Publications by authors named "Germán Morís"

43 Publications

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.

Neurology 2021 03 25;96(9):e1369-e1382. Epub 2021 Jan 25.

From the Department of Neurodegenerative Diseases (A.T., S.R., L.S., M. Synofzik), Hertie-Institute for Clinical Brain Research and Center of Neurology, and German Center for Neurodegenerative Diseases (DZNE) (A.T., S.R., L.S., M. Synofzik), University of Tübingen, Germany; MRC Centre for Neuromuscular Diseases (A.C., N.D., H.H.), Department of Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, London, UK; Department of Brain and Behaviour Sciences (A.C.), University Pavia, Italy; Department of Neurology (J.F., T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (J.F., H.J., T.K.), Bonn; Department of Neurology (H.J.), University Hospital of Heidelberg; Department of Psychiatry, Psychotherapy and Psychosomatics (A.M.H., D.R.), University of Halle, Germany; Département de Neurologie (S.M., M.A.), Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg; Department of Neurology (A.E.-L.), APHP, CHU de Bicêtre; French National Reference Center for Rare Neuropathies (NNERF) (A.E.-L.); Inserm U1195 and Paris-Sud University (A.E.-L.), Le Kremlin Bicêtre, France; Medical Faculty (S.E.), Department of Neurology, Uludag University, Bursa, Turkey; University of Zurich (V.C.S., A.A.T.); Department of Neurology (V.C.S., A.A.T.), University Hospital Zurich, Switzerland; Institute of Medical Genetics and Applied Genomics (M. Sturm, T.B.H.) and Center for Rare Diseases (T.B.H.), University of Tübingen, Germany; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (N.V.-D., H.P.); INSERM (N.V.-D., H.P.), U1258; CNRS (N.V.-D., H.P.), UMR7104, Illkirch; Université de Strasbourg (H.P.), France; Department of Neurology (B.P.v.d.W.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Neurology (M.P.), Karolinska University Hospital; Department of Clinical Neuroscience (M.P.), Karolinska Institute, Stockholm, Sweden; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Essen; Department of Medical Statistics (R.-D.H.), RWTH Aachen University, Germany; Department of Neurology (J.G.), Hospital Universitario Miguel Servet. Zaragoza, Spain; Department of Neurology (M. Strupp), University Hospital, and German Center for Vertigo and Balance Disorders (M.Strupp), Ludwig Maximilians University, Munich, Germany; Neurology Service (G.M.), Hospital Unversitario Central de Asturias (HUCA), SESPA, Oviedo, Spain; Department of Neurosciences and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Institute of Genetics and Molecular and Cellular Biology (M.A.), INSERM-U964/CNRS-UMR7104, University of Strasbourg, Illkirch; Strasbourg Federation of Translational Medicine (M.A.), University of Strasbourg, Strasbourg, France; Service of Neurology (J.I.), University Hospital "Marqués de Valdecilla (IDIVAL)," University of Cantabria, "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)," Santander, Spain; and Suna and Inan Kıraç Foundation (A.N.B.), Neurodegeneration Research Laboratory, KUTTAM, Koç University School of Medicine, Istanbul, Turkey.

Objective: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).

Methods: Multimodal repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.

Results: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.

Conclusions: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.

Classification Of Evidence: This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
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http://dx.doi.org/10.1212/WNL.0000000000011528DOI Listing
March 2021

Recurrent rhabdomyolysis and exercise intolerance: A new phenotype of late-onset thymidine kinase 2 deficiency.

Mol Genet Metab Rep 2021 Mar 6;26:100701. Epub 2021 Jan 6.

Neuromuscular Unit, Department of Neurology, Hospital 12 de Octubre, Madrid, Spain.

