OBJECTIVES:Dysferlinopathy is an autosomal recessive muscular dystrophy caused by pathogenic variants of the DYSF gene. Currently, no clinical effective treatment is available. Given the myopathologic and animal model evidence on complement activation in dysferlinopathy, we explored the potential therapeutic effect of complement inhibition. METHODS:We reported a case of teenager-onset dysferlinopathy with progressive proximal weakness, markedly elevated serum creatine kinase levels, and assistance requirement for ambulation when admission. Muscle biopsy showed dysferlin deficiency and marked deposition of complement C5b-9 on nonnecrotic sarcolemma. Based on these findings and previous preclinical studies, the patient received eculizumab (900 mg weekly for 4 weeks) with informed consent. RESULTS:Clinical improvement was observed following complement inhibition therapy. By week 5, all tested muscle groups reached Medical Research Council grade 5/5, and the North Star Assessment for Dysferlinopathy score increased from 28 to 39. The 6-minute walk test (6MWT) improved from 220 m to 363 m. The muscle MRI revealed reduced muscle edema after eculizumab treatment. These benefits were sustained at 13-month follow-up. DISCUSSION:Complement inhibition showed promising clinical improvement in this single case of dysferlinopathy. Further studies with larger sample sizes are needed to investigate the efficacy and safety of complement inhibitors in dysferlinopathy.

ABSTRACT Objective Driven by pathogenic variants in the TTR gene, hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) presents as a systemic autosomal dominant disorder. This cross‐sectional study aimed to investigate the clinical utility of in vivo corneal confocal microscopy (CCM) for assessing structural changes in corneal nerve fibers among ATTRv‐PN patients and presymptomatic carriers. Methods A total of 41 ATTRv‐PN patients, 15 ATTRv‐PN presymptomatic carriers, and 15 healthy controls underwent CCM assessment. Clinical neurological scores, electrophysiological data, and sural biopsy data from ATTRv‐PN patients and carriers were analyzed. We calculated the corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), inferior whorl fiber length (IWFL), inferior whorl fiber density (IWFD), inferior whorl branch density (IWBD), corneal Langerhans cell density (CLCD), and inferior whorl Langerhans cell density (IWLCD). We compared the CCM parameters between patients, carriers, and healthy controls and analyzed their correlations with clinical, electrophysiological, and pathological changes in patients with ATTRv‐PN. Results CCM parameters, including CNFL, CNFD, CNBD, IWFL, CLCD, and IWLCD, were abnormal in ATTRv‐PN patients (p < 0.05). Statistical analysis revealed no significant variation in evaluated CCM parameters between the early‐onset and late‐onset ATTRv‐PN patient subgroups. Similarly, there were not statistically significant differences in these parameters between Stage I patients and Stage II patients. All CCM parameters except CNFD and IWFL were abnormal in presymptomatic carriers (p < 0.05). The CNFL and IWLCD (p < 0.05) were correlated with disease duration. The CNFL, CNFD, and CNBD were positively correlated with sural large myelinated nerve fiber density (p < 0.05), so were CNFL and IWFL with the total myelinated nerve fiber density (p < 0.05) in the sural nerve. Conclusion As an in vivo, noninvasive imaging technique, CCM facilitates the detailed evaluation of corneal nerve fiber morphology in both symptomatic ATTRv‐PN individuals and asymptomatic mutation carriers. We have confirmed the significant abnormalities of CCM parameters of corneal nerve fibers in ATTRv‐PN patients and presymptomatic carriers.

