RESUMEN
BACKGROUND: 47,XYY syndrome (XYY) is a male sex chromosome disorder where subjects have one X chromosome and two copies of the Y chromosome. XYY is associated with a physical phenotype and carries increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Imbalance of excitation and inhibition has been proposed as a putative biological basis of disorders such as ASD [1-3] and several studies have reported atypical brain γ-aminobutyric acid (GABA) levels in this population. Given the male preponderance in the prevalence of ASD, the unique presence of the Y chromosome in males leads to the intriguing possibility of investigating boys with XYY syndrome as a model of excess Y-chromosome genes. METHOD: In this study, we investigated the associations of genotype and clinical phenotype with levels of GABA, estimated by regionally localized edited magnetic resonance spectroscopy in boys with 47, XYY syndrome compared to age-matched typically developing (XY) peers. RESULTS: Overall, we observed a decrease in GABA levels in XYY vs. XY, which appeared more significant in the left compared to the right hemisphere. There was no additional significant modulation of GABA levels in XYY according to presence/absence of ASD diagnosis. Interestingly, a positive correlation between bilateral GABA levels and testosterone levels was observed in pubescent XY boys that was not observed in XYY. CONCLUSION: The inhibitory neurotransmitter GABA appears to be reduced in boys with 47,XYY, especially in the left hemisphere. Further, the typical association between GABA and testosterone levels, observed in older typically developing control boys was not evident in boys with 47,XYY.
Asunto(s)
Trastornos de los Cromosomas Sexuales/metabolismo , Lóbulo Temporal/metabolismo , Cariotipo XYY/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Adolescente , Niño , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Trastornos de los Cromosomas Sexuales/diagnóstico por imagen , Lóbulo Temporal/diagnóstico por imagen , Cariotipo XYY/diagnóstico por imagenRESUMEN
One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-κB. Yet, whether NF-κB exerts similar functions in central myelin formation by oligodendrocytes remains largely unknown. We previously reported white matter abnormalities with unusual discordance between T2 and FLAIR sequences in a patient with intellectual disability and defective NF-κB signalling. These observations prompted us to hypothesise that NF-κB signalling may have a role in the axon myelination process of central neurons. We report here on five male patients with Xq28 duplications encompassing MECP2, three of which presented white matter anomalies on brain MRI. Array-CGH and FISH analyses demonstrated that brain abnormalities correlate with additional copies of the IKBKG, a gene encoding a key regulator of NF-κB activation. Quantitative RT-PCR experiments and κB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-κB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-κB signalling in astroglial cells for normal myelin formation of the central nervous system.
Asunto(s)
Encéfalo , Duplicación Cromosómica , Anomalías Craneofaciales , Facies , Enfermedades Genéticas Ligadas al Cromosoma X , Quinasa I-kappa B , Discapacidad Intelectual , Vaina de Mielina , FN-kappa B , Trastornos de los Cromosomas Sexuales , Axones/metabolismo , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Duplicación Cromosómica/genética , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/metabolismo , Anomalías Craneofaciales/fisiopatología , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/fisiopatología , Angiografía por Resonancia Magnética , Masculino , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Radiografía , Células de Schwann/citología , Células de Schwann/metabolismo , Trastornos de los Cromosomas Sexuales/genética , Trastornos de los Cromosomas Sexuales/metabolismo , Trastornos de los Cromosomas Sexuales/fisiopatología , Transducción de SeñalRESUMEN
OBJECTIVE: To evaluate the presence of spermatogonia in men diagnosed with Klinefelter syndrome (KS), in whom no testicular spermatozoa were recovered by testicular sperm extraction. DESIGN: Retrospective case series. SETTING: University hospital. PATIENT(S): Testicular samples from 22 nonmosaic 47,XXY men, aged 24-43 years, with no spermatozoa at multiple biopsies. INTERVENTION(S): Paraffin-embedded testicular tissue was sectioned and stained with hematoxylin-eosin, and immunostainings were performed for both MAGE-A4 and vimentin. MAIN OUTCOME MEASURE(S): The presence of spermatogonia. RESULT(S): Massive fibrosis and hyalinization were observed in all men with KS. Spermatogonia were observed in 4 of 22 men with KS, with differentiation up to the spermatocyte level in 2 of them. CONCLUSION(S): A few men with KS, having no spermatozoa after testicular sperm extraction, still had few spermatogonia. These patients may eventually benefit from in vitro maturation using spermatogonial stem cells. The adult KS population can thus be divided into three subgroups: one subgroup showing focal spermatogenesis, a second having spermatogonia, and a third group in which no germ cells can be recovered. Further research is necessary to unravel the mechanism leading to these different patterns in patients with KS.
Asunto(s)
Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patología , Trastornos de los Cromosomas Sexuales/genética , Trastornos de los Cromosomas Sexuales/patología , Recuperación de la Esperma , Espermatogonias/patología , Espermatozoides/patología , Cariotipo XYY/genética , Cariotipo XYY/patología , Adulto , Antígenos de Neoplasias/análisis , Bélgica , Biomarcadores/análisis , Biopsia , Hospitales Universitarios , Humanos , Inmunohistoquímica , Síndrome de Klinefelter/metabolismo , Masculino , Proteínas de Neoplasias/análisis , Adhesión en Parafina , Estudios Retrospectivos , Trastornos de los Cromosomas Sexuales/metabolismo , Recuento de Espermatozoides , Espermatogénesis/genética , Espermatogonias/química , Espermatozoides/química , Vimentina/análisis , Cariotipo XYY/metabolismo , Adulto JovenRESUMEN
Autoimmune diseases appear to have multiple contributing factors including genetics, epigenetics, environmental factors, and aging. The predominance of females among patients with autoimmune diseases suggests possible involvement of the X chromosome and X chromosome inactivation. X chromosome inactivation is an epigenetic event resulting in multiple levels of control for modulation of the expression of X-linked genes in normal female cells such that there remains only one active X chromosome in the cell. The extent of this control is unique among the chromosomes and has the potential for problems when regulation is disrupted. Here we discuss the X chromosome inactivation process and how the X chromosome and X chromosome inactivation may be involved in development of autoimmune disorders.