Publications by authors named "Gorka Fernández-Eulate"

14 Publications

  • Page 1 of 1

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

Eur J Neurol 2021 Mar 13. Epub 2021 Mar 13.

Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.

Background: To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients.

Methods: Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited.

Results: Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30-57) years and most patients showed a limb-girdle (n = 26) or distal (n = 10) phenotype. However, compared with EO dysferlinopathy patients (n = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p = 0.01), and higher NSAD (p = 0.008) and ACTIVLIM scores (p = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; p = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p = 0.021), no differences in dysferlin protein expression were found on Western blot.

Conclusions: Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.
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http://dx.doi.org/10.1111/ene.14821DOI Listing
March 2021

[Sarcoglycanopathies: state of the art and therapeutic perspectives].

Med Sci (Paris) 2020 Dec 11;36 Hors série n° 2:22-27. Epub 2021 Jan 11.

Centre de Référence des maladies neuromusculaires Nord/Est/Île-de-France, APHP, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France.

Sarcoglycanopathies are the third most common cause of autosomal recessive limb girdle muscular dystrophies (LGMD). They are the result of a deficiency in one of the sarcoglycans a, b, g, or d. The usual clinical presentation is that of a symmetrical involvement of the muscles of the pelvic and scapular girdles as well as of the trunk, associated with more or less severe cardio-respiratory impairment and a marked increase of serum CK levels. The first symptoms appear during the first decade, the loss of ambulation occurring often during the second decade. Lesions observed on the muscle biopsy are dystrophic. This is associated with a decrease or an absence of immunostaining of the sarcoglycan corresponding to the mutated gene and, to a lesser degree, of the other three sarcoglycans. Many mutations have been reported in the four incriminated genes and some of them are prevalent in certain populations. To date, there is no curative treatment, which does not prevent the development of many clinical trials, especially in gene therapy.
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http://dx.doi.org/10.1051/medsci/2020243DOI Listing
December 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.
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http://dx.doi.org/10.1080/21678421.2020.1730904DOI Listing
May 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.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104652DOI Listing
April 2020

Cryptococcal meningoencephalitis presenting as cerebral venous thrombosis.

J Neurovirol 2020 04 20;26(2):289-291. Epub 2019 Dec 20.

Neurology Department, University Hospital Donostia, San Sebastian, Spain.

Cerebral venous thrombosis (CVT) is characterized by its variety of neurological manifestations and difficulty in diagnosis. In subacute cases, the main symptoms are secondary to increased intracranial pressure. This condition is associated with an extensive range of medical disorders, but only 2% are caused by a CNS infection in recent series. We report a 45-year-old patient, with no previous medical history, who developed a syndrome of increased intracranial pressure as the presentation of a cryptococcal meningoencephalitis (CM) complicated with a CVT. The patient was first diagnosed of a CVT, and later on, the VIH infection and the CM diagnosis were made. Despite being treated with anticoagulation, liposomal amphotericin B, and a therapeutic lumbar puncture, the patient continued to deteriorate and suffered a respiratory arrest secondary to the increased intracranial pressure, with subsequent brain death. Cryptococcus is an infrequent cause of CNS infection in developed countries, despite being the most frequent cause of meningits in adults in several countries with high rates of HIV infection. CVT is a very rare complication of CM which can contribute to worsen the increased intracranial pressure and in consequence, its prognosis and outcome. A high level of suspicion is needed for diagnosing CM as the underlying cause of CVT and the subsequent increased intracranial pressure should be managed exhaustively.
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http://dx.doi.org/10.1007/s13365-019-00813-3DOI Listing
April 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.
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http://dx.doi.org/10.1002/acn3.50967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952318PMC
January 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.
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http://dx.doi.org/10.18632/aging.102517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914389PMC
November 2019

Vemurafenib as first-line therapy in -V600E-mutant Erdheim-Chester disease with CNS involvement.

BMJ Case Rep 2019 Nov 19;12(11). Epub 2019 Nov 19.

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

Erdheim-Chester disease (ECD) is a rare histiocytosis that may affect the central nervous system (CNS). Infiltration by the disease occurs throughout the neuroaxis, usually involving the dentate nucleus and the pons, manifested as a pyramido-cerebellar syndrome. CNS involvement is an adverse prognostic factor which warrants prompt evaluation and treatment. mutation occurs in more than half of the cases and has become central in the therapeutic approach. There is rapidly growing evidence that BRAF inhibitors such as vemurafenib or dabrafenib are effective in treating CNS-spread disease. We present a patient with -V600E-mutant ECD with a classical pyramido-ataxic onset of disease who improved after prompt diagnosis with vemurafenib treatment as first-line therapy.
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http://dx.doi.org/10.1136/bcr-2018-228280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887387PMC
November 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

Gut microbiome and serum metabolome analyses identify molecular biomarkers and altered glutamate metabolism in fibromyalgia.

EBioMedicine 2019 Aug 18;46:499-511. Epub 2019 Jul 18.

