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1.
BMC Neurol ; 19(1): 89, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053103

RESUMO

BACKGROUND: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. CASE PRESENTATION: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686 T > G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. CONCLUSIONS: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.


Assuntos
Doenças Desmielinizantes/genética , Leucoencefalopatias/genética , Doenças do Sistema Nervoso Periférico/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Pré-Escolar , Cistos/genética , Feminino , Humanos , Lactente , Recém-Nascido , Mutação , Mutação de Sentido Incorreto , Fenótipo
2.
Medicine (Baltimore) ; 98(22): e15802, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145310

RESUMO

RATIONALE: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a rare disease with white matter lesions of the central nervous system, and it usually has autosomal dominant inheritance. Its pathogenesis and causes are complex, and it has obvious clinical and genetic heterogeneities; also, it is classed as a neurodegenerative disease. PATIENT CONCERNS: In preliminary clinical work, we identified a family with rapid progressive dementia. DIAGNOSIS: Within this family, all patients had a CSF1R gene c.2696delA mutation (a deletion mutation), and head magnetic resonance imaging showed extensive white matter lesions. We diagnosed these patients with HDLS. INTERVENTIONS: The proband was given hormonal treatments and immunoglobulin therapy, and his dementia symptoms have been relieved to a certain extent. OUTCOMES: After treatment, the symptoms of dementia were still progressively aggravated. However, the mutation site has not previously been reported. LESSONS: This newly discovered mutation site may provide a new basis for the genetic diagnosis of HDLS disease in clinical work.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Humanos , Masculino , Mutação , Linhagem
3.
Mol Genet Genomic Med ; 7(4): e00595, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30729751

RESUMO

BACKGROUND: Colony-stimulating factor 1 receptor is a tyrosine kinase transmembrane protein that mediates proliferation, differentiation, and survival of monocytes/macrophages and microglia. CSF1R gene mutations cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an autosomal-dominantly inherited microgliopathy, leading to early onset dementia with high lethality. METHODS: By interdisciplinary assessment of a complex neuropsychiatric condition in a 44-year old female patient, we narrowed down the genetic diagnostic to CSF1R gene sequencing. Flow cytometric analyses of uncultivated peripheral blood monocytes were conducted sequentially to measure the cell surface CSF1 receptor and autophosphorylation levels. Monocyte subpopulations were monitored during disease progression. RESULTS: We identified a novel heterozygous deletion-insertion mutation c.2527_2530delinsGGCA, p.(Ile843_Leu844delinsGlyIle) in our patient with initial signs of HDLS. Marginally elevated cell surface CSF1 receptor levels with increased Tyr723 autophosphorylation suggest an enhanced receptor activity. Furthermore, we observed a shift in monocyte subpopulations during disease course. CONCLUSION: Our data indicate a mutation-related CSF1R gain-of-function, accompanied by an altered composition of the peripheral innate immune cells in our patient with HDLS. Since pharmacological targeting of CSF1R with tyrosine kinase inhibitors prevents disease progression in mouse models of neurodegenerative disorders, a potential pharmacological benefit of CSF1R inhibition remains to be elucidated for patients with HDLS.


Assuntos
Mutação com Ganho de Função , Leucoencefalopatias/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo
4.
Mol Genet Genomic Med ; 7(4): e00582, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30706699

