Currently, no curative therapies exist for Amyotrophic Lateral Sclerosis (ALS). This study aimed to evaluate the efficacy and safety of Huoling Shengji granules (HLSJ), a traditional Chinese medicine (TCM), compared to the standard treatment riluzole. A multicenter, randomized, double-blind, double-dummy, active-controlled Phase II clinical trial was conducted across 11 centers in China. A total of 140 ALS patients were randomly assigned (1:1) to receive either HLSJ or riluzole for 48 weeks. The primary endpoint, analyzed in the full analysis set (FAS), was the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from baseline to Week 48. Safety profiles were comparable between groups, with no significant difference in adverse events (80.28% vs. 80.56%, P = 0.9671). Analysis using the pre-specified Last Observation Carried Forward (LOCF) method showed a numerical advantage for HLSJ (1.07 points) but lacked statistical superiority. However, a more scientific analysis using the Mixed Model for Repeated Measures (MMRM), recommended for progressive diseases, indicated that HLSJ was significantly superior to riluzole in slowing ALSFRS-R score decline (Least Squares Mean Difference [LSMD]: 2.29 points; 95% confidence interval [CI]: 0.52 to 4.06; P = 0.0114). While the LOCF model showed no statistical difference, the MMRM analysis confirmed that HLSJ demonstrated significant efficacy superior to riluzole with a favorable safety profile. These findings provide a critical basis for conducting pivotal Phase III confirmatory trials of HLSJ for ALS treatment.

BackgroundMutations in the SPAST gene cause autosomal dominant hereditary spastic paraplegia (HSP) type 4 (SPG4), which is the most common type of HSP with variable frequencies in different ethnic backgrounds. The clinical and genetic characteristics of SPG4 in Central China have not been well documented.MethodsWe screened for SPAST variants by whole exome sequencing in a cohort of 63 unrelated families with HSP from Central China. The clinical manifestations were evaluated.Results21 variants of SPAST were identified in 21 index patients with a frequency of 33.3% (21/63). Seven novel variants were identified, including one missense variant (p.S399W), five frameshift variants (p.Q170Vfs*2, p.S527Vfs*3, p.I605Vfs*17, p.I605Nfs*26, and p.V443Afs*2), and one splicing variant (c.871-1G>A). We also detected four previously reported exon deletions of SPAST. The mean age of disease onset was 34.0 years. Anticipation and variability of disease severity were observed in some autosomal dominant families. Two patients exhibited a complicated phenotype, one of whom presented with hyposmia, which had never been previously reported with SPG4.ConclusionSPG4 is the most common type of HSP in our cohort. Complicated phenotype, although rare, can also be observed in SPG4 patients. The hyposmia might be a new phenotype associated with SPG4. The SPAST rearrangement is common and should be considered during genetic analysis. The novel SPAST variants identified in this study expand the mutational spectrum.

This study employed shotgun metagenomic sequencing to characterize the ocular surface microbiome in 20 progressive supranuclear palsy-Richardson’s syndrome (PSP-RS) patients, 17 Parkinson’s disease (PD) patients, and 30 healthy controls (HC). Comparative analysis revealed that PSP-RS patients exhibited significantly altered microbial β-diversity compared to HC, while PD patients showed no such significant changes. Both patient groups demonstrated decreased abundance of g_Vibrio, with PSP-RS patients additionally showing marked increases in g_Acinetobacter and g_Anaerococcus. Importantly, correlation analyses identified that increased g_Acinetobacter abundance was positively associated with ocular motor impairment severity, while elevated g_Anaerococcus levels correlated with both freezing of gait severity and longer disease duration in PSP-RS patients. This is the first shotgun metagenomic investigation of the ocular surface microbiome in PSP-RS and these findings provide evidence that specific alterations in the ocular surface microbiome may contribute to PSP-RS pathogenesis and disease progression.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy and currently lacks disease-modifying therapy. PXT3003, a low-dose oral combination targeting PMP22 overexpression, has shown efficacy in two trials, while one recent confirmatory trial failed to meet its primary efficacy endpoints. In this trial, eligible participants aged 16 to 65 years with genetically confirmed mild-to-moderate CMT1A were randomly assigned to receive oral PXT3003 or placebo twice daily for 15 months. The primary endpoint was the change in the overall neuropathy limitations scale (ONLS) total score from baseline to month 15. At month 15, mean ONLS change from baseline was -0.268 (SD: 0.82) in the PXT3003 group versus 0.013 (SD: 0.65) in the placebo group, with a between-group difference of -0.249 (95% confidence interval [CI]: -0.467 to -0.030; p = 0.0257). Significant improvements were observed in the ONLS leg subscore and ankle-dorsiflexion strength. These findings support PXT3003 as a promising therapeutic option for alleviating limb symptoms in patients with CMT1A.

