reservoir area have not been sufficiently explained. Thus, the mechanism underlying reservoir-induced seismicity in this area remains unclear. In this study, we utilized a microseismic catalogue compiled based on the LOC-FLOW workflow (Li et al., 2023), alongside long-term observation data from a dense seismic array in the Jinsha River downstream, to obtain high-precision 3D VP, VS and VP/VS structures, as well as refined seismic relocations in the XLD Reservoir area. Additionally, we incorporated petrological, geomagnetic, gravity, crustal density, geodetic observation and numerical simulation data, which demonstrate that seismicity in the reservoir head area and near the Manao Fault is influenced by fluids. Moreover, the two M4 earthquakes that occurred east of the Lianfeng Fault are indicative of tectonic activity. Of these earthquakes, the Tianba earthquake cluster in the reservoir head area is located in a high-VP/VS zone, while a low-VS anomaly channel is observed here, which suggests that large amounts of fluid infiltrated along the fault, increasing the pore pressure and reducing the effective stress on the fault. The Wuji earthquake cluster in the head area is also located in a low-VP/VS zone, which indicates a low porosity and possibly undrained conditions. Thus, the earthquakes in this area are the result of coupled elastic stress-pore water pressure interactions.

ABSTRACT The Xiluodu reservoir, as the third reservoir developed in the lower Jinsha River, is the fourth largest reservoir in the world in terms of power generation. It is located in an area of historically high seismic intensity. A large amount of seismic activity has occurred in the reservoir area because the reservoir was impounded in 2013, but the mechanism of seismogenesis is still not clear. In this study, we collected continuous seismic records from July 2020 to October 2022 in the Xiluodu reservoir area, built a high-precision microseismic catalog for this region based on a deep learning seismic detection and location workflow called LOC-FLOW, and eventually obtained high-precision locations of 4924 earthquakes (five times more than the routine catalog). We sketched the main seismogenic structures based on the spatial and temporal distribution of the earthquakes in the catalog. According to the relationship between periodic variation of water level and seismic activity, seismicity in the reservoir area is active at the stage when the water level is filling to the highest point and starts to draw down. Especially, the sudden change in the rate of water level variation can easily trigger seismic activity. Combined with the spatiotemporal distribution of seismicity in each region and the previous results of numerical simulation, we concluded that the seismic activity in the reservoir head area and around the Manao fault is likely induced by the increase of normal stress and pore pressure diffusion caused by reservoir impoundment, whereas the ML 4.6 earthquake that occurred at the intersection of the Lianfeng fault and the Zhongcun fault was likely tectonic activity occurring on a concealed fault.

This case report describes a patient experiencing involuntary contractions in his right pectoralis muscles with anti-Tr antibodies in his serum, which is characteristic of myorhythmia.

The Luding M(s)6. 8 earthquake on September 5, 2022, marked the largest destructive quake in the vicinity of the Xianshuihe fault in recent six years, providing crucial insights into potential strong seismic activity along the eastern boundary of the Chuandian block. This study employed hypoDD method to precisely locate 11,103 earthquakes in the Luding region from 2009 to 2022. Waveform fitting techniques were then utilized to derive focal mechanism solutions for the mainshock, 12 aftershocks >= M(s)33. 0, and two strong earthquakes >= M(s)5. 0 near Gongga Mountain. The results revealed that the Luding n6. 8 earthquake originated from the Moxi fault, specifically along the Heigou Yanzigou Tianwan section. This quake cover a previously sparse seismic activity gap along the Moxi fault, spanning approximately 40 kilometers and trending at similar to 160 degrees, exhibiting a nearly vertical orientation. The aftershocks along the fault were primarily of the leftlateral strike-slip type. Since 2009, there has been continuous seismic activity near Gongga Mountain to the west of the Luding earthquake, peaking in 2015. Following the mainshock, shallow seismic activity around Gongga Mountain intensified, characterized by tensile fracturing. Notably, these shallow events were triggered and distinct from the seismicity along the Moxi fault. Analysis of b-values indicates distinct stress segmentation along the Moxi fault. The southern and eastern segment, from Wandong to Tianwan, exhibited low b-values (similar to 0.5), whereas the northern and western segment, from Wandong to Heigou, showed higher b-values ranging from O. 8 to 1. O. This indicates that the stress on the Moxi fault zone has obvious segmented characteristics, with energy mainly concentrate and release from Yanzigou to Tianwan.

