Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31479583

RESUMO

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.

3.
Clin Genet ; 95(6): 693-703, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859559

RESUMO

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

4.
Genet Med ; 21(9): 2059-2069, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

5.
Eur J Hum Genet ; 27(4): 525-534, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30622331

RESUMO

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

6.
Genet Med ; 21(7): 1639-1643, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30546084

RESUMO

PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

7.
Am J Med Genet B Neuropsychiatr Genet ; 177(1): 35-39, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29095566

RESUMO

A consistent feature of predictive testing guidelines for Huntington's disease (HD) is the recommendation not to undertake predictive tests on those < 18 years. Exceptions are made but the extent of, and reasons for, deviation from the guidelines are unknown. The UK Huntington's Prediction Consortium has collected data annually on predictive tests undertaken from the 23 UK genetic centers. DNA analysis for HD in the Netherlands is centralized in the Laboratory for Diagnostic Genome Analysis in Leiden. In the UK, 60 tests were performed on minors between 1994 and 2015 representing 0.63% of the total number of tests performed. In the Netherlands, 23 tests were performed on minors between 1997 and 2016. The majority of the tests were performed on those aged 16 and 17 years for both countries (23% and 57% for the UK, and 26% and 57% for the Netherlands). Data on the reasons for testing were identified for 36 UK and 22 Netherlands cases and included: close to the age of 18 years, pregnancy, currently in local authority care and likely to have less support available after 18 years, person never having the capacity to consent and other miscellaneous reasons. This study documents the extent of HD testing of minors in the UK and the Netherlands and suggests that, in general, the recommendation is being followed. We provide some empirical evidence as to reasons why clinicians have departed from the recommendation. We do not advise changing the recommendation but suggest that testing of minors continues to be monitored.


Assuntos
Testes Genéticos/métodos , Testes Genéticos/normas , Doença de Huntington/diagnóstico , Adolescente , Feminino , Testes Genéticos/ética , Humanos , Masculino , Menores de Idade , Países Baixos/epidemiologia , Reino Unido/epidemiologia
8.
Genet Med ; 20(1): 42-54, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28617417

RESUMO

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.


Assuntos
Alelos , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Estudos de Associação Genética , Mutação , Peptidilprolil Isomerase/genética , Fenótipo , Criança , Pré-Escolar , Mapeamento Cromossômico , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética , Masculino
10.
Neurobiol Dis ; 83: 115-21, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26297319

RESUMO

Previous studies have shown activation of the immune system and altered immune response in Huntington's disease (HD) gene carriers. Here, we hypothesized that peripheral and central immune responses could be concurrent pathophysiological events and represent a global innate immune response to the toxic effects of mutant huntingtin in HD gene carriers. We sought to investigate our hypothesis using [(11)C]PK11195 PET as a translocator protein (TSPO) marker of central microglial activation, together with assessment of peripheral plasma cytokine levels in a cohort of premanifest HD gene carriers who were more than a decade from predicted symptomatic conversion. Data were also compared to those from a group of healthy controls matched for age and gender. We found significantly increased peripheral plasma IL-1ß levels in premanifest HD gene carriers compared to the group of normal controls (P=0.018). Premanifest HD gene carriers had increased TSPO levels in cortical, basal ganglia and thalamic brain regions (P<0.001). Increased microglial activation in somatosensory cortex correlated with higher plasma levels of IL-1ß (rs=0.87, P=0.013), IL-6 (rs=0.85, P=0.013), IL-8 (rs=0.68, P=0.045) and TNF-α (rs=0.79; P=0.013). Our findings provide first in vivo evidence for an association between peripheral and central immune responses in premanifest HD gene carriers, and provide further supporting evidence for the role of immune dysfunction in the pathogenesis of HD.


Assuntos
Encéfalo/imunologia , Citocinas/sangue , Encefalite/imunologia , Doença de Huntington/imunologia , Doença de Huntington/metabolismo , Inflamação/imunologia , Microglia/imunologia , Adulto , Amidas , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalite/diagnóstico por imagem , Encefalite/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Inflamação/sangue , Mediadores da Inflamação/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Isoquinolinas , Masculino , Microglia/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Fator de Necrose Tumoral alfa/sangue
11.
Nat Neurosci ; 18(6): 807-16, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25938884

RESUMO

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.


Assuntos
Doença de Huntington/genética , Doença de Huntington/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idade de Início , Alelos , Estudos de Coortes , DNA/genética , Regulação da Expressão Gênica/fisiologia , Genes Reporter/genética , Humanos , Proteína Huntingtina , Doença de Huntington/fisiopatologia , Pessoa de Meia-Idade , Mutagênese Sítio-Dirigida , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica
13.
Brain ; 137(Pt 3): 819-33, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24459107

RESUMO

Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington's disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NFκB pathway, whereby it interacts with IKKγ, leads to increased degradation of IκB and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function-the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington's disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington's disease.