BACKGROUND:Multiple system atrophy (MSA) shares clinical features with idiopathic Parkinson' s disease (iPD) and progressive supranuclear palsy (PSP), yet reliable biomarkers for differential diagnosis remain elusive. OBJECTIVES:This study aimed to evaluate Piezo1/2 expression in urinary exfoliated cells as a potential biomarker for MSA differentiation. METHODS:Piezo1/2 expression levels were quantified in urinary exfoliated cells from 76 MSA patients, 103 iPD patients, 59 PSP patients, and 126 healthy controls (HCs) across three independent cohorts using multiple analytical techniques. RESULTS:In the discovery cohort, Piezo1 expression was significantly reduced in MSA patients compared with HCs, iPD, and PSP (area under the curve: 0.9421, 0.8218, and 0.8036, respectively). These findings were validated in two independent cohorts, confirming consistently lower Piezo1 levels in MSA patients and their utility in distinguishing MSA from other groups. CONCLUSION:Reduced Piezo1 levels in urinary exfoliated cells show strong potential as a non-invasive biomarker for diagnosing MSA. © 2025 International Parkinson and Movement Disorder Society.

Taste impairment is a prevalent issue among individuals with idiopathic Parkinson’s disease (iPD). However, understanding taste disorders among different Parkinsonism remains incomplete. Our objective was to assess the incidence and severity of taste responses to sweet, salty, sour, bitter, and umami substances in patients with iPD, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Taste function was evaluated by assessing the intensity ratings of four concentrations of sweet, salty, sour, bitter, and umami in 221 healthy controls (HCs), 251 iPD patients, 156 PSP patients, and 60 MSA patients. The Kruskal–Wallis one-way analysis was employed to discern differences in taste function among groups. Logistic regression models were utilized to analyze the association between disease severity and taste function. Participants with iPD, PSP, and MSA exhibited lower total taste scores (TTS) compared to HCs (P < 0.0001, P < 0.0001, and P = 0.0002, respectively). The TTS was significantly lower in iPD patients compared to PSP and MSA patients (P = 0.0024 and P = 0.0464, respectively), with no discernible difference between PSP and MSA patients (P = 0.9998). Furthermore, in patients with iPD, both disease severity and gastrointestinal function exhibited a significant negative correlation with the TTS. However, the taste test lacked the potency to reliably distinguish iPD from PSP and MSA. These research findings suggest that taste impairment emerges as a phenotype of Parkinsonism, serving as a basis for differential diagnosis and guiding dietary adjustments for patients.

