Motor and mental dysfunction in mother-daughter transmitted FXTAS.

OBJECTIVES: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neuropsychiatric degenerative disorder that occurs predominantly in male FMR1 premutation carriers. Recently, a broader FXTAS spectrum that, besides the core features of tremor and gait ataxia, also includes neuropsychiatric symptoms and neuropathy as further clinically relevant symptoms has been described among females. Herein 2 fragile X syndrome families with a mother-daughter FXTAS transmission are described in detail in order to shed more light on the female FXTAS phenotype. METHODS: Molecular characterization included CGG repeat length, X-chromosome inactivation pattern determination, as well as FMR1 mRNA and FMRP levels quantification. Neuroradiologic examination was performed by 3-T MRI. Neuropsychological assessment included global cognitive, attention, and executive prefrontal functions, verbal fluencies, verbal memory, and visuospatial perception. RESULTS: Molecular, neurologic, neuropsychiatric, psychological, cognitive, and neuroradiologic features description of 2 fragile X syndrome families with a mother-daughter FXTAS transmission in which dementia is present in both mothers. CONCLUSIONS: Although it is not yet clear to what extent FXTAS shortens lifespan, our findings show that FXTAS progresses from mild tremor and/or ataxia to disabling motor and cognitive impairment, compromising the patients' quality of life. Furthermore, our results show that FXTAS in women can also develop as a multisystem neurodegenerative disorder with central and peripheral nervous system involvement, and both motor and mental disturbances.

Estudio de reordenamientos subteloméricos en 300 pacientes con retraso mental y anomalías congénitas múltiples: caracterización clínica y molecular / A study of subtelomeric rearrangements in 300 patients with mental retardation and multiple congenital

Introducción. El estudio del retraso mental es uno de los campos más complejos de la genética humana debido a la alta heterogeneidad clínica y genética que presenta. De ahí que actualmente casi un 50% de los casos permanezca sin diagnosticar. Aproximadamente, un 6-10% de los casos de retraso mental inespecífico se debe a microdeleciones o microduplicaciones en regiones subteloméricas de los cromosomas. Algunos de estos síndromes confieren un fenotipo clínicamente reconocible, como es el caso del síndrome 1p36 o la microdeleción 22q13.33, pero otros afectan a pocos pacientes y son todavía poco reconocidos. Pacientes y métodos. Se ha analizado a 300 pacientes afectados de retraso mental para reordenamientos de las regiones subteloméricas mediante una técnica sencilla, rápida y poco costosa como es la amplificación múltiple dependiente de ligación (MLPA). Resultados. Un 5,3% de los pacientes presentaron reordenamientos subteloméricos; el 75% de los casos corresponde a casos de novo, el 18,7% fueron heredados de alguno de los dos progenitores. En 14 casos las alteraciones detectadas pudieron considerarse como causantes del fenotipo que presentaban los pacientes, y en dos casos, como posibles polimorfismos. Conclusiones. Se confirma la elevada frecuencia de reordenamientos subteloméricos como causa de retraso mental y se refuerza la idea de analizar de forma rutinaria las regiones subteloméricas para llegar a un diagnóstico, establecer una correlación genotipo-fenotipo detallada y poder ofrecer un consejo genético adecuado (AU)

Introduction. The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of cases are due to subtelomeric rearrangements. Some of these are responsible for a clinically recognized phenotype, i.e. 1p36 or 22q13.33 microdeletion syndromes, but others affect few patients and are not well characterized. Patients and methods. We have analyzed 300 consecutive mentally retarded patients for subtelomeric rearrangements by MLPA. Results. About 5.3% of patients presented subtelomeric rearrangements; from these, 75% contained de novo rearrangements and 18.7% included inherited aberrations from a healthy parent. In 14 cases, aberrations were likely related to disease and in two cases were putative polymorphisms. Conclusions. This study confirms the high frequency of subtelomeric rearrangements in mental retardation and reinforces the idea of a routine subtelomeric screening in these patients in order to get a correct diagnosis, establish genotypephenotype correlations and offer an accurate genetic counseling (AU)

Fragile X syndrome prenatal diagnosis: parental attitudes and reproductive responses.

Fragile X syndrome (FXS) is the most common inherited form of mental retardation. It is caused by a CGG repeat expansion, which results in hypermethylation and silencing of the FMR1 gene. The results from 213 FXS prenatal diagnoses performed in the study centre were reviewed. Family history of FXS or undiagnosed mental retardation (MR) were the reasons for referral and 64% of mothers were not aware of their status so prenatal and mother tests were performed at the same time. Among those women referred for family history of unknown MR, 17.6% were found to be FXS carriers. The attitudes and perceptions of the syndrome of 52 FXS carriers were also evaluated. Most of them had been diagnosed as carriers when the child was already born and the most common feeling was sadness, followed by impotence and guilt. The majority of them had received genetic counselling and they considered it useful. Regarding reproductive options, prenatal diagnosis was chosen by 40.5% of women. Prenatal diagnosis for FXS is a good reproductive option and it should be carried out whenever family history of MR is present. A high percentage of FXS carriers are detected following this approach.

Induction of complete and incomplete chromosome aberrations by bleomycin in human lymphocytes.

Bleomycin (BLM) is a clastogenic compound, which due to the overdispersion in the cell distribution of induced dicentrics has been compared to the effect of high-LET radiation. Recently, it has been described that in fibroblast derived cell lines BLM induces incomplete chromosome elements more efficiently than any type of ionizing radiation. The objective of the present study was to evaluate in human lymphocytes the induction of dicentrics and incomplete chromosome elements by BLM. Peripheral blood samples have been treated with different concentrations of BLM. Two cytogenetic techniques were applied, fluorescence plus Giemsa (FPG) and FISH using pan-centromeric and pan-telomeric probes. The observed frequency of dicentric equivalents increases linearly with the BLM concentration, and for all BLM concentrations the distribution of dicentric equivalents was overdispersed. In the FISH study the ratio between total incomplete elements and multicentrics was 0.27. The overdispersion in the dicentric cell distribution, and the linear BLM-concentration dependence of dicentrics can be compared to the effect of high-LET radiation, on the contrary the ratio of incomplete elements and multicentrics is similar to the one induced by low-LET radiation (~0.40). The elevated proportion of interstitial deletions in relation to total acentric fragments, higher than any type of ionizing radiation could be a characteristic signature of the clastogenic effect of BLM.