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1.
Rev Med Suisse ; 12(500): 62, 64-6, 2016 Jan 13.
Artigo em Francês | MEDLINE | ID: mdl-26946707

RESUMO

In 2015, cerebral stimulation becomes increasingly established in the treatment of pharmacoresistant epilepsy. Efficacy of endovascular treatment has been demonstrated for acute ischemic stroke. Deep brain stimulation at low frequency improves dysphagia and freezing of gait in Parkinson patients. Bimagrumab seems to increase muscular volume and force in patients with inclusion body myositis. In cluster-type headache, a transcutaneous vagal nerve stimulator is efficient in stopping acute attacks and also reducing their frequency. Initial steps have been undertaken towards modulating memory by stimulation of the proximal fornix. Teriflunomide is the first oral immunomodulatory drug for which efficacy has been shown in preventing conversion from clinical isolated syndrome to multiple sclerosis.


Assuntos
Doenças do Sistema Nervoso/terapia , Neurologia/tendências , Terapia por Estimulação Elétrica/métodos , Humanos , Doenças do Sistema Nervoso/fisiopatologia
3.
Rev Med Suisse ; 11(472): 968-71, 2015 Apr 29.
Artigo em Francês | MEDLINE | ID: mdl-26062222

RESUMO

An eligibility assessment for deep brain stimulation is performed in order to select patients who are likely to benefit from it. Parkinson's patients have to stop dopaminergic drugs the day before surgery. During the operation, the patient must remain awake for recording of neuronal activity and for test stimulations to optimize the position of the electrodes. Postoperatively, the stimulation is increased progressively in parallel with a decrease of dopaminergic treatments. After about ten days, the patient can return to home and controls continue as an outpatient. Three months postoperatively, a complete testing of the neurostimulator is performed and at the one year follow-up visit, the effectiveness of the DBS is assessed.


Assuntos
Estimulação Encefálica Profunda/métodos , Doença de Parkinson/terapia , Seleção de Pacientes , Humanos , Cuidados Pós-Operatórios/métodos , Cuidados Pré-Operatórios/métodos , Fatores de Tempo , Resultado do Tratamento
4.
Parkinsonism Relat Disord ; 21(7): 675-82, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25952959

RESUMO

Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs.


Assuntos
Conferências de Consenso como Assunto , Progressão da Doença , Internacionalidade , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Humanos , Illinois , Doença de Parkinson/epidemiologia , Resultado do Tratamento
5.
BMC Neurol ; 15: 55, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25884655

RESUMO

BACKGROUND: LEOPARD syndrome (LS) belongs to the family of neuro-cardio-facio-cutaneous syndromes, which include Neurofibromatosis-1 (NF1), Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius syndrome. These conditions are caused by mutations in genes encoding proteins involved in the RAS-MAPK cellular pathway. Clinical heterogeneity and phenotype overlaps across those different syndromes is already recognized. CASE PRESENTATION: We hereby report a heterozygous de novo mutation in the PTPN11 gene (c.1403C > T) manifesting with a clinical picture of LS during childhood, and later development of neuropathic pain with hypertrophic plexi, which are typically observed in NF1 but have not been reported in LS. CONCLUSION: LS caused by PTPN11 mutations may be associated with hypertrophic roots and plexi. Consequently, clinicians should be aware of the possible development of neuropathic pain and consider specific diagnostic work-up and management.


Assuntos
Síndrome LEOPARD/genética , Neuralgia/fisiopatologia , Doenças do Sistema Nervoso Periférico/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adulto , Feminino , Humanos , Síndrome LEOPARD/complicações , Mutação , Neuralgia/etiologia , Doenças do Sistema Nervoso Periférico/etiologia
6.
Rev Med Suisse ; 11(456-457): 91-6, 2015 Jan 14.
Artigo em Francês | MEDLINE | ID: mdl-25799659

RESUMO

In 2014, breastfeeding during maternal antiepileptic therapy seems to be safe for the children and can be recommended. Intravenous thrombolysis by Alteplase improves the outcome after a stroke if administered within 4.5 hours and it is also recommended in elderly population over 80 years. ProSavin genic therapy for Parkinson disease is under investigation. The Transcranial Magnetic Stimulation (TMS) has an analgesic effect in neuropathic pain as well as an antidepressant effect. Antagonists of calcitonin gene-related peptide can have a beneficial role in migraine prevention. Diagnostic biomarker panels for Alzheimer disease are under investigation. Oral teriflunomide and dimethyl fumarate (BG-12) for relapsing multiple sclerosis treatment are now available in Switzerland.