>The Ms 6.4 earthquake occurred on May 21, 2021 in Yangbi County, Dali Prefecture, Yunnan Province, which was the largest earthquake after the 2014 Jinggu Ms 6.6 earthquake, in western Yunnan. After the earthquake, the rapid field investigation and earthquake relocation reveal that there was no obvious surface rupture and the earthquake did not occur on pre-existing active fault, but on a buried fault on the west side of Weixi–Qiaohou–Weishan fault zone in the eastern boundary of Baoshan sub-block. Significant foreshocks appeared three days before the earthquake. These phenomena aroused scholars' intensive attention. What the physical process and seismogenic mechanism of the Yangbi Ms 6.4 earthquake are revealed by the foreshocks and aftershocks? These scientific questions need to be solved urgently.

AbstractAfter impounding the Baihetan Water Reservoir in a historically seismically active area, numerous earthquakes occurred, but it is uncertain if they are connected to the impoundment. Based on the dense seismic network, this study used local earthquake tomography to construct high‐resolution VP (P‐wave velocity) and VP/VS models (P‐ to S‐wave velocity ratio) and update earthquake locations after the impoundment of Baihetan reservoir. Our study revealed that the reservoir water spreads from the dam site to the Qiaojia Basin and the Heishuihe branch, and pore pressure diffusion along faults induces many earthquakes. Reservoir water migrates through hidden faults and fractures beneath Hulukou, spreading to both sides and saturating some rocks below 7 km beneath the dam site‐Lianhuatang section, causing multiple magnitude 3.5+ earthquakes. This study reveals that reservoir water migration drives earthquakes in the reservoir area, offering new insights into seismogenesis following the Baihetan reservoir's impoundment, potentially applicable to understanding reservoir‐induced earthquakes in other reservoirs.

The Xiluodu Reservoir (XLD), the third hydropower station developed downstream of the Jinsha River, is currently the fourth largest hydropower station worldwide. The reservoir has been impounded for 10 years, and numerous earthquakes have occurred, thus indicating an increased seismic risk. In existing studies, the deep tectonics and fine-scale structure in the reservoir area have not been sufficiently explained. Thus, the mechanism underlying reservoir-induced seismicity in this area remains unclear. In this study, we utilized a microseismic catalogue compiled based on the LOC-FLOW workflow (Li et al., 2023), alongside long-term observation data from a dense seismic array in the Jinsha River downstream, to obtain high-precision 3D VP, VS and VP/VS structures, as well as refined seismic relocations in the XLD Reservoir area. Additionally, we incorporated petrological, geomagnetic, gravity, crustal density, geodetic observation and numerical simulation data, which demonstrate that seismicity in the reservoir head area and near the Manao Fault is influenced by fluids. Moreover, the two M4 earthquakes that occurred east of the Lianfeng Fault are indicative of tectonic activity. Of these earthquakes, the Tianba earthquake cluster in the reservoir head area is located in a high-VP/VS zone, while a low-VS anomaly channel is observed here, which suggests that large amounts of fluid infiltrated along the fault, increasing the pore pressure and reducing the effective stress on the fault. The Wuji earthquake cluster in the head area is also located in a low-VP/VS zone, which indicates a low porosity and possibly undrained conditions. Thus, the earthquakes in this area are the result of coupled elastic stress-pore water pressure interactions.

