Publications by authors named "Adolfo López de Munaín"

177 Publications

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis.

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

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

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

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

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

Conclusions: Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.14820DOI Listing
March 2021

Discovery of a novel family of FKBP12 "reshapers" and their use as calcium modulators in skeletal muscle under nitro-oxidative stress.

Eur J Med Chem 2021 Mar 14;213:113160. Epub 2021 Jan 14.

Instituto de Investigación Sanitaria Biodonostia, Grupo de Enfermedades Neuromusculares, Paseo Dr Begiristain s/n, 20014, San Sebastián, Spain; CIBERNED, Instituto de Salud Carlos III, 28031, Madrid, Spain; Grupo de Neurosciencias, Departamentos de Pediatría y Neurociencias, Universidad Del País Vasco UPV/EHU, Hospital Donostia, Paseo Dr Begiristain S/n, 20014, San Sebastián, Spain. Electronic address:

The hypothesis of rescuing FKBP12/RyR1 interaction and intracellular calcium homeostasis through molecular "reshaping" of FKBP12 was investigated. To this end, novel 4-arylthioalkyl-1-carboxyalkyl-1,2,3-triazoles were designed and synthesized, and their efficacy was tested in human myotubes. A library of 17 compounds (10a-n) designed to dock the FKBP12/RyR1 hot-spot interface contact residues, was readily prepared from free α-amino acids and arylthioalkynes using CuAAC "click" protocols amenable to one-pot transformations in high overall yields and total configurational integrity. To model nitro-oxidative stress, human myotubes were treated with the peroxynitrite donor SIN1, and evidence was found that some triazoles 10 were able to normalize calcium levels, as well as FKBP12/RyR1 interaction. For example, compound 10 b at 150 nM rescued 46% of FKBP12/RyR1 interaction and up to 70% of resting cytosolic calcium levels in human myotubes under nitro-oxidative stress. All compounds 10 analyzed showed target engagement to FKBP12 and low levels of cytotoxicity in vitro. Compounds 10b, 10c, 10h, and 10iR were identified as potential therapeutic candidates to protect myotubes in muscle disorders with underlying nitro-oxidative stress, FKBP12/RyR1 dysfunction and calcium dysregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2021.113160DOI Listing
March 2021

Genealogy of the neurodegenerative diseases based on a meta-analysis of age-stratified incidence data.

Sci Rep 2020 11 3;10(1):18923. Epub 2020 Nov 3.

Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, Calle Doctor Beguiristain S/N, 20014, San Sebastián, Spain.

While the central common feature of the neurodegenerative diseases (NDs) is the accumulation of misfolded proteins, they share other pathogenic mechanisms. However, we miss an explanation for the onset of the NDs. The mechanisms through which genetic mutations, present from conception are expressed only after several decades of life are unknown. We aim to find clues on the complexity of the disease onset trigger of the different NDs expressed in the number of steps of factors related to a disease. We collected brain autopsies on diseased patients with NDs, and found a dynamic increase of the ND multimorbidity with the advance of age. Together with the observation that the NDs accumulate multiple misfolded proteins, and the same misfolded proteins are involved in more than one ND, motivated us to propose a model for a genealogical tree of the NDs. To collect the dynamic data needed to build the tree, we used a Big-data approach that searched automatically epidemiological datasets for age-stratified incidence of NDs. Based on meta-analysis of over 400 datasets, we developed an algorithm that checks whether a ND follows a multistep model, finds the number of steps necessary for the onset of each ND, finds the number of common steps with other NDs and the number of specific steps of each ND, and builds with these findings a parsimony tree of the genealogy of the NDs. The tree discloses three types of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5 to 6 steps; and the crown NDs with more than 7 steps. The tree provides a comprehensive understanding of the relationship across the different NDs, as well as a mathematical framework for dynamic adjustment of the genealogical tree of the NDs with the appearance of new epidemiological studies and the addition of new NDs to the model, thus setting the basis for the search for the identity and order of these steps. Understanding the complexity, or number of steps, of factors related to disease onset trigger is important prior deciding to study single factors for a multiple steps disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-75014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609593PMC
November 2020

Metabolic alterations in plasma from patients with familial and idiopathic Parkinson's disease.