Assuntos
Doença de Huntington/genética , Doença de Huntington/patologia , Células Mieloides/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/fisiologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Transdução de Sinais/genética , Regulação da Expressão Gênica/imunologia , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Imunidade Inata/genética , Células Mieloides/imunologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , RNA Interferente Pequeno/uso terapêutico , Transdução de Sinais/imunologia , Células U937
14.
J Huntingtons Dis ; 2(1): 125-34, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-25063434

RESUMO

BACKGROUND: Huntington's Disease (HD) is a hereditary, progressive neurodegenerative disorder characterised by both neurological and systemic symptoms. In HD, immune changes can be observed before the onset of overt clinical features raising the possibility that inflammatory markers in plasma could be used to track disease progression. It has previously been demonstrated that a widespread, progressive innate immune response is detectable in plasma throughout the course of HD. OBJECTIVE: The aim of the present study was to investigate the potential of several components of inflammation and innate immunity as plasma biomarkers in HD. METHODS: We utilised antibody-based detection technologies as well as mass spectrometric quantification, multiple reaction monitoring (MRM-MS). RESULTS: Levels of several markers previously described as altered in HD, such as clusterin, complement component 4, complement component 9 and α-2 macroglobulin did not differ between healthy controls and HD subjects as measured by Luminex, ELISA or MRM-MS. C-reactive protein was decreased in early HD, while the other immune markers tested were unaltered. CONCLUSIONS: Although only C-reactive protein was found to be reduced in early HD, some of the inflammatory markers measured correlated with clinical measures.


Assuntos
Biomarcadores/sangue , Doença de Huntington/sangue , Doença de Huntington/imunologia , Inflamação/sangue , Adulto , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , Cromatografia Líquida , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Adulto Jovem
15.
J Huntingtons Dis ; 2(2): 185-200, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-25063515

RESUMO

BACKGROUND: Huntington's disease is a neurodegenerative disorder characterized by transcriptional alterations both in central and peripheral tissues. Therefore, the identification of a transcriptional signature in an accessible tissue can meaningfully complement current efforts in clinical biomarker development. Gene expression normalization represents an essential step in transcriptional signatures identification, and since many reference genes show altered expressions in several pathologies, the definition of stable genes in the desired tissue is required to allow correct result interpretations. OBJECTIVE: The present work aimed at identifying a set of suitable reference genes for expression normalization in blood of HD patients and R6/2 mice. METHODS: By crossing literature investigation and analysis of microarrays performed on blood of HD patients and healthy subjects, a set of genes was selected and tested by RT-qPCR. Employment of statistical algorithms allowed the identification of the most stable genes in human samples that were than confirmed in R6/2. RESULTS: PPIB, PGK1, ACTB and YWHAZ represent the best possible genes combination, useful to normalize blood transcriptional analysis. To link clinical and preclinical studies, the identified genes were investigated also in blood of R6/2 and wild type mice, confirming that Ppib, Actb and Ywhaz were appropriate for expression normalization. Selected references were subsequently applied to evaluate expression of genes known to be involved in Huntington's pathological progression. CONCLUSIONS: This work highlights the importance for correct data normalization to avoid misinterpretation of results, while providing a suitable method to support quantitative gene expression analysis in preclinical and clinical investigations.


Assuntos
Perfilação da Expressão Gênica/métodos , Expressão Gênica/genética , Doença de Huntington/genética , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Padrões de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
J Clin Invest ; 122(10): 3731-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22996692

RESUMO

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Therapeutic approaches to lower mutant HTT (mHTT) levels are expected to proceed to human trials, but noninvasive quantification of mHTT is not currently possible. The importance of the peripheral immune system in neurodegenerative disease is becoming increasingly recognized. Peripheral immune cells have been implicated in HD pathogenesis, but HTT levels in these cells have not been quantified before. A recently described time-resolved Förster resonance energy transfer (TR-FRET) immunoassay was used to quantify mutant and total HTT protein levels in leukocytes from patients with HD. Mean mHTT levels in monocytes, T cells, and B cells differed significantly between patients with HD and controls and between pre-manifest mutation carriers and those with clinical onset. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in patients with HD. mHTT N-terminal fragments detected in HD PBMCs may explain the progressive increase in mHTT levels in these cells. These findings indicate that quantification of mHTT in peripheral immune cells by TR-FRET holds significant promise as a noninvasive disease biomarker.


