Rare neurological diseases account for over one-third of the diseases included in the first and second batches of China's Rare Disease Catalogue.They are generally characterized by high disability rates,heavy care burdens,and prominent unmet clinical treatment needs.In recent years,China has been continuous-ly improving medication accessibility for patients with rare neurological diseases by optimizing the review and approval pathways for rare disease drugs,implementing dynamic medical insurance access,and providing policy support for scientific research.However,challenges remain,including weak independent research and develop-ment(R&D)capacity and insufficient translation of high-quality research achievements into clinical practice.Based on the supply gap of clinical treatment resources for rare neurological diseases in China and the overall landscape of global R&D pipelines,this paper summarizes and discusses the current status,characteristics,and future directions of drug development for rare neurological diseases in China.
Cerebral small vessel disease (CSVD) is an important cause of stroke and cognitive impairment, with complex pathogenesis and limited therapeutic options. Although monogenic hereditary CSVD has a low incidence, its well-defined causative genes provide a unique " natural model" for revealing the core molecular pathways of CSVD. Based on previous studys, this article systematically sorts out the newly identified pathogenic genes of monogenic CSVD, such as NIT1, MAP3K6 and ARHGEF15, and precisely identifies core pathophysiological processes including vascular smooth muscle cell dysfunction and extracellular matrix homeostasis imbalance. Furthermore, it reviews the latest advances in genome-wide association studies (GWAS) on sporadic CSVD and its imaging markers, and confirms an overlap in their genetic architectures. Finally, this article discusses the research strategy of integrating multi-omics data such as transcriptomics and proteomics to deeply analyze the biological mechanisms of risk variants, and summarizes the clinical translational value of genetic research in the precision diagnosis, risk stratification, drug target mining and drug repositioning of CSVD.
Alacrima-achalasia-mental retardation syndrome(AAMR) is an extremely rare autosomal recessive genetic disorder caused by mutation in the GMPPA gene. Its pathogenesis is associated with congenital disorders of glycosylation. The clinical manifestations involve multiple system impairments, with alacrima, achalasia, and mental retardation as the core features. This article reports the diagnosis, treatment process and long-term follow-up outcomes after deep brain stimulation in one patient with AAMR complicated with dystonia, aiming to improve clinicians' understanding of this disease.
Repeat expansion diseases(REDs) are a group of genetic disorders caused by the pathological expansion of specific short tandem repeats(STRs) in genomic DNA. They are characterized by significant clinical and genetic heterogeneity. Owing to the complexity of their pathogenesis, effective treatments remain elusive. With the in-depth analysis of the pathogenesis of these diseases, along with the development and innovation of targeting tools in recent years, targeted therapy strategies have become a research hotspot, and some antisense oligonucleotide drugs have entered the clinical trial stage. This article aims to review the latest advances in basic research and clinical trial outcomes of targeted therapy at the DNA, RNA and protein levels. Currently, this field still faces key bottlenecks including a high risk of off-target effects, low delivery efficiency, and challenges in clinical translation. Future efforts should focus on the optimization and refinement of targeting tools and delivery vectors, as well as multilevel collaborative combination therapeutic strategies.Combined with precise clinical classification and staging, this will promote the fundamental transformation of REDs treatment from symptomatic supportive care to etiological intervention.
Hereditary transthyretin amyloidosis(ATTRv) is a rare autosomal dominant multisystem disease caused by pathogenic variations in the TTR gene, mainly affecting peripheral nerves, heart, digestive tract, eyes, kidneys, and leptomeninges, among others. The isolated single-organ involvement is uncommon, and multidisciplinary collaboration is required for the disease management.The age of onset and clinical manifestations of ATTRv patients vary greatly, and individualized management of each patient's systemic symptoms is needed. To this end, we organized domestic experts in Neurology, Cardiology, Gastroenterology, and Medical Genetics to write the ATTRv multidisciplinary management consensus. This consensus aims to improve the multidisciplinary management of ATTRv patients among clinical physicians in China, while also providing a reference for the prevention, control, and healthcare policy formulation of this disease in China.