BackgroundThis study aimed to investigate the clinical, serological and myopathological features of Chinese patients with inclusion body myositis (IBM).MethodsThis study retrospectively recruited patients diagnosed with IBM according to the 2024 European Neuromuscular Center (ENMC) criteria at Peking University First Hospital between 2004 and 2024. Clinical features, pathological changes and laboratory data were collected. Subgroups were analyzed by sex, dysphagia, anti-cN1A antibody status, and complement deposition.ResultsForty-three IBM patients (25 males) were included in this cohort. The mean age at onset was 54.9 ± 9.6 years old. All the patients developed weakness in hip flexion, and 81.4% of them with weakness in both knee extension and finger flexion. Dysphagia was reported in 17 patients (39.5%). Endomysial inflammation was observed in all the patients, and 79.1% with rimmed vacuoles, and 76.9% with mitochondrial abnormalities. Female patients more frequently developed dysphagia (P = 0.005) and neck flexion weakness (P < 0.001). Anti-cN1A antibody was positive in 20 patients (66.7%). Seropositive cases were associated with a later age of onset (P = 0.034). Complement deposition was observed in 77.4% of patients and was associated with more severe muscle weakness.ConclusionThis cohort of Chinese IBM patients suggested an earlier age at onset than previously reported. Hip flexors were most commonly affected. Female patients showed a higher frequency of dysphagia and neck flexor weakness. Our study reported a high frequency of complement deposition in muscle tissue. Complement deposition was associated with disease severity, suggesting a potential role of complement in the pathophysiology of IBM.

Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fibre size variation, nuclear centralization and abnormal mitochondrial distribution. The mechanisms underlying this disease are unclear and there is currently no specific treatment for limb-girdle muscular dystrophy R7.This study established a Tcap-deficient mouse model to explore the disease mechanism of mitochondria dislocation and potential therapeutic strategies. We used methods such as proteomics, immunofluorescence, histopathological staining and western blotting to explore the mechanism of mitochondrial dislocation. Moreover, in the quest for a prospective therapeutic intervention for this disorder, the adeno-associated virus (AAV) serotype 2/9 was employed to deliver the Tcap gene into the muscles of these mice, facilitating preclinical experimentation. After 2 months and 7 months, the muscular phenotype was evaluated and selected mice were humanely euthanized for subsequent molecular and histological analysis.The phenotype of Tcap-/- mice mimicked that observed in individuals diagnosed with limb-girdle muscular dystrophy R7. This study elucidated the mechanism of mitochondrial dislocation in limb-girdle muscular dystrophy R7. Through our in vitro experiments, we discovered that telethonin aids in preserving the integrity of desmin by preventing truncation at the N-terminus. Additionally, telethonin combined with desmin and co-localized at the Z-disc. Research has shown that the Tcap gene plays a crucial role in controlling the desmin cytoskeleton organization. The absence of telethonin leads to a collapsed desmin cytoskeleton. This causes disorganization of the mitochondrial network, leading to mitochondrial dysfunction. In addition, the study investigated the efficacy of AAV-mediated Tcap replacement in Tcap-/- mice. By intramuscular delivery of AAV, we observed dramatic improvements in muscle phenotype, muscle pathology, CK levels, muscle MRI, mitochondrial network organization and mitochondrial function.The results of this study demonstrated that telethonin deficiency led to desmin cytoskeleton collapse that caused mitochondrial dislocation. AAV-mediated replacement therapy could be a promising safe and efficient treatment option for limb-girdle muscular dystrophy R7. The study highlights the potential of AAV-mediated replacement therapy for specific types of limb-girdle muscular dystrophy. Lv et al. developed a Tcap-/- mouse model to study limb-girdle muscular dystrophy R7, caused by TCAP mutations that result in the loss of telethonin. They found that telethonin deficiency leads to desmin cytoskeleton collapse and mitochondrial network disorganisation, and that these effects can be reduced with AAV-mediated Tcap delivery.

OBJECTIVES:The occurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) in patients with end-stage renal disease (ESRD) has been rarely studied. This study was intended to explore the clinical, electrophysiological and neuropathological features of six patients with CIDP and ESRD. METHODS:The medical records collected in Peking University First Hospital between 2021 and 2024 were reviewed before six patients were identified who had developed CIDP with ESRD. The data on their clinical features, electrophysiological tests, nerve ultrasound, laboratory examinations and sural biopsies was retrieved. RESULTS:All the six patients were males ages 35 to 63. Before and after dialysis, all these patients presented with varying degrees of limb sensory impairment and weakness, and reduced or absent tendon reflexes. Albuminocytologic dissociation of cerebrospinal fluid was observed in all of them. Nerve conduction studies identified the demyelinating features while nerve ultrasound showed nerve enlargement of upper limbs. Sural nerve biopsies showed mild to moderate decreases of myelinated nerve fiber density, with differences between different nerve fascicles. Thin myelinated fibers were seen, without onion bulb-like structure. Varying degrees of axonal degeneration with regeneration were identified in some of these patients. Immunotherapy was effective in all these patients. CONCLUSIONS:The diagnosis of CIDP should be considered if an ESRD patient develops progressive demyelinating neuropathy. Immune therapy has shown clinical efficacy despite the underlying mechanisms that remain poorly understood.