Aging (Albany NY) 2020 Sep 9;12(17):16690-16708. Epub 2020 Sep 9.

Departamento de Bioquímica y Biología Molecular y Genética. Facultad de Enfermería y Terapia Ocupacional. Universidad de Extremadura, Cáceres, Spain.

The research of new biomarkers for Parkinson's disease is essential for accurate and precocious diagnosis, as well as for the discovery of new potential disease mechanisms and drug targets. The main objective of this work was to identify metabolic changes that might serve as biomarkers for the diagnosis of this neurodegenerative disorder. For this, we profiled the plasma metabolome from mice with neurotoxin-induced Parkinson's disease as well as from patients with familial or sporadic Parkinson's disease. By using mass spectrometry technology, we analyzed the complete metabolome from healthy volunteers compared to patients with idiopathic or familial (carrying the G2019S or R1441G mutations in the gene) Parkinson's disease, as well as, from mice treated with 6-hydroxydopamine to induce Parkinson disease. Both human and murine Parkinson was accompanied by an increase in plasma levels of unconjugated bile acids (cholic acid, deoxycholic acid and lithocholic acid) and purine base intermediary metabolites, in particular hypoxanthine. The comprehensive metabolomic analysis of plasma from Parkinsonian patients underscores the importance of bile acids and purine metabolism in the pathophysiology of this disease. Therefore, plasma measurements of certain metabolites related to these pathways might contribute to the diagnosis of Parkinson's Disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521510PMC
September 2020

Neurodegeneration trajectory in pediatric and adult/late DM1: A follow-up MRI study across a decade.

Ann Clin Transl Neurol 2020 10 2;7(10):1802-1815. Epub 2020 Sep 2.

Personality, Assessment and psychological treatment department; Psychology Faculty, University of the Basque Country (UPV/EHU), San Sebastián, Gipuzkoa, Spain.

Objective: To characterize the progression of brain structural abnormalities in adults with pediatric and adult/late onset DM1, as well as to examine the potential predictive markers of such progression.

Methods: 21 DM1 patients (pediatric onset: N = 9; adult/late onset: N = 12) and 18 healthy controls (HC) were assessed longitudinally over 9.17 years through brain MRI. Additionally, patients underwent neuropsychological, genetic, and muscular impairment assessment. Inter-group comparisons of total and voxel-level regional brain volume were conducted through Voxel Based Morphometry (VBM); cross-sectionally and longitudinally, analyzing the associations between brain changes and demographic, clinical, and cognitive outcomes.

Results: The percentage of GM loss did not significantly differ in any of the groups compared with HC and when assessed independently, adult/late DM1 patients and their HC group suffered a significant loss in WM volume. Regional VBM analyses revealed subcortical GM damage in both DM1 groups, evolving to frontal regions in the pediatric onset patients. Muscular impairment and the outcomes of certain neuropsychological tests were significantly associated with follow-up GM damage, while visuoconstruction, attention, and executive function tests showed sensitivity to WM degeneration over time.

Interpretation: Distinct patterns of brain atrophy and its progression over time in pediatric and adult/late onset DM1 patients are suggested. Results indicate a possible neurodevelopmental origin of the brain abnormalities in DM1, along with the possible existence of an additional neurodegenerative process. Fronto-subcortical networks appear to be involved in the disease progression at young adulthood in pediatric onset DM1 patients. The involvement of a multimodal integration network in DM1 is discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545612PMC
October 2020

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Brain 2020 09;143(9):2696-2708

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

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa228DOI Listing
September 2020

Genotype-phenotype correlations in recessive titinopathies.

Genet Med 2020 Dec 11;22(12):2029-2040. Epub 2020 Aug 11.