ObjectiveTo summarize the clinical characteristics, antibody spectrum and neuroelectrophysiological features of autoimmune nodopathy(AN), and to explore the phenotypic differences among different antibody-positive subgroups.MethodsThe clinical and electrophysiological data of patients definitely diagnosed with AN in Beijing Tiantan Hospital, Capital Medical University, from October 2018 to January 2026 were retrospectively analyzed.ResultsA total of 33 patients with AN were included. Antibody examination results showed that, anti-neurofascin(NF)155 antibody was the most prevalent, detected in 17 patients(51.50%), followed by anti-contactin-1(CNTN1) antibody in 8 patients(24.24%). Anti-NF186 antibody(4 cases, 12.12%), anti-contactin-associated protein 1(Caspr1) antibody(2 cases, 6.06%) and dual-target antibody positivity(2 cases, 6.06%) were relatively uncommon. The main clinical manifestations of AN patients included symmetric distal paresthesia of the extremities(32 cases, 96.97%), limb weakness(31 cases, 93.93%) and sensory ataxia(25 cases, 75.76%). Different antibody-positive subgroups presented distinct phenotypic features: patients with positive anti-NF155 antibody had a relatively younger age of onset, chronic onset and a high incidence of tremor, which was dominated by immunoglobulin(Ig)G4 subclass antibodies; patients with positive anti-CNTN1 antibody had a relatively advanced age of onset, mostly presented with acute or subacute onset, and were prone to complicated nephrotic syndrome; patients with positive anti-NF186 antibody had relatively mild nerve conduction damage; patients with anti-Caspr1 antibody manifested acute or subacute onset, with relatively elevated cerebrospinal fluid protein level and 24-h intrathecal IgG synthesis rate. The prominent neuroelectrophysiological manifestations of AN included decreased motor and sensory nerve conduction velocities, prolonged distal latency, frequent non-compressive conduction block and abnormal temporal dispersion. Definite sensory nerve action potentials could not be elicited in more than half of the patients.ConclusionsPatients with AN show high heterogeneity in clinical and neuroelectrophysiological characteristics, and different antibody-positive subgroups correspond to specific clinical and neuroelectrophysiological phenotypes.
Frontotemporal dementia (FTD) refers to a spectrum of neurodegenerative disorders primarily affecting the frontal and/or temporal lobes. Given the marked clinical, genetic, and pathological heterogeneity, achieving accurate antemortem diagnosis and pathological subtyping remains a significant challenge. Recent genetic studies have revealed differences in the genetic landscape of FTD across populations; meanwhile, progress in body fluid and peripheral tissue biomarkers, seed amplification assays, and neuroimaging technologies has provided powerful tools for pathology-based early diagnosis. The research focus in the field of FTD treatment has gradually shifted from symptomatic treatment to disease-modifying therapies and neuromodulation. This review focuses on the latest advances in clinical research of FTD, aiming to provide a reference for the formulation of precise diagnosis and treatment strategies for this disease.
Juvenile dermatomyositis(JDM) is the most common idiopathic inflammatory myopathy in children, characterized by symmetric proximal muscle weakness and characteristic skin rashes, which may be accompanied by involvement of major organs. Aberrant upregulation of the interferon signaling pathway has been confirmed as the core pathological mechanism of JDM, and is closely associated with mitochondrial dysfunction, peripheral blood immune cell dysregulation, muscle damage and repair dysfunction, as well as cutaneous and pulmonary lesions. Interferon-related biomarkers and interferon scores can serve as evaluation indicators for disease activity. Type Ⅰ interferon inhibitors and Janus kinase inhibitors provide new therapeutic options for refractory JDM. This review systematically summarizes the role of the interferon signaling pathway in the pathogenesis of JDM and its potential therapeutic targets, aiming to provide references for the mechanistic research and precise treatment of JDM.