Variants in GBA1 represent the most prevalent genetic risk factors for Parkinson’s disease (PD), yet how environmental exposures interact with these mutations to drive disease remains unclear. Epidemiological evidence implicates high dairy consumption as a potential modifiable risk factor for PD, but the mechanistic basis remains elusive. Here, we identify hepatic deposition of phosphorylated α-synuclein (pα-syn) in two PD patients carrying the pathogenic GBA1 L444P variant with histories of excessive dairy intake. Using Gba1L444P/+ mice, we demonstrate that a dairy-rich diet enriched in calcium and casein could induce pathological α-syn aggregation within Kupffer cells (KCs) of the liver. Proteomic profiling reveals that this diet triggers mitochondrial oxidative stress and aggravates GBA1 mutation-induced autophagy defects in KCs, creating a permissive environment for α-synucleinopathy. Notably, hepatic pα-syn pathology propagates to discrete brain regions, including the dorsal nucleus of the vagus nerve, substantia nigra, striatum, and prefrontal cortex, leading to both motor and cognitive impairments. Surgical disruption of liver-brain communication via liver transplantation or hepatic denervation can postpone cerebral pα-syn deposition, confirming a neural conduit for disease transmission. These findings establish the liver as a novel origin site for α-syn pathology in a genetically susceptible context, and define a previously unrecognized liver-brain axis in PD pathogenesis. Our work highlights the interplay between environmental and genetic factors in shaping α-syn dynamics and uncovers potential targets for early intervention in PD.

Perivascular spaces (PVSs) as the anatomical basis of the glymphatic system, are increasingly recognized as potential imaging biomarkers of neurological conditions. However, it is not clear whether enlarged PVSs are associated with alcohol-related brain damage (ARBD). We aimed to investigate the effect of long-term alcohol exposure on dyslipidemia and the glymphatic system in ARBD. We found that patients with ARBD exhibited significantly enlargement of PVSs in the frontal cortex and basal ganglia, as well as a notable increased levels of total cholesterol (TC) and triglycerides (TG). The anatomical changes of the glymphatic drainage system mentioned above were positively associated with TC and TG. To further explore whether enlarged PVSs affects the function of the glymphatic system in ARBD, we constructed long alcohol exposure and high fat diet mice models. The mouse model of long alcohol exposure exhibited increased levels of TC and TG, enlarged PVSs, the loss of aquaporin-4 polarity caused by reactive astrocytes and impaired glymphatic drainage function which ultimately caused cognitive deficits, in a similar way as high fat diet leading to impairment in glymphatic drainage. Our study highlights the contribution of dyslipidemia due to long-term alcohol abuse in the impairment of the glymphatic drainage system.

BackgroundSpinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy.ObjectiveOur aim was to investigate the safety and efficacy of high-dose ganglioside GM1 (ganglioside-monosialic acid) pulse treatment in patients with SCA3.MethodsPatients were randomly allocated to receive either high-dose GM1 (400 mg on the first day followed by 200 mg/day), low-dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post-treatment, is central to evaluating treatment efficacy. Secondary outcomes included changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients.ResultsA total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention-to-treat analysis). The least-squares mean change in the SARA score from baseline to 12 weeks post-treatment was -3.80 (standard error [SE], 0.39; 95% confidence interval [CI], -4.58 to -3.02) in the high-dose GM1 group, 0.34 (SE, 0.40; 95% CI, -0.46 to 1.13) in the low-dose GM1 group, and 0.73 (SE, 0.40; 95% CI, -0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high-dose GM1 group compared to the low-dose GM1 and placebo groups. All treatments were well-tolerated and safe.ConclusionsHigh-dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. (c) 2024 International Parkinson and Movement Disorder Society.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients. Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9

Objective:To analyze the risk factors of hemorrhagic transformation after intravenous thrombolysis in patients with acute cerebral infarction.Methods:One hundred and eight patients with acute cerebral infarction treated in Henan Provincial People’s Hospital from March 2021 to June 2022 were selected as the study subjects. All patients received intravenous thrombolysis; among them, 31 patients with hemorrhagic transformation after intravenous thrombolysis were enrolled in the study group, while 77 patients without hemorrhagic transformation were included in the control group. The various indicators of the two groups were analyzed, and the influencing factors of hemorrhagic transformation after acute cerebral infarction were summarized through multivariate logistic regression analysis.Results:The proportion of patients with history of atrial fibrillation, high fasting blood glucose, diabetes history and large-area acute cerebral infarction in the study group were higher than those in the control group, and the difference was statistically significant ( P<0.05). The results of multivariate logistic regression analysis showed that high blood glucose level, history of atrial fibrillation, large-area acute infarction were all the risk factors for hemorrhagic transformation after acute cerebral infarction (all P<0.05). Conclusions:High fasting blood glucose level, history of atrial fibrillation and large-area acute cerebral infarction are independent risk factors of hemorrhagic transformation after intravenous thrombolysis in patients with acute cerebral infarction.

