Publications by authors named "Josep Gamez"

65 Publications

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants.

Brain Pathol 2021 Feb 12:e12942. Epub 2021 Feb 12.

Neurological Tissue Bank, Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.

Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer's disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups.
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http://dx.doi.org/10.1111/bpa.12942DOI Listing
February 2021

First Case of Parkinsonian-Pyramidal Syndrome Associated with a TBK1 Mutation.

Mov Disord 2021 02 27;36(2):523-525. Epub 2020 Nov 27.

Institute of Neurogenetics, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.

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http://dx.doi.org/10.1002/mds.28405DOI Listing
February 2021

Haplotype Analysis of the First A4V- Spanish Family: Two Separate Founders or a Single Common Founder?

Front Genet 2019 8;10:1109. Epub 2019 Nov 8.

ALS Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Despite the genetic heterogeneity reported in familial amyotrophic lateral sclerosis (ALS) (fALS), Cu/Zn superoxide-dismutase (SOD1) gene mutations are the second most common cause of the disease, accounting for around 20% of all families (ALS1) and isolated sporadic cases (sALS). At least 186 different mutations in the SOD1 gene have been reported to date. The possibility of a single founder and separate founders have been investigated for D90A (p.D91A) and A4V (p.A5V), the most common mutations worldwide. High-throughput single nucleotide polymorphism genotyping studies have suggested two founders for A4V (one for the Amerindian population and another for the European population) although the possibility that the two populations are descended from a single ancient founder cannot be ruled out. We used 15 genetic variants spanning the human chromosome 21 from the SOD1 gene to the gene, comparing them with the population reference panels, to demonstrate that the first A4V Spanish pedigree shared the genetic background reported in the European population.
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http://dx.doi.org/10.3389/fgene.2019.01109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857184PMC
November 2019

Consensus-based care recommendations for adults with myotonic dystrophy type 2.

Neurol Clin Pract 2019 Aug;9(4):343-353

Ludwig-Maximilians- Universität (BS); Friedrich-Baur-Institut (FM), Munich, Germany; Institut de Myologie (GB), Paris, France; U.O. Neurologia (BF), IRCCS Policlinico San Donato, Milan, Italy; Vall d'Hebron University Hospital (JG), Barcelona, Spain; University of Rochester (CH, JH, RM, CT), Rochester, NY; University Hospital of Bonn (CK), Germany; Medical University of Warsaw (AK-P), Poland; University of Texas (RK) MD Anderson cancer center; Medical University of Warsaw (AL), Poland; Department of Biomedical Sciences for health (GM), University of Milan, Italy; Tampere University (BU), Finland; Myotonic Dystrophy Foundation (PF), San Francisco.

Purpose Of Review: Myotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients.

Summary: The resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists.
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http://dx.doi.org/10.1212/CPJ.0000000000000645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745739PMC
August 2019

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

Intravenous immunoglobulin to prevent myasthenic crisis after thymectomy and other procedures can be omitted in patients with well-controlled myasthenia gravis.

Ther Adv Neurol Disord 2019 17;12:1756286419864497. Epub 2019 Jul 17.

Department of Thoracic Surgery, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: Myasthenic crisis (MC) is a potentially life-threatening complication of myasthenia gravis. Its precipitating factors include surgical procedures, particularly thymectomy. The role of preoperative intravenous immunoglobulin (IVIg) in preventing MC in patients scheduled for thymectomy and other surgery with general anaesthesia is unknown. Our objective was to test the hypothesis that preoperative IVIg is effective in preventing myasthenic crisis in patients with myasthenia gravis scheduled for surgery under general anaesthesia, including thymectomy.

Methods: A prospective, randomized, double-blind, single-centre study was conducted over a 4-year period. The treatment group received IVIg, 0.4 g/kg/day preoperatively for 5 consecutive days, and the placebo group received saline solution under the same conditions. The two groups were age-matched, with similar functional status, and Myasthenia Gravis Foundation of America class. All patients had well-controlled myasthenia gravis with minimal manifestations before surgery. The primary outcome measured was MC. Intubation times, time in the recovery room, number of postoperative complications, and days of hospitalization were the secondary outcomes measured.