A 29-year-old man developed, since the age of 18, exercise intolerance and exercise-induced rhabdomyolysis, with myoglobinuria. Muscle biopsy showed ragged-red fibers. Multiple mitochondrial DNA deletions were detected. The previously reported pathogenic homozygous mutation c.323C>T (p.Thr108Met) in was identified. This case expands the phenotypic spectrum of TK2 deficiency and indicates that it should be considered in the differential diagnosis of episodic rhabdomyolysis and exercise intolerance, along with other metabolic and mitochondrial myopathies. Since a new treatment is under development, it is essential improving knowledge of the natural history of TK2 deficiency.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797901PMC
March 2021

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

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

Study of the effect of anti-rhGAA antibodies at low and intermediate titers in late onset Pompe patients treated with ERT.

Mol Genet Metab 2019 Sep - Oct;128(1-2):129-136. Epub 2019 Jul 23.

Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Centro de Investigación en Red en Enfermedades Raras (CIBERER), Spain. Electronic address:

Late onset Pompe disease (LOPD) is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzyme replacement therapy (ERT) with alglucosidase alpha (rhGAA). Although most of ERT treated patients develop antibodies against rhGAA, their influence on clinical progression is not completely known. We studied the impact of anti-rhGAA antibodies on clinical progression of 25 ERT treated patients. We evaluated patients at visit 0 and, after 1 year, at visit 1. We performed several muscle function tests, conventional spirometry and quantitative muscle MRI (qMRI) using 3-point Dixon analysis of thigh muscles at both visits. We also obtained serum samples at both visits and anti-rhGAA antibodies were quantified using ELISA. Antibody titers higher than 1:200 were identified in 18 patients (72%) of our cohort. Seven patients (28%) did not develop antibodies (0 to <1:200), 17 patients (68%) developed low to intermediate titers (1:200 to <1:31,200) and 1 patient (4%) developed high titers (>1:31,200). We analyzed the effect of low and intermediate antibody titers in clinical and radiological progression. There were no differences between the results of muscle function tests, spirometry or fat fraction analyzed using qMRI between patients with and without antibodies groups at baseline. Moreover, antibody titers did not influence muscle function test, spirometry results or qMRI results at year 1 visit. Most of the LOPD patients developed antibodies against ERT that persisted over time at low or intermediate levels. However, antibodies at these low and intermediate titers might not influence clinical response to the drug.
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http://dx.doi.org/10.1016/j.ymgme.2019.07.013DOI Listing
April 2020

Late-onset thymidine kinase 2 deficiency: a review of 18 cases.

Orphanet J Rare Dis 2019 05 6;14(1):100. Epub 2019 May 6.

Neurology Department, Neuromuscular Disorders Unit, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, CSIC, Universidad de Sevilla, Avd. Manuel Siurot s/n, 41013, Sevilla, Spain.

Background: TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the 'myopathic form' of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity.

Methods: We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12.

Results: The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients.

Conclusions: The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency.
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http://dx.doi.org/10.1186/s13023-019-1071-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501326PMC
May 2019

HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease.

Neurobiol Aging 2019 04 28;76:215.e9-215.e14. Epub 2018 Nov 28.

Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Department of Neurology, Hospital Universitario de Cabueñes, Gijón, Spain.

Huntington's disease (HD) is an autosomal progressive neurodegenerative disorder caused by the expansion of CAG repeats in the HTT gene. Intermediate alleles (IAs) are in the range of 27-35 repeats and have been associated to a normal phenotype. The aim of this work was to analyze the association between intermediate huntingtin CAG-repeat alleles (IAs) and neurodegenerative diseases, other than HD. We screened the HTT CAG repeats in patients with Alzheimer's disease (AD) (n = 1126), Parkinson's disease (PD) (n = 610), and frontotemporal lobar degeneration (FTLD) (n = 225). We also studied 509 healthy controls (HCs). The relative frequency of IAs for each group was 6.03% in AD, 5.3% in FTLD, 3.5% in PD, and 2.9% in HCs. The frequency of IA was significantly higher among patients with AD when compared to HCs (p = 0.011, OR = 2.11, 95% CI = 1.19-3.74); no significant difference was observed in FTLD (p = 0.17; OR = 1.88, 95% CI = 0.85-4.03) and PD (p = 0.69; OR = 1.21; 95% CI (0.61-2.37) versus HCs. No atypical symptoms or clinical features distinctive of HD were found among carriers of IAs. We found 3 cases with CAG expansions within the pathological range, one diagnosed with AD, one with PD, and one with FTD. Results suggest that IAs might have a role in the pathogenesis of AD. In addition, HD patients might be misdiagnosed with other neurodegenerative diseases, particularly when CAG repeats are in the lower pathological range.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.014DOI Listing
April 2019