Neuronal intranuclear inclusion disease(NIID)is a rare,chronic progressive neurodegener-ative disease predominantly presenting with adult-onset cases in China.This disease exhibits high clinical phe-notypic heterogeneity,with neurological manifestations as the predominant symptoms in most patients and prom-inent involvement of other systems in a minority of cases.Some patients without characteristic early cranial mag-netic resonance imaging(MRI)findings are prone to misdiagnosis and missed diagnosis.Herein,we report an adult female patient with NIID characterized by cyclic vomiting.She initially presented with difficult micturition,followed by the onset of cyclic vomiting several years later,without other neurological involve-ments throughout the disease course.Cranial MRI revealed symmetric progressive periventricular white matter lesions in the lateral ventricles.Genetic testing identified abnormal GGC repeat expansion in the NOTCH2NLC gene.Pathological examination of labial gland biopsy showed intranuclear inclusions positive for p62 and ubiq-uitin.By summarizing the clinical characteristics of this patient,this article aims to deepen clinicians'under-standing of NIID.
ObjectiveTo analyze the clinical and genetic features of oculopharyngodistal myopathy (OPDM) patients and compare the phenotypic differences among various causative genes.MethodsA total of 65 genetically confirmed OPDM patients from 43 unrelated families, who were admitted to the Department of Neurology, Peking University First Hospital between January 2008 and December 2025, were retrospectively included.The general demographic data, clinical manifestations, laboratory/auxiliary examinations, muscle pathology, and genetic test results were systematically collected and analyzed. The clinical and pathological characteristics among different OPDM subtypes were compared.ResultsAmong the 65 patients(39 male and 26 female), the mean age of onset was (31.20±10.43) years (range: 14 to 63 years). The initial symptom was predominantly distal limb weakness (67.44%), which gradually progressed to involve the extraocular muscles, pharyngeal muscles, facial muscles and proximal limb muscles. Serum creatine kinase levels were mildly to moderately elevated. Muscle pathological examinations revealed rimmed vacuoles and intranuclear inclusions (within muscle fibers). The mean duration from onset to diagnosis was (12.33±7.88) years (range: 1 to 32 years). All probands had negative results on conventional next-generation whole-exome sequencing; pathogenic variants were identified through third-generation long-read sequencing or OPDM-targeted repeat-primed polymerase chain reaction(RP-PCR). Among the 43 families, OPDM2 subtype was the most common genetic subtype (n=25), followed by OPDM4 subtype (n=8), OPDM3 subtype (n=6), OPDM1 subtype (n=3), and OPDM5 subtype (n=1). All OPDM probands subtypes were highly similar in age at onset and muscle pathological changes. However, OPDM3 subtype may be complicated by cerebral white matter lesions and other extra-muscular organ involvement. The proportion of OPDM4 patients who developed distal limb weakness only after 10 years of disease onset(40.0%) was significantly higher than that of other subtypes (all 0.0%, P=0.0122).ConclusionsOPDM2 was the predominant subtype in this study. All subtypes share similar age of onset and muscular pathological changes, yet exhibit distinct disease progression patterns. Future multicenter prospective cohort studies are warranted to further elucidate the clinical characteristics, pathogenetic mechanisms, and prognostic differences among OPDM subtypes.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has a relatively low incidence in the general population, but it is the most common monogenic hereditary cerebral small vessel disease in adults. White matter hyperintensities (WMH) are the earliest and most common magnetic resonance imaging (MRI) manifestations of CADASIL. However, the total WMH burden on imaging often shows a weak correlation with cognitive impairment, the degree of disability, and stroke risk, suggesting that WMH may not be single homogeneous lesions but rather have significant heterogeneity. To thoroughly elucidate the heterogeneous characteristics of WMH, this article systematically analyzes representative recent studies on postmortem human brain histopathology and in vivo advanced quantitative MRI, summarizes the histopathological features, imaging manifestations, and clinical correlations of WMH heterogeneity related to CADASIL, and explores the sources and formation mechanisms of WMH heterogeneity. Given that WMH are the earliest and most characteristic imaging manifestations of CADASIL, a comprehensive understanding of their heterogeneity at the pathological and imaging levels as well as their clinical associations will not only help deepen the understanding of the occurrence and development of WMH and the pathogenesis of CADASIL, but also enable refined risk stratification and prognostic assessment in the early stage of the disease based on their heterogeneous characteristics, thereby providing a basis for the individualized management and intervention of the disease.