The Baihetan Reservoir, the second largest in the world, is located at the intersection of multiple large active fault zones on the eastern boundary of the Sichuan-Yunnan rhombic block. After impoundment on 6 April 2021, many earthquakes occurred around the reservoir area submerged by water. The largest ML 4.7 earthquake in the reservoir area occurred after the water level reached its highest point. But the seismogenic structures and mechanisms of earthquakes in the reservoir area are still unclear. Based on dense array data from the reservoir area, this paper uses the experimental site submodel of USTC-Pickers, transfer learned with 'DiTing' data set of China to obtain a high-precision earthquake catalogue that is twice as large as that the manual catalogue. This study show that earthquakes in the reservoir region primarily occur on secondary faults of pre-existing ones, characterized by a prominent feature of high dip angles trending northwest to southeast. Combined with the spatiotemperal migration characteristics of earthquakes and the relationship between earthquakes and water levels, we infer that most earthquakes are rapid response type and may be induced by rapid increase in elastic stress. Only the spatiotemporal distribution image of the ML 3.2 earthquakes sequence in the dam site-Toudaogou section conforms to the law of pore pressure diffusion, and belongs to the fast response type, which may be induced by the poroelasiticity coupling mechanism. The ML 3.0 earthquake swarm with deep depths in the Heishui River section belongs to the delayed response type and may be induced by the poroelasiticity coupling mechanism.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The Baihetan Reservoir was impounded on 6 April 2021, after which the water level rose significantly. Notably, after one week of impoundment, microseismic activities were prominent around the reservoir area, which was highly associated with the water level change. From 6 April 2021 to 31 December 2021, over 7000 microearthquakes were recorded by the seismic stations in the vicinity of the reservoir, including 12 ML > 3 events. The maximum was the 21 December 2021 ML3.9 earthquake in Qiluogou town, Sichuan. The post-impoundment seismic events were clustered in Hulukou town in the Qiaojia Basin, with an overall “Y-shaped” pattern. In this study, taking advantage of the high-frequency waveform matching approach, the pre- and post-impoundment focal mechanism solutions totaling 207 ML > 2 earthquakes are successfully obtained. The impoundment-induced stress change is analyzed, and the iterative joint inversion method is used to invert the stress field. Major results and conclusions include the following: (1) After impoundment, the number of normal fault earthquakes remarkably increased in the reservoir area; (2) Impoundment has led to a vertical compressive stress field and horizontal tensile stress field in the area where microearthquakes occurred. It is necessary to pay close attention to possible moderate-to-strong earthquakes in the future.

PLA2G6-related parkinsonism is named PARK14 and is inherited in an autosomal recessive manner [[1]Paisan-Ruiz C. Bhatia K.P. Li A. Hernandez D. Davis M. Wood N.W. Hardy J. Houlden H. Singleton A. Schneider S.A. Characterization of PLA2G6 as a locus for dystonia-parkinsonism.Ann. Neurol. 2009; 65: 19-23https://doi.org/10.1002/ana.21415Crossref PubMed Scopus (355) Google Scholar]. It is relatively rare compared with typical examples of autosomal recessive early onset parkinsonism, such as mutations in the genes encoding parkin (PARK2), PINK1 (PARK6), and DJ-1 (PARK7). It predominantly manifests as a complex phenotype, including dopa-responsive parkinsonism combined with other neurological/psychiatric features, dystonia, ataxia, and spastic paraplegia [[1]Paisan-Ruiz C. Bhatia K.P. Li A. Hernandez D. Davis M. Wood N.W. Hardy J. Houlden H. Singleton A. Schneider S.A. Characterization of PLA2G6 as a locus for dystonia-parkinsonism.Ann. Neurol. 