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Fortea J.,Alzheimers Disease and Other Cognitive Disorders Unit | Llado A.,Alzheimers Disease and Other Cognitive Disorders Unit | Bosch B.,Alzheimers Disease and Other Cognitive Disorders Unit | Antonell A.,Alzheimers Disease and Other Cognitive Disorders Unit | And 3 more authors.
Neurodegenerative Diseases | Year: 2011

Background/Aims: Familial Alzheimer's disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total tau (t-tau) and phospho-tau181 (p-tau) levels in PSEN1 families and correlated the results with the genetic status, age and clinical stage. Methods: Thirteen subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) were recruited from the genetic counseling program for familial dementia. Eight mutation carriers (MC) and 5 noncarriers (NC) underwent clinical and cognitive evaluations. CSF concentrations were obtained by ELISA methodology. Results: Symptomatic MC presented reduced CSF Aβ1-42 (mean = 175 pg/ml) and elevated t-tau (mean = 635 pg/ml) compared to controls, but not asymptomatic MC (mean = 684 and 255 pg/ml, respectively) at a median of -12.8 years from the predicted disease onset (adjusted age). Aβ1-42 levels presented an inverse correlation with the adjusted age (r = -1, p < 0. 01) in asymptomatic MC, but not in symptomatic MC or NC. t-tau presented a trend towards a negative correlation with Mini Mental State Examination (MMSE; r = -0.949, p = 0.051) in symptomatic MC but not in asymptomatic MC. In the whole group of MC, t-tau presented a significant positive correlation with Clinical Dementia Rating sum of boxes (r = 0.913, p = 0.002) and a negative correlation with MMSE (r = -0.946, p < 0.001). Conclusions: CSF Aβ1-42 levels correlate with time to disease onset in asymptomatic MC to reach floor levels when symptoms appear. CSF t-tau levels become elevated in symptomatic MC and correlate with clinical severity. These findings may suggest that the changes in Aβ1-42 precede t-tau elevation in PSEN1 MC. Copyright © 2011 S. Karger AG, Basel.

Rodriguez-Revenga L.,CIBER ISCIII | Pagonabarraga J.,Neurology Service and Neuroradiology Unit | Pagonabarraga J.,CIBER ISCIII | Gomez-Anson B.,Neurology Service and Neuroradiology Unit | And 9 more authors.
Neurology | Year: 2010

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. Copyright © 2010 by AAN Enterprises, Inc.

Badenas C.,Biochemistry and Molecular Genetics Service | Badenas C.,University of Barcelona | Badenas C.,Institute Salud Carlos III ISCIII | Rodriguez-Revenga L.,Biochemistry and Molecular Genetics Service | And 22 more authors.
Journal of Molecular Diagnostics | Year: 2010

Quantitative fluorescent PCR (QF-PCR) has been used by many laboratories for prenatal diagnosis of the most common aneuploidies. QF-PCR is rapid, cost-effective, and suitable for automation and can detect most abnormalities diagnosed by conventional karyotyping. Whether QF-PCR should be used alone in most of the samples and in which karyotyping should also be offered is currently a topic of debate. We evaluated and compared the results obtained from 7679 prenatal samples in which conventional karyotype and QF-PCR had been performed, including 1243 chorionic villi and 6436 amniotic fluid samples. Concordant QF-PCR and karyotype results were obtained in 98.75% of the samples. An abnormal karyotype associated with adverse clinical outcome undetected by QF-PCR was found in 0.05% of samples. Therefore, QF-PCR can be used alone in a large number of samples studied in a prenatal laboratory, thereby reducing both the workload in cytogenetic laboratories and parental anxiety when awaiting results. Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology.

Rodriguez-Revenga L.,Biochemistry and Molecular Genetics Service | Rodriguez-Revenga L.,CIBER ISCIII | Rodriguez-Revenga L.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Pagonabarraga J.,Neurology Service | And 18 more authors.
Cerebellum | Year: 2016

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity. © 2016 Springer Science+Business Media New York

Jodar M.,University of Barcelona | Oliva R.,Biochemistry and Molecular Genetics Service | Oliva R.,University of Barcelona
Advances in Experimental Medicine and Biology | Year: 2014

Protamines are the major nuclear proteins in sperm cells, having a crucial role in the correct packaging of the paternal DNA. The fact that protamine haploinsufficiency in mice resulted in abnormal chromatin packaging and male infertility suggested that the protamines could also be important candidates in explaining some of the idiopathic male infertility cases in humans. The first clinical studies focused on analyzing protamines at the protein level. Various studies have found the presence of an altered amount of protamines in some infertile patients, in contrast to the normal situation in fertile individuals where the two protamines, protamine 1 and protamine 2, are both present in approximately equal quantities. Subsequently, the protamine genes were the subject of various mutational genetic screening studies in search of variants that could be associated with deregulation in the protamine expression observed. The results of these protamine mutational studies showed that the presence of high penetrant mutations is a very rare cause of male infertility. However, some variants and some haplotypes described may behave as risk factors for male infertility. More recently, the presence of RNA in the mature sperm cell has also been investigated. The present chapter will introduce the basic aspects of protamine evolution and function and review the various articles published to date on the relationship between the protamines studied at the DNA, RNA, and protein levels and male infertility. © 2014 Springer Science+Business Media New York.

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