Primary brain calcification(PBC)is a hereditary neurodegenerative disorder with symmetrical calcification in the bilateral basal ganglia and other brain regions as its core imaging feature,and presents diverse heterogeneous clinical manifestations such as movement disorders,cognitive impairment,and psychiatric disturbances.The identification of multiple causative genes has not only facilitated the exploration of PBC pathogenesis but also continuously expanded its phenotypic spectrum.The diagnosis,evaluation,and management of this disease are experiencing pivotal shifts,accompanied by new challenges.In 2025,the first international expert consensus on PBC was published,laying a foundation for the standardized diagnosis and treatment of PBC worldwide.Based on China's clinical practice and research status,and referring to the inter-national consensus,domestic experts in related fields conducted multiple rounds of discussions,supplemented and revised the contents covering clinical manifestations,auxiliary examinations,diagnostic criteria,differen-tial diagnosis,molecular classification and characteristics,genetic testing and counseling,disease management and treatment of PBC,and finally developed this consensus.This consensus aims to provide guidance for the standardized diagnosis,treatment,and research of PBC in China,help improve the quality of diagnosis and treatment,and drive the steady advancement of relevant research in this field.
Objective Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoen-cephalopathy(CADASIL)is caused by NOTCH3 gene variants and is predominantly characterized by cerebral small vessel disease.Previous studies have suggested that CADASIL may also involve the macrovas-cular system.This study aimed to explore the association between rare NOTCH3 variants and macrovascular lesions.Methods Based on the large population database UK Biobank,participants who completed distal common carotid artery ultrasonography and had available carotid intima-media thickness(CIMT)measure-ments were included.All participants were divided into three groups according to NOTCH3 variant carrier sta-tus:non-carriers,carriers of rare non-classical CADASIL mutations,and carriers of classical CADASIL mu-tations.The evaluated outcomes included CIMT parameters and cardiovascular and cerebrovascular events.Linear regression and Logistic regression models were used to analyze the association between rare NOTCH3 variants and macrovascular lesions.Results A total of 512 rare NOTCH3 variants were identified,including 480 rare non-classical CADASIL mutations and 32 classical CADASIL mutations.A total of 47 664 partici-pants were included,among whom 44 977(94.36%)were non-carriers,2555(5.36%)carried rare non-classical CADASIL mutations,and 132(0.28%)carried classical CADASIL mutations.Logistic regression analysis showed that carriers of classical CADASIL mutations had a significantly higher risk of carotid intima-media thickening than non-carriers(OR=1.54,95%CI:1.07-2.22,P=0.021),as well as an elevated risk of ischemic stroke/transient ischemic attack(OR=5.51,95%CI:2.72-10.03,P＜0.001).No sig-nificant differences in cardiovascular events were observed between non-carriers and the two groups of rare va-riant carriers.Conclusions In the UK Biobank population,carriage of classical CADASIL pathogenic vari-ants in the NOTCH3 gene is associated with an increased risk of carotid intima-media thickening and ischemic cerebrovascular events.
ObjectiveTo summarize the clinical characteristics and genetic mutation spectrum of patients with SELENON-related myopathy(SELENON-RM), in order to improve awareness among physicians.MethodsA total of 12 patients from independent families with genetically confirmed SELENON-RM at Peking Union Medical College Hospital between January 2016 and December 2025 were retrospectively included. Clinical data were collected, and their clinical and genetic features were analyzed.ResultsThe mean age at presentation was(16.7±9.7) years(range: 6-35 years), with males accounting for 66.7%(8/12). Patients presented with delayed motor development since early childhood, followed by a relatively stable disease course without significant progression over several years. Among 10 patients tested for serum creatine kinase, 4 had normal levels and 6 showed elevated levels. Electromyography performed in 9 patients indicated myogenic damage in both upper and lower limbs. Muscle biopsy in 6 patients revealed myopathic changes, including variation in muscle fiber size and fiber-type disproportion with predominance of type Ⅰ fibers. Pulmonary function tests in 5 patients demonstrated restrictive ventilatory defects. Overnight polysomnography in 6 patients revealed severe nocturnal hypoxemia. Genetic analysis showed that among the 12 patients, 9 patients had compound heterozygous mutations in the SELENON gene, 1 patient had a homozygous mutation(with each allele inherited from one parent), and 2 patients had a pathogenic mutation identified in only one allele. 13 distinct mutation sites were detected, of which 12 had been previously reported in the ClinVar database, while 1 was novel.ConclusionsPatients with SELENON-RM usually develop symptoms in early life, presenting with motor developmental delay, scoliosis or rigid spine, and frequently with occult but significant respiratory involvement. Patients in this study appear to predominantly carry compound heterozygous variants, and exons 1 and 11 of the SELENON gene may represent important mutational hotspots. The diagnosis of SELENON-RM can be challenging. Appropriate genetic testing should be selected based on characteristic clinical features, and early respiratory monitoring and supportive interventions, including non-invasive ventilation, should be strengthened to improve patient outcomes.