2009; 65: 19-23https://doi.org/10.1002/ana.21415Crossref PubMed Scopus (355) Google Scholar]. Magrinelli [[2]Magrinelli F. Mehta S. Di Lazzaro G. Latorre A. Edwards M.J. Balint B. Basu P. Kobylecki C. Groppa S. Hegde A. Mulroy E. Estevez-Fraga C. Arora A. Kumar H. Schneider S.A. Lewis P.A. Jaunmuktane Z. Revesz T. Gandhi S. Wood N.W. Hardy J.A. Tinazzi M. Lal V. Houlden H. Bhatia K.P. Dissecting the phenotype and genotype of PLA2G6-related parkinsonism.Mov. Disord. 2022; 37: 148-161https://doi.org/10.1002/mds.28807Crossref PubMed Scopus (27) Google Scholar] performed a systematic review and found that there were 86 PLA2G6-parkinsonism cases from 68 pedigrees worldwide and only 10 from mainland China. There were only two cases of deep brain stimulation (DBS) therapy [[3]Ravat P. Shinde S. Shinde S.R. Bangar S. Nayak N. Agarwal P.A. Juvenile PLA2G6-parkinsonism due to Indian 'Asian' p.R741Q mutation, and response to STN DBS.Mov. Disord. 2022; 37: 657-658https://doi.org/10.1002/mds.28950Crossref PubMed Scopus (2) Google Scholar,[4]Wirth T. Weibel S. Montaut S. Bigaut K. Rudolf G. Chelly J. Tranchant C. Anheim M. Severe early-onset impulsive compulsive behavior and psychosis in PLA2G6-related juvenile Parkinson's disease.Park. Relat. Disord. 2017; 41: 127-129https://doi.org/10.1016/j.parkreldis.2017.05.014Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. Here, we report and review the motor and non-motor responses to DBS in two cases of early onset parkinsonism from China with compound heterozygote PLA2G6 mutations [[3]Ravat P. Shinde S. Shinde S.R. Bangar S. Nayak N. Agarwal P.A. Juvenile PLA2G6-parkinsonism due to Indian 'Asian' p.R741Q mutation, and response to STN DBS.Mov. Disord. 2022; 37: 657-658https://doi.org/10.1002/mds.28950Crossref PubMed Scopus (2) Google Scholar,[4]Wirth T. Weibel S. Montaut S. Bigaut K. Rudolf G. Chelly J. Tranchant C. Anheim M. Severe early-onset impulsive compulsive behavior and psychosis in PLA2G6-related juvenile Parkinson's disease.Park. Relat. Disord. 2017; 41: 127-129https://doi.org/10.1016/j.parkreldis.2017.05.014Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. A 38-year-old woman presented with pain and bradykinesia in the right leg and difficulty in walking five years ago. Bradykinesia appeared in the left leg three years ago, and both upper limbs were gradually involved. She had difficulty turning over in bed and walked independently for two years. She fell down frequently when walking and turning. Owing to a fall one year ago, she was bedridden for three months because of a lower limb fracture. Mild dyskinesia was observed in her on-medication state, and she could walk independently. According to the patient's medical records, she has been always responding well to levodopa. By the time she was hospitalized, her daily levodopa equivalent dose (LEDD) was 1200 mg. We requested targeted sequencing for early onset Parkinson's disease-related genes, which revealed compound heterozygous mutations in PLA2G6 (c.1937C > A,p.P646H from the father and c.1A > G,p.M1V from the mother) and single heterozygote GIGYF2 (c.898A > G from the mother). The patient underwent the levodopa challenge test. In the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, she scored 71 in her off-medication state and 26 in her on-medication state (with mild dyskinesia, MDS-UPDRS-IV 4.1–4.2, 2), with an improvement rate of 63.38%. She had severe gait and balance disorders in the off-medication state (19 for MDS-UPDRS-III 