Assuntos
Linfócitos B/química , Doença de Huntington/sangue , Leucócitos/química , Monócitos/química , Proteínas do Tecido Nervoso/sangue , Linfócitos T/química , Atrofia , Biomarcadores , Western Blotting , Núcleo Caudado/patologia , Progressão da Doença , Transferência Ressonante de Energia de Fluorescência , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/imunologia , Doença de Huntington/patologia , Imunoprecipitação , Mutação , Proteínas do Tecido Nervoso/genética
17.
Front Biosci (Elite Ed) ; 4: 950-7, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22201927

RESUMO

Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present work we have investigated levels of hemoglobin and markers of oxidative damage, including the heme- and radical-scavenger alpha1-microglobulin, in plasma and urine samples from two separate sample cohorts, including controls, premanifest gene carriers and subjects at different stages of Huntington's disease. The results show statistically significant increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease urine samples. Interestingly, urine hemoglobin levels correlate with clinical severity. The results suggest that hemolysis may be linked to the pathogenesis of Huntington's disease and that assay of hemoglobin and alpha1-microglobulin may provide biomarkers that are linked to biologically relevant processes.


Assuntos
alfa-Globulinas/metabolismo , Hemoglobinas/metabolismo , Doença de Huntington/sangue , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioimunoensaio
18.
PLoS Curr ; 3: RRN1231, 2011 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-21826115

RESUMO

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. Immune activation is a well-established feature of the HD brain and we have previously demonstrated a widespread, progressive innate immune response detectable in plasma throughout the course of HD. In the present work we used multiplex ELISA to quantify levels of chemokines in plasma from controls and subjects at different stages of HD. We found an altered chemokine profile tracking with disease progression, with significant elevations of five chemokines (eotaxin-3, MIP-1ß, eotaxin, MCP-1 and MCP-4) while three (eotaxin-3, MIP-1ß and eotaxin) showed significant linear increases across advancing disease stages. We validated our results in a separate sample cohort including subjects at different stages of HD. Here we saw that chemokine levels (MCP-1 and eotaxin) correlated with clinical scores. We conclude that, like cytokines, chemokines may be linked to the pathogenesis of HD, and that immune molecules may be valuable in tracking and exploring the pathogenesis of HD.

19.
PLoS One ; 6(8): e22966, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21857974

RESUMO

Reduced Brain-Derived Neurotrophic Factor (BDNF) levels have been described in a number of patho-physiological conditions, most notably, in Huntington's disease (HD), a progressive neurodegenerative disorder. Since BDNF is also produced in blood, we have undertaken the measurement of its peripheral levels in the attempt to identify a possible link with HD prognosis and/or its progression. Here we evaluated BDNF level in 398 blood samples including 138 controls, 56 preHD, and 204 HD subjects. We found that BDNF protein levels were not reliably different between groups, whether measured in plasma (52 controls, 26 preHD, 105 HD) or serum (39 controls, 5 preHD, 29 HD). Our experience, and a re-analysis of the literature highlighted that intra-group variability and methodological aspects affect this measurement, especially in serum. We also assessed BDNF mRNA levels in blood samples from 47 controls, 25 preHD, and 70 HD subjects, and found no differences among the groups. We concluded that levels of BDNF in human blood were not informative (mRNA levels or plasma protein level) nor reliable (serum protein levels) as HD biomarkers. We also wish to warn the scientific community in interpreting the significance of changes measured in BDNF protein levels in serum from patients suffering from different conditions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Doença de Huntington/sangue , Doença de Huntington/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anexinas/genética , Antidepressivos Tricíclicos/uso terapêutico , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , França , Expressão Gênica , Humanos , Doença de Huntington/tratamento farmacológico , Itália , Londres , Masculino , Pessoa de Meia-Idade , Inibidores da Captação de Neurotransmissores/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem , Quinases Associadas a rho/genética
20.
PLoS Curr ; 3: RRN1232, 2011 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-21686312

RESUMO

Movement artifacts and other sources of noise are a matter of concern particularly in the neuroimaging research of movement disorders such as Huntington's disease (HD). Using diffusion weighted imaging (DWI) and fractional anisotropy (FA) as a compound marker of white matter integrity, we investigated the effect of movement on HD specific changes in magnetic resonance imaging (MRI) data and how post hoc compensation for it affects the MRI results. To this end, we studied by 3T MRI: 18 early affected, 22 premanifest gene-positive subjects, 23 healthy controls (50 slices of 2.3 mm thickness per volume, 64 diffusion-weighted directions (b = 1000 s/mm2), 8 minimal diffusion-weighting (b = 100 s/mm2)); and by 1.5 T imaging: 29 premanifest HD, 30 controls (40 axial slices of 2.3 mm thickness per volume, 61 diffusion-weighted directions (b = 1000 s/mm2), minimal diffusion-weighting (b = 100 s/mm2)). An outlier based method was developed to identify movement and other sources of noise by comparing the index DWI direction against a weighted average computed from all other directions of the same subject. No significant differences were observed when separately comparing each group of patients with and without removal of DWI volumes that contained artifacts. In line with previous DWI-based studies, decreased FA in the corpus callosum and increased FA around the basal ganglia were observed when premanifest mutation carriers and early affected patients were compared with healthy controls. These findings demonstrate the robustness of the FA value in the presence of movement and thus encourage multi-center imaging studies in HD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA