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Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole-exome sequencing, mitochondrial DNA sequencing and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were leukoencephalopathies related to NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%). Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%) and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R and HTRA1.
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Leucoencefalopatias , Criança , Humanos , Adulto , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação/genética , Bainha de Mielina/patologia , Análise de Sequência de DNA , Receptor Notch3/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Proteína do X Frágil da Deficiência IntelectualRESUMO
BACKGROUND AND PURPOSE: Neuronal intranuclear inclusion disease (NIID) is a rare complex neurodegenerative disorder presents with various radiological features. The study aimed to investigate the structural abnormalities in NIID using multi-shell diffusion MR. MATERIALS AND METHODS: Twenty-eight patients with adult-onset NIID and 32 healthy controls were included. Volumetric and diffusion MRI measures, including volume, fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) of six brain structures, including cortex, subcortical GM, cerebral WM, cerebellar GM and WM, and brainstem, were obtained and compared between NIID and healthy controls. Associations between MRI measures and clinical variables were investigated. RESULTS: Brain lesions of NIID included corticomedullary junction lesions on DWI, confluent leukoencephalopathy, lesions on callosum, cerebellar middle peduncle, cerebellar paravermal area and brainstem, and brain atrophy. Compared to healthy controls, NIID showed extensive volume loss of all the six brain regions (all p < 0.001); lower FA in cerebral WM (p < 0.001); higher MD in all WM regions; lower ODI in cortex (p < 0.001); higher ODI in subcortical GM (p < 0.001) and brainstem (p = 0.016); lower ICVF in brainstem (p = 0.001), and cerebral WM (p < 0.001); higher ISOVF in all the brain regions (p < 0.001). Higher MD of cerebellar WM was associated with worse cognitive level as evaluated by MoCA scores (p = 0.011). CONCLUSIONS: NIID patients demonstrated widespread brain atrophy but heterogeneous diffusion alterations. Cerebellar WM integrity impairment was correlated with the cognitive decline. The findings of the current study offer a sophisticated picture of brain structural alterations in NIID.
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Imagem de Difusão por Ressonância Magnética , Corpos de Inclusão Intranuclear , Doenças Neurodegenerativas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Corpos de Inclusão Intranuclear/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Estudos de Casos e Controles , Idoso , Adulto , Anisotropia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
The GGC repeat expansions in the NOTCH2NLC gene are associated with multiple neurodegenerative disorders. Herein, we report the clinical phenotype in a family with biallelic GGC expansions in NOTCH2NLC. Autonomic dysfunction was a prominent clinical manifestation in three genetically confirmed patients without dementia, parkinsonism, and cerebellar ataxia for > 12 years. A 7-T brain magnetic resonance imaging in two patients revealed a change in the small cerebral veins. The biallelic GGC repeat expansions may not modify the disease progression in neuronal intranuclear inclusion disease. Autonomic dysfunction-dominant may expand the clinical phenotype of NOTCH2NLC.
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Doenças do Sistema Nervoso Autônomo , Proteínas do Tecido Nervoso , Doenças Neurodegenerativas , Expansão das Repetições de Trinucleotídeos , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , População do Leste Asiático , Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/genética , Fenótipo , Proteínas do Tecido Nervoso/genética , Peptídeos e Proteínas de Sinalização Intercelular/genéticaRESUMO
OBJECTIVE: To examine the frequency and clinical features of excessive daytime sleepiness (EDS) and its association with cognitive and behavioural impairments in patients with amyotrophic lateral sclerosis (ALS). METHODS: We conducted a cross-sectional investigation to explore the frequency and clinical features of EDS in a group of 121 Chinese patients with ALS compared with 121 age-matched and sex-matched healthy subjects. EDS was diagnosed using the Epworth Sleepiness Scale (ESS). Other characteristics of patients with ALS including sleep quality, REM sleep behaviour disorder (RBD), restless legs syndrome (RLS), cognition, behaviour, depression and anxiety were also evaluated. RESULTS: EDS was significantly more frequent in patients with ALS than in controls (26.4% vs 8.3%; p<0.05). Patients with ALS with EDS scored lower scores on the revised ALS Functional Rating Scale (ALSFRS-R), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and MMSE and MoCA delayed memory subitems and higher on the Frontal Behavioural Inventory (FBI) than patients with ALS without EDS. ESS scores correlated with global ALSFRS-R, FBI, MMSE and MoCA scores and MMSE and MoCA delayed memory scores. RLS and global ALSFRS-R scores were independently associated with EDS in patients with ALS. CONCLUSIONS: We identified a high frequency of EDS symptoms in Chinese patients with ALS, and these patients might have more serious physical, cognitive and frontal behaviour impairment. Patients with ALS might improve quality of life from the timely recognition and optimised management of EDS symptoms. Our results further suggest that ALS is a heterogeneous disease that might exhibit abnormal sleep-wake patterns.