3.10–3.13 score). The patient had mild cognitive impairment and mild anxiety and depression (21/30 for MMSE, 14/30 for MoCA, 16/52 for HAMD, and 13/56 for HAMA, with a primary school education). Other non-motor symptoms included fatigue, sleep disorders, pain, increased sweating, salivation, constipation, and urinary symptoms. To improve the patient's quality of life, she underwent bilateral subthalamic nucleus (STN) DBS. Two years after DBS, there was a significant improvement of the MDS-UPDRS-III score in her off-medication state by 50.7%. The LEDD was reduced to 700 mg, with a 41.6% reduction. Subsequently, she could walk independently, but falls still occurred. Dyskinesia was not observed after DBS. The patient could take care of herself after two years of STN-DBS but still experienced walking instability and falls. The changes before and after STN-DBS are presented in Table 1.Table 1Clinical data and response to STN-DBS of cases of PLA2G6-related parkinsonism.Case1Case2Case3 [[4]Wirth T. Weibel S. Montaut S. Bigaut K. Rudolf G. Chelly J. Tranchant C. Anheim M. Severe early-onset impulsive compulsive behavior and psychosis in PLA2G6-related juvenile Parkinson's disease.Park. Relat. Disord. 2017; 41: 127-129https://doi.org/10.1016/j.parkreldis.2017.05.014Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]Case4 [[5]Zhao Y. Qin L. Pan H. Liu Z. Jiang L. He Y. Zeng Q. Zhou X. Zhou X. Zhou Y. Fang Z. Wang Z. Xiang Y. Yang H. Wang Y. Zhang K. Zhang R. He R. Zhou X. Zhou Z. Yang N. Liang D. Chen J. Zhang X. Zhou Y. Liu H. Deng P. Xu K. Xu K. Zhou C. Zhong J. Xu Q. Sun Q. Li B. Zhao G. Wang T. Chen L. Shang H. Liu W. Chan P. Xue Z. Wang Q. Guo L. Wang X. Xu C. Zhang Z. Chen T. Lei L. Zhang H. Wang C. Tan J. Yan X. Shen L. Jiang H. Zhang Z. Hu Z. Xia K. Yue Z. Li J. Guo J. Tang B. The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.Brain. 2020; 143: 2220-2234https://doi.org/10.1093/brain/awaa167Crossref PubMed Scopus (75) Google Scholar]Sex/current age (y)F/38F/34M/20M/23EthnicityChineseChineseIndianCaucasianFamily historyUnremarkableUnremarkableUnremarkableUnremarkableAge at onset (y)33301723Symptom at onsetBradykinesiaBradykinesia, stiffnessBradykinesiaResting tremorDepression and anxietyMotor featuresparkinsonism++++early dyskinesia++++dystonia–+NA+pyramidalsigns–+NANAbalance disorder+++NAlimbs ataxia–––NANonmotor featurespain++NA+Autonomic dysfunction++NANACognitive impairment+–++psychiatric+ Depression anxiety+ Depression anxietyNA+Depression, anxiety, delusionotherSleep disorderSleep disorderNAHypersexuality and binge eatingResponse to l-dopaGoodGoodGoodGoodBrain MRIMild cerebellar atrophy without iron depositionMild cerebellar atrophy without iron depositionMild cerebellar atrophy without iron depositionNormalGeneticsPLA2G6 (NM_003560.4)Compound hetero c.1937C > A(p.P646H); c.1A > G(p.M1V)Compound hetero c.991G>T(p.D331Y);c.1934_1938del GACCC(p.R645Qfs)Homozygous c.2222G >A (p. Arg741Gln)Compound hetero, c.109C > T (p.R37X);c.2321G>T(p.Ser774Iso)Target of DBSSTNSTNSTNSTNChange of motor symptomFrom 71 to35, by 50.7%aComparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.From 56 to 27, by 51.8%aComparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.From 61 to 16, by 73.8%bComparison of UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.From 32 to 10, by 68.8%bComparison of UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.Change of non-motor symptom(MDS-UPDRS-I)From 17 to 10,41.2%From 17 to 8, 52.9%NANAChange of FOG (MDS-UPDRS-III 3.11)From 4 to 2aComparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.From 4 to 0aComparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.NANAChange of balance (MDS-UPDRS-III 3.12)From 3 to 1 but with daily several fallsaComparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.From 4 to 3aComparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.NANAChange of LEDDFrom 1200mg to 700 mg, reduction by 41.6%From 1000mg to 600mg, reduction by 40%From 1050mg to 275mg,reduction by 73.8%NAChange of dyskinesia (MDS-UPDRS- IV 4.1–4.2)From 2 to 0From 3 to 2relief in dyskinesia (>90%)NANA:Not available;MRI:Magnetic resonance imaging;FOG:freezing of gait;LEDD: levodopa equivalent daily dose;MDS-UPDRS:Movement Disorder Society-Unified Parkinson's Disease Rating Scale;DBS: deep brain stimulation;STN: subthalamic nucleus.a Comparison of MDS-UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative.b Comparison of UPDRS-III score between off-medication score preoperative with off-medication/on-stimulation score postoperative. Open table in a new tab NA:Not available;MRI:Magnetic resonance imaging;FOG:freezing of gait;LEDD: levodopa equivalent daily dose;MDS-UPDRS:Movement Disorder Society-Unified Parkinson's Disease Rating Scale;DBS: deep brain stimulation;STN: subthalamic nucleus. A 34-year-old woman without a personal or family history of neurological problems had poor movement coordination with occasional falls since childhood. At age 30, she presented with pain and clumsy movement in her right leg, gradually developed bradykinesia, and dragged her feet when walking. After three months, she developed the same symptoms in her right arm, with a dramatic improvement in response to low-dose levodopa. At age 32, she developed hypertonia in all of her extremities, instability in her lower limbs with frequent falls, and severe akinesia causing her to be bedridden in off-medication state. Because she continued to respond well to levodopa when the dosage was increased (LEDD 1000 mg/day), the MDS-UPDRS-III score was 56 in her off-medication state and 16 in her on-medication state in the levodopa challenge test. She developed severe dyskinesia during her on-medication state, which lasted only an hour. She also exhibited non-motor symptoms characterised by sleep disorders (difficulty falling asleep and rapid eye movement behaviour disorder), decreased appetite, emotional anxiety, and depression (24/52 for HAMD,18/56 for HAMA). An off-medication state examination showed severe rigidity and bradykinesia without rest tremor, and she was wheelchair-bound and communicated in a slow and unclear voice. An on-medication state examination revealed generalised dyskinesia, lower extremity dystonia, and mild gait ataxia, leading to walking instability. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy without abnormal iron deposition. Whole-exome sequencing revealed the presence of two heterozygous mutations in PLA2G6: (c.991G>T; p.D331Y from the mother) and (c.1934_1938del GACCC; p.R645Qfs from the father) and a heterozygous mutation in PRKN (C.2T > C, p.0). The patient underwent bilateral STN-DBS because of severe motor symptom fluctuations and dyskinesia. The hypertonia of limbs and gait disturbance were significantly improved, and non-motor symptoms, such as pain, were relieved after four months of follow-up (27 for MDS-UPDRS-III score on the state of DBS-on without medication). Postoperative LEDD was reduced to 600 mg/day, resulting in a reduction in levodopa-induced dyskinesia. Changes before and after STN-DBS are presented in Table 1. PLA2G6-parkinsonism is rare in China. In a large cohort (n = 1676) study in the Chinese mainland population, there were only nine patients [[5]Zhao Y. Qin L. Pan H. Liu Z. Jiang L. He Y. Zeng Q. Zhou X. Zhou X. Zhou Y. Fang Z. Wang Z. Xiang Y. Yang H. Wang Y. Zhang K. Zhang R. He R. Zhou X. Zhou Z. Yang N. Liang D. Chen J. Zhang X. Zhou Y. Liu H. Deng P. Xu K. Xu K. Zhou C. Zhong J. Xu Q. Sun Q. Li B. Zhao G. Wang T. Chen L. Shang H. Liu W. Chan P. Xue Z. Wang Q. Guo L. Wang X. Xu C. Zhang Z. Chen T. Lei L. Zhang H. Wang C. Tan J. Yan X. Shen L. Jiang H. Zhang Z. Hu Z. Xia K. Yue Z. Li J. Guo J. Tang B. The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.Brain. 