Abstract Hypertrophic olivary degeneration (HOD) is a transsynaptic degeneration characterized by the disruption of dentato-rubro-olivary tract, a region also known as the Guillain-Mollaret triangle (GMT), which often occurs because of posterior fossa or brainstem lesions. Infratentorial cerebrovascular diseases (ICVD) has been linked to HOD in previous studies. The underlying mechanism of ICVD patients developed HOD, however, remains undetermined. In this study, we analyzed clinical features of 334 patients with ICVD and the results showed that brainstem hemorrhage was most likely to develop HOD (43.5%) among four types of ICVD. In addition, multivariate regression analysis revealed that PSP-RS was an independent risk factor (OR = 6.69, 95% CI: 1.58–28.32) for ICVD-HOD, and the presence of HOD was obviously higher in PSP-RS patients complicated by ICVD (43.5%) than that in PSP-RS patients uncomplicated by ICVD (4.2%). Furthermore, DTI study showed that the PSP-RS, HOD, PSP-RS with HOD, and PSP-RS with ICVD-HOD groups displayed the impaired microstructural integrity of the GMT compared to iPD and HCs groups. Moreover, some DTI parameters of the GMT showed correlation with the Progressive Supranuclear Palsy Rating Scale (PSPRS) score in PSP-RS patients. Taken together, our study demonstrated that PSP-RS was an independent etiological factor for ICVD-HOD which might due to impaired microstructural integrity of the GMT. More importantly, these findings suggest that PSP-RS patients should aim for the prevention of ICVD to reduce the occurrence of HOD.

Objective:To analyze the clinical, imaging and genetic characteristics of 2 pedigrees with hereditary spastic paraplegia type 7 (SPG7).Methods:The clinical data of the probands and related members of 2 families hospitalized in the Department of Neurology of Henan Provincial People′s Hospital from December 2018 to December 2021 were collected. The probands and all family members were subjected to cranial MRI imaging and genetic testing, and the clinical characteristics and genetic variation of SPG7 families were compared with those reported in the literature.Results:Four patients from the 2 families were observed with adult-onset age in this group. The main manifestations were wide-base ataxic gait in 4 cases, and spastic gait in 1 case during follow-up. Pyramidal tract involvement mainly in the lower limbs were found in all cases, and dysarthria in 3 cases. MRI of 3 patients showed varying degrees of cerebellar atrophy. Genetic testing revealed compound heterozygous or homozygous variants of the SPG7 gene in the 4 patients, of which c.2062C>T and c.2176C>T were novel mutations. At present, only 5 SPG7 families have been reported in China. Among the 12 patients in all groups, 12 cases of pyramidal tract involvement, 10 cases of cerebellar ataxia, 7 cases of dysarticulation, 3 cases of cognitive impairment, 11 cases of complex hereditary spastic paraplegia, 1 case of simple hereditary spastic paraplegia, and 9 cases of cerebellar atrophy were reported. Six novel mutations have been reported in 5 families. Conclusions:SPG7 family is rarely reported in China, mainly manifested as pyramidal tract involvement combined with cerebellar ataxia, accompanied by cerebellar atrophy. SPG7 mutation is confirmed by genetic detection, and there are many novel mutations in SPG7 family in China.

