Publications by authors named "Miguel Urtasun"

9 Publications

  • Page 1 of 1

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

Clinical response to thalidomide in the treatment of intracranial tuberculomas: case report.

Clin Neuropharmacol 2013 Mar-Apr;36(2):70-2

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

We describe a patient with multiple intracranial tuberculomas resistant to standard care with antituberculosis drugs and corticosteroids who responded well to thalidomide. Adjunctive thalidomide may have a role in the management of refractory intracranial tuberculomas, although it should be used conservatively owing to its potential adverse events.
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http://dx.doi.org/10.1097/WNF.0b013e318285caa1DOI Listing
December 2013

[Functions and organisation of a neuro-oncology committee in hospitals with a neurosurgery service].

Neurocirugia (Astur) 2012 Jul 15;23(4):151-6. Epub 2012 Jul 15.

Comité de Neurooncología, Hospital Universitario Donostia, San Sebastián, EspañaMiembros del Grupo de Trabajo de Neurooncología de la SENEC.

The Neuro-Oncology Study Group (NOSG) at SENEC has commissioned the elaboration of the present document to the Neuro-Oncology Committee at Donostia University Hospital. It is intended to serve as a NOSG Consensus Guide and a proposed recommendation for the management of this pathological condition at all Spanish Hospitals, both public and private. Neuro-Oncology Committees must be established and active at all centres with a Neurosurgery Service, taking into account the specific diagnostic and therapeutic capacity available. The work presents an example of the constitution, functioning and experience of such a Committee, drawing on 8 years of multidisciplinary work with brain tumour patients.
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http://dx.doi.org/10.1016/j.neucir.2012.01.001DOI Listing
July 2012

Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations?

Muscle Nerve 2011 Nov;44(5):710-4

Biodonostia Institute, Hospital Donostia, Po. Dr. Begiristain s/n, 20014 San Sebastián, Basque Country, Spain.

Introduction: Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported.

Methods: We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation.

Results: The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain-3, suggesting "molecular complementation" in these patients.

Conclusion: We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain-3, resulting in an exceptionally benign phenotype.
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http://dx.doi.org/10.1002/mus.22194DOI Listing
November 2011

Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings.

Biol Psychiatry 2008 May 22;63(10):946-52. Epub 2007 Oct 22.

Servicio de Neurología, Hospital Donostia, San Sebastián, Spain.

Background: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease.

Methods: We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects.

Results: Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects.

Conclusions: Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.
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http://dx.doi.org/10.1016/j.biopsych.2007.08.015DOI Listing
May 2008

A common haplotype associated with the Basque 2362AG --> TCATCT mutation in the muscular calpain-3 gene.

Hum Biol 2004 Oct;76(5):731-41

Unidad de Genética, Hospital Donostia, San Sebastián, Basque Country, Spain.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG --> TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG --> TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG ----> TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG --> TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.
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http://dx.doi.org/10.1353/hub.2005.0002DOI Listing
October 2004

Familial prion diseases in the Basque Country (Spain).

Neuroepidemiology 2005 24;24(1-2):103-9. Epub 2004 Sep 24.

Service of Neurology, Hospital Cruces, Department of Neurosciences, University of the Basque Country, Baracaldo, Spain.

In 1995, a surveillance system for prion diseases was set up in the Basque Country, an autonomous region in northern Spain (2.1 million inhabitants). In the period from January 1993 to December 2003, we diagnosed 21 patients with familial prion diseases prospectively and another 4 patients retrospectively. They represent 35% of all the cases referred to the epidemiological registry. Two main possible explanations for this unusual high incidence of familial prion diseases are proposed: first, comprehensive case ascertainment by public health neurologists; second, a probable cluster of the D178N mutation within families of Basque origin related to a still unconfirmed common ancestor. Further genetic and genealogical studies should resolve this issue.
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http://dx.doi.org/10.1159/000081057DOI Listing
January 2005