2020; 143: 2220-2234https://doi.org/10.1093/brain/awaa167Crossref PubMed Scopus (75) Google Scholar]. The c.G991T (p.D331Y) mutation was the most common in PLA2G6-parkinsonism in China. Our two cases carried compound heterozygous mutations. The clinical manifestations in our two cases were similar to those in reported PLA2G6-parkinsonism cases [[2]Magrinelli F. Mehta S. Di Lazzaro G. Latorre A. Edwards M.J. Balint B. Basu P. Kobylecki C. Groppa S. Hegde A. Mulroy E. Estevez-Fraga C. Arora A. Kumar H. Schneider S.A. Lewis P.A. Jaunmuktane Z. Revesz T. Gandhi S. Wood N.W. Hardy J.A. Tinazzi M. Lal V. Houlden H. Bhatia K.P. Dissecting the phenotype and genotype of PLA2G6-related parkinsonism.Mov. Disord. 2022; 37: 148-161https://doi.org/10.1002/mds.28807Crossref PubMed Scopus (27) Google Scholar], with early-onset parkinsonism, severe motor symptoms, early levodopa-induced dyskinesia, remarkable depression and anxiety, mild cerebellar atrophy, absence of iron deposition on MRI, and one case with obvious pyramidal signs and dystonia. Both cases did not present with limb ataxia, although there was cerebellar hemisphere atrophy on MRI, with remarkable balance disorder and postural instability. Our cases, as well as the previously reported cases, all responded well to levodopa, though there were disabling motor fluctuations and troublesome dyskinesia in one case. As shown in our cases and the reported cases in the literature [[3]Ravat P. Shinde S. Shinde S.R. Bangar S. Nayak N. Agarwal P.A. Juvenile PLA2G6-parkinsonism due to Indian 'Asian' p.R741Q mutation, and response to STN DBS.Mov. Disord. 2022; 37: 657-658https://doi.org/10.1002/mds.28950Crossref PubMed Scopus (2) Google Scholar,[4]Wirth T. Weibel S. Montaut S. Bigaut K. Rudolf G. Chelly J. Tranchant C. Anheim M. Severe early-onset impulsive compulsive behavior and psychosis in PLA2G6-related juvenile Parkinson's disease.Park. Relat. Disord. 2017; 41: 127-129https://doi.org/10.1016/j.parkreldis.2017.05.014Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], patients with PLA2G6-parkinsonism responded well to STN-DBS, and motor fluctuations and dyskinesia were remarkably improved (with 50–70% improvement of MDS-UPDRS III) with a 40–70% reduction in LEDD. Non-motor symptoms in our cases improved moderately (with a 40–50% improvement in MDS-UPDRS-I). Balance disorder and posture instability in our cases did not improve significantly, and patients still had several daily falls after STN-DBS. However, freezing gait problems improved remarkably, implying instability resulting from cerebellar dysfunction that did not respond well to DBS in the short term. We documented excellent motor and non-motor responses of PLA2G6-parkinsonism to STN-DBS with detailed data, which might justify STN-DBS as a potentially useful intervention for patients with Parkinson's disease with these kinds of mutations. However, more cases and long-term follow-up are still needed. HAMD:A 17-item version was used in this study, which was divided according to the total score: <7 points: no depression present, 7–17 points: mild depression, 17–24 points: definite depression, >24 points: severe depression. HAMA:The total score ≥29 points, may be severe anxiety; ≥21 points, there must be obvious anxiety; ≥14 points, must have anxiety; More than 7 points, may have anxiety; If the score is less than 7, there are no anxiety symptoms. This study was supported by the Qingdao Clinical Medicine Study Centre Project (22-3-7-lczx-3-nsh).