Results: A total of 47 patients were randomized, 25 to the IVIg group and 22 to placebo. There were 19 men and 28 women, with a mean age of 58.6 years, mean body mass index of 27.8 kg/m, and mean acetylcholine receptor antibodies of 12.9 nmol/l. The mean forced vital capacity was 84.4%. The mean quantitative myasthenia gravis sum score was 6.3. Ten patients (five in each arm) had a history of MC. Thymectomy was performed in 16 patients. Only one patient in the placebo group presented with MC requiring non-invasive ventilation (but no reintubation) for 6 days. Neither differences between groups in the univariate analysis nor risk factors for MC in the multivariate analysis were found.

Conclusions: Preoperative IVIg to prevent MC does not appear to be justified in well-controlled myasthenia gravis patients. This study provides class I evidence that preparation with IVIg to prevent MC is not necessary in well-controlled myasthenia gravis patients scheduled for surgery with general anaesthesia.
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http://dx.doi.org/10.1177/1756286419864497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640060PMC
July 2019

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

Amyotroph Lateral Scler Frontotemporal Degener 2020 02 7;21(1-2):5-14. Epub 2019 Jul 7.

AB Science, Paris, France.

To assess masitinib in the treatment of ALS. Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. For the primary efficacy population, masitinib ( = 99) showed significant benefit over placebo ( = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.
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http://dx.doi.org/10.1080/21678421.2019.1632346DOI Listing
February 2020

Transthyretin stabilization activity of the catechol--methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study.

Amyloid 2019 Jun 23;26(2):74-84. Epub 2019 May 23.

b Research and Development Department , SOM Biotech, S.L , Barcelona , Spain.

To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers. A phase IIa proof-of-concept trial included two phases separated by a 6-week washout period. Phase A: single 200 mg dose of tolcapone; phase B: three 100 mg doses taken at 4 h intervals. The primary efficacy variable was TTR stabilization. Seventeen subjects were included (wild type,  = 6; mutation TTR Val30Met,  = 11). TTR stabilization was observed in all participants. Two hours after dosing, 82% of participants in phase A and 93% of those in phase B reached a TTR stabilization value of at least 20%. In phase A, there was an increase of 52% in TTR stabilization vs baseline values 2 h after dosing, which decreased to 22.9% at 8 h. In phase B, there was a significant increase of 38.8% in TTR stabilization 2 h after the first 100 mg dose. This difference was maintained after 10 h and decreased after 24 h. No serious adverse events were observed. The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis. : 2014-001586-27 : NCT02191826.
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http://dx.doi.org/10.1080/13506129.2019.1597702DOI Listing
June 2019

Variably protease-sensitive prionopathy presenting within ALS/FTD spectrum.

Ann Clin Transl Neurol 2018 Oct 21;5(10):1297-1302. Epub 2018 Sep 21.

Neurological Tissue Bank of the Biobanc-Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Spain.

We report clinico-pathological features of a 65-year-old woman and a 56-year-old man with a 5-year clinical history who had clinical and neuropathological characteristics of upper and lower motor neuron disease consistent with amyotrophic lateral sclerosis, and a frontotemporal atrophy pattern in case 2 without TDP-43 pathology. Instead, spongiform change and pathological prion protein deposits were observed in several brain regions. No prion protein gene mutations were found. Western blot analysis showed a five-band profile compatible with variably protease-sensitive prionopathy. We conclude that this disease can display prolonged disease duration and clinico-pathological features within the ALS/FTLD spectrum.
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http://dx.doi.org/10.1002/acn3.632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186932PMC
October 2018

Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.