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

J Neurol Neurosurg Psychiatry 2019 05 8;90(5):576-585. Epub 2018 Dec 8.

Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain

Background And Objective: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data.

Methods: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data.

Results: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the and the were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment.

Conclusions: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, and can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.
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http://dx.doi.org/10.1136/jnnp-2018-319578DOI Listing
May 2019

Fecal microbiota profile in a group of myasthenia gravis patients.

Sci Rep 2018 09 26;8(1):14384. Epub 2018 Sep 26.

Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), 33300, Villaviciosa, Asturias, Spain.

The intestinal microbiota plays a key role in the maintenance of human health. Alterations in this microbiota have been described in several autoimmune diseases, including nervous system diseases. Nevertheless, the information regarding neuromuscular conditions is still limited. In this study, we aimed at characterizing the intestinal microbiota composition in myasthenia gravis patients (MG). To this end fecal samples were taken from ten patients, with antibodies against the acetylcholine receptor, and ten age and sex matched controls from the same population (Asturias region, Spain). Fecal samples were submitted to microbiota analyses by 16S rRNA gene profiling, bifidobacterial ITS-region profiling and qPCR. The fecal levels of short chain fatty acids were determined by gas chromatography. MG patients were found to harbor lower relative proportions of Verrucomicrobiaceae and Bifidobacteriaceae, among others, and increased of the phylum Bacteroidetes and the family Desulfovibrionaceae. The increase of these latter microbial groups was also confirmed at quantitative level by qPCR. In contrast, no statistically significant differences were found between MG patients and the control group in the bifidobacterial population at the species level or in short chain fatty acids profiles. Our data indicates an altered fecal microbiota pattern in MG patients and point out at specific microbiota targets for intervention in this population.
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http://dx.doi.org/10.1038/s41598-018-32700-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158187PMC
September 2018

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

Lancet Neurol 2018 09 23;17(9):760-772. Epub 2018 Jul 23.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Neurology, University of Pennsylvania, PA, USA; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address:

Background: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.

Methods: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.

Findings: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).

Interpretation: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.

Funding: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.
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http://dx.doi.org/10.1016/S1474-4422(18)30244-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128696PMC
September 2018

Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2018 03 7;57(3):380-387. Epub 2017 Nov 7.

MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Central Parkway Newcastle upon Tyne NE1 3 BZ, United Kingdom.

Introduction: Earlier small case series and clinical observations reported on chronic pain playing an important role in facioscapulohumeral dystrophy (FSHD). The aim of this study was to determine the characteristics and impact of pain on quality of life (QoL) in patients with FSHD.

Methods: We analyzed patient reported outcome measures collected through the U.K. FSHD Patient Registry.

Results: Of 398 patients, 88.6% reported pain at the time of study. The most frequent locations were shoulders and lower back. A total of 203 participants reported chronic pain, 30.4% of them as severe. The overall disease impact on QoL was significantly higher in patients with early onset and long disease duration. Chronic pain had a negative impact on all Individualised Neuromuscular Quality of Life Questionnaire domains and overall disease score.

Discussion: Our study shows that pain in FSHD type 1 (FSHD1) is frequent and strongly impacts on QoL, similar to other chronic, painful disorders. Management of pain should be considered when treating FSHD1 patients. Muscle Nerve 57: 380-387, 2018.
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http://dx.doi.org/10.1002/mus.25991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836962PMC
March 2018

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.

