Publications (26)106.99 Total impact
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Article: Distinctive age-related temporal cortical thinning in asymptomatic granulin gene mutation carriers.
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ABSTRACT: Studies in asymptomatic granulin gene (GRN) mutation carriers are essential to improve our understanding of the pattern and timing of early morphologic brain changes in frontotemporal lobar degeneration. The main objectives of this study were to assess the effect of age in cortical thickness changes (CTh) in preclinical GRN mutation carriers and to study the relationship of CTh with cognitive performance in GRN mutation carriers. We calculated CTh maps in 13 asymptomatic carriers of the c.709-1G>A GRN mutation and 13 age- and sex-matched healthy subjects. Asymptomatic GRN mutation carriers presented different patterns of age-related cortical thinning in the right superior temporal and middle temporal gyri and the banks of the superior temporal sulcus bilaterally when compared with controls. Cortical thickness was correlated with neuropsychological test scores: Trail Making Tests A and B, and the Boston Naming Test. Distinctive age-related cortical thinning in asymptomatic GRN mutation carriers in lateral temporal cortices suggests an early and disease-specific effect in these areas.Neurobiology of aging 12/2012; · 5.94 Impact Factor -
Article: Neuropsychological Features of Asymptomatic c.709-1G>A Progranulin Mutation Carriers.
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ABSTRACT: Mutations in the progranulin (PGRN) gene have been identified as a cause of frontotemporal dementia (FTD). However, little is known about the neuropsychological abilities of asymptomatic carriers of these mutations. The aim of the study was to assess cognitive functioning in asymptomatic c.709-1G>A PGRN mutation carriers. We hypothesized that poorer neuropsychological performance could be present before the development of clinically significant FTD symptoms. Thirty-two asymptomatic first-degree relatives of FTD patients carrying the c.709-1G>A mutation served as study participants, including 13 PGRN mutation carriers (A-PGRN+) and 19 non-carriers (PGRN-). A neuropsychological battery was administered. We found that the A-PGRN+ participants obtained significantly poorer scores than PGRN- individuals on tests of attention (Trail-Making Test Part A), mental flexibility (Trail-Making Test Part B), and language (Boston Naming Test). Poorer performance on these tests in asymptomatic PGRN mutation carriers may reflect a prodromal phase preceding the onset of clinically significant symptoms of FTD. (JINS, 2012, 18, 1086-1090).Journal of the International Neuropsychological Society 11/2012; 18(6):1086-90. · 2.76 Impact Factor -
Article: C3KO mouse expression analysis: downregulation of the muscular dystrophy Ky protein and alterations in muscle aging.
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ABSTRACT: Mutations in CAPN3 gene cause limb-girdle muscular dystrophy type 2A (LGMD2A) characterized by muscle wasting and progressive degeneration of scapular and pelvic musculature. Since CAPN3 knockout mice (C3KO) display features of muscle pathology similar to those features observed in the earliest-stage or preclinical LGMD2A patients, gene expression profiling analysis in C3KO mice was performed to gain insight into mechanisms of disease. Two different comparisons were carried out in order to determine, first, the differential gene expression between wild-type (WT) and C3KO soleus and, second, to identify the transcripts differentially expressed in aging muscles of WT and C3KO mice. The up/downregulation of two genes, important for normal muscle function, was identified in C3KO mice: the Ky gene, encoding a protease implicated in muscle development, and Park2 gene encoding an E3 ubiquitin ligase (parkin). The Ky gene was downregulated in C3KO muscles suggesting that Ky protease may play a complementary role in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity. Park2 was upregulated in the aged WT muscles but not in C3KO muscles. Taking into account the known functions of parkin E3 ligase, it is possible that it plays a role in ubiquitination and degradation of atrophy-specific and damaged proteins that are necessary to avoid cellular toxicity and a cellular stress response in aging muscles.Neurogenetics 07/2012; 13(4):347-57. · 3.35 Impact Factor -
Article: Inactivation of CDK/pRb pathway normalizes survival pattern of lymphoblasts expressing the FTLD-progranulin mutation c.709-1G>A.
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ABSTRACT: Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP.PLoS ONE 01/2012; 7(5):e37057. · 4.09 Impact Factor -
Article: [Abdominal pain and wall distension as the onset form of neuroborreliosis].
Medicina Clínica 11/2011; 138(13):591-2. · 1.38 Impact Factor -
Article: Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations?
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ABSTRACT: Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported. We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation. The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain-3, suggesting "molecular complementation" in these patients. We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain-3, resulting in an exceptionally benign phenotype.Muscle & Nerve 11/2011; 44(5):710-4. · 2.37 Impact Factor -
Article: Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia.