N Engl J Med 2018 Jul;379(1):22-31

From the Indiana University School of Medicine, Indianapolis (M.D.B.); Centro de Estudos em Paramiloidose Antônio Rodrigues de Mello, National Amyloidosis Referral Center, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro (M.W.-C.); Amyloidosis Center, Boston University School of Medicine (J.L.B.) and Brigham and Women's Hospital, Harvard Medical School (A.M.S., S.D.S.), Boston; Johns Hopkins University, Baltimore (M.P.); Mayo Clinic, Rochester, MN (P.J.D., W.J.L., M.A.G.); University of California, Irvine, Irvine (A.K.W.); Amyloid Network-Hospital Henri Mondor-Assistance Publique-Hôpitaux de Paris (AP-HP)-Université Paris Est, Créteil, France (V.P.-B.); Institute for Neurologic Research Raúl Carrea, FLENI, Buenos Aires (F.A.B.); Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia (G.M., L.O.), and Unit of Neurology, University Hospital, Messina (G.V.) - both in Italy; Hospital AACD (Associação de Assistência à Criança Deficiente), São Paulo (M.S.); Columbia University Medical Center (T.H.B.) and Mount Sinai Medical Center (P.D.G.), New York; University College London-National Amyloidosis Centre, London (C.W.); Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.M.D.); Centre Hospitaliere Universitaire Bicêtre, AP-HP, Unité 1195, INSERM, Université Paris-Sud, Paris (D.A.); Oregon Health and Science University, Portland (S.B.H.); Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon (I.C.), and Centro Hospitalar do Porto, Porto (T.C.) - both in Portugal; Universitätsklinikum Münster, Münster, Germany (H.H.S.); Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (J.M.C.), and Hospital Universitari Vall d'Hebron (J.G.), Barcelona; Auckland City Hospital, Auckland, New Zealand (E.G.); and Ionis Pharmaceuticals, Carlsbad, CA (B.P.M., S.G.H., T.J.K., B.W.M., S.W.J., B.F.B., E.J.A.).

Background: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin.

Methods: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement.

Results: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring.

Conclusions: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).
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http://dx.doi.org/10.1056/NEJMoa1716793DOI Listing
July 2018

K Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis.

Mol Neurobiol 2018 Oct 28;55(10):7962-7972. Epub 2018 Feb 28.

Department of Biomedical Sciences, Institut de Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Barcelona, Spain.

The ATP-sensitive potassium (K) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the K channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in K channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the K channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of K channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the K channel plays a role in the pathophysiological mechanisms of ALS.
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http://dx.doi.org/10.1007/s12035-018-0970-7DOI Listing
October 2018

Intravenous immunoglobulin as monotherapy for myasthenia gravis during pregnancy.

J Neurol Sci 2017 Dec 6;383:118-122. Epub 2017 Nov 6.

Myasthenia Gravis Unit, Neonatology Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Introduction: Pregnant women with myasthenia gravis (MG) are at increased risk of complications and adverse outcomes, including the teratogenic effects of many drugs used to treat MG women of childbearing age. The effectiveness of intravenous immunoglobulins (IVIg) on other autoimmune mediated diseases has been extensively reported in recent years, although little is known about the role of IVIg in the treatment of MG during pregnancy. We designed this study to determine the effectiveness of IVIg as monotherapy during pregnancy for women with MG.

Material And Methods: Five pregnant MG patients (mean age at delivery 36.4years, SD 5.8, range 29.4-45.2) were studied in 2013-14. Their treatment was switched to monthly IVIg cycles 2months before the pregnancy. Follow-up included monthly neurological QMG throughout the pregnancy and postpartum, obstetrical monitoring during monthly visits in the first two trimesters of the pregnancy, fortnightly visits between week 32 and week 36, and weekly visits after 36weeks, and neonatal follow-up after delivery.

Results: We observed no exacerbations during pregnancy, delivery or post-partum. The mean QMG score at baseline (before pregnancy) was 7.4 points in five women with generalized forms of MG. The maximum mean value reached during pregnancy was 8.6 points. The mean pregnancy duration was 38 w+5 d. No infant with transient neonatal myasthenia gravis.

Conclusions: These results suggest that monotherapy with IVIg during pregnancy in MG patients could be promising, although confirmation is required in studies with larger populations.
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http://dx.doi.org/10.1016/j.jns.2017.10.037DOI Listing
December 2017

Influence of early neurological complications on clinical outcome following lung transplant.

PLoS One 2017 16;12(3):e0174092. Epub 2017 Mar 16.

Department of Thoracic Surgery, Lung Transplant Unit, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: Neurological complications after lung transplantation are common. The full spectrum of neurological complications and their impact on clinical outcomes has not been extensively studied.

Methods: We investigated the neurological incidence of complications, categorized according to whether they affected the central, peripheral or autonomic nervous systems, in a series of 109 patients undergoing lung transplantation at our center between January 1 2013 and December 31 2014.

Results: Fifty-one patients (46.8%) presented at least one neurological complication. Critical illness polyneuropathy-myopathy (31 cases) and phrenic nerve injury (26 cases) were the two most prevalent complications. These two neuromuscular complications lengthened hospital stays by a median period of 35.5 and 32.5 days respectively. However, neurological complications did not affect patients' survival.

Conclusions: The real incidence of neurological complications among lung transplant recipients is probably underestimated. They usually appear in the first two months after surgery. Despite not affecting mortality, they do affect the mean length of hospital stay, and especially the time spent in the Intensive Care Unit. We found no risk factor for neurological complications except for long operating times, ischemic time and need for transfusion. It is necessary to develop programs for the prevention and early recognition of these complications, and the prevention of their precipitant and risk factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354450PMC
September 2017

SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.

Neurogenetics 2017 01 22;18(1):63-67. Epub 2016 Dec 22.

MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, UK.

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.
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http://dx.doi.org/10.1007/s10048-016-0505-1DOI Listing
January 2017

Identification and characterization of the novel point mutation m.3634A>G in the mitochondrial MT-ND1 gene associated with LHON syndrome.

Biochim Biophys Acta Mol Basis Dis 2017 01 7;1863(1):182-187. Epub 2016 Sep 7.

Departament de Patología Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain; Àrea de Genètica Clínica i Molecular, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Electronic address:

Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by bilateral acute or subacute progressive central visual loss. Most cases of LHON syndrome are caused by point mutations in the MT-ND1, MT-ND4, and MT-ND6 genes. Here, we report a novel homoplasmic mutation in the MT-ND1 gene (m.3634A>G, p.Ser110Gly) in a patient with the classical clinical features of LHON syndrome. Several observations support the idea that the mutation is pathogenic and involved in the clinical phenotype of the patient: 1) The mutation affected a highly conserved amino acid, 2) A pathogenic mutation in the same amino acid (m.3635G>A, p.Ser110Asn) was previously reported in a patient with LHON syndrome, 3) The mutation is not recorded in the Mitomap or Human Mitochondrial Genome Database, 4) In silico predictors classified the mutation as "probably damaging", and 5) Cybrids carrying the mutation showed decreased Complex I enzyme activity, lower cell proliferation, and decreased mitochondrial membrane potential relative to control cybrids.
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http://dx.doi.org/10.1016/j.bbadis.2016.09.002DOI Listing
January 2017

A coordinated transition model for patients with cystinosis: from pediatrics to adult care.

Nefrologia 2016 Nov - Dec;36(6):616-630. Epub 2016 Aug 30.

Grupo de Trabajo multidisciplinar para el tratamiento de los pacientes con cistinosis y su transición desde las unidades pediátricas a las de adultos, Barcelona, España.

Introduction: Improved outcome and longer life-expectancy in patients with cystinosis, and disease complexity itself, justify planning a guided-transition of affected patients from Pediatrics to adult medicine. The aims of the process are to guarantee the continuum of care and patient empowerment, moving from guardian-care to self-care.

Methods: review of articles, expert opinion and anonymous surveys of patients, relatives and patient advocacy groups.

Results: elaboration a new document to support and coordinate the transition of patients with cystinosis providing specific proposals in a variety of medical fields, and adherence promotion. Nephrologists play a key role in transition due the fact that most cystinotic patients suffer severe chronic kidney disease, and need kidney transplantation before adulthood.

Conclusion: we present a document providing recommendations and suggesting a chronogram to help the process of transition of adolescents and young adults with cystinosis in our area.
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http://dx.doi.org/10.1016/j.nefro.2016.05.012DOI Listing
April 2018

Study of the prevalence of familial autoimmune myasthenia gravis in a Spanish cohort.