Objective:To investigate the muscle MRI features of the lower extremities and correlations between MRI fatty degeneration total scores and other clinical features in limb girdle muscular dystrophy type R1 (LGMDR1) patients.Methods:Clinical data of 8 patients with LGMDR1 diagnosed by genetic examination in Department of Neurology, He'nan Provincial People's Hospital&People's Hospital of Zhengzhou University from May 2016 to November 2021 were retrospectively analyzed. Disease severity was evaluated by Gardner-Medwin and Walton (GM-W) scale. Pathological staining results of the lower limb muscles were observed; the fatty infiltration and edema of the muscles were observed by MRI T1WI and short-tau inversion recovery (STIR) sequences. Lower limb muscles were scored using Mercuri's scale. Spearman rank correlation was used to analyze the correlations of MRI fatty degeneration total scores of the lower extremities with age, age of onset, disease duration, GM-W scale scores and creatinine kinase (CK) level.Results:Of the 8 patients with LGMDR1, 7 had decreased muscle strength in the proximal lower extremity, including 4 with decreased muscle strength in the distal lower extremity at the same time. Muscular dystrophy-like pathological changes of skeletal muscles were noted. All 8 LGMDR1 patients showed different degrees of fatty infiltration in the lower extremities: at the thigh level, the adductor magnus, biceps femoris long head, semimembranes, semitendinosus and adductor longus were the most severely fatty degeneration muscles (mean scores>4), with relatively sparing of the sartorius and rectus femoris; regarding the calves, gastrocnemius medial head was the mostly involved, followed by soleus, with relative sparing of the tibialis posterior and anterior compartment. Edema-like changes (mild) were observed in 7 patients; the muscles that most frequently and relatively severely displayed edema-like changes were the gastrocnemius lateral head and quadriceps. The fatty degeneration total scores of the lower extremities were positively correlated with GM-W scale scores ( r=0.872, P=0.005) and negatively correlated with CK level ( r=-0.929, P=0.001), but not significantly correlated with age, age of onset or disease duration ( r=0.635, P=0.091; r=0.571, P=0.139; r=0.551, P=0.157). Conclusion:The lower limb muscles with severe fatty infiltration are less prone to show edema-like changes; fatty degeneration can be used to evaluate LGMDR1 progress; involvement pattern of muscle MRI of the lower extremities is helpful in diagnosing and differentially diagnosing LGMDR1.

Objective:To investigate the clinical and genetic features of Pompe disease, and analyze the effect of enzyme replacement therapy on it.Methods:A retrospective study was performed. The clinical data and genetic results of 14 patients with Pompe disease from 12 families, admitted to our hospital from January 2017 to June 2021, were collected. Some patients were followed up after therapies.Results:Twelve of the 14 patients were late onset, with onset age ranged from 1.5 to 37.0 years (mean 15.2 years), and the other 2 patients were infantile onset. The predominant manifestations included proximal lower limb weakness, accompanied by easy fatigue and myalgia; 8 patients presented with dyspnea, of which one had dyspnea as initial presentation. Serum creatine kinase ranged from 172 to 1397 IU/L (mean 878 IU/L). Electromyography revealed myogenic pattern in 6 patients and myotonic discharge in 4 patients. Forced vital capacity decreased in 10 patients, and scoliosis was detected in 5 patients; 13 patients had decreased acid-alpha-glucosidase (GAA) activity; muscle pathology indicated vacuolar myopathy in 8 patients. Genetic test revealed 17 variants in GAA gene, among which c.2331G>C, c.1622C>T, c.1585T>C, and c.1837T>C were 4 novel likely pathogenic variants. The c.2238G>C and c.2662G>T were found in 5 and 3 families, respectively. Muscle strength and lung function got improvement in 1 patient who received enzyme replacement therapy and had regular follow-up, while muscle strength and lung function were worsened in those who did not receive enzyme replacement therapy. Conclusions:Pompe disease is characterized by skeletal muscle weakness and pulmonary dysfunction, and may be associated with spinal deformity; creatine kinase is mildly to moderately elevated, and myotonic discharge can be detected. GAA c.2238G>C and c.2662G>T are hotspot mutations in China; the 4 novel variants enrich the GAA mutational spectrum. Enzyme replacement therapy may improve motor and pulmonary function.