Objective Amyotrophic lateral sclerosis(ALS)is a chronic,progressive degenerative disease affecting both upper and lower motor neurons,primarily characterized by skeletal muscle weakness and atrophy.Notably,the same muscle group may exhibit asynchronous involvement.This study aims to investigate the involvement patterns of the orbicularis oculi(OOc)and orbicularis oris(OOr)in ALS patients,compare the findings with healthy controls(HCs)and myasthenia gravis(MG)patients,and explore the characteristics and clinical significance of facial muscle involvement in ALS.Methods Clinical and neuroelec-trophysiological data were collected and analyzed in ALS patients(ALS group),HCs(HCs group)and MG patients(MG group).Clinical data included age,gender,clinical symptoms and signs,and the revised ALS Functional Rating Scale(ALSFRS-R)score.Split-face(SF)phenomenon was defined as OOc muscle strength being greater than OOr muscle strength.The negative peak amplitudes of compound motor action poten-tial(CMAP)recorded from OOc and OOr,namely CMAPOOc and CMAPOOr,were collected for electrophysio-logical evaluation.Results Number of patients enrolled in each group:137 in the ALS group,42 in the HCS group,and 33 in the MG group.Of the 137 ALS patients,74 presented clinical SF manifestation.The CMAPOOc amplitude in the ALS group was 2.00(1.66,2.40)mV,showing no significant difference compared with 2.20(1.86,2.58)mV in the HCs group(P＞0.05).The CMAPOOr amplitude in the ALS group was significantly lower than that in the HCs group[2.80(1.91,3.85)mV vs.4.50(4.00,5.10)mV,P＜0.0001],while the CMAPOOc/CMAPOOr ratio was significantly higher[0.71(0.54,1.06)vs.0.47(0.40,0.54),P＜0.0001].Compared with ALS patients without SF,those with SF had a higher proportion of bulbar onset ALS(ALS-BO)(26/74 vs.7/63,P=0.0012),a faster disease progression rate[ΔFS:0.75(0.50,1.17)vs.0.50(0.25,1.00),P=0.0081],and lowerALSFRS-Rbulbar scores[9(6,12)vs.12(11,12),P＜0.0001].No SF was observed in all MG patients.The CMAPOOc/CMAPOOr ratio was significantly higher in ALS-BO patients than in MG patients[0.82(0.59,1.22)vs.0.48(0.38,0.59),P＜0.0001].The sensitivity and specificity of SF for distinguishing ALS-BO from MG were 78.79%and 100%,respectively.Conclusions More than half of ALS patients have SF phenomenon,and neuroelectrophysiological indicators can provide objective evidence for SF.SF is correlated with bulbar onset,severe bulbar symptoms and rapid disease progression,and can serve as a poten-tial indicator for the differential diagnosis between ALS-BO and MG.