J Neurol Sci 2016 Jan 27;360:110-4. Epub 2015 Nov 27.

Myasthenia Gravis Unit, Clinic of Neuromuscular Disorders and Rare Diseases, Neurology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

Background: Myasthenia gravis (MG) is an autoimmune disease caused by a failure of neuromuscular transmission. Familial clustering has been reported despiteMG usually manifesting as a sporadic condition presumed not to be inherited. Our study investigated the prevalence of FAMG in a Spanish cohort, characterizing their phenotype,antibody titres and thymus findings.

Material/methods: We investigated the presence of familial cases in 462 MG patients, characterizing by age and MGFA class at debut, quantitative MG score, antibody titres, MGFA post-intervention status and thymus pathology.

Results: Sixteen cases from8 unrelated pedigrees were identified. The prevalence of FAMG caseswas 3.46%.Mean age at onset was 57.8 ± 17.4 years (range=23–82). Distribution at debut was: 6 ocular, 4 IIa, 4IIb, 1 IIIa and 1 IIIb. Thymoma was identified in two of the 7 thymectomized individuals.

Conclusions: The prevalence of FAMG in Spain is similar to other populations. Post-intervention status did not differ from sporadic autoimmune MG. As in other neuromuscular disorders, phenotype and inheritance heterogeneity are present in FAMG. In addition to the interfamilial heterogeneity observed, members of the same family affected with FAMG may even present different ages of onset, severity and thymus involvement. Further studies are necessary to clarify the role of genetic risk factors in this form of autoimmune MG.
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http://dx.doi.org/10.1016/j.jns.2015.11.049DOI Listing
January 2016

Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis.

Nefrologia 2015 ;35(3):304-21

Introduction: Cystinosis is a rare lysosomal systemic disease that mainly affects the kidney and the eye. Patients with cystinosis begin renal replacement therapy during the first decade of life in absence of treatment. Prognosis of cystinosis depends on early diagnosis, and prompt starting and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in those patients that do not follow treatment. The objective of this work was to elaborate recommendations for the comprehensive care of cystinosis and the facilitation of patient transition from paediatric to adult treatment, based on clinical experience. The goal is to reduce the impact of the disease, and to improve patient quality of life and prognosis.

Methods: Bibliographic research and consensus meetings among a multidisciplinary professional team of experts in the clinical practice, with cystinotic patients (T-CiS.bcn group) from 5 hospitals located in Barcelona.

Results: This document gathers specific recommendations for diagnosis, treatment and multidisciplinary follow-up of cystinotic patients in the following areas: nephrology, dialysis,renal transplant, ophthalmology, endocrinology, neurology, laboratory, genetic counselling,nursing and pharmacy.

Conclusions: A reference document for the comprehensive care of cystinosis represents a support tool for health professionals who take care of these patients. It is based on the following main pillars: (a) a multi-disciplinary approach, (b) appropriate disease monitoring and control of intracellular cystine levels in leukocytes, (c) the importance of adherence to treatment with cysteamine, and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated transition model between paediatric and adult care services which will contemplate the specific needs of cystinosis.
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http://dx.doi.org/10.1016/j.nefroe.2015.06.010DOI Listing
April 2017

Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient.

World J Gastroenterol 2015 Sep;21(36):10475-9

Maria Salvado, Josep Gamez, ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.

We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication.
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http://dx.doi.org/10.3748/wjg.v21.i36.10475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579895PMC
September 2015

Incomplete penetrance in the Spanish family with limb-girdle muscular dystrophy type 1F.

Muscle Nerve 2016 Jan 23;53(1):156-7. Epub 2015 Sep 23.

Neurology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1002/mus.24900DOI Listing
January 2016

Absence of HINT1 mutations in a UK and Spanish cohort of patients with inherited neuropathies.

J Neurol 2015 Aug 21;262(8):1984-6. Epub 2015 Jul 21.

MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Box 108, Queen Square, London, WC1N 3BG, UK.