Biallelic variants in sorbitol dehydrogenase (SORD) have been reported to be a major cause of autosomal recessive distal hereditary motor neuropathy (dHMN). In this study, the clinical and pathological features of 10 patients with SORD gene-related dHMN are reported. Homozygous c.757delG variant was detected in 6 patients while c.757delG, c.786 + 1G>A, c.218C>T, and a novel c.104T>A compound heterozygous variants were observed in the others. Serum sorbitol, xylitol, and D-arabinitol were measured by gas chromatography-mass spectrometry; increased sorbitol and xylitol, and decreased D-arabinitol were identified. Sural nerve biopsies showed mild loss of large, myelinated fibers, and a few thin myelinated fibers. Skeletal muscle biopsies exhibited a neurogenic pattern with vacuoles, tubular aggregates, and abnormal mitochondria. Proteomic analyses of muscle tissue were performed to explore potential mechanisms. Complex I deficiency was dominant in the proteomic analysis and the malic acid/oxaloacetic acid ratio was significantly higher in the patients than in controls. In summary, SORD gene-related dHMN is a systemic disorder of carbohydrate metabolism with subclinical myopathologic changes, including tubular aggregates and vacuoles. Mitochondrial complex I deficiency, may be a key mechanism in SORD gene-related dHMN.

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by amyloid fibril deposition. The TTR c.148G > T mutation (V30L) in ATTR is rarely reported, and its biochemical properties are unknown. Seven patients and two asymptomatic carriers from two unrelated families diagnosed with V30L variant of ATTR were included. Data on clinical manifestations, laboratory examination, electrophysiology, ophthalmological corneal confocal microscopy (CCM), pathology and molecular biological experiments was collected and analyzed. Most patients initially experienced paresthesia, with varying degrees of peripheral neuropathy, autonomic dysfunction, and cardiac involvement. Nerve conduction studies showed extensive motor and sensory nerve involvement in upper and lower limbs. CCM revealed reduced corneal nerve density and fiber length. Sural nerve biopsies indicated loss of myelinated nerve fibers, with neurogenic patterns in gastrocnemius muscle biopsies. Asymptomatic carriers had nearly normal electrophysiology but mild reductions in corneal nerve fiber density and length. Sural nerve biopsies in carriers showed mild reductions in small myelinated nerve fibers. V30L mutation impaired thermodynamic and kinetic stability of the mutant protein. Plasma TTR tetramer concentration was lower in ATTR V30L patients compared to healthy donors. Small molecule stabilizers failed to exhibit satisfactory inhibition on fibril formation of V30L mutation in vitro. This study highlights the multisystem involvement in ATTR V30L patients, including neuropathy and cardiac issues. Both patients and carriers showed abnormalities in nerve conduction, corneal microscopy, and pathology. The V30L mutation impaired protein stability and reduced plasma TTR tetramer levels. Small molecule stabilizers were ineffective, indicating a need for alternative treatments.