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ABSTRACT: Dystonias are a clinically and genetically heterogeneous group of movement disorders characterized by involuntary, sustained muscular contractions affecting one or more sites of the body, and abnormal postures. In this study, we describe an autosomal recessive family that presents with a progressive and early-onset form of generalized dystonia. The nuclear family consists of two healthy parents and two affected daughters. To elucidate the genetic causes underlying disease, whole-exome sequencing analysis was performed in one affected sibling, followed by validation, biochemical analyses and MRI brain imaging. A homozygous, disease-segregating mutation (p.Val400Met) was identified in the glutaryl-CoA dehydrogenase (GCDH) gene at chromosome 19p13. The mutation, in an amino acid that is highly conserved among species, was absent in large number of neurologically normal individuals. Biochemical analyses demonstrated increased 3-hydroxy glutaric acid present in urine samples from both patients. MRI imaging revealed a T2 and flair hyperintense signal in lenticular nuclei with bilateral and symmetrical distribution. We conclude that both GCDH activity and GCDH mutation analysis should be considered in the differential diagnosis of progressive forms of early-onset generalized dystonia and that mitochondrial fatty acid metabolism is one important pathway in the development of dystonia. As lysine restriction and L: -carnitine supplementation are important treatments for GCDH deficiency, identification of this deficiency in patients with progressive forms of early-onset generalized dystonia has potential treatment implications.Human Genetics 09/2011; 131(3):435-42. · 5.07 Impact Factor -
Article: Olfactory deficits and cardiac 123I-MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations.
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ABSTRACT: It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I-metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac (123) I-metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty-six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty-six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2.Movement Disorders 05/2011; 26(11):2026-31. · 4.51 Impact Factor -
Article: [Parkinsonism induced by sulpiride and veralipride: two different stories].
Medicina Clínica 02/2011; 137(10):473-4. · 1.38 Impact Factor -
Article: Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia.
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ABSTRACT: Frontotemporal lobar degeneration with neuronal inclusions containing TAR DNA binding protein 43 (TDP-43) is associated in most cases with null-mutations in the progranulin gene (PGRN). While the mechanisms by which PGRN haploinsufficiency leads to neurodegeneration remained speculative, increasing evidence support the hypothesis that cell cycle reentry of postmitotic neurons precedes many instances of neuronal death. Based in the mitogenic and neurotrophic activities of PGRN, we hypothesized that PGRN deficit may induce cell cycle disturbances and alterations in neuronal vulnerability. Because cell cycle dysfunction is not restricted to neurons, we studied the influence of PGRN haploinsufficiency, on cell cycle control in peripheral cells from patients suffering from frontotemporal dementia, bearing the PGRN mutation c.709-1G>A. Here we show that progranulin deficit increased cell cycle activity in immortalized lymphocytes. This effect was associated with increased levels of cyclin-dependent kinase 6 (CDK6) and phosphorylation of retinoblastoma protein (pRb), resulting in a G(1)/S regulatory failure. A loss of function of TDP-43 repressing CDK6 expression may result from altered subcellular TDP-43 distribution. The distinct functional features of lymphoblastoid cells from c.709-1 G>A carriers offer an invaluable, noninvasive tool to investigate the etiopathogenesis of frontotemporal lobar degeneration.Neurobiology of aging 01/2011; 33(2):429.e7-20. · 5.94 Impact Factor -
Article: Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain).
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ABSTRACT: The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson's disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counseling. A total of 59 sibships containing 244 individuals, with a total of 40 PD-affected relatives, were studied. Genetic testing for the R1441G mutation in the LRRK2 gene was performed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differences were found in penetrance.Movement Disorders 10/2010; 25(14):2340-5. · 4.51 Impact Factor -
Article: A novel PRNP Y218N mutation in Gerstmann-Sträussler-Scheinker disease with neurofibrillary degeneration.
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ABSTRACT: Gerstmann-Sträussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase K-resistant prion protein (PrP(res)), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrP deposits, and expression of mutant ubiquitin (UBB(+1)) in neurofibrillary tangles and dystrophic neurites. Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease andresembles those reported in other GSS cases. The approximately 10kd band was recognized with anti-PrP C-terminus antibodies but not with anti-N terminus antibodies, suggesting PrP truncation at the N terminal. This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical heterogeneity. Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.Journal of Neuropathology and Experimental Neurology 08/2010; 69(8):789-800. · 4.26 Impact Factor -
Article: Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2.
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ABSTRACT: We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G-LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without alpha-synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2.Movement Disorders 10/2009; 24(13):1998-2001. · 4.51 Impact Factor -
Article: Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget's disease of bone and frontotemporal dementia.
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ABSTRACT: We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Paget's disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Paget's disease or cognitive impairment.Neuromuscular Disorders 05/2009; 19(5):316-23. · 2.80 Impact Factor -
Article: Differential micro RNA expression in PBMC from multiple sclerosis patients.
