Publications by authors named "Ivonne Jericó"

23 Publications

  • Page 1 of 1

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis.

Eur J Neurol 2021 Mar 15. Epub 2021 Mar 15.

Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Background And Purpose: Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG.

Methods: This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18 years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed.

Results: We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95-4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15-2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43-3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47-4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up.

Conclusions: Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.
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http://dx.doi.org/10.1111/ene.14820DOI Listing
March 2021

Clinical features and incidence trends of amyotrophic lateral sclerosis in Navarre, Spain, 2007-2018: a population-based study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Feb 27:1-9. Epub 2021 Feb 27.

Department of Health Sciences, Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.

: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder with a median survival of 3 years. The aim of our study is to analyze the incidence, age-related phenotype and clinical onset, geographical distribution, survival and diagnostic delay of ALS in Navarre. : This is a population-based observational retrospective study, including all residents of Navarre (a northern Spanish region) from 2007 to 2018, who were followed until 30th September 2020. : We observed a global incidence 2.47/100,000 person-years, with an upward trend throughout the study, with the highest being in the age group of 70-74 years old. Point prevalence in December 2018 was 6.64/100,000 inhabitants (95%CI: 4.52-8.45). Upper limbs weakness onset was the most frequent in young people (<60 years), and bulbar, lower limbs weakness, generalized and respiratory associated with older age. Bulbar phenotype is the most frequent in women and in 80+ group. The median survival from clinical onset was 27.7 months (95%CI: 24.0-31.4), higher in spinal phenotype and younger onset age, and the diagnosis delay was 10.0 months (95%CI: 8.9-11.2) from clinical onset. : We have observed a trend of increasing incidence in older people where the bulbar phenotype and female predominance.
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http://dx.doi.org/10.1080/21678421.2021.1891249DOI Listing
February 2021

Novel PLEKHG5 mutations in a patient with childhood-onset lower motor neuron disease.

Ann Clin Transl Neurol 2021 01 4;8(1):294-299. Epub 2020 Dec 4.

Neurology Department, Complejo Universitario de Navarra, IdisNa, Navarra, 31008, Spain.

The PLEKHG5 gene encodes a protein that activates the nuclear factor kappa B (NFκB) signaling pathway. Mutations in this gene have been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both with an autosomal recessive mode of inheritance. Two families with low motor neuron disease (LMND) caused by mutations in PLEKHG5 have been reported to date. We present a third LMND family, the first nonconsanguineous, due to two not previously reported PLEKHG5 mutations. Our results confirm and extend previous findings linking PLEKHG5 mutations to lower motor neuron diseases.
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http://dx.doi.org/10.1002/acn3.51265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818229PMC
January 2021

Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.

Genes (Basel) 2020 05 11;11(5). Epub 2020 May 11.

Genetics Department Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain.

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as , and We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.
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http://dx.doi.org/10.3390/genes11050539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288461PMC
May 2020

Clinical and therapeutic features of myasthenia gravis in adults based on age at onset.

Neurology 2020 03 18;94(11):e1171-e1180. Epub 2020 Feb 18.

From the Neuromuscular Diseases Unit, Department of Neurology (E.C.-V., R.Á.-V., R.R.-G., J.D.-M., L.Q., E.G., I.I.), Hospital de la Santa Creu i Sant Pau; Department of Medicine (E.C.-V., R.Á.-V., I.I.), Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.C.-V., R.Á.-V., S.S., C.C., T.S., R.R.-G., J.D.-M., L.Q., E.G., I.I.) and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (C.P., A.L.d.M., A.L.P.-N.), Instituto de Salud Carlos III, Madrid; Neurology Department (C.P., B.V.), Neuromuscular Disorders Unit, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, CSIC, Universidad de Sevilla; Unitat de Neuromuscular (C.C., M.A.A.), Neurology Department, Hospital Universitari de Bellvitge-IDIBELL, l'Hospitalet de Llobregat, Barcelona; Neuromuscular Diseases Unit (A.-G.S., L.G.), Department of Neurology, Institute of Neurosciences, Hospital Universitario Clínico San Carlos, Madrid; Neurology Department (J.P., T.G.-S.), Hospital Clínico, Santiago de Compostela; Neuromuscular Diseases Unit (A.R.-F., A.M.-P.), Department of Neurology, Hospital Germans Trias i Pujol; Department of Medicine (A.R.-F.), Universitat Autònoma de Barcelona, Badalona; Neuromuscular Unit (T.S., A.L.-M.), Neurology Department, Hospital Universitari i Politècnic La Fe; Department of Medicine (T.S.), Universitat de València; Neurology Department (A.L.d.M., A.F.-T.), Donostia University Hospital; Neurosciences Area (A.L.d.M.), Biodonostia Research Institute, University of the Basque Country, San Sebastián; Neurology Department (M.T.G.), Hospital Universitario Reina Sofía, Córdoba; Department of Neurology (I.J.), Complejo Hospitalario de Navarra, Pamplona; Neuromuscular Diseases Unit (G.G.-G.), Department of Neurology, Hospital Universitario Infanta Sofía, Universidad Europea de Madrid, San Sebastián de los Reyes, Madrid; Complejo asistencial hospitalario de Burgos (M.A.M.), Burgos; Hospital Universitario de Gran Canaria Doctor Negrín (M.D.M.), Las Palmas de Gran Canaria; Hospital Central de Asturias (G.M.), Oviedo; and Service of Neurology (A.L.P.-N., Á.C.-A.), University Hospital "Marqués de Valdecilla (IDIVAL)," University of Cantabria, Santander, Spain.

