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2.
Nat Commun ; 11(1): 2175, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358547

RESUMO

Cerebral small vessel disease is a major cause of stroke and dementia, but its genetic basis is incompletely understood. We perform a genetic study of three MRI markers of the disease in UK Biobank imaging data and other sources: white matter hyperintensities (N = 42,310), fractional anisotropy (N = 17,663) and mean diffusivity (N = 17,467). Our aim is to better understand the disease pathophysiology. Across the three traits, we identify 31 loci, of which 21 were previously unreported. We perform a transcriptome-wide association study to identify associations with gene expression in relevant tissues, identifying 66 associated genes across the three traits. This genetic study provides insights into the understanding of the biological mechanisms underlying small vessel disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/complicações , Feminino , Regulação da Expressão Gênica/genética , Ontologia Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Transcriptoma/genética
3.
Am J Hum Genet ; 106(5): 694-706, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32359472

RESUMO

How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which monitors ribosome biogenesis. Further, we demonstrate that fibroblasts from individuals with LCC are defective in rRNA processing. Human precursor-U8 (pre-U8) containing a 3' extension rescued mutant U8 zebrafish, and this result indicates conserved biological function. Analysis of LCC-associated U8 mutations in zebrafish revealed that one null and one functional allele contribute to LCC. We show that mutations in three nucleotides at the 5' end of pre-U8 alter the processing of the 3' extension, and we identify a previously unknown base-pairing interaction between the 5' end and the 3' extension of human pre-U8. Indeed, LCC-associated mutations in any one of seven nucleotides in the 5' end and 3' extension alter the processing of pre-U8, and these mutations are present on a single allele in almost all individuals with LCC identified to date. Given genetic data indicating that bi-allelic null U8 alleles are likely incompatible with human development, and that LCC is not caused by haploinsufficiency, the identification of hypomorphic misprocessing mutations that mediate viable embryogenesis furthers our understanding of LCC molecular pathology and cerebral vascular homeostasis.


Assuntos
Alelos , Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Cistos/genética , Leucoencefalopatias/genética , Mutação , RNA Nucleolar Pequeno/genética , Peixe-Zebra/genética , Animais , Sequência de Bases , Calcinose/patologia , Cistos do Sistema Nervoso Central/patologia , Sequência Conservada , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Humanos , Leucoencefalopatias/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
4.
Stroke ; 51(6): 1750-1757, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32397933

RESUMO

Background and Purpose- Distribution patterns of iron deposition in deep gray matter and their association with clinical characteristics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) remain unclear. We aimed to evaluate iron deposition in deep gray matter in patients with CADASIL using 7.0-T susceptibility-weighted imaging and mapping and to explore its correlations with clinical characteristics. Methods- Thirty-nine patients with CADASIL, confirmed via genetic analysis or skin biopsy, were enrolled. We examined patients using the Mini-Mental State Examination, modified Rankin Scale, and brain 7.0-T magnetic resonance imaging and obtained magnetic resonance imaging lesion loads, small vessel disease scores, and susceptibility mapping. The following regions of interest were selected: caudate nucleus, putamen, globus pallidus, thalamus, substantia nigra, and red nucleus. The quantitative differences in the susceptibility of deep gray matter between the CADASIL and control groups and the correlations between deep gray matter susceptibility and clinical characteristics were identified. Results- Compared with the control group, the CADASIL group showed significantly increased susceptibility of caudate nucleus, putamen, thalamus, substantia nigra, and red nucleus. The susceptibility of deep gray matter in basal ganglia region, including caudate nucleus, putamen, and thalamus, significantly increased with age or disease duration and positively correlated with small vessel disease scores in patients with CADASIL. Moreover, the susceptibility of thalamus positively correlated with modified Rankin Scale scores after adjusting for age and disease duration and that of putamen negatively correlated with Mini-Mental State Examination scores in patients with CADASIL after adjusting for age. Conclusions- Our findings indicate an association between abnormal iron deposition in deep gray matter of patients with CADASIL and their clinical characteristics. Therefore, excess iron deposition in deep gray matter, as indicated by 7.0-T susceptibility-weighted imaging and mapping, might not only be a novel magnetic resonance imaging feature but also a potential biomarker for CADASIL severity.