RESUMO

BACKGROUND: Mutations in the mitochondrial alanyl-transfer (t)RNA synthetase 2 (AARS2,OMIM:612035) have been linked to leukoencephalopathy recently. Till now, there have been 19 cases reported so far. However, the clinical and genetic characteristics of this disease are not fully understood. We reported an adult-onset male leukoencephalopathy patient related to novel AARS2 gene mutations and reviewed all previous cases regarding the clinical and genetic features of AARS2 leukoencephalopathy. METHODS: The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with AARS2 gene mutations. RESULTS: Here, we present a 30-year-old man with progressive motor deficits in the right lower limb and severe cerebellar ataxia for one year. MRI revealed extensive white matter lesions in periventricular regions and along the corticospinal tract. Genetic analysis revealed two new heterogeneous missense mutations in AARS2: c.179C>A and c.1703_1704del. We described the ragged red fiber (RRF) for the first time, suggesting that AARS2-related leukoencephalopathy be a new variant of mitochondrial encephalomyopathy. Gradual improvement in motor function was observed with intravenous coenzyme complex treatment. We also summarized our case and all previously reported cases to provide an overview of AARS2-related late-onset leukoencephalopathy. Then, we compared clinical and neuroimaging features of AARS2-related leukoencephalopathy with three other frequently diagnosed types of adult-onset leukoencephalopathy to provide insight into diagnostic strategies. CONCLUSION: The characteristic MRI abnormalities and clinical symptoms described here may help to distinguish AARS2-related leukoencephalopathy from other adult-onset leukoencephalopathies. The combination of encephalopathy and myopathy strongly suggest that AARS2-related leukoencephalopathy is a new variant of mitochondrial encephalomyopathy. The response to coenzyme complex will shed light on future therapy investigation.


Assuntos
Alanina-tRNA Ligase/genética , Leucoencefalopatias/genética , Encefalomiopatias Mitocondriais/genética , Mutação de Sentido Incorreto , Fenótipo , Adulto , Encéfalo/diagnóstico por imagem , Humanos , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Masculino , Encefalomiopatias Mitocondriais/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia
6.
BMJ Case Rep ; 12(1)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30635318

RESUMO

Leucoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a very rare autosomal recessive, slowly progressive neurological disorder characterised by distinctive clinical findings including cerebellar, pyramidal and dorsal column dysfunction. This is caused by a mutation in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase. MRI shows distinctive abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. Here, we present a case of LBSL, with a novel c.1192-2A>G mutation.


Assuntos
Aspartato-tRNA Ligase/genética , Tronco Encefálico/diagnóstico por imagem , Leucoencefalopatias/genética , Medula Espinal/diagnóstico por imagem , Assistência ao Convalescente , Aspartato-tRNA Ligase/metabolismo , Tronco Encefálico/patologia , Tratamento Conservador , Humanos , Ácido Láctico , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Leucoencefalopatias/terapia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Doenças Raras , Medula Espinal/patologia
7.
J Neurol ; 265(10): 2415-2424, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30136118

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 Jovem
8.
J Stroke Cerebrovasc Dis ; 27(10): 2840-2842, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30068478

RESUMO

Our objective is to reported a Chinese CARASIL patient caused by novel compound heterozygous mutations in HTRA1. Detailed clinical and neuroimaging examination were conducted in proband and her available family members. Sanger sequencing of NOTCH3 and HTRA1 was used to investigate causative mutations. The patient was born in an outbred family. She experienced recurrent transient ischemic attacks, hair loss, and low back pain. Brain magnetic resonance imaging showed multiple lacunar infarctions, diffuse leukoencephalopathy, and multiple microbleeds of white matter. A compound heterozygous mutation, c.958G > A (p.D320N) and c.1021G > A (p.G341J), were identified in the proband. This report highlights that screening of HTRA1 should be considered in young SVD patient despite from outbred families.


Assuntos
Alopecia/genética , Grupo com Ancestrais do Continente Asiático/genética , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Alopecia/diagnóstico por imagem , Alopecia/etnologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etnologia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/genética , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/etnologia , Imagem por Ressonância Magnética , Linhagem , Fenótipo , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/etnologia , Acidente Vascular Cerebral Lacunar/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/genética
9.
Acta Neurol Scand ; 138(4): 278-283, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29749055

RESUMO

INTRODUCTION: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is the most frequent non-vascular adult-onset leukoencephalopathy. It is caused by autosomal dominant mutations in CSF1R gene. Recently, also autosomal recessive mutations in AARS2 gene were found to be the cause of an adult-onset leukodystrophy with axonal spheroids. Our aim was to achieve a genetic diagnosis in a cohort of CSF1R-negative patients, performing a sequence analysis of AARS2 gene. MATERIAL AND METHODS: AARS2 sequencing was performed in 38 CSF1R-negative patients with clinical and magnetic resonance imaging (MRI) findings of adult-onset leukoencephalopathy. RESULTS: Three patients carrying AARS2 compound heterozygous mutations have been found. All patients were female with ovarian failure and leukoencephalopathy. In 2 patients, MRI findings were consistent with previous reports while the third patient showed focal white matter (WM) lesions in the centrum semiovale and the corpus callosum in the absence of extensive involvement and rarefaction of the WM. MRI spectroscopy showed the presence of increased lactate in 2 patients, thus linking AARS2-related leukoencephalopathy with other mitochondrial leukoencephalopathies with high levels of cerebral lactate. CONCLUSION: We recommend screening for mutations in AARS2 gene in CSF1R-negative patients, also in the absence of a clear family history and peculiar MRI findings. Our results also suggest that findings of conventional MRI and MR spectroscopy may be useful in prompting the genetic screening.


Assuntos
Alanina-tRNA Ligase/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética/métodos , Mutação/genética , Doenças Ovarianas/diagnóstico por imagem , Doenças Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Corpo Caloso/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos
10.
J Hum Genet ; 63(7): 841-846, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29666464

RESUMO

Mutations in the mitochondrial alanyl-transfer (t)RNA synthetase 2 (AARS2; OMIM 612035) have been linked to leukoencephalopathy recently. Until now, there have been only 13 cases reported in the literature. Hence, the clinical and genetic characteristics of this disease are not fully understood. Here, we reported an adolescence-onset male leukoencephalopathy patient characterized by progressive limb tremor at the age of 17 years. He had no signs of a cardiomyopathy. Magnetic resonance imaging scanning demonstrated severe cerebellar atrophy and white matter abnormalities involving descending tracts. Focused exome sequencing revealed he had novel compound heterozygous mutations in AARS2 gene (c.2265dupA; p.Arg756fs and c.650C>T; p.Pro217Leu). The patient was diagnosed with AARS2 mutation-related leukodystrophy (AARS2-L). We report a case with novel AARS2 gene mutations with developed striking cerebellar atrophy and leukoencephalopathy, which helps to further understand the clinical and genetic heterogeneity of AARS2-L.


Assuntos
Alanina-tRNA Ligase/genética , Doenças Cerebelares/genética , Leucoencefalopatias/genética , Mutação , Adolescente , Alanina-tRNA Ligase/metabolismo , Atrofia , Sequência de Bases , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/patologia , Expressão Gênica , Heterozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/patologia , Sequenciamento Completo do Exoma
11.
Biochem Biophys Res Commun ; 500(2): 158-162, 2018 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-29625105

RESUMO

We sequenced the mitochondrial genome from a 40-year-old woman with myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications. Histological and biochemical features of mitochondrial respiratory chain dysfunction were present. Direct sequencing showed a novel heteroplasmic mutation at nucleotide 5513 in the MT-TW gene that encodes tRNATrp. Restriction Fragment Length Polymorphism analysis confirmed that about 80% of muscle mtDNA harboured the mutation while it was present in minor percentages in mtDNA from other tissues. The mutation is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA. This is the 17° mutation in MT-TW gene and expands the known causes of late-onset mitochondrial diseases.