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ABSTRACT: Differences in gene expression patterns have been documented not only in Multiple Sclerosis patients versus healthy controls but also in the relapse of the disease. Recently a new gene expression modulator has been identified: the microRNA or miRNA. The aim of this work is to analyze the possible role of miRNAs in multiple sclerosis, focusing on the relapse stage. We have analyzed the expression patterns of 364 miRNAs in PBMC obtained from multiple sclerosis patients in relapse status, in remission status and healthy controls. The expression patterns of the miRNAs with significantly different expression were validated in an independent set of samples. In order to determine the effect of the miRNAs, the expression of some predicted target genes of these were studied by qPCR. Gene interaction networks were constructed in order to obtain a co-expression and multivariate view of the experimental data. The data analysis and later validation reveal that two miRNAs (hsa-miR-18b and hsa-miR-599) may be relevant at the time of relapse and that another miRNA (hsa-miR-96) may be involved in remission. The genes targeted by hsa-miR-96 are involved in immunological pathways as Interleukin signaling and in other pathways as wnt signaling. This work highlights the importance of miRNA expression in the molecular mechanisms implicated in the disease. Moreover, the proposed involvement of these small molecules in multiple sclerosis opens up a new therapeutic approach to explore and highlight some candidate biomarker targets in MS.PLoS ONE 02/2009; 4(7):e6309. · 4.09 Impact Factor -
Article: [DNA arrays: a general overview and specific applications].
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ABSTRACT: Difficulties derived from the big complexity of the human genome (because of the great amount of genes) and difficulties at the time of performing a correct molecular diagnosis have led to the utilization of advanced technologies such as DNA arrays. By this technique, it is possible to analyze in a single experiment great sequences of genomic regions, to detect mutations or polymorphisms (characteristic of each individual), and to analyze variations in the expression of genes implicated in different disorders or in the utilization of drugs. Similarly, the use of DNA arrays-derived information has led to a considerable advance in the personalized medicine that is applied to every patient, avoiding unwanted adverse effects and the consecution of the best performance effectiveness for each drug.Medicina Clínica 05/2008; 130(13):504-9. · 1.38 Impact Factor -
Article: Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings.
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ABSTRACT: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.Biological psychiatry 05/2008; 63(10):946-52. · 8.93 Impact Factor -
Article: Gene expression profiling in limb-girdle muscular dystrophy 2A.
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ABSTRACT: Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that beta-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies.PLoS ONE 02/2008; 3(11):e3750. · 4.09 Impact Factor -
Article: Parkinson's disease due to the R1441G mutation in Dardarin: a founder effect in the Basques.
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ABSTRACT: The recent discovery of mutations in Dardarin (LRRK2) have been related to the appearance of Parkinson's disease in several families. Notably, one single mutation in this gene (R1441G) not only appeared in familial, but also in apparently sporadic Parkinson disease (PD) patients of Basque descent. A clinical population was ascertained, and subjects were classified into Basque and non-Basque descent according to their known ancestry. The R1441G mutation was assayed using an allele-specific polymerase chain reaction, and several single nucleotide polymorphisms surrounding this mutation were analyzed by direct sequencing. In addition to 22 members of the original Basque families where R1441G was identified, we observed 17 carriers of the mutation who were apparently related through a common ancestor. From a clinical perspective, the disease observed in mutation carriers is indistinguishable from that in noncarriers. The R1441G mutation causes a form of Parkinson's disease that is equivalent to that observed in idiopathic Parkinson's disease. This mutation appears in 16.4% and 4.0% of familial and sporadic PD in this Basque population, respectively.Movement Disorders 12/2006; 21(11):1954-9. · 4.51 Impact Factor -
Article: A neonatal form of Steinert's myotonic dystrophy in twins after in vitro fertilization.
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ABSTRACT: To report a case of nonidentical twins affected with a congenital form of Steinert's myotonic dystrophy (DM1), conceived by IVF owing to parental sterility, in which the mother presented a paucisymptomatic form of DM1 which was diagnosed as a result of the condition inherited by the twins. Case report. Neonatal intensive care unit of a tertiary hospital. Newborn twins affected with the congenital form of DM1 and a 35-year-old nulliparous mother. In vitro fertilization. Molecular study of the CTG triplet expansion related with DM1. Molecular study evidenced a pathologic expansion in both twins as well as in their mother. This case should serve as a reminder to practitioners that assisted reproductive techniques have opened the possibility that asymptomatic or paucisymptomatic carriers of a genetic syndrome can inadvertently conceive fetuses affected with more serious forms of the illness.Fertility and sterility 10/2005; 84(3):756. · 3.97 Impact Factor
Top co-authors
Top Journals
- Medicina Clínica (3)
- Movement Disorders (3)
- PLoS ONE (3)
- Thérapie (2)
- Neurobiology of aging (2)
Institutions
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2002–2012
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Hospital Universitario Donostia
San Sebastián, Basque Country, Spain
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2009
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Biodonostia Institute
San Sebastián de los Reyes, Madrid, Spain
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