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Esclerose Lateral Amiotrófica/complicações , Transtornos Cognitivos/complicações , Cognição/fisiologia , Transtornos do Sono-Vigília/complicações , Sonolência , Adulto , Esclerose Lateral Amiotrófica/psicologia , China , Transtornos Cognitivos/psicologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polissonografia , Qualidade de Vida , Transtornos do Sono-Vigília/psicologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: L-2-hydroxyglutaric aciduria is a rare autosomal recessive encephalopathy caused by mutations in the L-2-hydroxyglutarate dehydrogenase gene. We describe some novel clinical and molecular characteristics found in a boy with L-2-hydroxyglutaric aciduria. CASE PRESENTATION: We report an 8-year-old Chinese boy, who had characteristic developmental delay, ataxia and acrocephaly as the main symptoms. He also complained of paroxysmal headache and palpitation. Brain image revealed a symmetrical, extensive subcortical white matter lesion. Urine test for organic acids showed a significantly increased level of 2-hydroxyglutaric acid (106.74 mmol/mol cre, normal range 0.6 ~ 5.9 mmol/mol cre), leading to the diagnosis of L-2-hydroxyglutaric aciduria. Genetic testing uncovered two heterozygous missense mutations in L-2-hydroxyglutarate dehydrogenase gene: c.169G > A in exon 2 and c.542G > T in exon 5, not hitherto been described. CONCLUSION: Novel gene mutation and associated clinical symptoms can contribute for the understanding and identification of this rare disease. Possible genotype-phenotype correlation waits for further study.
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Oxirredutases do Álcool/genética , Povo Asiático/genética , Encefalopatias Metabólicas Congênitas/genética , Encéfalo/patologia , Mutação de Sentido Incorreto , Encefalopatias Metabólicas Congênitas/sangue , Encefalopatias Metabólicas Congênitas/patologia , Encefalopatias Metabólicas Congênitas/fisiopatologia , Criança , Testes Genéticos , Genótipo , Glutaratos/sangue , Heterozigoto , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Neuroimagem , FenótipoRESUMO
Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease that mainly manifests as dementia, muscle weakness, sensory disturbances, and autonomic nervous dysfunction. Herein, we report a 68-year-old Chinese woman who was hospitalized because of resting tremor and bradykinesia that had been present for 7 years. Five years prior, bradykinesia and hypermyotonia had become apparent. She had urinary incontinence and rapid eye movement sleep behavior disorder. She was diagnosed with Parkinson's disease (PD) and received levodopa and pramipexole, which relieved her motor symptoms. During hospitalization, diffusion-weighted imaging revealed a high-intensity signal along the cortical medullary junction. Moreover, a skin biopsy revealed the presence of intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells. NIID was diagnosed by testing the Notch 2 N-terminal-like C (NOTCH2NLC) gene. We report this case to remind doctors to consider NIID when diagnosing patients with symptoms indicative of Parkinson's disease. Moreover, we note that further research is needed on the mechanism by which levodopa is effective for NIID.