Folkhälsan Research Center, Helsinki, Finland.

Purpose: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort.

Methods: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families).

Results: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364).

Conclusion: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0914-2DOI Listing
December 2020

Clinical and preclinical evidence of somatosensory involvement in amyotrophic lateral sclerosis.

Br J Pharmacol 2021 Mar 5;178(6):1257-1268. Epub 2020 Aug 5.

Centro de Investigación en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto Carlos III, Madrid, Spain.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron neurodegenerative disease. Although it has been classically considered as a disease limited to the motor system, there is increasing evidence for the involvement of other neural and non-neuronal systems. In this review, we will discuss currently existing literature regarding the involvement of the sensory system in ALS. Human studies have reported intradermic small fibre loss, sensory axonal predominant neuropathy, as well as somatosensory cortex hyperexcitability. In line with this, ALS animal studies have demonstrated the involvement of several sensory components. Specifically, they have highlighted the impairment of sensory-motor networks as a potential mechanism for the disease. The elucidation of these "non-motor" systems involvement, which might also be part of the degeneration process, should prompt the scientific community to re-consider ALS as a pure motor neuron disease, which may in turn result in more holistic research approaches. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15202DOI Listing
March 2021

Toxicity of Necrostatin-1 in Parkinson's Disease Models.

Antioxidants (Basel) 2020 Jun 15;9(6). Epub 2020 Jun 15.

Depto. Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia Ocupacional, Universidad de Extremadura Avda de la Universidad s/n, 10003 Cáceres, Spain.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. This neuronal loss, inherent to age, is related to exposure to environmental toxins and/or a genetic predisposition. PD-induced cell death has been studied thoroughly, but its characterization remains elusive. To date, several types of cell death, including apoptosis, autophagy-induced cell death, and necrosis, have been implicated in PD progression. In this study, we evaluated necroptosis, which is a programmed type of necrosis, in primary fibroblasts from PD patients with and without the G2019S ( mutation and in rotenone-treated cells (SH-SY5Y and fibroblasts). The results showed that programmed necrosis was not activated in the cells of PD patients, but it was activated in cells exposed to rotenone. Necrostatin-1 (Nec-1), an inhibitor of the necroptosis pathway, prevented rotenone-induced necroptosis in PD models. However, Nec-1 affected mitochondrial morphology and failed to protect mitochondria against rotenone toxicity. Therefore, despite the inhibition of rotenone-mediated necroptosis, PD models were susceptible to the effects of both Nec-1 and rotenone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox9060524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346148PMC
June 2020

Amyotrophic lateral sclerosis (ALS), cancer, autoimmunity and metabolic disorders: An unsolved tantalizing challenge.

Br J Pharmacol 2021 Mar 18;178(6):1269-1278. Epub 2020 Jun 18.

Centro de Investigación en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto Carlos III, Madrid, Spain.

Amyotrophic lateral sclerosis (ALS) commonly referred to as motor neurone disease, is a neurodegenerative disease of unknown pathogenesis that progresses rapidly and has attracted an increased amount of scholarly interest in recent years. The current conception of amyotrophic lateral sclerosis has transitioned into a more complex theory in which individual genetic risk, ageing and environmental factors interact, leading to disease onset in subjects in whom the sum of these factors reach a determined threshold. Based on this conceptualization, the environmental conditions, particularly those that are potentially modifiable, are becoming increasingly relevant. In this review, the current integrative model of the disease is discussed. In addition, we explore the role of cancer, autoimmunity and metabolic diseases as examples of novel, non-genetic and environmental factors. Together with the potential triggers or perpetuating pathogenic mechanisms along with new insights into potential lines of future research are provided. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15151DOI Listing
March 2021

Frizzled related protein deficiency impairs muscle strength, gait and calpain 3 levels.

Orphanet J Rare Dis 2020 05 24;15(1):119. Epub 2020 May 24.

Biodonostia Health Research Institute, Neurosciences Area, San Sebastian, Spain.