Objective: To describe the characteristics of patients with very-late-onset myasthenia gravis (MG).

Methods: This observational cross-sectional multicenter study was based on information in the neurologist-driven Spanish Registry of Neuromuscular Diseases (NMD-ES). All patients were >18 years of age at onset of MG and onset occurred between 2000 and 2016 in all cases. Patients were classified into 3 age subgroups: early-onset MG (age at onset <50 years), late-onset MG (onset ≥50 and <65 years), and very-late-onset MG (onset ≥65 years). Demographic, immunologic, clinical, and therapeutic data were reviewed.

Results: A total of 939 patients from 15 hospitals were included: 288 (30.7%) had early-onset MG, 227 (24.2%) late-onset MG, and 424 (45.2%) very-late-onset MG. The mean follow-up was 9.1 years (SD 4.3). Patients with late onset and very late onset were more frequently men ( < 0.0001). Compared to the early-onset and late-onset groups, in the very-late-onset group, the presence of anti-acetylcholine receptor (anti-AChR) antibodies ( < 0.0001) was higher and fewer patients had thymoma ( < 0.0001). Late-onset MG and very-late-onset MG groups more frequently had ocular MG, both at onset (<0.0001) and at maximal worsening ( = 0.001). Although the very-late-onset group presented more life-threatening events (Myasthenia Gravis Foundation of America IVB and V) at onset ( = 0.002), they required fewer drugs ( < 0.0001) and were less frequently drug-refractory ( < 0.0001).

Conclusions: Patients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly.
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http://dx.doi.org/10.1212/WNL.0000000000008903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220233PMC
March 2020

Epidemiological study and genetic characterization of inherited muscle diseases in a northern Spanish region.

Orphanet J Rare Dis 2019 12 2;14(1):276. Epub 2019 Dec 2.

Department of Neurology, Complejo Hospitalario de Navarra, IdiSNA (Navarre Institute for Health Research), Pamplona, Spain.

Background: Inherited muscle diseases are a group of rare heterogeneous muscle conditions with great impact on quality of life, for which variable prevalence has previously been reported, probably due to case selection bias. The aim of this study is to estimate the overall and selective prevalence rates of inherited muscle diseases in a northern Spanish region and to describe their demographic and genetic features. Retrospective identification of patients with inherited muscle diseases between 2000 and 2015 from multiple data sources. Demographic and molecular data were registered.

Results: On January 1, 2016, the overall prevalence of inherited muscle diseases was 59.00/ 100,000 inhabitants (CI 95%; 53.35-65.26). Prevalence was significantly greater in men (67.33/100,000) in comparison to women (50.80/100,000) (p = 0.006). The highest value was seen in the age range between 45 and 54 (91.32/100,000) years. Myotonic dystrophy type 1 was the most common condition (35.90/100,000), followed by facioscapulohumeral muscular dystrophy (5.15/100,000) and limb-girdle muscular dystrophy type 2A (2.5/100,000).

Conclusions: Prevalence of inherited muscle diseases in Navarre is high in comparison with the data reported for other geographical regions. Standard procedures and analyses of multiple data sources are needed for epidemiological studies of this heterogeneous group of diseases.
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http://dx.doi.org/10.1186/s13023-019-1227-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889463PMC
December 2019

A novel mutation in the mitochondrial MT-ND5 gene in a family with MELAS. The relevance of genetic analysis on targeted tissues.

Mitochondrion 2020 01 19;50:14-18. Epub 2019 Oct 19.

Department of Neurology, Hospital Universitario, 12 de Octubre, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Department of Neurology, Neuromuscular Disorders Unit, Hospital Universitario, 12 de Octubre, Madrid, Spain. Electronic address:

We report the case of two members of the same family with a novel mitochondrial DNA (mtDNA) gene variant in the MT-ND5 gene associated with MELAS syndrome and discuss limitations of genetics studies. The m.13045A > G mutation was detected at very low load in the daughter's urine cells (5%) and at different levels in the skeletal muscle of both mother (50%) and daughter (84%), being absent in blood, hair and saliva. Our findings suggest that non-invasive genetic assessment in urine cells may not be a sensitive diagnostic method neither a good predictor of disease development in relatives of some families with mtDNA-associated MELAS, particularly if involving MT-ND5 gene.
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http://dx.doi.org/10.1016/j.mito.2019.10.001DOI Listing
January 2020

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

Mov Disord 2019 10 21;34(10):1547-1561. Epub 2019 Aug 21.

Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.

Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.

Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.

Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).

Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27812DOI Listing
October 2019

DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis.

Clin Epigenetics 2019 06 19;11(1):91. Epub 2019 Jun 19.

Neuroepigenetics Laboratory, Navarrabiomed, Public University of Navarre (UPNA), IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, 31008, Pamplona, Spain.

Background: Drawing the epigenome landscape of Alzheimer's disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays.

Results: Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs.

Conclusions: These results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.
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http://dx.doi.org/10.1186/s13148-019-0672-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585076PMC
June 2019

Hippocampal Gene Expression is Increased in Late-Stage Alzheimer's Disease.

Int J Mol Sci 2019 Feb 18;20(4). Epub 2019 Feb 18.

Neuroepigenetics Laboratory-Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra (UPNA), IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra 31008, Spain.

Lamins are fibrillary proteins that are crucial in maintaining nuclear shape and function. Recently, B-type lamin dysfunction has been linked to tauopathies. However, the role of A-type lamin in neurodegeneration is still obscure. Here, we examined A-type and B-type lamin expression levels by RT-qPCR in Alzheimer's disease (AD) patients and controls in the hippocampus, the core of tau pathology in the brain. , and genes showed moderate mRNA levels in the human hippocampus with highest expression for the gene. Moreover, mRNA levels were increased at the late stage of AD (1.8-fold increase; -value < 0.05). In addition, a moderate positive correlation was found between age and mRNA levels (Pearson's = 0.581, -value = 0.018) within the control hippocampal samples that was not present in the hippocampal samples affected by AD. A-type and B-type lamin genes are expressed in the human hippocampus at the transcript level. mRNA levels are up-regulated in the hippocampal tissue in late stages of AD. The effect of age on increasing expression levels in control samples seems to be disrupted by the development of AD pathology.
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http://dx.doi.org/10.3390/ijms20040878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413092PMC
February 2019

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease.

Med Clin (Barc) 2019 07 24;153(2):82.e1-82.e17. Epub 2019 Jan 24.

Servicio de Neurología, Hospital Universitario 12 de Octubre, Madrid, España.

Background And Objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1.

Material And Methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide.

Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives.

Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.
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http://dx.doi.org/10.1016/j.medcli.2018.10.028DOI Listing
July 2019

Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

Int J Mol Sci 2018 Dec 20;20(1). Epub 2018 Dec 20.

Department of Neurology ComplejoHospitalario de Navarra (CHN), IdiSNA (Navarra Institute for Health Research), Irunlarrea 3, 31008 Pamplona, Spain.

(1) Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with an overlap in clinical presentation and neuropathology. Common and differential mechanisms leading to protein expression changes and neurodegeneration in ALS and FTD were studied trough a deep neuroproteome mapping of the spinal cord. (2) Methods: A liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the spinal cord from ALS-TAR DNA-binding protein 43 () subjects, ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) subjects and controls without neurodegenerative disease was performed. (3) Results: 281 differentially expressed proteins were detected among ALS versus controls, while 52 proteins were dysregulated among FTLD-U versus controls. Thirty-three differential proteins were shared between both syndromes. The resulting data was subjected to network-driven proteomics analysis, revealing mitochondrial dysfunction and metabolic impairment, both for ALS and FTLD-U that could be validated through the confirmation of expression levels changes of the Prohibitin () complex. (4) Conclusions: ALS-TDP-43 and FTLD-U share molecular and functional alterations, although part of the proteostatic impairment is region- and disease-specific. We have confirmed the involvement of specific proteins previously associated with ALS (Galectin 2 (), Transthyretin (), Protein S100-A6 (), and Protein S100-A11 ()) and have shown the involvement of proteins not previously described in the ALS context (Methanethiol oxidase (), Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (), Calcyclin-binding protein () and Rho-associated protein kinase 2 ()).
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http://dx.doi.org/10.3390/ijms20010004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337647PMC
December 2018

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis.