Assuntos
Epilepsias Mioclônicas/genética , Predisposição Genética para Doença , Leucoencefalopatias/genética , Mutação/genética , RNA de Transferência de Triptofano/genética , Retinite Pigmentosa/genética , Calcificação Vascular/genética , Adulto , Sequência de Bases , Epilepsias Mioclônicas/sangue , Epilepsias Mioclônicas/diagnóstico por imagem , Feminino , Humanos , Leucoencefalopatias/sangue , Leucoencefalopatias/diagnóstico por imagem , Retinite Pigmentosa/sangue , Retinite Pigmentosa/diagnóstico por imagem , Análise de Sequência de DNA , Tomografia Computadorizada por Raios X
12.
J Neurol ; 265(6): 1410-1418, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29663120

RESUMO

Vanishing white matter disease (VWM) is one of the most prevalent inherited leukoencephalopathies in childhood. Infantile VWM is more severe but less understood than the classic early childhood type. We performed a follow-up study on 14 infantile and 26 childhood patients to delineate the natural history and neuroimaging features of VWM. Infantile and childhood patients shared similarities in the incidence of epileptic seizure (35.7 vs. 38.5%) and episodic aggravation (92.9 vs. 84.6%). Developmental delay before disease onset was more common in infantile patients. Motor disability was earlier and more severe in infantile VWM. In survivors with disease durations of 1-3 years, the Gross Motor Function Classification System (GMFCS) was classified as IV-V in 66.7% of infantile and only 29.4% of childhood patients. Kaplan-Meier survival curve analysis indicated that the 5-year survival rates were 21.6 and 91.3% in infantile and childhood VWM, respectively. In terms of MRI, infantile patients showed more extensive involvement and earlier rarefaction, with more common involvement of subcortical white matter, internal capsule, brain stem and dentate nuclei of the cerebellum. Restricted diffusion was more diffuse or extensive in infantile patients. In addition, four novel mutations were identified. In conclusion, we identified some similarities and differences in the natural history and neuroimaging features between infantile and early childhood VWM.


Assuntos
Encéfalo/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/fisiopatologia , Idade de Início , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucoencefalopatias/genética , Leucoencefalopatias/mortalidade , Imagem por Ressonância Magnética , Masculino
13.
RNA ; 24(6): 841-852, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29632131

RESUMO

Mutations in eIF2B genes cause vanishing white matter disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation and translation initiation. During the ISR, eIF2α is phosphorylated and inhibits eIF2B, causing global translation suppression and stress-induced gene translation, allowing stress adaptation and recovery. We demonstrate that VWMD patient cells hypersuppress translation during the ISR caused by acute ER stress, delaying stress-induced gene expression and interrupting a negative feedback loop that allows translational recovery by GADD34-mediated dephosphorylation of phospho-eIF2α. Thus, cells from VWMD patients undergo a prolonged state of translational hyperrepression and fail to recover from stress. We demonstrate that small molecules targeting eIF2B or the eIF2α kinase PERK rescue translation defects in patient cells. Therefore, defects in the ISR could contribute to white matter loss in VWMD.


Assuntos
Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/genética , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação , Biossíntese de Proteínas , Estresse Fisiológico , Adulto , Estudos de Casos e Controles , Células Cultivadas , Feminino , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Fosforilação , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Adulto Jovem
14.
Zhonghua Er Ke Za Zhi ; 56(3): 211-215, 2018 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-29518832

RESUMO

Objective: To analyze the clinical and imaging features of hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) due to mutations in DARS, and to identify DARS mutations responsible for HBSL. Methods: Data on 2 HBSL patients who were admitted to the pediatric department of Peking University First Hospital from January 2009 through December 2016 were reviewed and the 2 patients were followed up. Targeted next generation sequencing, whole exome sequencing and Sanger sequencing were employed to identify potential genetic variations of the children and their parents. The clinical manifestations, MRI features and genotypic characteristics of two patients were reviewed, and the literature was reviewed. HBSL reported cases were searched with"leukoencephalopathies, DARS"on databases of PubMed, Wanfang, China National Knowledge Infrastructure and VIP from 1975 to 2017. The clinical manifestations and molecular features were analyzed. Results: Both patients showed delayed motor development, but had normal cognitive development. At the age of 8 years, case 1 reached the most significant motor development milestone of only standing with help during the last follow-up. At the age of 9, case 2 could walk independently during the last follow-up. On physical examination, both showed leg spastcity, active tendon reflex, positive Babinski sign. Both patients had brain MRI findings of high T2WI signal in bilateral deep cerebral white matter, slightly lower T1WI, and no abnormal DWI signal. Lesions of case 1 were relatively extensive and involved subcortical white matter, corpus callosum and internal capsule. Spinal MRI scans for both patients showed no abnormal signals. Novel mutations in DARS gene-namely, c.1498_1499insTCA (p.500_501insIle) and c.1210A>G (p.Met404Val) , c.1432A>G (p.Met478Val) and c.1210A>G (p.Met404Val) were identified in case 1 and case 2 respectively. On the database, 2 reports involving 13 foreign patients were retrieved. The age of disease onset was from 4 months to 18 years, and their initial symptoms were development delay or regression. Most of them presented with progressive lower extremity spasm, and the brain magnetic resonance imaging was characterized by hypomyelination in white matter. Clinical phenotypes of different age groups were significantly different. Conclusion: We have reported two patients with HBSL in China, and 3 novel mutations in DARS, which is helpful for the diagnosis and genetic counseling of HBSL.