Background: Limb-girdle muscular dystrophy recessive 1 calpain3-related (LGMDR1), previously known as LGMD2A, is a disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness and muscle degeneration. Frizzled related protein (FRZB), upregulated in LGMDR1, was identified as a key regulator of the crosstalk between Wnt and integrin signalling pathways. FRZB gene silencing showed a recovery in the expression of some of the costamere protein levels in myotubes.

Results: Here, we performed a comprehensive characterization of Frzb mice muscles to study the absence of Frzb in skeletal muscle and eventual links with the molecular characteristics of LGMDR1 patient muscles. Frzb mice showed reduced muscle size and strength. Gait analysis showed that Frzb mice moved more slowly but no impaired regeneration capacity was observed after muscle injury. Additionally, Frzb mice muscle showed an increased number of mesoangioblasts. Lack of Frzb gene in Frzb mice and its increased expression in LGMDR1 patients, showed contrary regulation of Rora, Slc16a1, Tfrc and Capn3 genes. The reciprocal regulation of Frzb and Capn3 genes further supports this axis as a potential target for LGMDR1 patients.

Conclusions: Our data confirm a role for Frzb in the regulation of Rora, Slc16a1, Tfrc, and Capn3 genes in muscle cells. In vivo, reduced muscle strength and gait in the Frzb mice are intriguing features. The reciprocal relationship between FRZB and CAPN3 further supports a key role for this axis in patients with LGMDR1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01372-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245871PMC
May 2020

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

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11050539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288461PMC
May 2020

Dermic-derived fibroblasts for the study of amyotrophic lateral sclerosis.

Neural Regen Res 2020 Nov;15(11):2043-2044

Centro de Investigación en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid; Neurosciences Area, Biodonostia Research Institute; Service of Neurology, Hospital Universitario Donostia; Department of Neurosciences, School of Medicine and Nursery, University of the Basque Country, San Sebastián, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1673-5374.282257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716046PMC
November 2020

Myotonic Dystrophy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin.

Aging (Albany NY) 2020 04 8;12(7):6260-6275. Epub 2020 Apr 8.

Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain.

Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of a multisystem accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. In this study, we characterized the impact of metabolism and mitochondria on fibroblasts and peripheral blood mononuclear cells (PBMCs) derived from patients with DM1 and healthy individuals. Our results revealed a decrease in oxidative phosphorylation system (OXPHOS) activity, oxygen consumption rate (OCR), ATP production, energy metabolism, and mitochondrial dynamics in DM1 fibroblasts, as well as increased accumulation of reactive oxygen species (ROS). PBMCs of DM1 patients also displayed reduced mitochondrial dynamics and energy metabolism. Moreover, treatment with metformin reversed the metabolic and mitochondrial defects as well as additional accelerated aging phenotypes, such as impaired proliferation, in DM1-derived fibroblasts. Our results identify impaired cell metabolism and mitochondrial dysfunction as important drivers of DM1 pathophysiology and, therefore, reveal the efficacy of metformin treatment in a pre-clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185118PMC
April 2020

The Discovery of the Dardarin Gene 15 Years Later: A Globalized Local History.

Mov Disord 2020 04;35(4):708

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Institute Carlos III, Madrid, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27969DOI Listing
April 2020

Kynurenic Acid Levels are Increased in the CSF of Alzheimer's Disease Patients.

Biomolecules 2020 04 8;10(4). Epub 2020 Apr 8.

Group of Neurodegenerative Diseases, Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain.

Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10040571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226436PMC
April 2020

A comprehensive serum lipidome profiling of amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 28;21(3-4):252-262. Epub 2020 Feb 28.

Department of Neurosciences, Biodonostia Health Research Institute, San Sebastián, Spain.