Neurodegener Dis 2018 22;18(4):208-215. Epub 2018 Aug 22.

Department of Neurology, Complejo Hospitalario de Navarra-IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.

Background: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential.

Objective: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers.

Methods: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory -biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects.

Results: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme.

Conclusions: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.
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http://dx.doi.org/10.1159/000490920DOI Listing
January 2019

Liquid biopsy: a new source of candidate biomarkers in amyotrophic lateral sclerosis.

Ann Clin Transl Neurol 2018 Jun 16;5(6):763-768. Epub 2018 Apr 16.

Department of Neurology Complejo Hospitalario de Navarra IdiSNA (Navarra Institute for Health Research) Pamplona Spain.

Noninvasive tests to diagnose and monitor the progression of neurodegenerative disorders have been a challenge for decades. The aim of this study was to explore the feasibility of applying liquid biopsy procedures to patients with a neurodegenerative disease such as amyotrophic lateral sclerosis (ALS). We isolated plasma cell-free DNA (cfDNA) in 20 ALS patients and 20 controls and used cfDNA to identify a novel differentially methylated mark in gene in ALS patients compared to controls. Our findings support the notion that liquid biopsy may be applied to living patients as a source of potential epigenetic biomarkers for neurodegenerative disorders.
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http://dx.doi.org/10.1002/acn3.565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989775PMC
June 2018

Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2.

Hum Mol Genet 2015 Feb 25;24(3):659-69. Epub 2014 Sep 25.

Department of Human Genetics.

Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1-10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1-6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7-10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD.
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http://dx.doi.org/10.1093/hmg/ddu486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291246PMC
February 2015

Expanding the clinical phenotypes of MT-ATP6 mutations.

Hum Mol Genet 2014 Dec 30;23(23):6191-200. Epub 2014 Jun 30.

Departamento de Bioquímica, Biología Molecular y Celular, Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain, Centro de Investigaciones Biomédicas en red de Enfermedades Raras (CIBERER), Spain,

Mitochondrial DNA mutations at MT-ATP6 gene are relatively common in individuals suffering from striatal necrosis syndromes. These patients usually do not show apparent histochemical and/or biochemical signs of oxidative phosphorylation dysfunction. Because of this, MT-ATP6 is not typically analyzed in many other mitochondrial disorders that have not been previously associated to mutations in this gene. To correct this bias, we have performed a screening of the MT-ATP6 gene in a large collection of patients suspected of suffering different mitochondrial DNA (mtDNA) disorders. In three cases, biochemical, molecular-genetics and other analyses in patient tissues and cybrids were also carried out. We found three new pathologic mutations. Two of them in patients showing phenotypes that have not been commonly associated to mutations in the MT-ATP6 gene. These results remark the importance of sequencing the MT-ATP6 gene in patients with striatal necrosis syndromes, but also within other mitochondrial pathologies. This gene should be sequenced at least in all those patients suspected of suffering an mtDNA disorder disclosing normal results for histochemical and biochemical analyses of respiratory chain.
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http://dx.doi.org/10.1093/hmg/ddu339DOI Listing
December 2014

Analysis of the C9orf72 gene in patients with amyotrophic lateral sclerosis in Spain and different populations worldwide.

Hum Mutat 2013 Jan 11;34(1):79-82. Epub 2012 Oct 11.

Department of Neurology, ALS Unit, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.
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http://dx.doi.org/10.1002/humu.22211DOI Listing
January 2013

Myasthenia gravis: sleep quality, quality of life, and disease severity.

Muscle Nerve 2012 Aug;46(2):174-80

Department of Neurology, Complejo Hospitalario de Navarra, Irunlarrea Street, 3, 31008 Pamplona, Spain.

Introduction: There is much research on quality of life in myasthenia gravis (MG), and its relationship to disease severity is well-established. However, evidence regarding sleep disturbance in MG is inconclusive.

Methods: To evaluate sleep and quality of life among clinically stable MG patients, 54 subjects were investigated by means of the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and 15-Item-Quality-Of-Life Instrument for MG (MG-QOL15).

Results: A pathological PSQI score, which was observed in 59% of patients, was increased in subjects with active disease compared with patients in clinical remission [odds ratio = 4.3; confidence interval 95% (1.0-17.6); P = 0.04]. We found a relationship between PSQI and MG-QOL15 scores in patients with clinically active disease (r = 0.62; P < 0.001).