Neurology 2017 Mar 1;88(13):1235-1242. Epub 2017 Mar 1.

From the Laboratorio de Neurología (E.T.-V., T.S., J.J.V., L.B.), Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, CIBERER, Valencia; Servicio de Anatomía Patológica (N.M.), Servicio de Neurofisiología Clínica (M.J.C.), and Servicio de Neurología (T.S., J.J.V., L.B.), Hospital Universitario y Politécnico La Fe, Valencia; Laboratorio de Neurobiología Comparada (A.C.-S., V.H.-P., J.M.G.-V.), Instituto Cavanilles, Universidad de Valencia, CIBERNED; Servicio de Neurología (G.M.), Hospital Central de Asturias, Oviedo, Spain; French Reference Center on Paraneoplastic Neurological Syndrome (B.J., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron, and Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310, Université de Lyon-Université Claude Bernard Lyon 1, France; Laboratori de Neurologia (J.D., F.G.), Institut d´Investigacions Biomèdiques August Pi I Sunyer, CIBERER, Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, Philadelphia, and Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

Objective: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications.

Methods: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers).

Results: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma ( < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome ( = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus.

Conclusions: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis.

Classification Of Evidence: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%).
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http://dx.doi.org/10.1212/WNL.0000000000003778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373776PMC
March 2017

Sudden paraplegia after lumbar puncture as a clue in the diagnosis of a patient with spinal dural arteriovenous fistula.

Eur Spine J 2017 05 1;26(Suppl 1):151-153. Epub 2017 Feb 1.

Neurology Department, Hospital Universitario Central de Asturias, Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain.

Purpose: Spinal dural arteriovenous fistula (SDAVF) is manifested as congestive myelopathy with progressive motor, sensory and urinary symptoms. Sometimes, clinical picture and magnetic resonance imaging of the spinal cord are not specific and the diagnosis becomes troublesome.

Methods: We present a 68-year-old male with a progressive paraparesis of unknown etiology over the course of 12 months. Immediately after LP, the patient remarked a sudden worsening in muscular balance of his inferior limbs and a worsening of urinary retention. This fact was the clue to the SDAVF diagnosis.

Results: SDAVF was totally resolved after surgical treatment. During next months, paraplegia slightly improved and he is currently receiving rehabilitation treatment.

Conclusions: Acute paraplegia or sudden worsening of previous symptoms secondary to decreasing in cerebrospinal fluid pressure after lumbar puncture has been described, so physicians should be aware of this dramatic and avoidable complication.
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http://dx.doi.org/10.1007/s00586-017-4946-5DOI Listing
May 2017

Autoimmune post-herpes simplex encephalitis of adults and teenagers.

Neurology 2015 Nov 21;85(20):1736-43. Epub 2015 Oct 21.

From the Neuroimmunology Program (T.A., S.L., M.R., F.G., J.D.), August Pi Sunyer Biomedical Research Institute (IDIBAPS), and the Department of Neurology (S.L., F.G), Hospital Clínic, University of Barcelona; the Department of Neurology (G.M.) and the Pediatric Neurology Unit, Pediatrics Department (I.M.), Hospital Universitario Central de Asturias, Oviedo; the Department of Pediatric Neurology (V.C.-E., L.G.-G.-S.), Hospital Universitario Niño Jesús, Madrid, Spain; the Department of Neurology (C.E.C., G.G.), Hospital Universitario Hernando Moncaleano Perdomo, Neiva, Colombia; the Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, Witten/Herdecke University, Witten, Germany; the Department of Neurology (M.E.E., I.C.-N.), Complejo Hospitalario de Navarra, Pamplona; the Department of Neurology (J.C.P.-C.), Hospital San Pedro de Alcántara, Cáceres; the Pediatric Neurology Unit (E.T.-V.), Hospital de la Santa Creu i Sant Pau, Barcelona; the Pediatric Neurology Unit (B.M.-C.), Hospital Universitario Virgen del Rocio, Sevilla; the Department of Pediatric Neurology (C.T.-T.), Hospital General La Mancha Centro, Alcázar de San Juan, Spain; the Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and the Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain.