: To perform a comprehensive lipid profiling to evaluate potential lipid metabolic differences between patients with amyotrophic lateral sclerosis (ALS) and controls, and to provide a more profound understanding of the metabolic abnormalities in ALS. : Twenty patients with ALS and 20 healthy controls were enrolled in a cross-sectional study. Untargeted lipidomics profiling in fasting serum samples were performed by optimized UPLC-MS platforms for broad lipidome coverage. Datasets were analyzed by univariate and a variety of multivariate procedures. : We provide the most comprehensive blood lipid profiling of ALS to date, with a total of 416 lipids measured. Univariate analysis showed that 28 individual lipid features and two lipid classes, triacylglycerides and oxidized fatty acids (FAs), were altered in patients with ALS, although none of these changes remained significant after multiple comparison adjustment. Most of these changes remained constant after removing from the analysis individuals treated with lipid-lowering drugs. The non-supervised principal component analysis did not identify any lipid clustering of patients with ALS and controls. Despite this, we performed a variety of linear and non-linear supervised multivariate models to select the most reliable features that discriminate the lipid profile of patients with ALS from controls. These were the monounsaturated FAs C24:1n-9 and C14:1, the triglyceride TG(51:4) and the sphingomyelin SM(36:2). : Peripheral alterations of lipid metabolism are poorly defined in ALS, triacylglycerides and certain types of FAs could contribute to the different lipid profile of patients with ALS. These findings should be validated in an independent cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2020.1730904DOI Listing
May 2020

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

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

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

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

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

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

Conclusions: Patients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220233PMC
March 2020

COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage.

J Stroke Cerebrovasc Dis 2020 Apr 6;29(4):104652. Epub 2020 Feb 6.

Neurology Department, Donostia University Hospital, San Sebastián, Gipuzkoa, Spain.

The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation. Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104652DOI Listing
April 2020

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Authors:
Sven J van der Lee Olivia J Conway Iris Jansen Minerva M Carrasquillo Luca Kleineidam Erik van den Akker Isabel Hernández Kristel R van Eijk Najada Stringa Jason A Chen Anna Zettergren Till F M Andlauer Monica Diez-Fairen Javier Simon-Sanchez Alberto Lleó Henrik Zetterberg Marianne Nygaard Cornelis Blauwendraat Jeanne E Savage Jonas Mengel-From Sonia Moreno-Grau Michael Wagner Juan Fortea Michael J Keogh Kaj Blennow Ingmar Skoog Manuel A Friese Olga Pletnikova Miren Zulaica Carmen Lage Itziar de Rojas Steffi Riedel-Heller Ignacio Illán-Gala Wei Wei Bernard Jeune Adelina Orellana Florian Then Bergh Xue Wang Marc Hulsman Nina Beker Niccolo Tesi Christopher M Morris Begoña Indakoetxea Lyduine E Collij Martin Scherer Estrella Morenas-Rodríguez James W Ironside Bart N M van Berckel Daniel Alcolea Heinz Wiendl Samantha L Strickland Pau Pastor Eloy Rodríguez Rodríguez Bradley F Boeve Ronald C Petersen Tanis J Ferman Jay A van Gerpen Marcel J T Reinders Ryan J Uitti Lluís Tárraga Wolfgang Maier Oriol Dols-Icardo Amit Kawalia Maria Carolina Dalmasso Mercè Boada Uwe K Zettl Natasja M van Schoor Marian Beekman Mariet Allen Eliezer Masliah Adolfo López de Munain Alexander Pantelyat Zbigniew K Wszolek Owen A Ross Dennis W Dickson Neill R Graff-Radford David Knopman Rosa Rademakers Afina W Lemstra Yolande A L Pijnenburg Philip Scheltens Thomas Gasser Patrick F Chinnery Bernhard Hemmer Martijn A Huisman Juan Troncoso Fermin Moreno Ellen A Nohr Thorkild I A Sørensen Peter Heutink Pascual Sánchez-Juan Danielle Posthuma Jordi Clarimón Kaare Christensen Nilüfer Ertekin-Taner Sonja W Scholz Alfredo Ramirez Agustín Ruiz Eline Slagboom Wiesje M van der Flier Henne Holstege

Acta Neuropathol 2020 05;139(5):959-962

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-02107-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181435PMC
May 2020

ALS-derived fibroblasts exhibit reduced proliferation rate, cytoplasmic TDP-43 aggregation and a higher susceptibility to DNA damage.