Biallelic mutations in the HINT1 gene were recently identified as the cause of axonal neuropathy with neuromyotonia. It has been suggested that HINT1 mutations may indeed account for 11% of all inherited neuropathies with autosomal recessive inheritance. However, 81% of patients HINT1-related neuropathies reported to date are originally from five European countries and the global prevalence of the disorder is still unknown. In our study, we aimed to determine the frequency of HINT1 mutations by direct sequencing in a cohort of 152 patients with inherited neuropathies from the UK and Spain, where no cases have been described to date. We failed to identify patients with clinical myotonia, neuromyotonia or pathogenic mutations in HINT1. Our results support that HINT1-related neuropathies are not homogeneously distributed among European populations, which may be explained by founder effects. This geographical variability also underlines the importance of considering the ethnic background when screening for mutations in neuropathy-related genes.
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http://dx.doi.org/10.1007/s00415-015-7851-zDOI Listing
August 2015

UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort.

J Neurol 2015 Oct 11;262(10):2285-92. Epub 2015 Jul 11.

ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d'Hebron 119, 08035, Barcelona, Spain.

To investigate the association of functional variants of the human UNC13A gene with the risk of ALS, survival and the disease progression rate in a Spanish ALS cohort. 136 sporadic ALS (sALS) patients and 487 healthy controls were genotyped for the UNC13A rs12608932 variant. Clinical characterization of ALS patients included gender, age at first symptom, initial topography, disease progression rate, and survival. Genetic association was analyzed under five inheritance models. The sALS patients with the rs12608932(CC) genotype had an increased risk of ALS under a recessive genetic model [OR 2.16; 95 % CI (1.23, 3.8), p = 0.009; corrected p = 0.028]. Genotypes with a C allele are also associated with increased risk [OR 1.47; 95 % CI (1.11, 1.95); p = 0.008; corrected p = 0.023] under an additive model. sALS patients with a C/C genotype had a shorter survival than patients with A/A and A/C genotypes [HR 1.44; 95 % CI (1.11, 1.873); p = 0.007] under a recessive model. In an overdominant model, heterozygous patients had a longer survival than homozygous patients [HR 0.36; 95 % CI (0.22, 0.59); p = 0.001]. The rs12608932 genotypes modify the progression of symptoms measured using the ALSFRS-R. No association with age of onset, initial topography or rate of decline in FVC was found. Our results show that rs12608932 is a risk factor for ALS in the Spanish population and replicate the findings described in other populations. The rs12608932 is a modifying factor for survival and disease progression rate in our series. Our results also corroborated that it did not influence the age of onset.
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http://dx.doi.org/10.1007/s00415-015-7843-zDOI Listing
October 2015

PFN1 mutations are also rare in the Catalan population with amyotrophic lateral sclerosis.

J Neurol 2014 Dec 24;261(12):2387-92. Epub 2014 Sep 24.

ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Passeig Vall d'Hebron, 119, Barcelona, Spain.

Evidence of genetic heterogeneity in ALS has been found, with at least 31 genes being identified to date as causing ALS, and other genes being suggested as risk factors for susceptibility to the disease and for phenotype modifications. In recent years, new molecular genetic methodologies, especially GWAS and exome sequencing, have contributed to the identification of new ALS genes. Some of these genes (SOD1, TARDBP, FUS, and C9orf72) have homogenous frequencies in different populations. However, a few genes are rare in populations other than those in which they were first identified. Here we investigate the frequency of the PFN1 gene in a Catalan ALS population. A mutational analysis of the PFN1 gene was carried out on a Catalan cohort of 42 ALS families (FALS) and 423 sporadic ALS patients (SALS). The screening included 600 healthy controls. No PFN1 mutations were identified in either the FALS or SALS group. We also found no mutations in the control group. Our results are consistent with those described in other populations with very low frequencies, suggesting that PFN1 is a very rare cause of ALS worldwide. Together with the absence of a distinctive phenotype associated with ALS18, these results mean that this gene should be a second or third line for inclusion in screening in patients requesting genetic counseling.
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http://dx.doi.org/10.1007/s00415-014-7501-xDOI Listing
December 2014

CX3CR1 is a modifying gene of survival and progression in amyotrophic lateral sclerosis.

PLoS One 2014 7;9(5):e96528. Epub 2014 May 7.

Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine - IDIBAPS, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.

The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27 ± 4.90) than patients with 249V/V genotype (67.65 ± 7.42; diff -25.49 months 95%CI [-42.79,-8.18]; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff =  -29.78 months; 95%CI [-49.42,-10.14]; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff =  -27.02 months; 95%CI [-49.57, -4.48]; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096528PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013026PMC
October 2015

Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies.

Neuromuscul Disord 2014 Mar 15;24(3):227-40. Epub 2013 Nov 15.

Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Programs in Human & Molecular Genetics, University of Texas at Houston Graduate School in Biomedical Sciences, Houston, TX, USA; Graduate Programs in Genes & Development, University of Texas at Houston Graduate School in Biomedical Sciences, Houston, TX, USA. Electronic address:

The prevailing pathomechanistic paradigm for myotonic dystrophy (DM) is that aberrant expression of embryonic/fetal mRNA/protein isoforms accounts for most aspects of the pleiotropic phenotype. To identify aberrant isoforms in skeletal muscle of DM1 and DM2 patients, we performed exon-array profiling and RT-PCR validation on the largest DM sample set to date, including Duchenne, Becker and tibial muscular dystrophy (NMD) patients as disease controls, and non-disease controls. Strikingly, most expression and splicing changes in DM patients were shared with NMD controls. Comparison between DM and NMD identified almost no significant differences. We conclude that DM1 and DM2 are essentially identical for dysregulation of gene expression, and DM expression changes represent a subset of broader spectrum dystrophic changes. We found no evidence for qualitative splicing differences between DM1 and DM2. While some DM-specific splicing differences exist, most of the DM splicing differences were also seen in NMD controls. SSBP3 exon 6 missplicing was observed in all diseased muscle and led to reduced protein. We conclude there is no widespread DM-specific spliceopathy in skeletal muscle and suggest that missplicing in DM (and NMD) may not be the driving mechanism for the muscle pathology, since the same pathways show expression changes unrelated to splicing.
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http://dx.doi.org/10.1016/j.nmd.2013.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943873PMC
March 2014

No need for more muscle biopsies in members of the Spanish LGMD1F family. The gene has been identified at last.

Authors:
Josep Gamez

Neuropathology 2014 Apr 27;34(2):217-8. Epub 2013 Aug 27.

Neurology Department, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, VHIR., Barcelona, Spain.

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http://dx.doi.org/10.1111/neup.12059DOI Listing
April 2014

ALS Untangled No. 20: the Deanna protocol.

Amyotroph Lateral Scler Frontotemporal Degener 2013 May 2;14(4):319-23. Epub 2013 May 2.

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http://dx.doi.org/10.3109/21678421.2013.788405DOI Listing
May 2013

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.

Brain 2013 May 29;136(Pt 5):1508-17. Epub 2013 Mar 29.

Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, VHIR, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129 08035 Barcelona, Spain.

In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies.
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http://dx.doi.org/10.1093/brain/awt074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634201PMC
May 2013

Progressive presynaptic dopaminergic deterioration in Huntington disease: a [123I]-FP-CIT SPECT two-year follow-up study.

Clin Nucl Med 2014 Mar;39(3):e227-8

From the *Neurology Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), and †Servei de Medicina Nuclear, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain; and ‡Department of Statistics, University of Barcelona, Barcelona, Spain.

To illustrate the potential of [I]-FP-CIT SPECT DaTSCAN® in investigating the progression of presynaptic dopaminergic degeneration in Huntington disease (HD), we performed a 2-year follow-up [I]-FP-CIT study on 4 HD patients, evaluating the SPECT imaging based on qualitative and semiquantitative analysis. The mean annual decline in [I]-FP-CIT uptake in caudate and putamen after 2 years of follow-up was 5.8% and 9.6%, respectively. Our findings suggest that [I]-FP-CIT SPECT is useful in investigating the progression of presynaptic dopaminergic degeneration in HD, and may be useful as a disease biomarker, providing an objective method for measuring the effectiveness of future neuroprotective therapies.
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http://dx.doi.org/10.1097/RLU.0b013e31828162cdDOI Listing
March 2014