Assuntos
Aspartato-tRNA Ligase/genética , Tronco Encefálico/patologia , Doenças Desmielinizantes/genética , Leucoencefalopatias/genética , Medula Espinal/patologia , Criança , China , Corpo Caloso , Humanos , Imagem por Ressonância Magnética , Espasticidade Muscular , Mutação , Fenótipo
15.
Handb Clin Neurol ; 148: 669-692, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29478607

RESUMO

Unique clinical presentations and magnetic resonance imaging patterns can help differentiate the various adult presentations of leukodystrophies and leukoencephalopathies. White-matter disorders are genetically based disorders affecting the central nervous system white matter, with or without peripheral nervous system involvement. These disorders predominantly affect patients in the pediatric population; however, a number of classic leukodystrophies can present in adulthood. Disease progression can be of variable onset with a broad range of symptoms, usually progressing from cognitive dysfunction. Recognition of specific disorders can have important implications for treatment, involvement of multidisciplinary services, and important conversations surrounding social issues the families may face. The focus of this chapter is to highlight the adult presentations of the classic childhood-onset leukodystrophies as well as to describe leukodystrophies which predominantly present in adulthood.


Assuntos
Encéfalo/patologia , Leucoencefalopatias , Imagem por Ressonância Magnética , Adulto , Encéfalo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/patologia
16.
Rinsho Shinkeigaku ; 58(2): 111-117, 2018 Feb 28.
Artigo em Japonês | MEDLINE | ID: mdl-29386495

RESUMO

A 40-year-old woman with renal dysfunction for 2 years was admitted to our hospital suffering from a headache. Family history revealed that her mother had a headache, renal dysfunction, and brain infarction in younger age. She had a retinal hemorrhage, a retinal atrophy, pitting edema in her lower extremities. Her neurological findings were unremarkable. Brain imaging showed multiple white matter lesions accompanied with calcifications and slightly enhancement. Kidney biopsy showed the thrombotic microangiopathy, Gene analysis demonstrated a causative mutation in three-prime repair exonuclease-1 (TREX1) gene, c.703_704insG (p.Val235GlyfsX6), thereby we diagnosed her as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). RVCL is an autosomal dominant condition caused by C-terminal frame-shift mutation in TREX1. TREX1 protein is a major 3' to 5' DNA exonuclease, which are important in DNA repair. While TREX1 mutations identified in Aicardi-Goutieres syndrome patients lead to a reduction of enzyme activity, it is suggested that mutations in RVCL alter an intracellular location of TREX1 protein. There are no treatments based evidences in RVCL. We administered cilostazol to protect endothelial function, and her brain lesions and renal function have not become worse for 10 months after. It is necessary to consider RVCL associated with TREX1 mutation if a patient has retinal lesions, white matter lesions accompanied with calcifications, and multiple organ dysfunction.