Objective: To report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children.

Methods: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously.

Results: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037).

Conclusion: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.
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http://dx.doi.org/10.1212/WNL.0000000000002125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653102PMC
November 2015

Peripheral neuropathy: an underreported neurologic manifestation of inflammatory bowel disease.

Eur J Intern Med 2015 Sep 23;26(7):468-75. Epub 2015 Jul 23.

Neurology Department, Hospital Universitario Central Asturias, Avda de Roma s/n, Oviedo, Asturias 33011, Spain. Electronic address:

Background And Aims: One of the most frequent neurologic complications reported in inflammatory bowel disease population is peripheral neuropathy; however, clinical aspects of peripheral nerve damage are not well characterized. The aim of the review is to present the existing literature on peripheral neuropathy in inflammatory bowel disease patients.

Methods: A literature search identified the publications reporting on epidemiology, clinical features, underlying mechanisms and management of ulcerative colitis and Crohn's disease patients with peripheral nerve involvement.

Results: The pathogenesis of peripheral nervous system damage in inflammatory bowel disease has yet to be elucidated, although it seems to be related to immune mechanisms; therefore, treatment with immunotherapy is recommended. In addition, peripheral neuropathy may appear as iatrogenic-related disorders associated with several drugs used in controlling inflammatory bowel disease activity; finally, peripheral neuropathy may also be caused by micronutrient deficiencies secondary to malabsorption-related disorders.

Conclusions: Although peripheral nervous nerve damage associated with inflammatory bowel disease is rarely reported, clinicians should be aware of the peripheral neuropathy clinical manifestations in order to recognize it and provide early treatment, which is crucial for preventing major neurologic morbidity. Heightened awareness is necessary for the successful management of these patients.
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http://dx.doi.org/10.1016/j.ejim.2015.07.013DOI Listing
September 2015

[Neuralgic amyotrophy associated to hepatitis E virus infection].

Med Clin (Barc) 2015 Nov 24;145(10):462-3. Epub 2015 Mar 24.

Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España. Electronic address:

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http://dx.doi.org/10.1016/j.medcli.2015.01.021DOI Listing
November 2015

MiRNA profile in the substantia nigra of Parkinson's disease and healthy subjects.

J Mol Neurosci 2014 Dec 5;54(4):830-6. Epub 2014 Oct 5.

Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, 33006, Oviedo, Spain.

The deregulation of several microRNAs (miRNAs) has been associated with neurodegenerative processes, including Parkinson's disease (PD). Our aim was to characterize the level of miRNAs in the substantia nigra (SN) of PD patients and healthy donors. This is an important issue to characterize new putative markers and therapeutic targets for PD. RNA was extracted from the SN of postmortem PD (n=8) and healthy (n=4) subjects, and the level of 733 human miRNAs was assayed with TaqMan low-density arrays (TLDAs). Overall, there was a miRNA downregulation in the SN of patients. The mean level of 11 miRNAs was significantly different (p<0.05) between patients and controls, with 10 downregulated among the patients. MiR-198, -135b, -485-5p, and -548d were the best candidates and were quantified with individual TaqMan assays in the 12 samples. MiR-135b showed the most significant difference between patients and healthy donors. The bioinformatic analysis suggested that this miRNA could bind to genes implicated in several neurodegenerative pathways.
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http://dx.doi.org/10.1007/s12031-014-0428-yDOI Listing
December 2014

The challenge of drug-induced aseptic meningitis revisited.

JAMA Intern Med 2014 Sep;174(9):1511-2

Department of Neurology, Hospital de Galdakao-Usansolo, Vizcaya, Spain.