This article reports a rare case of autoinflammatory disease presenting initially with skin induration and swelling after trauma as the initial manifestation, followed by progressive limb weakness. The patient was a middle-aged female who developed skin induration and swelling after trauma, which gradually progressed to limb weakness, dysarthria and bilateral facial paralysis, accompanied by livedo reticularis of the lower extremities, diffuse skin induration of the limbs, and beaded subcutaneous nodules in the right upper limb. The patient had a susceptibility to infection since childhood and a history of chronic livedo reticularis. Skin pathological examination revealed panniculitis. A comprehensive etiological screening for special infections and autoimmune diseases was completed with an unremarkable results, and whole-exome sequencing showed no abnormal findings. Following a multidisciplinary discussion combined with RNA sequencing results, the patient was diagnosed with an autoinflammatory disease, with a suspected type Ⅰ interferonopathy. Treatment with tofacitinib resulted in gradual improvement of clinical symptoms. This case highlights the importance of detailed medical history collection, systematic physical examination and multidisciplinary collaborative diagnosis and treatment, and underscores the pivotal role of molecular diagnosis in the confirmation of rare diseases. It can provide a reference for the clinical diagnosis and management of similar rare cases.
Primary pulmonary lymphoepithelioma-like carcinoma(PPLELC) is a rare subtype of non-small cell lung cancer that is closely associated with Epstein-Barr virus infection. PPLELC has unique pathologic and molecular characteristics, including high lymphocytic infiltration, high expression of programmed cell death-ligand 1, and low mutation rates of common driver genes. This article systematically reviews the epidemiological characteristics, clinical manifestations, pathological and molecular features, diagnosis and treatment strategies, and prognostic factors of PPLELC, aiming to provide reference for the clinical diagnosis and treatment of this disease.
A 51-year-old male presented with nasal obstruction, followed by progressive hearing loss and blurred vision. Imaging identified space-occupying lesions in the paranasal sinuses, orbits, and paraspinal regions, while laboratory tests confirmed positive anti-proteinase 3 anti-neutrophil cytoplasmic antibody(PR3- ANCA) immunoglobulin G (IgG)and markedly elevated serum IgG4. Despite treatment with corticosteroids, immunosuppressants, and radiotherapy, the patient exhibited steroid dependency with relentless disease progression. Following multidisciplinary consultation, a diagnosis of inflammatory myofibroblastic tumor (IMT) coexisting with ANCA- associated vasculitis (AAV) was favored, though IgG4-related disease remained a critical differential. Ultimately, profound immunosuppression precipitated a severe herpesvirus infection, leading to disseminated intravascular coagulation and multiple organ dysfunction syndrome. This case underscores the rarity and diagnostic complexity of concurrent IMT and AAV, highlights the therapeutic dilemma of balancing primary disease control against fatal opportunistic infections, and emphasizes the critical role of multidisciplinary collaboration in the diagnosis and treatment of complex diseases.
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene, classified as a rare congenital muscular disease. Its clinical features include progressive skeletal muscle weakness, often involving respiratory and cardiac muscles, and frequently associated with spinal deformities. This paper reports the diagnosis, perioperative management, and follow-up of a case of DMD with multisystem involvement and severe scoliosis, aiming to provide a reference for clinicians in the diagnosis and treatment of such diseases.
Objective To investigate the clinical efficacy of neoadjuvant imatinib in the treatment of rectal gastrointestinal stromal tumor(GIST).Methods Patients with rectal GIST who underwent surgery at Peking Union Medical College Hospital from January 2015 to January 2025 were included.Clinical data were retrospectively analyzed.Patients were divided into the neoadjuvant therapy group(received preoperative ima-tinib)and the control group(underwent direct surgery without preoperative imatinib).Clinical outcomes and recurrence rates were compared between the two groups.Results A total of 74 patients meeting the inclusion criteria were included,with 43 included in the neoadjuvant therapy group and 31 included in the control group.Baseline evaluation showed that the median tumor diameter was significantly larger in the neoadjuvant therapy group than that in the control group[5.0(2.9,7.1)cm vs.2.0(0.8,3.2)cm,P＜0.001].After treat-ment with imatinib,the median tumor diameter in the neoadjuvant group decreased significantly from 5.0(2.9,7.1)cm to 2.3(1.0,4.0)cm(P=0.003).There were no significant differences between the two groups in positive surgical margin rate,anal sphincter preservation rate,5-year disease-free survival,hospi-tal stay,or recurrence rate.Conclusions Neoadjuvant therapy with imatinib can effectively reduce tumor vol-ume in patients with rectal GIST.However,its therapeutic benefit still needs to be further validated by prospec-tive,large-sample clinical studies with long-term follow-up.