OBJECTIVE:To explore phenotypic and mutational characteristics of a pedigree with distal hereditary motor neuropathy (dHMN).METHODS:Clinical data of the proband and her family members was collected. Electrophysiology, muscle biopsy and whole exome sequencing were carried out for the proband.RESULTS:Patients of the family mainly presented with distal lower limb weakness. Electrophysiological test of the proband revealed distal motor neuropathy and sensory nerves were normal. Muscle biopsy suggested neurogenic atrophy of muscle fibers. Genetic analysis revealed a heterozygous c.421A>G (p.K141E) mutation in exon 2 of the HSPB8 gene, which was a hot spot mutation.CONCLUSION:This family was the first reported HSPB8 related dHMN2A in Chinese population, and p.K141E was the causative mutation, which enriched the mutational spectrum of dHMN in China.

Despite the increasing number of genes associated with Charcot–Marie‐Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl‐tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl‐tRNA synthetase 1 (SerRS) for 3 families affected with CMT.

Objective:To improve the clinician′s recognition of the clinical and molecular characteristics of primary familial brain calcification (PFBC).Methods:The detailed clinical information, imaging and molecular characteristics were analyzed in proband and family members of a genetically confirmed autosomal recessive PFBC family. The clinical and imaging features of junctional adhesion molecule 2 (JAM2) gene related PFBC were analyzed in combination with the literature review.Results:The proband was a 32-year-old man, with slurred speech and paroxysmal limb twitch as the first symptoms, accompanied by cognitive dysfunction, and rigidity in the limbs, with epilepsy in the past. Brain CT showed extensive, symmetrical, and bilateral calcification involving the cerebellum, basal ganglia, thalamus, subcortex and cortex. Other family members showed no related clinical symptoms. Brain CT of the parents of the proband showed no calcification. Gene testing of the proband revealed a homozygous c.685C>T(p.R229*) mutation in JAM2 gene, which has been reported as a pathogenic variation abroad, whereas has not been reported in China. The proband′s parents and children were found with heterozygous c.685C>T (p.R229*) mutation.Conclusions:Autosomal recessive inherited PFBC is a rare disease, and JAM2 mutation is a newly discovered pathogenic gene of PFBC in 2020. Patients with intracranial calcification should be alert of JAM2 gene mutation.

Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable. Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated. Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one. Conclusion: NIPA1-related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients.

Objective:To investigate the clinical characteristics and electron transfer flavoprotein dehydrogenase ( ETFDH) genetic mutations in patients with riboflavin responsive lipid storage myopathy (RR-LSM). Methods:A retrospective analysis was performed. The clinical data and muscular pathology of 26 patients with RR-LSM, admitted to our hospital from January 2009 to June 2021, were collected. Peripheral venous blood DNA was extracted, and the mutations of ETFDH gene were detected and analyzed by whole exome sequencing. Results:These 26 patients had onset of proximal limb myasthenia, 17 patients had difficulty in raising their head, 12 patients had mastication weakness, 6 had dysphagia, 5 had nausea and vomiting, and one was complicated with rhabdomyolysis and one was with reversible splenic lesion syndrome. Muscle biopsy indicated pathological deposition of lipid droplet, which type I fibers were involved mainly; degenerative necrotic muscle fibers were seen in a few cases. ETFDH gene mutations were detected in 26 patients; 23 patients had compound heterozygous mutation, two had single heterozygous mutation and one had homozygous mutation; 25 different mutation sites were found, mainly missense mutations; the C.770A>G frequency was the highest, accounting for 20% alleles (10/50); two novel mutation sites were found: c.1115A>G and c.1781T>C. Conclusion:RR-LSM is mainly characterized by proximal limb muscle weakness and fatigue intolerance, often accompanied by neck extensor and masticatory weakness; c. 770A>G is the hot site of ETFDH genetic mutations in RR-LSM patients.