Assuntos
Alopecia/diagnóstico por imagem , Alopecia/metabolismo , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/metabolismo , Substância Cinzenta , Ferro/metabolismo , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/metabolismo , Imagem por Ressonância Magnética , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/metabolismo , Adulto , Alopecia/genética , Infarto Cerebral/genética , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Humanos , Leucoencefalopatias/genética , Masculino , Pessoa de Meia-Idade , Doenças da Coluna Vertebral/genética
5.
Rinsho Shinkeigaku ; 60(6): 420-424, 2020 Jun 06.
Artigo em Japonês | MEDLINE | ID: mdl-32435043

RESUMO

A 64-year-old woman visited our hospital with early-onset dementia and progressive gait disturbance. She had demonstrated a mild communication disorder at the age of ~40 years; however, her psychiatric symptoms at that time were mild and were not accompanied by social problems. At the age of 59, she presented with memory loss, visual hallucinations, and delusions. Over the following five years she developed gait difficulties that gradually deteriorated and suffered frequent falls. On admission, neurological examinations revealed severe pyramidal and extrapyramidal signs of akinetic mutism. MRI of the brain showed cerebral atrophy, enlarged lateral ventricles, thinning of the corpus callosum, and leukoencephalopathy in the frontal-parietal lobes. Additionally, CT revealed a small spotty calcification in the frontal subcortical white matter. Genetic analysis revealed a single-base substitution (c.2330G>A/p.R777Q) in exon 18 of the colony stimulating factor 1 receptor (CSF1R) gene, encoding the CSF1R protein. She was diagnosed with hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS is included in the differential diagnosis of early-onset dementia and should be considered in patients with mild personality change and abnormal behavior in the early course of the illness.


Assuntos
Doenças dos Gânglios da Base/etiologia , Delusões/etiologia , Alucinações/etiologia , Leucoencefalopatias/complicações , Transtornos da Memória/etiologia , Neuroglia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Calcinose , Diagnóstico Diferencial , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Fatores de Tempo , Tomografia Computadorizada por Raios X
6.
Muscle Nerve ; 62(2): 266-271, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32363625

RESUMO

BACKGROUND: Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease. METHODS: Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples. RESULTS: A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients. CONCLUSIONS: Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.


Assuntos
Encefalopatias/genética , Mutação com Perda de Função , Hipotonia Muscular/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Proteínas Serina-Treonina Quinases/genética , Transtornos Psicomotores/genética , Convulsões/genética , Adolescente , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/genética , Feminino , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Debilidade Muscular/genética , Debilidade Muscular/patologia , Doenças Musculares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Reflexo Anormal/genética , Índice de Gravidade de Doença , Irmãos , Síndrome , Sequenciamento Completo do Exoma
7.
Am J Hum Genet ; 106(4): 570-583, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197074

RESUMO

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.


Assuntos
Deficiências do Desenvolvimento/genética , Variação Genética/genética , Leucoencefalopatias/genética , Malformações do Sistema Nervoso/genética , eIF-2 Quinase/genética , Adolescente , Ataxia/genética , Criança , Pré-Escolar , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Lactente , Masculino , Substância Branca/patologia
8.
Neurobiol Aging ; 89: 142.e1-142.e7, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32081467

RESUMO

Recently, the (GGC)n repeat expansion in the NOTCH2NLC gene has been identified to be associated with neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of dementia-dominant NIID with neurodegenerative dementia, we therefore hypothesized that the NOTCH2NLC repeat expansion might also contribute to these diseases. In the present study, repeat primed polymerase chain reaction (RP-PCR) and GC-rich PCR were conducted to detect the repeats of NOTCH2NLC in a cohort of 1004 patients with neurodegenerative dementias from mainland China. As a result, 4 sporadic patients were found to carry the NOTCH2NLC repeats expansion, totally accounting for 0.4% of all dementia individuals, and the accurate repeated sizes were 110, 133,120 and 76 respectively. Of 4 mutation carriers, three and one were clinically diagnosed Alzheimer's disease (AD) and frontotemporal dementia (FTD) respectively. In addition, 3 out of them revealed leukoencephalopathy in T2-Flair imaging. This study revealed that although rare, the NOTCH2NLC repeat expansions may be associated with AD or FTD-like phenotype as well as leukoencephalopathy.