BACKGROUND:A few patients with inflammatory myopathy showed anti-mitochondrial antibody (AMA) positivity. This study aimed to report the clinical and pathological findings with vacuoles in 3 cases of such patients.METHODS:Three cases with myositis from the Myositis Clinical Database of Peking University First Hospital were identified with AMA positivity. Their clinical records were retrospectively reviewed and the data was extracted. All the 3 cases underwent muscle biopsy.RESULTS:Three middle-aged patients presented with chronic-onset weakness of proximal limbs, marked elevation of creatine kinase, and AMA-positivity. Two of the 3 cases meet the criteria of primary biliary cholangitis. All the 3 cases presented with cardiac involvement and proteinuria. Two cases developed type 2 respiratory failure. MRI of the thigh muscle showed multiple patches of edema bilaterally in both cases, mostly in the adductor magnus. Pathological findings include degeneration of muscle fibers, diffused MHC-I positivity, and complement deposits on cell membranes. Vacuoles without rims of different sizes were discovered under the membrane of the muscle fibers. A few RBFs were discovered in case 1, while a diffused proliferation of endomysium and perimysium was shown in case 2.CONCLUSIONS:AMA-positive inflammatory myopathy is a disease that could affect multiple systems. Apart from inflammatory changes, the pathological findings of muscle can also present vacuoles.

BACKGROUND AND PURPOSE:The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients. METHODS:The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed. RESULTS:Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 105 mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038). CONCLUSION:Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.

Background and Objectives:Studies on the natural disease progression of detailed motor dysfunction in patients with GNE myopathy are rare. This study aimed to investigate motor function involvement during disease progression and its relationship with the genotype among Chinese patients with GNE myopathy. Methods:This retrospective observational cohort study included all patients with genetically confirmed GNE myopathy enrolled at Peking University First Hospital between 2000 and 2023. Patients with GNE myopathy were stratified into 2 subgroups based on with or without p.D207V mutation. Data on clinically significant muscular problems were collected from patients' medical history and follow-up assessments to evaluate motor function using the GNE Myopathy Functional Activity Scale and the modified Rankin Scale. Results:Eighty-three patients with GNE myopathy were included, with a median age at examination of 36 years (range 25-57) and a median age at onset (AAO) of 26 years (range 16-46). The Kaplan-Meier curves revealed that patients with the p.D207V mutation experienced a significantly later AAO (27 years [95% CI 25-29]) and onset age of wheelchair dependency (50 years [95% CI 46-54]) compared with those without the mutation, who had an AAO of 24 years (95% CI 22-26) and an onset age of wheelchair dependency of 45 years (95% CI 36-54). Multivariate Cox regression analysis, adjusted for sex and disease duration, revealed that patients without the p.D207V mutation had a higher risk of wheelchair dependency, with an adjusted hazard ratio of 2.361 (95% CI 1.030-5.411). Barthel indexes (BIs) were negatively correlated with the disease duration and positively correlated with AAOs. Patients with GNE with earlier AAO exhibited a shorter disease duration of developing functional dependency (BIs <60) than did those with later AAOs. Discussion:Our results provide insights into the motor function involvement observed during disease progression in Chinese patients with GNE myopathy, and relatively mild disease severity was observed in those with the p.D207V mutation.

Mitochondrial disease is a devastating genetic disorder, with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and m.3243A>G being the most common phenotype and genotype, respectively. The treatment for MELAS patients is still less effective. Here, we performed transcriptomic and proteomic analysis in muscle tissue of MELAS patients, and discovered that the expression of molecules involved in serine catabolism were significantly upregulated, and serine hydroxymethyltransferase 2 (SHMT2) increased significantly in both the mRNA and protein levels. The SHMT2 protein level was also increased in myoblasts with m.3243A>G mutation, which was transdifferentiated from patients derived fibroblasts, accompanying with the decreased nicotinamide adenine dinucleotide (NAD(+))/reduced NAD(+) (NADH) ratio and cell viability. After treating with SHMT2 inhibitor (SHIN1), the NAD(+)/NADH ratio and cell viability in MELAS myoblasts increased significantly. Taken together, our study indicates that enhanced serine catabolism plays an important role in the pathogenesis of MELAS and that SHIN1 can be a potential small molecule for the treatment of this disease.