Assuntos
Cérebro/patologia , Exodesoxirribonucleases/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Mutação , Fosfoproteínas/genética , Vasculite Retiniana/diagnóstico , Vasculite Retiniana/genética , Administração Oral , Adulto , Calcinose , Cérebro/diagnóstico por imagem , Cilostazol , Humanos , Leucoencefalopatias/complicações , Leucoencefalopatias/dietoterapia , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Vasculite Retiniana/complicações , Vasculite Retiniana/tratamento farmacológico , Tetrazóis/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
Mult Scler Relat Disord ; 20: 84-92, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29353736

RESUMO

BACKGROUND: There is emerging evidence implicating mitochondrial dysfunction in the pathogenesis of acquired demyelinating disorders such as multiple sclerosis. On the other hand, some of the primary mitochondrial disorders such as mitochondrial leukoencephalopathies exhibit evidence of neuroinflammation on MRI. The inter-relationship between mitochondrial disorders and episodic CNS inflammation needs exploration because of the therapeutic implications. OBJECTIVE: We sought to analyze the clinical course and MRI characteristics in a cohort of patients with mitochondrial leukoencephalopathy to determine features, if any, that mimic primary demyelinating disorders. Therapeutic implications of these findings are discussed. PATIENTS AND METHODS: Detailed analysis of the clinical course, magnetic resonance imaging findings and therapeutic response was performed in 14 patients with mitochondrial leukoencephalopathy. The diagnosis was ascertained by clinical features, histopathology, respiratory chain enzyme assays and exome sequencing. RESULTS: Fourteen patients [Age at evaluation: 2-7 yrs, M: F-1:1] were included in the study. The genetic findings included variations in NDUFA1 (1); NDUFV1 (4); NDUFS2 (2); LYRM (2);MPV17(1); BOLA3(2); IBA57(2). Clinical Features which mimicked acquired demyelinating disorder included acute onset focal deficits associated with encephalopathy [10/14, 71%], febrile illness preceding the onset [7/14, 50%] unequivocal partial or complete steroid responsiveness [11/11], episodic/ relapsing remitting neurological dysfunction [10/14, 71%] and a subsequent stable rather than a progressive course [12/14, 85%]. MRI characteristics included confluent white matter lesions [14/14, 100%], diffusion restriction [11/14,78.5%], contrast enhancement [13/13,100%], spinal cord involvement [8/13,61.5%], lactate peak on MRS [13/13] and white matter cysts [13/14, 92.8%]. CONCLUSION: Clinical presentations of mitochondrial leukoencephalopathy often mimic an acquired demyelinating disorder. The therapeutic implications of these observations require further exploration.


Assuntos
Encéfalo/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/fisiopatologia , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , Substância Branca/diagnóstico por imagem , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Inflamação/diagnóstico por imagem , Inflamação/genética , Inflamação/fisiopatologia , Inflamação/terapia , Leucoencefalopatias/genética , Leucoencefalopatias/terapia , Imagem por Ressonância Magnética , Masculino , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Estudos Retrospectivos , Substância Branca/patologia , Substância Branca/fisiopatologia
18.
Ophthalmic Genet ; 39(1): 99-102, 2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28820624

RESUMO

BACKGROUND: Optic atrophy may be the sequela of optic nerve injury due to any insult, including isolated and syndromic genetic diseases. Alanyl-tRNA synthetase 2 (AARS2) pathogenic variants have been reported to cause leukodystrophy with ovarian failure, and cardiomyopathy (#615889) as well as combined oxidative phosphorylation deficiency-8 (#614096). We report a young child who presented with decreased vision due to optic atrophy and was found to harbor missense variants in the AARS2 gene expanding the phenotypic expression of the AARS2 gene. MATERIALS AND METHODS: Single observational case report with genetic testing, laboratory testing, neurologic and ophthalmic clinical examinations, and neuroimaging performed at a tertiary academic medical center. RESULTS: An 18-month old Korean boy was noted to have a progressive decline in visual function. The physical exam revealed bilateral optic atrophy, peripheral retinal bone spicule pigmentation, and absent patellar reflexes. Electromyography was consistent with demyelinating polyneuropathy. Magnetic resonance imaging (MRI) of the brain and spine showed cerebellar and supratentorial white matter multifocal changes with areas of restricted diffusion, and dorsal column signal abnormalities. Whole exome sequencing revealed two missense variants in the AARS2 gene [c.1519G>C (p.V507L) and c.2165G>A (p.R722Q)], found to be in trans on parental testing. CONCLUSIONS: Missense variants in the AARS2 gene are the likely cause of the retinopathy and optic atrophy in this patient. This finding expands the phenotypic spectrum of the AARS2 gene.