Assuntos
Doenças do Sistema Nervoso , Humanos , Doenças do Sistema Nervoso/tratamento farmacológico
7.
Anesthesiology ; 122(2): 414-23, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25285947

RESUMO

BACKGROUND: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.


Assuntos
Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Transtornos Somatoformes/genética , Adolescente , Adulto , Amitriptilina/farmacologia , Antidepressivos Tricíclicos/farmacologia , Linhagem Celular , Criança , Temperatura Baixa , DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Técnicas de Patch-Clamp , Linhagem , Plasmídeos
9.
Parkinsonism Relat Disord ; 20 Suppl 1: S35-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24262184

RESUMO

The discovery of genes implicated in familial forms of Parkinson's disease (PD) has provided new insights into the molecular events leading to neurodegeneration. Clinically, patients with genetically determined PD can be difficult to distinguish from those with sporadic PD. Monogenic causes include autosomal dominantly (SNCA, LRRK2, VPS35, EIF4G1) as well as recessively (PARK2, PINK1, DJ-1) inherited mutations. Additional recessive forms of parkinsonism present with atypical signs, including very early disease onset, dystonia, dementia and pyramidal signs. New techniques in the search for phenotype-associated genes (next-generation sequencing, genome-wide association studies) have expanded the spectrum of both monogenic PD and variants that alter risk to develop PD. Examples of risk genes include the two lysosomal enzyme coding genes GBA and SMPD1, which are associated with a 5-fold and 9-fold increased risk of PD, respectively. It is hoped that further knowledge of the genetic makeup of PD will allow designing treatments that alter the course of the disease.


Assuntos
Predisposição Genética para Doença , Doença de Parkinson/genética , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco
11.
Parkinsonism Relat Disord ; 19(10): 869-77, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23787135

RESUMO

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.


Assuntos
Gliose/congênito , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação/genética , Mutação/fisiologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Adolescente , Adulto , Idade de Início , Idoso , Antiparkinsonianos/uso terapêutico , Bancos de Espécimes Biológicos , Encéfalo/patologia , Família , Feminino , Transtornos Neurológicos da Marcha/etiologia , Gliose/complicações , Gliose/genética , Gliose/patologia , Humanos , Hipocinesia/etiologia , Processamento de Imagem Assistida por Computador , Leucoencefalopatias/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/etiologia , Rigidez Muscular/fisiopatologia , Neuroimagem , Doença de Parkinson/etiologia , Receptor de Fator Estimulador de Colônias de Macrófagos/fisiologia , Tremor/etiologia , Reino Unido , Adulto Jovem
13.
Neurology ; 80(11): 1033-40, 2013 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-23408870

RESUMO

OBJECTIVE: Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD. METHODS: We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed. RESULTS: We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wild-type CSF1R. CONCLUSIONS: We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.


Assuntos
Ligação Genética/genética , Leucodistrofia de Células Globoides/genética , Leucoencefalopatias/genética , Transtornos da Pigmentação/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Feminino , Células HeLa , Humanos , Leucodistrofia de Células Globoides/diagnóstico , Leucoencefalopatias/diagnóstico , Pessoa de Meia-Idade , Mutação , Transtornos da Pigmentação/diagnóstico
14.
Eur Neurol ; 69(2): 119-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23207687

RESUMO

We report on a patient who developed, from 5 months of age, multiple seizure types, including myoclonic, associated with severe psychomotor delay, leading to the diagnosis of Dravet syndrome. Over the years, he developed refractory epilepsy and was implanted with a vagus nerve stimulator at the age of 19. After 3 months, he experienced a progressive improvement of partial and generalized seizures, with a >90% reduction, and better alertness. This meaningful clinical improvement is discussed in the light of the sudden unexpected death in epilepsy risk, which is high in this setting, and seems remarkably diminished in our patient in view of the reduction of generalized convulsions.