J Neurol 2020 May 14;267(5):1291-1299. Epub 2020 Jan 14.

Centro de Investigación en Red de Enfermedades Neurodegenerativas, CIBERNED. Instituto Carlos III, Madrid, Spain.

Background: Dermic fibroblasts have been proposed as a potential genetic-ALS cellular model. This study aimed to explore whether dermic fibroblasts from patients with sporadic-ALS (sALS) recapitulate alterations typical of ALS motor neurons and exhibit abnormal DNA-damage response.

Methods: Dermic fibroblasts were obtained from eight sALS patients and four control subjects. Cellular characterization included proliferation rate analysis, cytoarchitecture studies and confocal immunofluorescence assessment for TDP-43. Additionally, basal and irradiation-induced DNA damage was evaluated by confocal immunofluorescence and biochemical techniques.

Results: sALS-fibroblasts showed decreased proliferation rates compared to controls. Additionally, whereas control fibroblasts exhibited the expected normal spindle-shaped morphology, ALS fibroblasts were thinner, with reduced cell size and enlarged nucleoli, with frequent cytoplasmic TDP-43aggregates. Also, baseline signs of DNA damage were evidenced more frequently in ALS-derived fibroblasts (11 versus 4% in control-fibroblasts). Assays for evaluating the irradiation-induced DNA damage demonstrated that DNA repair was defective in ALS-fibroblasts, accumulating more than double of γH2AX-positive DNA damage foci than controls. Very intriguingly, the proportion of fibroblasts particularly vulnerable to irradiation (with more than 15 DNA damage foci per nucleus) was seven times higher in ALS-derived fibroblasts than in controls.

Conclusions: Dermic-derived ALS fibroblasts recapitulate relevant cellular features of sALS and show a higher susceptibility to DNA damage and defective DNA repair responses. Altogether, these results support that dermic fibroblasts may represent a convenient and accessible ALS cellular model to study pathogenetic mechanisms, particularly those related to DNA damage response, as well as the eventual response to disease-modifying therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-09704-8DOI Listing
May 2020

A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.

Ann Clin Transl Neurol 2020 01 18;7(1):105-111. Epub 2019 Dec 18.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Objective: To identify causative mutations in a patient affected by ataxia and spastic paraplegia.

Methods: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient's DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot.

Results: A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts.

Interpretation: Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952318PMC
January 2020

Leukocyte telomere length in patients with myotonic dystrophy type I: a pilot study.

Ann Clin Transl Neurol 2020 01 5;7(1):126-131. Epub 2019 Dec 5.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = -0.013 in DM1 vs. -0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952307PMC
January 2020

Regional brain atrophy in gray and white matter is associated with cognitive impairment in Myotonic Dystrophy type 1.

Neuroimage Clin 2019 6;24:102078. Epub 2019 Nov 6.

Neuroscience Area, Biodonostia Research Institute, San Sebastián, Gipuzkoa, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute Carlos III, Madrid, Spain; Personality, Assessment and psychological treatment department; Psychology Faculty, University of the Basque Country (UPV/EHU), San Sebastian, Gipuzkoa, Spain.

Background: Myotonic Dystrophy type 1 (DM1) is a slowly progressive myopathy characterized by varying multisystemic involvement. Several cerebral features such as brain atrophy, ventricular enlargement, and white matter lesions (WMLs) have frequently been described. The aim of this study is to investigate the structural organization of the brain that defines the disease through multimodal imaging analysis, and to analyze the relation between structural cerebral changes and DM1 clinical and neuropsychological profiles.