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Doenças do Sistema Nervoso Autônomo , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Feminino , Idoso , Doenças Neurodegenerativas/diagnóstico , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Corpos de Inclusão Intranuclear , Levodopa/uso terapêutico , Hipocinesia , Erros de DiagnósticoRESUMO
Background and Objectives: Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China. Methods: The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features were recorded. Brain MRI, skin pathologies, and the number of GGC repeat expansions in the 5' untranslated region of the NOTCH2NLC gene were evaluated in all patients. Results: In total, 223 patients (64.6% female) were recruited; the mean (SD) onset age was 56.7 (10.3) years. The most common manifestations were cognitive impairment (78.5%) and autonomic dysfunction (70.9%), followed by episodic symptoms (51.1%), movement disorders (50.7%), and muscle weakness (25.6%). Imaging markers included hyperintensity signals along the corticomedullary junction on diffusion-weighted imaging (96.6%), white matter lesions (98.1%), paravermis (55.0%), and focal cortical lesions (10.1%). The median size of the expanded GGC repeats in these patients was 115 (range, 70-525), with 2 patients carrying >300 GGC repeats. A larger number of GGC repeats was associated with younger age at onset (r = -0.329, p < 0.0001). According to the proposed clinical classification based on the most prominent manifestations, the patients were designated into 5 distinct types: cognitive impairment-dominant type (34.1%, n = 76), episodic neurogenic event-dominant type (32.3%, n = 72), movement disorder-dominant type (17.5%, n = 39), autonomic dysfunction-dominant type (8.5%, n = 19), and neuromuscular disease-dominant type (7.6%, n = 17). Notably, 32.3% of the episodic neurogenic event-dominant type of NIID has characteristic focal cortical lesions on brain MRI presenting localized cortical edema or atrophy. The mean onset age of the neuromuscular disease-dominant type was 47.2 (17.6) years, younger than the other types (p < 0.001). There was no significant difference in the sizes of GGC repeats among the patients in the 5 types (p = 0.547, Kruskal-Wallis test). Discussion: This observational study of NIID establishes an overall picture of the disease regarding clinical, imaging, and genetic characteristics. The proposed clinical classification of NIID based on the most prominent manifestation divides patients into 5 types.
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OBJECTIVE: Antibodies against nodal-paranodal junction proteins have been detected in some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which is a crucial step to define the most effective treatment strategies. In this paper, we tested the positive rates of these antibodies in CIDP and characterized the clinical and electrophysiological features of the antibodies-positive patients. METHODS: We prospectively recruited 47 patients with CIDP. We detected IgG antibodies against human neurofascin-155 (NF155), neurofascin-186 (NF186), contactin-1 (CNTN1), contactin-2 (CNTN2) and contactin-associated protein-1 (Caspr1), and identified the IgG isotype with cell-based assay (CBA). We collected the demographic, clinical, laboratory, and electrophysiological information of the patients that were seropositive. RESULTS: Five patients (10.6 %) had IgG against NF155, 3 (6.4 %) against Caspr1, 2 (4.3 %) against NF186 and 1 (2.1 %) against CNTN1. All the 11 antibody-positive patients (8 males and 3 females) presented with typical clinical features. Five of them needed assistance in walking, 5 had cranial nerve impairments and 3 had autonomic disturbances. The age at onset of the patients that were anti-NF155-positive was younger (19.60 ± 9.02 years vs. 55.33 ± 11.93 years, P = 0.003) than those that were anti-Caspr1-positive. No significant difference in the functional status was observed between these two groups. The action potentials of 11/79 (13.9 %) motor nerves and 62/93 (66.7 %) sensory nerves exhibited no response. Moreover, 16/68 (23.5 %) nerves presented conduction block and 13/68 (19.1 %) nerves presented temporal dispersion. Distal motor latency (DML) of ulnar nerve and tibial nerve tended to be longer (p = 0.008 and p = 0.006, respectively) in anti-NF155-positive patients than that in anti-Caspr1-positive patients. Of the 11 patients that were antibody-positive patients, corticosteroids were effective in 3/7 (42.9 %), intravenous immunoglobins (IVIG) were effective in 1/7 (14.3 %), and rituximab was effective in 6/8 (75.0 %). CONCLUSIONS: Our findings validate the previous observation on the clinico-serological correlation between CIDP and antibodies against nodal-paranodal proteins. Of note, the damage on nerves is more severe in anti-NF155-positive patients than that in anti-Caspr1-positive patients during electrophysiological diagnosis.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Contactinas , Nervos Cranianos , Imunoglobulina G , Proteína Nodal , Pessoa de Meia-Idade , IdosoRESUMO