Assuntos
Alanina-tRNA Ligase/genética , Mutação de Sentido Incorreto , Atrofia Óptica/genética , Doenças Retinianas/genética , Pré-Escolar , Testes Genéticos , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Atrofia Óptica/diagnóstico , Fenótipo , Doenças Retinianas/diagnóstico , Acuidade Visual/fisiologia , Sequenciamento Completo do Exoma
19.
Parkinsonism Relat Disord ; 46 Suppl 1: S39-S41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28827005

RESUMO

Adult-onset leukoencephalopathies are clinically and genetically heterogeneous disorders that affect predominantly the cerebral white matter of the central nervous system. Clinical and neuroimaging-based approaches have been developed to improve diagnostic processes for adult-onset leukoencephalopathies. However, the differential diagnosis is often challenging. Recently, knowledge of the genetic basis of leukoencephalopathies has been accumulated rapidly, which provides powerful diagnostic approaches. The article provides an overview of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), focusing on the clinical presentations of cognitive impairment and symptoms of movement disorders. ALSP is a subtype of dominantly inherited leukoencephalopathy caused by CSF1R mutations. ALSP typically develop in adulthood, with cognitive decline, psychiatric symptoms, and motor symptoms of movement disorders. Cognitive symptoms in ALSP are characterized by frontal lobe dysfunctions such as executive dysfunction, attention deficits and indifference. The cardinal motor symptoms of movement disorders ALSP were gait disturbance and bradykinesia, which may appear as the initial symptoms. Thus, ALSP should be recognized as both a cognitive disorder and a movement disorder.


Assuntos
Axônios/patologia , Transtornos Cognitivos/etiologia , Leucoencefalopatias/complicações , Leucoencefalopatias/patologia , Transtornos dos Movimentos/etiologia , Neuroglia/patologia , Transtornos Cognitivos/genética , Humanos , Leucoencefalopatias/genética , Transtornos dos Movimentos/genética , Mutação/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética
20.
Glia ; 66(4): 862-873, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29285798

RESUMO

Leukodystrophies are often devastating diseases, presented with progressive clinical signs as spasticity, ataxia and cognitive decline, and lack proper treatment options. New therapy strategies for leukodystrophies mostly focus on oligodendrocyte replacement to rescue lack of myelin in the brain, even though disease pathology also often involves other glial cells and the spinal cord. In this study we investigated spinal cord pathology in a mouse model for Vanishing White Matter disease (VWM) and show that astrocytes in the white matter are severely affected. Astrocyte pathology starts postnatally in the sensory tracts, followed by changes in the astrocytic populations in the motor tracts. Studies in post-mortem tissue of two VWM patients, a 13-year-old boy and a 6-year-old girl, confirmed astrocyte abnormalities in the spinal cord. For proper development of new treatment options for VWM and, possibly, other leukodystrophies, future studies should investigate spinal cord involvement.


Assuntos
Astrócitos/patologia , Leucoencefalopatias/patologia , Medula Espinal/patologia , Adolescente , Animais , Astrócitos/metabolismo , Criança , Modelos Animais de Doenças , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Feminino , Substância Cinzenta/embriologia , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Humanos , Imuno-Histoquímica , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Medula Espinal/embriologia , Medula Espinal/metabolismo , Substância Branca/embriologia , Substância Branca/metabolismo , Substância Branca/patologia
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