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http://dx.doi.org/10.1001/jamainternmed.2014.2918DOI Listing
September 2014

Abnormal electrocardiogram in a patient with amyotrophic lateral sclerosis mimicking myocardial ischaemia.

World J Clin Cases 2014 Jun;2(6):211-4

Juana Martínez, César Ramón, Julio Pascual, Germán Morís, Neurology Department, Hospital Universitario Central Asturias, 33006 Oviedo, Spain.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that almost exclusively involves motor neurons although autonomic dysfunction has also been reported. We present an 84-year-old female with no documented history of heart disease, who was admitted with negative T waves in the electrocardiogram precordial leads mimicking myocardial ischaemia. No other abnormalities were shown in the rest of the cardiologic evaluation, suggesting autonomic nervous system dysfunction. A neurophysiological study demonstrated acute and chronic denervation in multiple muscles with normal nerve conduction studies, confirming ALS diagnosis. Previous studies have shown that subclinical sympathetic hyperfunction and parasympathetic hypofunction might result in cardiovascular dysfunction in ALS patients. It is important to detect disturbances of autonomic cardiac control because this dysfunction may influence survival and quality of life, leading to a decrease in life expectancy in ALS patients. This Case Report may support the impairment of cardiac autonomic control in patients with ALS.
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http://dx.doi.org/10.12998/wjcc.v2.i6.211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061311PMC
June 2014

The screening of the 3'UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson's disease.

J Hum Genet 2014 Jun 24;59(6):346-8. Epub 2014 Apr 24.

Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the exon-coding sequence. Our aim was to determine whether LRRK2 3' untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n=743) and controls (n=523) from Spain. We identified a total of 12 3'UTR variants (two new). Single-nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P=0.005; odds ratio=1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation-negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n=9) who were rs66737902 C carriers (P=0.01). This SNP was predicted to affect a binding site for miR-138-2-3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles.
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http://dx.doi.org/10.1038/jhg.2014.26DOI Listing
June 2014

Inflammatory bowel disease: an increased risk factor for neurologic complications.

Authors:
Germán Morís

World J Gastroenterol 2014 Feb;20(5):1228-37

Germán Morís, Neurology Department, Hospital Universitario Central Asturias, Oviedo, 33006 Asturias, Spain.

Only a very few systematic studies have investigated the frequency of neurologic disorders in patients with Crohn's disease (CD) and ulcerative colitis (UC), which are the two main types of inflammatory bowel disease (IBD). Results have been inconsistent and variable, owing to differences in case-finding methods and evaluated outcomes in different studies. The most frequent neurologic manifestations reported in CD and UC populations are cerebrovascular disease (with either arterial or venous events), demyelinating central nervous system disease, and peripheral neuropathy (whether axonal or demyelinating); however, the literature describes numerous nervous system disorders as being associated with IBD. The pathogenesis of nervous system tissue involvement in IBD has yet to be elucidated, although it seems to be related to immune mechanisms or prothrombotic states. The recently-introduced tumor necrosis factor (TNF) inhibitors have proven successful in controlling moderate to severe IBD activity. However, severe neurologic disorders associated with TNF inhibitors have been reported, which therefore raises concerns regarding the effect of anti-TNF-α antibodies on the nervous system. Although neurological involvement associated with IBD is rarely reported, gastroenterologists should be aware of the neurologic manifestations of IBD in order to provide early treatment, which is crucial for preventing major neurologic morbidity.
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http://dx.doi.org/10.3748/wjg.v20.i5.1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921505PMC
February 2014

Alpha-synuclein transcript isoforms in three different brain regions from Parkinson's disease and healthy subjects in relation to the SNCA rs356165/rs11931074 polymorphisms.

Neurosci Lett 2014 Mar 10;562:45-9. Epub 2014 Jan 10.

Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain. Electronic address:

Mutations in the alpha-synuclein (SNCA) gene cause autosomal dominant Parkinson's disease (PD). Common SNCA polymorphisms have been associated with the risk of developing PD. Abnormal expression and post-translational modification of SNCA has been found in PD-brains. In addition to a full length transcript (SNCA-140) there are three short isoforms (SNCA-98, -112, and -126) that could be prone to aggregation. The association between SNCA polymorphisms and PD could be explained through an increased expression of these alternative transcripts. Our aim was to measure the different SNCA transcripts in the substantia nigra (SN), cerebellum (CB), and occipital cortex (OC) from PD-patients (n=9) and healthy subjects (n=6). In addition, we determined whether two SNCA polymorphisms (SNPs rs356165 and rs11931074) were related to differences in transcript isoform expression. PD brain tissues showed higher levels of the three short transcripts in the SN, but only SNCA-112 and SNCA-98 were significantly increased in the CB of patients vs. controls (p=0.02, p=0.03). The genotyping of a large cohort of PD-patients and controls showed that haplotype rs356165-A+rs11931074-G had a protective effect (OR=0.71; CI=0.59-0.83), while the G-T haplotype increased the risk for PD (OR=1.44; CI=1.06-1.96). We did not find significant differences for the SNCA levels between the haplotypes. In conclusion, we found statistically significant higher levels of the SNCA-112 and SNCA-98 transcripts in the CB of PD brains, and a trend toward higher levels of the short transcript isoforms in the SN of PD brains.
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http://dx.doi.org/10.1016/j.neulet.2014.01.009DOI Listing
March 2014

A painless burn due to lack of painkillers.

JAMA Neurol 2014 Feb;71(2):240-1

Department of Neurology, Hospital Universitario Central Asturias, Oviedo, Asturias, Spain.

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http://dx.doi.org/10.1001/jamaneurol.2013.2192DOI Listing
February 2014

Chronic migraine does not increase posterior circulation territory (PCT) infarct-like lesions.

J Neurol Sci 2014 Jan 29;336(1-2):180-3. Epub 2013 Oct 29.

Neuroscience Area, Service of Neurology, University Hospital Central de Asturias and Ineuropa, Oviedo, Spain. Electronic address:

Unlabelled: Two population-based studies have found an increased prevalence of posterior circulation territory (PCT) infarct-like lesions in migraine, which seemed to increase with attack frequency.

Objective: To determine whether chronic migraine (CM) patients are at increased risk of PCT infarct-like lesions.

Methods: We prospectively obtained brain MRIs from adult women fulfilling CM criteria. To keep radiologists blinded we also obtained brain MRIs in 15 episodic migraine (EM) patients. MRIs were acquired on a 1.5 T unit. Protocol included whole brain weighted images in sagittal T1 (5 mm slices), axial FLAIR T2 (3 mm) and combined proton density and T2 fast spin echo (3 mm). Two independent neuroradiologists carefully analyzed all the images.

Results: One hundred women with CM participated. Their ages ranged from 18 to 68 years (mean 43.7) and the length of CM ranged from 0.5 to 38 years (mean 9.8). Sixty-three patients (63%) had at least one vascular risk factor. Thirty-three met analgesic overuse criteria. Fifty-one had a history of migraine with aura attacks, though aura frequency was below one per month in all patients except one. Eleven were not on preventatives. We found PCT infarct-like lesions in only 6 CM patients aged 42-64 years (mean age 54 years) who had at least two vascular risk factors.

Conclusions: As frequency of PCT infarct-like lesions in our CM patients was in the low range than that found for EM in general population studies, we conclude that frequency of migraine attacks itself is not a factor increasing PCT infarct-like lesion risk.
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http://dx.doi.org/10.1016/j.jns.2013.10.035DOI Listing
January 2014

Mutational screening of PARKIN identified a 3' UTR variant (rs62637702) associated with Parkinson's disease.

J Mol Neurosci 2013 Jun 30;50(2):264-9. Epub 2012 Dec 30.

Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain.

PRKN mutations have been linked to Parkinson's disease (PD). Most of the mutational screenings have focused on the coding exons. The 3' untranslated region (UTR) could also harbor functionally relevant nucleotide changes. We performed a mutational screening of PRKN in a cohort of early-onset PD patients (n = 235) from Spain. We found 16 mutations (five new): 16 patients (7 %) carried two mutations and only one mutation was found in 28 (12 %). Patients with two mutations had significantly lower mean age (30 ± 9 years) compared to patients with one (40 ± 7) or no mutation (42 ± 7). We found a total of 15 nucleotide variants (three new) in the 3' UTR region. The frequency of carriers of the rare rs62637702 G allele (*94A/G) was significantly lower among the patients compared to healthy controls (n = 418) (0.03 vs. 0.004; p < 0.001), suggesting a protective role for this allele. In order to investigate the basal effect of this variant, we performed luciferase assays. No different basal activity was observed between the two alleles. In conclusion, the rs62637702 polymorphism was associated with PD. This could be a surrogate marker for disease risk, in linkage disequilibrium with other non-identified functional variant.
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http://dx.doi.org/10.1007/s12031-012-9942-yDOI Listing
June 2013

Trunk muscle involvement in late-onset Pompe disease: study of thirty patients.

Neuromuscul Disord 2012 Oct;22 Suppl 2:S148-54

Neuromuscular Disorders Unit, Department of Neurology, Universitat Autónoma de Barcelona, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.

Late-onset Pompe disease is characterized by progressive weakness involving proximal limb and respiratory muscles. Recently, treatment with enzyme replacement therapy (ERT) has been introduced partially improving patients' prognosis, but a standard consensus on when to start ERT is still lacking. There is also a lack of biomarkers related to the clinical progression of the disease. Here we used muscle magnetic resonance imaging (MRI) or computed tomography (CT) to study the abdominal and paravertebral muscles of 30 late-onset Pompe patients at different stages of disease. We observed a selective pattern of muscle damage, with early involvement of the Multifidus muscle, followed by the Obliquus internus abdominis and Longissimus muscle. Some degree of trunk involvement on MRI occurred even in asymptomatic patients. Severity of muscle involvement in MRI correlated with patients' functional stage. We suggest that: (a) the combination of paravertebral and abdominal muscle involvement may serve as a useful tool in the diagnostic work-up of patients with a clinical suspicion of Pompe disease; (b) trunk abnormalities appear at very early stages of disease and even in asymptomatic patients, possibly "announcing" the onset of the disease and thus the need for a closer clinical follow-up.
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http://dx.doi.org/10.1016/j.nmd.2012.05.011DOI Listing
October 2012

A search for SNCA 3' UTR variants identified SNP rs356165 as a determinant of disease risk and onset age in Parkinson's disease.

J Mol Neurosci 2012 Jul 11;47(3):425-30. Epub 2011 Nov 11.

Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, 33006, Oviedo, Spain.

Alpha-synuclein gene (SNCA) polymorphisms have been associated with the common sporadic form of Parkinson's disease (PD). We searched for DNA variants at the SNCA 3' UTR through single strand conformation analysis and direct sequencing in a cohort of Spanish PD patients and controls. We have genotyped the rs356165 SNCA 3' UTR polymorphism in a total of 1,135 PD patients and 772 healthy controls from two Spanish cohorts (Asturias and Navarre). We identified six SNCA 3' UTR variants. Single nucleotide polymorphism (SNP) rs356165 was significantly associated with PD risk in the Spanish cohort (p = 0.0001; odd ratio = 1.37, 95%CI = 1.19-1.58). This SNP was also significantly associated with early age at onset of PD. Our work highlights rs356165 as an important determinant of the risk of developing PD and early age at onset and encourages future research to identify a functional effect on SNCA expression.
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http://dx.doi.org/10.1007/s12031-011-9669-1DOI Listing
July 2012