Exosomes Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, Derio, Spain; Metabolomics Platform, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, Derio, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. Electronic address:

Background: Fibromyalgia is a complex, relatively unknown disease characterised by chronic, widespread musculoskeletal pain. The gut-brain axis connects the gut microbiome with the brain through the enteric nervous system (ENS); its disruption has been associated with psychiatric and gastrointestinal disorders. To gain an insight into the pathogenesis of fibromyalgia and identify diagnostic biomarkers, we combined different omics techniques to analyse microbiome and serum composition.

Methods: We collected faeces and blood samples to study the microbiome, the serum metabolome and circulating cytokines and miRNAs from a cohort of 105 fibromyalgia patients and 54 age- and environment-matched healthy individuals. We sequenced the V3 and V4 regions of the 16S rDNA gene from faeces samples. UPLC-MS metabolomics and custom multiplex cytokine and miRNA analysis (FirePlex™ technology) were used to examine sera samples. Finally, we combined the different data types to search for potential biomarkers.

Results: We found that the diversity of bacteria is reduced in fibromyalgia patients. The abundance of the Bifidobacterium and Eubacterium genera (bacteria participating in the metabolism of neurotransmitters in the host) in these patients was significantly reduced. The serum metabolome analysis revealed altered levels of glutamate and serine, suggesting changes in neurotransmitter metabolism. The combined serum metabolomics and gut microbiome datasets showed a certain degree of correlation, reflecting the effect of the microbiome on metabolic activity. We also examined the microbiome and serum metabolites, cytokines and miRNAs as potential sources of molecular biomarkers of fibromyalgia.

Conclusions: Our results show that the microbiome analysis provides more significant biomarkers than the other techniques employed in the work. Gut microbiome analysis combined with serum metabolomics can shed new light onto the pathogenesis of fibromyalgia. We provide a list of bacteria whose abundance changes in this disease and propose several molecules as potential biomarkers that can be used to evaluate the current diagnostic criteria.
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http://dx.doi.org/10.1016/j.ebiom.2019.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710987PMC
August 2019

Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloidβ Are Strongly Associated With Healthy Aging in the Oldest Old.

Front Aging Neurosci 2018 28;10:380. Epub 2018 Nov 28.

Department of Neurology, Donostia Universitary Hospital, San Sebastián, Spain.

Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell or PBMC telomere length, circulating Aβ peptides, anti-Aβ antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians ( = 20) and functionally impaired, institutionalized nonagenarians ( = 38) recruited between 2014 and 2015. We recruited 58 nonagenarians (41 women, 70.7%; mean age: 92.37 years in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths (mean = 7, = 0.001), this being inversely correlated with functional impairment, and lower circulating Aβ40 (total in plasma fraction or TP and free in plasma fraction or FP), Aβ42 (TP and FP) and Aβ17 (FP) levels (FP40 131.35, = 0.004; TP40 299.10, = 0.007; FP42 6.29, = 0.009; TP42 22.53, = 0.019; FP17 1.32 = 0.001; TP17 4.47, = 0.3), after adjusting by age. Although healthy nonagenarians had higher anti-Aβ40 antibody levels (net adsorbed signal or NAS ± SD: 0.211 ± 0.107), the number of participants that pass the threshold (NAS > 3) to be considered as positive did not show such a strong association. There was no association with ApoE status. Additionally, we propose a " combining TP40 and mean PBMC telomere length, the strongest correlation of measured biomarkers with neurologically healthy status in nonagenarians (AUC = 0.904).
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http://dx.doi.org/10.3389/fnagi.2018.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280560PMC
November 2018

Clinical evidences supporting the Src/c-Abl pathway as potential therapeutic target in amyotrophic lateral sclerosis.

J Neurol Sci 2018 10 11;393:80-82. Epub 2018 Aug 11.

CIBERNED (Center for Networked Biomedical Research on Neurodegenerative Diseases), Ministry of Economy and Competitiveness, Institute Carlos III, Madrid, Spain; Neurosciences Area, Institute Biodonostia, San Sebastián, Spain; Department of Neurology, University Hospital Donostia, San Sebastián, Spain; Department of Neurosciences, University of the Basque Country UPV-EHU, San Sebastián, Spain.

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http://dx.doi.org/10.1016/j.jns.2018.08.013DOI Listing
October 2018

Internal Carotid Artery Web as the Cause of Recurrent Cryptogenic Ischemic Stroke.

J Stroke Cerebrovasc Dis 2018 May 10;27(5):e86-e87. Epub 2018 Jan 10.

Neurology Department, Hospital Universitario Donostia, Gipuzkoa, Spain.

Carotid artery web is considered an exceptional cause of recurrent ischemic strokes in the affected arterial territory. The underlying pathology proposed for this entity is an atypical fibromuscular dysplasia. We present the case of a 43-year-old woman with no cardiovascular risk factors who had experienced 2 cryptogenic ischemic strokes in the same arterial territory within an 11-month period. Although all diagnostic tests initially yielded normal results, detailed analysis of the computed tomography angiography images revealed a carotid web; catheter angiography subsequently confirmed the diagnosis. Carotid surgery was performed, since which time the patient has remained completely asymptomatic. The histological finding of intimal hyperplasia is consistent with previously reported cases of carotid artery web. Carotid artery web is an infrequent cause of stroke, and this diagnosis requires a high level of suspicion plus a detailed analysis of vascular imaging studies.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.012DOI Listing
May 2018