Method: 31 DM1 patients and 57 healthy controls underwent an MRI scan protocol, including T1, T2 and DTI. Global gray matter (GM), global white matter (WM), and voxel-level Voxel Based Morphometry (VBM) and voxel-level microstructural WM abnormalities through Diffusion Tensor Imaging (DTI) were assessed through group comparisons and linear regression analysis with age, degree of muscular impairment (MIRS score), CTG expansion size and neuropsychological outcomes from a comprehensive assessment.

Results: Compared with healthy controls, DM1 patients showed a reduction in both global GM and WM volume; and further regional GM decrease in specific primary sensory, multi-sensory and association cortical regions. Fractional anisotropy (FA) was reduced in both total brain and regional analysis, being most marked in frontal, paralimbic, temporal cortex, and subcortical regions. Higher ratings on muscular impairment and longer CTG expansion sizes predicted a greater volume decrease in GM and lower FA values. Age predicted global GM reduction, specifically in parietal regions. At the cognitive level, the DM1 group showed significant negative correlations between IQ estimate, visuoconstructive and executive neuropsychological scores and both global and regional volume decrease, mainly distributed in the frontal, parietal and subcortical regions.

Conclusions: In this study, we describe the structural brain signatures that delineate the involvement of the CNS in DM1. We show that specific sensory and multi-sensory - as well as frontal cortical areas - display potential vulnerability associated with the hypothesized neurodegenerative nature of DM1 brain abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2019.102078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861566PMC
September 2020

T cells and immune functions of plasma extracellular vesicles are differentially modulated from adults to centenarians.

Aging (Albany NY) 2019 11 27;11(22):10723-10741. Epub 2019 Nov 27.

Biodonostia Health Research Institute, Multiple Sclerosis Group, San Sebastian, Spain.

Aging is a universal and complex process that affects all tissues and cells types, including immune cells, in a process known as immunosenescence. However, many aspects of immunosenescence are not completely understood, as the characteristics of the immune cells of nonagenarians and centenarians or the features and implications of extracellular vesicles (EVs). In this study, we analyzed blood samples from 51 individuals aged 20-49 and 70-104 years. We found that senescent CD8 cells accumulate with age, while there is a partial reduction of senescent CD4 cells in nonagenarians and centenarians. Moreover, plasma EVs carry T cell specific markers, but no accumulation of "senescent-like EVs" was found within any of analyzed age groups. Our functional studies of cocultures of peripheral blood mononuclear cells and EVs showed that EVs enhance T cell viability and, under phytohemagglutinin stimulation, they influence cytokine secretion and cell activation in an age-dependent manner. These results underline the importance of EVs on the immune system functioning, and open new perspectives to further study their implication in human aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914389PMC
November 2019

Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models.

Proc Natl Acad Sci U S A 2019 12 21;116(50):25203-25213. Epub 2019 Nov 21.

Translational Genomics Group, Incliva Health Research Institute, 46010 Valencia, Spain;

Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3' UTR of the gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in and mouse (HSA) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSA mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1820297116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911202PMC
December 2019

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.