Assuntos
Morte Súbita/etiologia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/terapia , Estimulação do Nervo Vago , Humanos , Masculino , Comportamento de Redução do Risco , Resultado do Tratamento , Adulto Jovem
15.
Neurology ; 79(6): 566-74, 2012 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-22843259

RESUMO

OBJECTIVE: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. METHODS: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan. RESULTS: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. CONCLUSION: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.


Assuntos
Encéfalo/patologia , Leucoencefalopatias/classificação , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Atrofia/etiologia , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
16.
J Neurol Neurosurg Psychiatry ; 83(4): 424-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22291217

RESUMO

PURPOSE: The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies. METHODS: A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented. RESULTS: MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology. CONCLUSION: This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , alfa-Sinucleína/genética , Proteínas tau/genética , Idoso de 80 Anos ou mais , Encéfalo/patologia , Feminino , Haplótipos , Humanos , Corpos de Lewy/patologia , Masculino , Tamanho do Órgão , Doença de Parkinson/genética , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único
17.
Parkinsonism Relat Disord ; 18(2): 130-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21975262

RESUMO

OBJECTIVE: Ability to work and live independently is of particular concern for patients with Parkinson's disease (PD). We studied a series of PD patients able to work or live independently at baseline, and evaluated potential risk factors for two separate outcomes: loss of ability to work and loss of ability to live independently. METHODS: The series comprised 495 PD patients followed prospectively. Ability to work and ability to live independently were based on clinical interview and examination. Cox regression models adjusted for age and disease duration were used to evaluate associations of baseline characteristics with loss of ability to work and loss of ability to live independently. RESULTS: Higher UPDRS dyskinesia score, UPDRS instability score, UPDRS total score, Hoehn and Yahr stage, and presence of intellectual impairment at baseline were all associated with increased risk of future loss of ability to work and loss of ability to live independently (P ≤ 0.0033). Five years after initial visit, for patients ≤70 years of age with a disease duration ≤4 years at initial visit, 88% were still able to work and 90% to live independently. These estimates worsened as age and disease duration at initial visit increased; for patients >70 years of age with a disease duration >4 years, estimates at 5 years were 43% able to work and 57% able to live independently. CONCLUSIONS: The information provided in this study can offer useful information for PD patients in preparing for future ability to perform activities of daily living.


Assuntos
Atividades Cotidianas , Avaliação da Deficiência , Doença de Parkinson/fisiopatologia , Trabalho , Atividades Cotidianas/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Estudos Prospectivos , Fatores de Risco , Trabalho/psicologia
18.
Parkinsonism Relat Disord ; 18 Suppl 1: S138-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22166413

RESUMO

Essential tremor (ET) is a prevalent condition manifesting with progressive action tremor. Although ET was traditionally viewed as a sporadic disease, a significant proportion of cases report a positive family history of tremor. Autosomal dominant inheritance can be demonstrated in many families. Previously, genome-wide linkage studies in families mapped three loci for ET, hereditary essential tremor-1 (ETM1), ETM2 and ETM3. However, no causal mutation has been replicated in candidate genes within these loci, including dopamine D3 receptor (DRD3) and HS1-binding protein 3 (HS1BP3). Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive. Given the possibility that ET as a complex trait may be influenced by the combined effects of rare variants, novel high-throughput technologies sequencing all exons across the genome (exome sequencing) or the whole genome (genome sequencing) may become crucial in understanding/deciphering the genetic background of ET.


Assuntos
Tremor Essencial/genética , Estudo de Associação Genômica Ampla/métodos , Animais , Tremor Essencial/diagnóstico , Humanos , Polimorfismo de Nucleotídeo Único/genética
19.
Parkinsonism Relat Disord ; 18 Suppl 1: S158-61, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22166420

RESUMO

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.


Assuntos
Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Animais , Distúrbios Distônicos/terapia , Humanos
20.
Nat Genet ; 44(2): 200-5, 2011 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-22197934

RESUMO

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.


Assuntos
Leucodistrofia de Células Globoides/genética , Mutação , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Exoma , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fosforilação , Proteínas Tirosina Quinases/genética , Análise de Sequência de DNA , Adulto Jovem
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