Conclusions: Our study highlights the high prevalence of sleep disturbance among MG patients. Disease severity may be considered to be a MG-specific risk factor for patient-reported sleep disturbance. The MG-QOL15 and PSQI should be used to estimate the impact of the disease on sleep and quality of life.
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http://dx.doi.org/10.1002/mus.23296DOI Listing
August 2012

Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy.

Neuromuscul Disord 2011 Aug 14;21(8):533-42. Epub 2011 Jun 14.

Institute of Neuropathology, Department of Pathology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.

Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRYAB, MYOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 MFM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in MYOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis.
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http://dx.doi.org/10.1016/j.nmd.2011.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148150PMC
August 2011

Association and linkage disequilibrium analyses of APOE polymorphisms in atherosclerosis.

Dis Markers 2008 ;24(2):65-72

Laboratory of Molecular Investigation, University Hospital Miguel Servet, Aragonian Health Sciences Institute, Zaragoza, Spain.

Background: Apolipoprotein E (apo E) plays a major role in lipid metabolism, and its genetic variations have been associated with cardiovascular risk. The objective of this study was to investigate the influence of the APOE promoter (-491 A/T, -427 T/C and -219 G/T) and coding region (APOE epsilon2/epsilon3/epsilon4) polymorphisms in atherosclerosis disease by association and linkage disequilibrium analyses.

Materials And Methods: We analyzed these polymorphisms in a sample of 286 subjects with atherosclerosis disease: 153 subjects with atherothrombotic stroke (ATS) and 133 subjects with ischemic heart disease (IHD); and in two control groups, 103 newborns and 114 elderly subjects.

Results: The epsilon4 allele was associated with more severe carotid stenosis in the ATS group, being the percentages of epsilon4 carriers 26.7% and 11.4% for the higher and lower carotid stenosis groups, respectively (p=0,066). The -491 T/T IHD subjects presented higher vessel scores than subjects A/A and A/T genotypes at that position (p=0,041), and the frequencies of -2 (5.1% versus 14.1%, p=0,060) and -427C (10.3% versus 24.4%, p=0,019) alleles were lower in IHD subjects with higher extent score versus lower extent score. The epsilon2 allele was in linkage disequilibrium with the -427C allele in all studied groups, and the -219T allele was associated with the epsilon4 allele in the IHD group.

Conclusion: In summary, the epsilon2 allele was in linkage disequilibrium with the -427C allele in all studied groups, and only slight associations between the analyzed APOE polymorphisms in the promoter and in the coding region and carotid and coronary vascular disease have been observed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850622PMC
http://dx.doi.org/10.1155/2008/650410DOI Listing
April 2008

Serum chitotriosidase activity is increased in subjects with atherosclerosis disease.

Arterioscler Thromb Vasc Biol 2003 Sep 31;23(9):1645-52. Epub 2003 Jul 31.

Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Isabel la Católica, 1-3, 50009 Zaragoza, Spain.

Objective: This study was undertaken to analyze the relation between serum activity of chitotriosidase enzyme, a protein synthesized exclusively by activated macrophages, and atherosclerotic lesion extent in subjects with atherothrombotic stroke (ATS) and in subjects with ischemic heart disease (IHD).

Methods And Results: We assayed the serum chitotriosidase activity and a common chitotriosidase gene polymorphism that causes deficiency in chitotriosidase activity in 3 Spanish populations, ATS (n=153), IHD (n=124), and control (n=148) subjects. Statistical differences were found in serum chitotriosidase activity between ATS (88.1+/-4.6 nmol/mL. h, P<0.0001) and IHD subjects (79.0+/-6.3, P=0.002) versus control group (70.9+/-5.2). These observed differences were not attributable to a distinct allelic or genotype distribution. The extension of the atherosclerotic lesion in carotids of ATS subjects was measured by duplex sonography. Chitotriosidase activities were 66.9+/-9.6, 88.7+/-8.3, and 107.7+/-11.8 for subjects with carotid stenosis 60%, respectively. Statistical differences were observed between subjects with major and intermediate stenosis grade compared with subjects with minor stenosis, P=0.005 and P=0.016, respectively.

Conclusions: Serum chitotriosidase activity is significantly increased in individuals suffering from atherosclerosis disease and is related to the severity of the atherosclerotic lesion, suggesting a possible role as atherosclerotic extent marker.
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http://dx.doi.org/10.1161/01.ATV.0000089329.09061.07DOI Listing
September 2003