Assuntos
Doença de Alzheimer/genética , Expansão das Repetições de DNA , Demência Frontotemporal/genética , Leucoencefalopatias/genética , Doenças Neurodegenerativas/genética , Receptor Notch2/genética , Idoso , China , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Corpos de Inclusão Intranuclear/genética , Masculino , Pessoa de Meia-Idade
9.
Stroke ; 51(1): 300-307, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31805844

RESUMO

Background and Purpose- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the TREX1 gene that encodes the major mammalian 3' to 5' DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown. Methods- Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment. Results- The mutant mice show increased mortality starting at midlife (P=0.03 with hazard ratio, 3.14 [95% CI, 1.05-9.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7, P=0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: Emax: 37±8% versus WT: Emax: 65±6%, P=0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4±2.7 mm3 versus WT: 52.9±5.6 mm3, P=0.01). Conclusions- Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.


Assuntos
Exodesoxirribonucleases , Leucoencefalopatias , Fosfoproteínas , Doenças Retinianas , Doenças Vasculares , Animais , Modelos Animais de Doenças , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Técnicas de Introdução de Genes , Humanos , Leucoencefalopatias/enzimologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Camundongos , Camundongos Mutantes , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Doenças Retinianas/enzimologia , Doenças Retinianas/genética , Doenças Retinianas/patologia , Doenças Vasculares/enzimologia , Doenças Vasculares/genética , Doenças Vasculares/patologia
10.
Neurology ; 94(1): e87-e96, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31792094

RESUMO

OBJECTIVE: To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations. METHODS: The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups. RESULTS: Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke (p = 0.0001 and 3.9 × 10-10, respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age. CONCLUSION: The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL.


Assuntos
Cisteína/genética , Receptor Notch3/genética , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Adulto , Fatores Etários , Idoso , CADASIL/diagnóstico por imagem , CADASIL/genética , Feminino , Variação Genética , Genótipo , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Taiwan/epidemiologia , Substância Branca/diagnóstico por imagem , Adulto Jovem
11.
Brain ; 143(1): 94-111, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855247

RESUMO

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.


Assuntos
Antígenos CD/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Adolescente , Ataxia/genética , Ataxia/fisiopatologia , Atrofia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Colina/farmacologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Vesículas Citoplasmáticas/efeitos dos fármacos , Vesículas Citoplasmáticas/ultraestrutura , Transtornos de Deglutição/genética , Transtornos de Deglutição/fisiopatologia , Disartria/genética , Disartria/fisiopatologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Incontinência Fecal/genética , Incontinência Fecal/fisiopatologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/ultraestrutura , Mutação da Fase de Leitura , Globo Pálido/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Nootrópicos/farmacologia , Atrofia Óptica/genética , Atrofia Óptica/fisiopatologia , Linhagem , Ribossomos/efeitos dos fármacos , Ribossomos/ultraestrutura , Substância Negra/diagnóstico por imagem , Síndrome , Tremor/genética , Tremor/fisiopatologia , Incontinência Urinária/genética , Incontinência Urinária/fisiopatologia
12.
Brain ; 143(2): 503-511, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31840744

RESUMO

Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.


Assuntos
Encéfalo/fisiopatologia , Leucoencefalopatias/genética , Microglia/patologia , Neuroglia/citologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Progressão da Doença , Feminino , Humanos , Leucoencefalopatias/terapia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos
13.
BMC Neurol ; 19(1): 325, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842800

RESUMO

BACKGROUND: The X-linked form of Charcot-Marie-Tooth disease type 1 (CMTX1) is an inherited peripheral neuropathy that arises in patients with mutations in the gap-junction beta-1 gene (GJB1). CASE PRESENTATION: Three young male patients from Southern China with pes cavus experienced multiple episodes of transient central nervous system (CNS) dysfunction. Three patients all had reversible posterior leukoencephalopathy as detected by brain diffusion-weighted magnetic resonance imaging (MRI-DWI). Nerve conduction velocity (NCV) showed sensorimotor polyneuropathy with mixed demyelinating and axonal features. Genetic testing indicated a c.425G > A (p.Arg142Glu) or c.563 C > T (p.Thr188Ile) or c.103G > C (p.Val35Leu) mutation in GJB1. The unique feature of this report is the identification of two novel mutations: c.563 C > T and sc.103G > C of the GJB1 gene detected in two families respectively. Another unique feature is that peripheral neuropathy symptoms in the three patients were insidious and found at the onset of CNS symptoms. CONCLUSIONS: Posterior leukoencephalopathy is involved in CMTX1 patients. The white matter changes in MRI of CMTX1 patients are reversible and recover later than CNS symptoms.