Background: Neuronal intranuclear inclusion disease (NIID), which pathogenesis remains largely unclear, is a neurodegenerative disease caused by GGC repeat expansion in NOTCH2NLC gene. As case studies have reported dynamic cortical perfusion changes in NIID, this study aimed to explore the cerebral perfusion pattern in NIID patients. Materials and methods: A total of 38 NIID patients and 34 healthy controls (HCs) were recruited, and 2 NIID patients who had had episodic symptoms within 2 months were excluded. Data on demographic characteristics and clinical features were collected. All participants underwent three-dimensional pseudo-continuous arterial spin labeling perfusion magnetic resonance imaging (MRI) scanning. Voxel-based comparisons of cerebral blood flow (CBF) were conducted. Results: NIID patients showed decreased perfusion in the cortex but increased perfusion in the deep brain regions compared with HCs. The regions with significant hypoperfusion were distributed in the bilateral frontal, temporal, parietal, and occipital gyri, with the left frontal gyrus being the most prominent. The regions with significant hyperperfusion included the bilateral basal ganglia, midbrain, pons, para-hippocampal, and parts of the bilateral cerebellum, fusiform, lingual, rectus, orbital, and cingulum anterior gyri, which were adjacent to the midline (all FDR-corrected p <0.05). When comparing the mean CBF value of the whole brain, no significant differences were observed between NIID patients and HCs (28.81 ± 10.1 vs. 27.99 ± 5.68 ml/100 g*min, p = 0.666). Voxel-based analysis showed no significant difference in cerebral perfusion between NIID patients with and without episodic symptoms. The perfusion within the bilateral middle frontal and anterior cingulate gyri showed positive correlations with MMSE and MoCA scores using age, sex, and education as covariates (p <0.005 uncorrected). Conclusion: NIID patients exhibited characteristic cortical hypoperfusion and deep brain hyperperfusion. The perfusion in the bilateral frontal lobe and cingulate gyrus was correlated with the severity of cognitive dysfunction. Cerebral perfusion change may be involved in NIID pathophysiology and serve as a potential indicator for monitoring NIID severity and progression.
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Mutations in the myelin protein zero gene are responsible for the autosomal dominant Charcot-Marie-Tooth disease (CMT). We summarized the genetic and clinical features of six unrelated Chinese families and the genetic spectrum of Chinese patients with myelin protein zero (MPZ) mutations. Our study reports data from a group of Chinese patients consisting of five males and one female with the age of disease onset ranging from 16 to 55 years. The initial symptom in all the patients was the weakness of the lower limbs. Electrophysiological presentations suggested chronic progressive sensorimotor demyelinating polyneuropathy. Overall six mutations were identified in the cohort, including four known mutations [c.103G>T (p.D35Y), c.233C>T (p.S78L), c.293G>A (p.R98H), and c.449-1G>T], and two novel mutations [c.67+4A>G with a mild CMT1B phenotype, and (c.79delG) p.A27fs with a rapidly progressive CMT1B phenotype]. According to the literature review, there are 35 Chinese families with 28 different MPZ mutations. The MPZ mutational spectrum in Chinese patients is very heterogeneous and differs from that of Japanese and Korean individuals, although they do share several common hot spot mutations.
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OBJECTIVES: To explore the cause of long survival but early onset and other prognostic factors among Chinese sporadic amyotrophic lateral sclerosis (ALS) patients. METHODS: Patients with ALS were recruited and followed up from Jan 2013 to Jan 2017. Phenotype and survival were compared among different age-at-onset groups. Candidate prognostic factors were analyzed by Kaplan-Meier method, Cox regression and Royston Parmar (RP) model dealing with breaches of proportional hazard assumption. RESULTS: In the cohort of 531 patients, mean age-at-onset was 53.68â¯years (SD:10.85) and overall estimated median survival time was 59â¯months (95% CI: 48.29-69.71). Pairwise comparison showed that patients above 65â¯years at onset were more frequently bulbar onset (adjusted residual: 3.0), less frequently lumbosacral onset (adjusted residual: -3.0), and had shorter survival compared with other age groups (pâ¯=â¯0.002). Cox and RP model demonstrated independent prognostic variables including age at onset, bulbar onset, diagnostic delay, MRC-score at first diagnosis and region of residence. CONCLUSIONS: This clinic-based study suggested that Chinese sporadic ALS patients had relatively long survival probably due to young age and less bulbar onset cases. Short diagnostic delay, low MRC-score and northern residence were also predicative of short survival. Reallocation of resources is needed to optimize quality care and prolong survival time.