Limb-girdle muscular dystrophy R7 (LGMDR7) is an autosomal recessive hereditary muscular dystrophy caused by mutations in titin-cap (TCAP). Here, we summarized the clinical characteristics and TCAP mutations in a Chinese cohort of 30 patients with LGMDR7. The onset age of Chinese patients was 19.89 ± 6.70 years old, which is later than European and South Asian patients (P < 0.05). Clinically speaking, 20.0% of patients presented with predominant distal weakness, and 73.3% of patients presented with predominant pelvic girdle weakness. Radiological study revealed semitendinosus and magnus adductor were severely involved in Chinese LGMDR7 patients. Rectus femoris, vastus lateralis, vastus intermedius, soleus and tibialis anterior were moderately to severely involved. The most prevalent mutation in this cohort is c.26_33dupAGGTGTCG, while c.165dupG and c.110 + 5G > A are unique in Chinese population as two of the common mutations. Besides, variant c.26_33dupAGGGTGTCG might be a founder mutation in Asian patients. Internal nuclei, lobulated fibers, and scattered rimmed vacuoles were typical morphological changes in Chinese LGMDR7 patients. This is the largest LGMDR7 cohort in the Chinese population and in the world. This article also expands the clinical, pathological, mutational and radiological spectrum of patients with LGMDR7 in China and in the world.

患者男性，63岁。因双下肢乏力10年、进行性加重伴双上肢乏力4年，突发呼吸困难2个月，于2022年7月24日入院。患者10年前（2012年10月）无明显诱因出现爬楼梯后下肢乏力，5年前（2017年6月）家属发现其夜间睡眠伴呼吸暂停（患者无特殊不适）。

OBJECTIVE:The co-morbidity of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)/autoimmune nodopathies with nephropathy has been gradually known in recent years. This study was intended to explore the clinical, serological and neuropathological features of seven patients with CIDP/autoimmune nodopathies and nephropathy.METHODS:Among 83 CIDP patients, seven were identified with nephropathy. Their clinical, electrophysiological and laboratory examination data were collected. The nodal/paranodal antibodies were tested. The sural biopsies were performed in all the patients, and renal biopsies were operated in 6 patients.RESULTS:Six patients had chronic onsets and one had an acute onset. Four patients exhibited peripheral neuropathy preceding nephropathy while two showed concurrent onset of neuropathy and nephropathy, and one started with nephropathy. All the patients showed demyelination in electrophysiological examination. Nerve biopsies showed mild to moderate mixed neuropathies including demyelinating and axonal changes in all patients. Renal biopsies showed membranous nephropathy in all 6 patients. Immunotherapy was effective in all patients, with two patients showing good response to corticosteroid treatment alone. Four of the patients were positive to anti-CNTN1 antibody. Compared with anti-CNTN1 antibody-negative patients, antibody-positive patients had a higher proportion of ataxia (3/4 vs. 1/3), autonomic dysfunction (3/4 vs. 1/3), less frequent antecedent infections (1/4 vs. 2/3), higher cerebrospinal fluid proteins (3.2 g/L vs. 1.69 g/L), more frequent conduction block on electrophysiological examination (3/4 vs. 1/3), higher myelinated nerve fiber density, and positive CNTN1 expression in the glomeruli of kidney tissues.CONCLUSION:Anti-CNTN1 antibody was the most frequent antibody in this group of patients with CIDP/autoimmune nodopathies and nephropathy. Our study suggested that there might be some clinical and pathological differences between the antibody positive and negative patients.

The mutations of the feline leukemia virus subgroup C receptor-related protein 1 (FLVCR1) cause ataxia with retinitis pigmentosa. Recent studies indicated a large variation in the phenotype of FLVCR1-associated diseases. In this report, we describe an adult male who manifested first with tremors in his third decade, followed by retinitis pigmentosa, sensory ataxia, and sensory neuropathy in his fourth decade. While retinitis pigmentosa and sensory ataxia are well-recognized features of FLVCR1-associated disease, tremor is rarely described. Whole-exome sequencing revealed novel compound heterozygous pathogenic FLVCR1 variants: c.498 G > A; p.(Trp166*) and c.369 T > G; p.(Phe123Leu). In addition, we have highlighted the ultrastructural abnormalities of the sural biopsy in this patient.

Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.