Assuntos
Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Leucoencefalopatias/genética , Adolescente , China , Testes Genéticos , Humanos , Leucoencefalopatias/patologia , Masculino , Mutação , Linhagem
14.
PLoS One ; 14(10): e0224173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671122

RESUMO

Several inherited human diseases have been linked to mitochondrial aminoacyl-tRNA synthetases (mtARSs). Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a leukodystrophy caused by mutations in the DARS2 gene which encodes mitochondrial aspartyl-tRNA synthetase. As mitochondrial ARSs are key components of the mitochondrial translation apparatus, we investigated the effects of DARS2 mutations on mitochondrial functions and mitochondrial morphology in an LBSL patient. In fibroblasts from the patient with LBSL, biosynthesis of respiratory chain complex proteins encoded by mitochondrial DNA was decreased, while those encoded by nuclear DNA were not. Cellular oxygen consumption rates and respiratory control ratio were decreased in the LBSL patient; in addition, fragmentation of mitochondria was increased, while their tubular elongation and interconnectivity were decreased. Taken together, these findings suggest that DARS2 mutations impair translations of mitochondrial DNA-encoded respiratory chain complex proteins, consequently causing dysfunction of cellular respiration and impediment of mitochondrial dynamics, which highlights the role of mtARSs in the maintenance of normal mitochondrial bioenergetics and dynamics.


Assuntos
Aspartato-tRNA Ligase/deficiência , Leucoencefalopatias/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Aspartato-tRNA Ligase/genética , Sequência de Bases , Fibroblastos/patologia , Humanos , Leucoencefalopatias/genética , Doenças Mitocondriais/genética , Mutação
15.
Rev Cardiovasc Med ; 20(3): 179-186, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601092

RESUMO

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathyis a rare form of inherited cerebral small vessel disease associated with mutations in the high-temperature requirement serine peptidase A1 gene. As of now, only about 50 cases have been reported. In 2012, our group reported a family with a novel mutant of the high-temperature requirement serine peptidase A1 gene in China for the first time. To further explore the molecular pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a recombination mouse model expressed human high-temperature requirement serine peptidase A1 gene mutant identified by our group was generated using the Donor & Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 system and termed the Mut-high-temperature requirement serine peptidase A1 geneL364P mouse model. Results show that Mut-high-temperature requirement serine peptidase A1 geneL364P mice present similar pathological characteristics to patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, suggesting that the Mut-high-temperature requirement serine peptidase A1 geneL364P mouse model was generated successfully. Moreover, apoptosis was induced in mouse brain vascular smooth muscle cells derived from Mut-high-temperature requirement serine peptidase A1 geneL364P mice. In summary, the cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy mouse model described in this study will be beneficial to demonstrate the pathological mechanism of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy and provide new therapeutic targets for clinical treatment.


Assuntos
Alopecia/genética , Encéfalo/irrigação sanguínea , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Alopecia/enzimologia , Alopecia/patologia , Animais , Apoptose , Células Cultivadas , Infarto Cerebral/enzimologia , Infarto Cerebral/patologia , Predisposição Genética para Doença , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Leucoencefalopatias/enzimologia , Leucoencefalopatias/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fenótipo , Doenças da Coluna Vertebral/enzimologia , Doenças da Coluna Vertebral/patologia
16.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484286