Authors:
Sara Bandres-Ciga Sarah Ahmed Marya S Sabir Cornelis Blauwendraat Astrid D Adarmes-Gómez Inmaculada Bernal-Bernal Marta Bonilla-Toribio Dolores Buiza-Rueda Fátima Carrillo Mario Carrión-Claro Pilar Gómez-Garre Silvia Jesús Miguel A Labrador-Espinosa Daniel Macias Carlota Méndez-Del-Barrio Teresa Periñán-Tocino Cristina Tejera-Parrado Laura Vargas-González Monica Diez-Fairen Ignacio Alvarez Juan Pablo Tartari Mariateresa Buongiorno Miquel Aguilar Ana Gorostidi Jesús Alberto Bergareche Elisabet Mondragon Ana Vinagre-Aragon Ioana Croitoru Javier Ruiz-Martínez Oriol Dols-Icardo Jaime Kulisevsky Juan Marín-Lahoz Javier Pagonabarraga Berta Pascual-Sedano Mario Ezquerra Ana Cámara Yaroslau Compta Manel Fernández Rubén Fernández-Santiago Esteban Muñoz Eduard Tolosa Francesc Valldeoriola Isabel Gonzalez-Aramburu Antonio Sanchez Rodriguez María Sierra Manuel Menéndez-González Marta Blazquez Ciara Garcia Esther Suarez-San Martin Pedro García-Ruiz Juan Carlos Martínez-Castrillo Lydia Vela-Desojo Clara Ruz Francisco Javier Barrero Francisco Escamilla-Sevilla Adolfo Mínguez-Castellanos Debora Cerdan Cesar Tabernero Maria Jose Gomez Heredia Francisco Perez Errazquin Manolo Romero-Acebal Cici Feliz Jose Luis Lopez-Sendon Marina Mata Irene Martínez Torres Jonggeol Jeffrey Kim Clifton L Dalgard Janet Brooks Sara Saez-Atienzar J Raphael Gibbs Rafael Jorda Juan A Botia Luis Bonet-Ponce Karen E Morrison Carl Clarke Manuela Tan Huw Morris Connor Edsall Dena Hernandez Javier Simon-Sanchez Mike A Nalls Sonja W Scholz Adriano Jimenez-Escrig Jacinto Duarte Francisco Vives Raquel Duran Janet Hoenicka Victoria Alvarez Jon Infante Maria José Marti Jordi Clarimón Adolfo López de Munain Pau Pastor Pablo Mir Andrew Singleton

Mov Disord 2019 12 29;34(12):1851-1863. Epub 2019 Oct 29.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.

Objectives: To perform the largest PD genome-wide association study restricted to a single country.

Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses.

Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.

Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27864DOI Listing
December 2019

Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with Mutations.

Int J Mol Sci 2019 Sep 13;20(18). Epub 2019 Sep 13.

Biodonostia, Neurosciences Area, Group of Neuromuscular Diseases, 20014 San Sebastian, Spain.

Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a rare disease caused by mutations in the gene. It is characterized by progressive weakness of shoulder, pelvic, and proximal limb muscles that usually appears in children and young adults and results in loss of ambulation within 20 years after disease onset in most patients. The pathophysiological mechanisms involved in LGMDR1 remain mostly unknown, and to date, there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of Ca homeostasis in the skeletal muscle is a significant underlying event in this muscular dystrophy. We also review and discuss specific clinical features of LGMDR1, CAPN3 functions, novel putative targets for therapeutic strategies, and current approaches aiming to treat LGMDR1. These novel approaches may be clinically relevant not only for LGMDR1 but also for other muscular dystrophies with secondary calpainopathy or with abnormal Ca homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20184548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770289PMC
September 2019

Gene Correction of LGMD2A Patient-Specific iPSCs for the Development of Targeted Autologous Cell Therapy.

Mol Ther 2019 12 28;27(12):2147-2157. Epub 2019 Aug 28.

Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Limb girdle muscular dystrophy type 2A (LGMD2A), caused by mutations in the Calpain 3 (CAPN3) gene, is an incurable autosomal recessive disorder that results in muscle wasting and loss of ambulation. To test the feasibility of an autologous induced pluripotent stem cell (iPSC)-based therapy for LGMD2A, here we applied CRISPR-Cas9-mediated genome editing to iPSCs from three LGMD2A patients to enable correction of mutations in the CAPN3 gene. Using a gene knockin approach, we genome edited iPSCs carrying three different CAPN3 mutations, and we demonstrated the rescue of CAPN3 protein in myotube derivatives in vitro. Transplantation of gene-corrected LGMD2A myogenic progenitors in a novel mouse model combining immunodeficiency and a lack of CAPN3 resulted in muscle engraftment and rescue of the CAPN3 mRNA. Thus, we provide here proof of concept for the integration of genome editing and iPSC technologies to develop a novel autologous cell therapy for LGMD2A.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymthe.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904833PMC
December 2019