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Esclerose Lateral Amiotrófica/mortalidade , Idade de Início , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/patologia , Povo Asiático , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , PrognósticoRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly involving central and peripheral motor neurons. The etiology of ALS is not clear. In China, there is a preliminary exploration of genetic factors, but the study on environmental factors is relatively inadequate, which needs to be further clarified. To investigate the protective or harmful effects of different environmental factors on ALS, and explore the possible etiology of ALS of the Chinese for further study. Case-control study were used in 123 patients and 239 healthy controls from 2013 to 2016. Statistical analysis and description were performed with SPSS24.0. The risk factors of ALS include head trauma (ORâ¯=â¯3.397, 95% [1.298, 8.893], Pâ¯=â¯0.013), drinking (ORâ¯=â¯1.760, 95% CI [1.110,2.790], pâ¯=â¯0.016), smoking (ORâ¯=â¯3.196, 95% [1.375, 7.427], Pâ¯=â¯0.351), low BMI (ORâ¯=â¯1.231, 95% CI [1.115, 1.319], Pâ¯=â¯0.000), workers or famers (ORâ¯=â¯2.539, 95% [1.441,4.475], Pâ¯=â¯0.001, 30-34 yrs); factors that reduce incidence of ALS including hypertension (ORâ¯=â¯0.526, 95% [0.313, 0.883], Pâ¯=â¯0.015), severe physical activities (ORâ¯=â¯0.808, 95% [0.711, 0.918], Pâ¯=â¯0.001), longer duration of education (ORâ¯=â¯0.183, 95% [0.078, 0.428], Pâ¯=â¯0.000, >12 yrs), reading (ORâ¯=â¯0.225, 95% [0.126, 0.516], Pâ¯=â¯0.000, 13-30 yrs), retirement or unemployment (ORâ¯=â¯0.040, 95% [0.005, 0.291], Pâ¯=â¯0.000, 30-34 yrs); family history of neurologic disorder, general trauma, years and numbers of smoking, artistic activities, and other occupational factors did not show correlation with ALS. Head trauma, alcohol consumption, smoking, low BMI, workers or farmers are risk factors for ALS; high blood pressure, severe physical activity, longer duration of education, reading, retirement or unemployment are protective factors for ALS; whether there is a connection between ALS and family history, general trauma, years or numbers of smoking, artistic activities, and other occupational factors need to be confirmed by further study.
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Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Esclerose Lateral Amiotrófica/epidemiologia , Traumatismos Craniocerebrais/epidemiologia , Fumar/efeitos adversos , Fumar/epidemiologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Estudos de Casos e Controles , China/epidemiologia , Traumatismos Craniocerebrais/diagnóstico , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Amyotrophic lateral sclerosis (ALS) is an age-related fatal neurodegenerative orphan disorder that is characterized by progressive injury of both the upper and lower motor neurons. Recently, loss-of-function mutations predominately disrupting the C-terminal amino acid sequence of KIF5A via aberrant exon 27 splicing have been reported in European ALS cohorts. However, the contributions of KIF5A mutations in Asian patients with ALS remain unclear. KIF5A sequences, including exons 26 and 27, were analyzed in a large Chinese ALS cohort comprising 33 unrelated familial ALS probands, 645 sporadic ALS (SALS) patients, 15 ALS patients presenting with concomitant frontotemporal dementia, 400 in-house controls, and 12,951 East Asian individuals from the Exome Aggregation Consortium and Genome Aggregation Database databases. As a result, the previously reported canonical splicing site mutation c.2993-1G>A was found in 1 SALS patient, while no mutations were detected in familial ALS case or ALS patients presenting with concomitant frontotemporal dementia. The frequency of KIF5A mutations accounts for 0.16% (1/645) of Chinese SALS patients, implying that it is an uncommon genetic determinant of ALS in Chinese patients.