RESUMO

Cerebral small vessel diseases (SVD) have been causally correlated with ischemic strokes, leading to cognitive decline and vascular dementia. Neuroimaging and molecular genetic tests could improve diagnostic accuracy in patients with potential SVD. Several types of monogenic, hereditary cerebral SVD have been identified: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), hereditary diffuse leukoencephalopathy with spheroids (HDLS), COL4A1/2-related disorders, and Fabry disease. These disorders can be distinguished based on their genetics, pathological and imaging findings, clinical manifestation, and diagnosis. Genetic studies of sporadic cerebral SVD have demonstrated a high degree of heritability, particularly among patients with young-onset stroke. Common genetic variants in monogenic disease may contribute to pathological progress in several cerebral SVD subtypes, revealing distinct genetic mechanisms in different subtype of SVD. Hence, genetic molecular analysis should be used as the final gold standard of diagnosis. The purpose of this review was to summarize the recent discoveries made surrounding the genetics of cerebral SVD and their clinical significance, to provide new insights into the pathogenesis of cerebral SVD, and to highlight the possible convergence of disease mechanisms in monogenic and sporadic cerebral SVD.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Leucoencefalopatias/genética , Acidente Vascular Cerebral/genética , Animais , Demência Vascular/metabolismo , Humanos , Esferoides Celulares/metabolismo
17.
Med Sci Monit Basic Res ; 25: 199-209, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31554780

RESUMO

BACKGROUND This study aimed to identify NOTCH3 mutations and describe the genetic and clinical features and magnetic resonance imaging results in 11 unrelated patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) from Henan province in China. MATERIAL AND METHODS NOTCH3 was directly sequenced in 11 unrelated patients of Chinese descent. The clinical presentations and magnetic resonance imaging features were retrospectively analyzed in the 11 index patients with a definite diagnosis. RESULTS Seven different mutations were identified in 11 unrelated patients, including 4 novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) in China and 3 reported mutations (p.C117R, p.R578C, and p.R607C). Four novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) were predicted to be probably pathogenic using an online pathogenicity prediction program through comprehensive analysis. Clinical presentations in symptomatic patients included stroke, cognitive decline, psychiatric disturbances, and migraine. Multiple lacunars infarcts and leukoaraiosis were detected on MRI in most symptomatic patients, while white-matter lesions were identified in the temporal pole or the external capsule in all affected patients. CONCLUSIONS The mutation spectrum of CADASIL patients from Henan province in China displayed some differences from that of those reported previously. DNA sequencing was used to diagnose all 11 patients as having CADASIL, and we found 4 novel mutations. The present results further contribute to the enrichment of NOTCH3 mutation databases.


Assuntos
CADASIL/genética , Receptor Notch3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , CADASIL/fisiopatologia , Infarto Cerebral/genética , China , Feminino , Humanos , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Receptor Notch3/metabolismo , Estudos Retrospectivos , Análise de Sequência de DNA
18.
J Stroke Cerebrovasc Dis ; 28(11): 104354, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494012

RESUMO

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a heritable, rare small vessel disease, which is caused by HTRA1 mutations and mostly reported Japanese and Chinese population. CARASIL is an orphan disease, which presents with progressive motor and cognitive impairment, alopecia, and spondylosis. The disease typically starts with lumbago at early twenties. Ischemic strokes start at mid-twenties. Patients have no cardiovascular or any other risk factors. Multiple lacunar infarcts and leukoencephalopathy cause progressive neurologic involvement. Leukoencephalopathy and small vessel disease without any risk factors is a significant finding for the differential diagnosis of HTRA1 gene pathology. This report presents clinical and genetic features of a rare case of typical CARASIL from Turkey who was followed with uncertain diagnoses for years.


Assuntos
Alopecia/genética , Infarto Cerebral/genética , Heterozigoto , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Alopecia/diagnóstico por imagem , Alopecia/fisiopatologia , Alopecia/psicologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/fisiopatologia , Infarto Cerebral/psicologia , Análise Mutacional de DNA , Predisposição Genética para Doença , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/fisiopatologia , Leucoencefalopatias/psicologia , Imagem por Ressonância Magnética , Masculino , Fenótipo , Fatores de Risco , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/fisiopatologia , Doenças da Coluna Vertebral/psicologia
19.
Ann Neurol ; 86(6): 962-968, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31433517

RESUMO

Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962-968.


Assuntos
Variação Genética/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Receptor Notch2/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
BMC Neurol ; 19(1): 203, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438897

RESUMO

BACKGROUND: Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized. CASE PRESENTATION: The patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients. CONCLUSIONS: The present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1-5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.


Assuntos
Fator de Iniciação 2B em Eucariotos/genética , Leucoencefalopatias/genética , Menorragia/etiologia , Doenças Ovarianas/genética , Adulto , Feminino , Humanos , Leucoencefalopatias/complicações , Imagem por Ressonância Magnética , Mutação , Doenças Ovarianas/complicações
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