RESUMO
BACKGROUND AND PURPOSE: Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: CSF1R mutations were identified in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3 bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. Two partial deletions of CSF1R were identified that resulted in lack of the C-terminal region, including the distal TKD, in two patients. Various clinical features including cognitive impairment, psychiatric symptoms and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on magnetic resonance imaging and characteristic calcifications on computed tomography were observed as imaging features. CONCLUSIONS: Our results highlight the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveals no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.
Assuntos
Leucoencefalopatias , Mutação de Sentido Incorreto , Receptores de Fator Estimulador de Colônias , Adulto , Humanos , Variações do Número de Cópias de DNA , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação , Receptores de Fator Estimulador de Colônias/genéticaRESUMO
Brain biopsies are often considered for patients who cannot be diagnosed with various laboratory test results. However, physicians tend to be hesitant regarding their application in possibly non-neoplastic brain diseases, due to the invasiveness and risks. The aim was to determine the indications for brain biopsies in cases of neurological diseases of unknown etiology. We retrospectively evaluated diagnostic accuracy, laboratory findings (including a liquid biopsy for malignant lymphoma), magnetic resonance imaging (MRI) characteristics and the post-treatment outcomes of patients undergoing brain biopsies for neurological diseases of unknown etiology. The data of patients who had undergone a brain biopsy during their admission to Niigata University Hospital, between 2011 and 2024, were reviewed. Moreover, the laboratory data and MRI findings between patients with definitive and nonspecific biopsy diagnoses were compared. Twenty-six patients underwent a brain biopsy, and a definitive diagnosis was obtained in 14 patients (53.8%). Even in cases where a nonspecific diagnosis was made, biopsy findings helped rule out malignancy and guide clinical diagnosis and treatment decisions. The liquid biopsy for malignant lymphoma was performed in eight patients, with one yielding a positive result, consistent with primary central nervous system lymphoma. The sensitivity and specificity of liquid biopsy were 0.5 and 1, respectively. Diffusely contrasted cortical lesions and the presence of mass effects on MRI, were significantly associated with a definitive diagnosis, compared to a nonspecific diagnosis. In conclusion, brain MRI and liquid biopsies can assist in determining the appropriate indications for brain biopsies in neurological diseases of unknown etiology.
Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Doenças do Sistema Nervoso , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Adulto , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Biópsia , Biópsia Líquida/métodos , Idoso de 80 Anos ou mais , Encefalopatias/patologia , Encefalopatias/diagnóstico por imagemRESUMO
INTRODUCTION: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD. METHODS: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals. RESULTS: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0). CONCLUSIONS: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low.
Assuntos
Dor Musculoesquelética , Doença de Parkinson , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Japão , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Qualidade de Vida , Reprodutibilidade dos Testes , Inquéritos e Questionários , Masculino , Adulto Jovem , AdultoRESUMO
Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor, and it traps lymphocytes in secondary lymphoid organs and precludes their migration into the central nervous system. We report the case of a patient who suffered a relatively severe relapse of multiple sclerosis (MS) during the initial 3 months of fingolimod therapy, with retention of CCR7 expression on CD4(+) T cells in the cerebrospinal fluid (CSF) despite decreased numbers of lymphocytes and decreased expression of CCR7 on CD4(+) T cells in the blood. These data suggest that fingolimod may cause differential effects on the CSF and blood lymphocytes of patients with MS during the initial months of therapy.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Encéfalo/patologia , Cloridrato de Fingolimode , Citometria de Fluxo , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Receptores CCR7/imunologia , Esfingosina/uso terapêutico , Adulto JovemRESUMO
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.
RESUMO
BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. METHODS: We performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), ß-amyloid42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). RESULTS: The levels of CSF α-syn, Aß42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. CONCLUSIONS: Our results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.
Assuntos
Atrofia de Múltiplos Sistemas , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Humanos , Filamentos Intermediários , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/diagnóstico , Neuroglia , Neurônios , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
Objectives: Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP). Methods: Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses. Results: The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected. Discussion: These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.
Assuntos
Afasia , Cerebelo , Humanos , Afasia/etiologia , Cerebelo/diagnóstico por imagem , Doenças Cerebelares/complicações , Doenças Cerebelares/diagnóstico por imagem , Masculino , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico por imagem , Pessoa de Meia-Idade , FemininoRESUMO
We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.
Assuntos
Síndrome de Creutzfeldt-Jakob/patologia , Ataxias Espinocerebelares/patologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/metabolismo , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismoRESUMO
OBJECTIVE: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). METHODS: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. RESULTS: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. CONCLUSIONS: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.
RESUMO
OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.
Assuntos
Mutação da Fase de Leitura , Leucoencefalopatias/genética , Mutação de Sentido Incorreto , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Análise Mutacional de DNA , Éxons , Feminino , Células HEK293 , Haploinsuficiência , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Fosforilação , RNA Mensageiro/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Adulto JovemRESUMO
A 21-year-old woman underwent surgery for a pituitary tumor. On the 11th postoperative day, blood examination revealed severe hyponatremia, with a serum sodium level of 111â mEq/l, and two days later this increased rapidly to 137â mEq/l. On the 20th postoperative day, the patient developed dysarthria and gait disturbance. Head MRI on the 30th postoperative day demonstrated intense high-signal lesions in the pons and bilateral corpus striatum on FLAIR and DWI, and central pontine and extrapontine myelinolysis was diagnosed. The patient's symptoms improved gradually after rehabilitation and antispasticity treatment. It was suggested that the changes in serum sodium levels after pituitary surgery were due to impaired secretion of antidiuretic hormone due to degeneration of nerve terminals in the posterior pituitary. As pituitary surgery may trigger changes in serum sodium leading to myelinolysis, this possibility should always be borne in mind when treating such patients.
Assuntos
Cistos do Sistema Nervoso Central/cirurgia , Mielinólise Central da Ponte/etiologia , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/etiologia , Adulto , Anticonvulsivantes/uso terapêutico , Cistos do Sistema Nervoso Central/complicações , Feminino , Humanos , Hiponatremia/etiologia , Síndrome de Secreção Inadequada de HAD/etiologia , Imageamento por Ressonância Magnética , Mielinólise Central da Ponte/diagnóstico por imagem , Mielinólise Central da Ponte/dietoterapia , Mielinólise Central da Ponte/reabilitação , Neoplasias Hipofisárias/complicações , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/reabilitação , Resultado do Tratamento , Adulto JovemRESUMO
Hepatic intravascular large B-cell lymphoma (IVL) is a rare disease entity that involves invasion into various organs. Due to the aggressive behavior and poor prognosis of the disease and the difficulty in making an early diagnosis, some cases are diagnosed at autopsy. Early suspicion and the use of imaging studies and liver biopsies are key for diagnosing IVL; however, no reports have described the results of imaging studies due to the limited number of cases. We herein report the results of imaging studies of hepatic IVL, including the findings PET-CT, dynamic-CT, EOB-MRI and CEUS. These results may help physicians to make an early diagnosis and improve the prognosis.