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Esclerose Lateral Amiotrófica/genética , Estudos de Associação Genética , Cinesinas/genética , Mutação com Perda de Função , Adulto , Idoso , Esclerose Lateral Amiotrófica/complicações , Povo Asiático/genética , Estudos de Coortes , Éxons , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Several studies have attempted to reduce diagnostic delay and identify biomarkers for drug development in amyotrophic lateral sclerosis (ALS). In this study, we aimed to evaluate the diagnostic accuracy for ALS of cerebrospinal fluid (CSF) neurofilament (Nf), Tau protein, and inflammatory factors such as interleukin (IL)-2, IL-6, IL-10, IL-15, and granulocyte-macrophage colony-stimulating factor (GMCSF) in Chinese patients. Our prospective study measured the concentration of phosphorylated Nf heavy chain (pNfH), Nf light chain (NfL), Tau, pTau, and inflammatory factors in the CSF of 85 patients. Detailed clinical data and laboratory, neuroimaging, and neurophysiological findings were recorded. The concentrations of pNfH and NfL were higher in the ALS group than in the control group. At the 1104 pg/mL pNfH cutoff, the specificity was 68.8%, the sensitivity 100%, and the area under the curve (AUC) 0.907. At the 1,139 pg/mL NfL cutoff, the specificity was 56.3%, the sensitivity 96.2%, and the AUC 0.775. There was no significant difference in the concentrations of Tau, pTau, IL-2, IL-6, IL-10, IL-15, and GMCSF between the ALS and control groups (p > 0.05). In the ALS group, the concentration of pNfH in the CSF was correlated with disease duration (r = -0.475, p < 0.001). This is the first prospective study to confirm the diagnostic value of Nf for ALS in Chinese patients.
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Objective: To evaluate the frequency and clinical features of restless legs syndrome (RLS) in a group of Chinese patients with amyotrophic lateral sclerosis (ALS). Methods: 109 Patients included in this study fulfilled the revised El Escorial diagnostic criteria for clinically definite, probable and lab-supported probable ALS, and a group of 109 control subjects was matched for age and sex to the ALS group. Disease severity was assessed by the revised ALS functional rating scale (ALSFRS-R). The diagnosis of RLS was made according to the criteria of the International RLS Study Group. Other characteristics including sleep quality, excessive daytime sleepiness (EDS), REM sleep behavior disorder (RBD), depression and anxiety were also evaluated in ALS patients. Results: RLS was significantly more frequent in ALS patients than in control subjects (14.6 vs. 0.9%; P < 0.05). Compared to those without RLS, ALS patients with RLS reported a higher frequency of anxiety and EDS. ALS patients with RLS showed more severe legs dysfunction. EDS and legs function scores of the ALSFRS-R were independent factors significantly associated with RLS in ALS patients. Conclusions: Our findings suggest that Chinese ALS patients exhibit a high frequency of RLS symptoms and that these patients may benefit from recognition of the condition and optimized management of its symptoms. Moreover, ALS patients might cause circadian rhythms disturbance and our study further supports that ALS is a heterogeneous disorder involving multiple systems; further studies are needed to confirm these preliminary findings.
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Mutations in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1) was recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in non-Hispanic white populations. We sequenced the TIA1 exons 11-13 encoding LCD in a series of 588 Chinese ALS/ALS-FTD patients (Familial ALS = 29; Sporadic ALS = 546; ALS-FTD = 13) and 500 neurologically normal control subjects. We found a novel heterozygous missense mutation (c.973A>G, p.N325D) in a sporadic ALS patient, which suggests that TIA1 LCD mutations are not common in Chinese ALS/ALS-FTD.
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Esclerose Lateral Amiotrófica/genética , Estudos de Associação Genética , Mutação de Sentido Incorreto , Antígeno-1 Intracelular de Células T/genética , Povo Asiático/genética , Demência Frontotemporal/genética , HumanosRESUMO
OBJECTIVE: To characterize the patterns of brain atrophy and perfusion as measured by arterial spin labeling (ASL)-MRI, in amyotrophic lateral sclerosis (ALS) patients with varying levels of cognitive deficit, including ALS with frontotemporal dementia (FTD). METHODS: A total of 55 ALS patients and 20 healthy controls (HCs) were included, and all participants underwent neuropsychological assessments and MRI scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, n = 27), ALS with cognitive impairment (ALS-Ci, n = 17), and ALS-FTD (n = 11). Voxel-based comparisons of gray matter (GM) changes and cerebral blood flow (CBF) were conducted among the subgroups. RESULTS: The whole-brain comparisons of GM changes and CBF among ALS-Ci, ALS-Cn, and HCs were not significantly different. However, the ALS-FTD patients demonstrated a similar pattern of GM loss and hypoperfusion with more significant alterations in the left frontal and temporal lobe compared with the HCs, ALS-Cn, and ALS-Ci patients. Decreased CBF was found in many of the same brain areas wherein structural alterations occurred, although isolated GM loss and hypoperfusion were also observed. In addition, for both GM and CBF abnormalities, a similar pattern of changes was found in the comparisons of ALS-FTD vs. ALS-Ci, ALS-FTD vs. ALS-Cn, and ALS-FTD vs. HCs, with the differences being most significant between ALS-FTD and HCs. CONCLUSION: The cognitive status of ALS patients is associated with different patterns of GM changes and cerebral perfusion. ASL-MRI might be a useful tool with which to investigate the pathological burden of ALS and to disclose the early signature of possible cognitive impairment.
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OBJECTIVE: To investigate the genetic contribution of ANXA11, a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia. METHODS: Sequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR. RESULTS: We identified 6 nonsynonymous heterozygous mutations (5 novel and 1 recurrent), 1 splice site mutation, and 1 deletion of 10 amino acids (not accounted in the mutant frequency) in 11 unrelated patients, accounting for a mutant frequency of 5.6% (1/18) in FALS, 2.3% (8/353) in SALS, and 8.3% (1/12) in ALS-FTD. The deletion of 10 amino acids was detected in 1 clinically undetermined male with an ALS family history who had atrophy in hand muscles and myotonic discharges revealed by EMG. The novel p. P36R mutation was identified in 1 FALS index, 1 patient with SALS, and 1 ALS-FTD. The splicing mutation (c.174-2A>G) caused in-frame skipping of the entire exon 6. The rest missense mutations including p.D40G, p.V128M, p.S229R, p.R302C and p.G491R were found in 6 unrelated patients with SALS. CONCLUSIONS: The ANXA11 gene is one of the most frequently mutated genes in Chinese patients with SALS. A canonical splice site mutation leading to skipping of the entire exon 6 further supports the loss-of-function mechanism. In addition, the study findings further expand the ANXA11 phenotype, first highlighting its pathogenic role in ALS-FTD.
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BACKGROUND: Ongoing efforts have been made to identify new neuroimaging markers to track amyotrophic lateral sclerosis (ALS) progression. This study aimed to explore the monitoring value of multimodal magnetic resonance imaging (MRI) in the disease progression of ALS. METHODS: From September 2015 to March 2017, ten patients diagnosed with ALS in Peking Union Medical College Hospital completed head MRI scans at baseline and during follow-up. Multimodal MRI analyses, including gray matter (GM) volume measured by voxel-based morphometry; cerebral blood flow (CBF) evaluated by arterial spin labeling; functional connectivity, including low-frequency fluctuation (fALFF) and regional homogeneity (ReHo), measured by resting-state functional MRI; and integrity of white-matter (WM) fiber tracts evaluated by diffusion tensor imaging, were performed in these patients. Comparisons of imaging metrics were made between baseline and follow-up using paired t-test. RESULTS: In the longitudinal comparisons, the brain structure (GM volume of the right precentral gyri, left postcentral gyri, and right thalami) and perfusion (CBF of the bilateral temporal poles, left precentral gyri, postcentral gyri, and right middle temporal gyri) in both motor and extramotor areas at follow-up were impaired to different extents when compared with those at baseline (all P < 0.05, false discovery rate adjusted). Functional connectivity was increased in the motor areas (fALFF of the right precentral gyri and superior frontal gyri, and ReHo of right precentral gyri) and decreased in the extramotor areas (fALFF of the bilateral middle frontal gyri and ReHo of the right precuneus and cingulate gyri) (all P < 0.001, unadjusted). No significant changes were detected in terms of brain WM measures. CONCLUSION: Multimodal MRI could be used to monitor short-term brain changes in ALS patients.