Publications by authors named "Jorge Alonso-Perez"

14 Publications

  • Page 1 of 1

Intramuscular fatty infiltration and physical function in controlled acromegaly.

Eur J Endocrinol 2021 Jun 5;185(1):167-177. Epub 2021 Jun 5.

IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain.

Introduction: Patients with acromegaly show musculoskeletal symptoms which may persist despite disease control. Increased i.m. fat fraction is a known cause of muscle dysfunction in several disorders.

Objective: To assess the degree of fat fraction in thigh muscles of controlled acromegaly patients and its relationship with muscle dysfunction.

Methods: In a cross-sectional study, we included 36 patients with controlled acromegaly and 36 matched controls. We assessed the percentage of fat fraction in each thigh muscle, using MRI 2-point Dixon sequence, and muscle performance and strength using the gait speed, timed up and go, 30-s chair stand, and hand grip strength tests. We evaluated joint symptoms using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC).

Results: Intramuscular fat fraction was greater in patients than controls (P < 0.05 for muscle compartments, rectus femoris (RF), vastus intermedius (VI), adductor magnus (AM) and semimembranosus). Patients had slower gait speed and poorer performance on the 30-s chair stand and timed up and go tests than controls (P < 0.05). The greater fat fraction in the combined anterior-posterior compartment and in each muscle was associated with worse performance on timed up and go (P < 0.05). The fat fraction in the anterior-posterior compartment predicted performance on timed up and go after adjusting for muscle area, IGF-I and WOMAC functional and pain scores (β = 0.737 P < 0.001).

Conclusions: Patients with controlled acromegaly have greater thigh i.m. fatty infiltration, which is associated with muscle dysfunction. Futures studies are needed to elucidate the mechanisms underlying this relationship.
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http://dx.doi.org/10.1530/EJE-21-0209DOI Listing
June 2021

Magnetization Transfer Ratio in Lower Limbs of Late Onset Pompe Patients Correlates With Intramuscular Fat Fraction and Muscle Function Tests.

Front Neurol 2021 16;12:634766. Epub 2021 Mar 16.

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

Magnetization transfer (MT) imaging exploits the interaction between bulk water protons and protons contained in macromolecules to induce signal changes through a special radiofrequency pulse. MT detects muscle damage in patients with neuromuscular conditions, such as limb-girdle muscular dystrophies or Charcot-Marie-Tooth disease, which are characterized by progressive fiber loss and replacement by fatty tissue. In Pompe disease, in which there is, in addition, an accumulation of glycogen inside the muscle fibers, MT has not been tested yet. Our aim is to estimate MT ratio (MTR) in the skeletal muscle of these patients and correlate it with intramuscular fat fraction (FF) and results of muscle function tests. We obtained two-point axial Dixon and Dixon-MT sequences of the right thigh on a 1.5 Teslas MRI scanner in 60 individuals, including 29 late onset Pompe disease patients, 2 patients with McArdle disease, and 29 age and sex matched healthy controls. FF and MTR were estimated. Muscle function using several muscle function tests, including quantification of muscle strength, timed test quality of life scales, conventional spirometry obtaining forced vital capacity while sitting and in the supine position, were assessed in all patients. MTR was significantly lower in Pompe patients compared with controls (45.5 ± 8.5 vs. 51.7 ± 2.3, Student -test, < 0.05). There was a negative correlation between the MTR and FF muscles studied (correlation coefficient: -0.65, Spearman test: < 0.05). MTR correlated with most of the muscle function test results. We analyzed if there was any difference in MTR values between Pompe patients and healthy controls in those muscles that did not have an increase in fat, a measure that could be related to the presence of glycogen in skeletal muscles, but we did not identify significant differences except in the adductor magnus muscle (48.4 ± 3.6 in Pompe vs. 51 ± 1.3 in healthy controls, Student -test = 0.023). MTR is a sensitive tool to identify muscle loss in patients with Pompe disease and shows a good correlation with muscle function tests. Therefore, the MT technique can be useful in monitoring muscle degeneration in Pompe disease in clinical trials or natural history studies.
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http://dx.doi.org/10.3389/fneur.2021.634766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009135PMC
March 2021

Correlation Between Respiratory Accessory Muscles and Diaphragm Pillars MRI and Pulmonary Function Test in Late-Onset Pompe Disease Patients.

Front Neurol 2021 1;12:621257. Epub 2021 Mar 1.

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

Pompe disease is a rare genetic disease produced by mutations in the GAA gene leading to progressive skeletal and respiratory muscle weakness. T1-weighted magnetic resonance imaging is useful to identify fatty replacement in skeletal muscles of late-onset Pompe disease (LOPD) patients. Previous studies have shown that replacement by fat correlates with worse results of muscle function tests. Our aim was to investigate if fat replacement of muscles involved in the ventilation process correlated with results of the spirometry and predicted respiratory muscle impairment in LOPD patients over time. We studied a cohort of 36 LOPD patients followed up annually in our center for a period of 4 years. We quantified muscle fat replacement using Mercuri score of the thoracic paraspinal and abdominal muscles and the pillars of the diaphragm. We correlated the combined Mercuri scores of these areas with spirometry results and the need of respiratory support. We found a statistically significant correlation (Spearman test, < 0.05; coefficient of correlation > 0.6) between forced vital capacity seated and lying and fat fraction score of all muscle groups studied. The group of patients who needed respiratory support had higher fat fraction scores than patients not requiring ventilatory support. Higher fat replacement in these areas correlated with worse progression in spirometry values over time. Fat replacement of paraspinal, abdominal, and trunk muscles correlates with results of spirometry and is able to predict worsening in respiratory muscle function tests that could lead to an emerging ventilatory dysfunction. Therefore, the identification of fat replacement in these muscle groups should lead to a closer monitorization of patients. Radiologic evaluation of diaphragm pillars in T1-weighted imaging axial sequences could also be helpful to predict respiratory insufficiency.
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http://dx.doi.org/10.3389/fneur.2021.621257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957052PMC
March 2021

STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa.

J Neurol 2021 Feb 5. Epub 2021 Feb 5.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University Munich, Ziemssenstr. 1, 80336, Munich, Germany.

Background: Pompe disease is one of the few neuromuscular diseases with an approved drug therapy, which has been available since 2006. Our study aimed to determine the real-world long-term efficacy and safety of alglucosidase alfa.

Methods: This multicenter retrospective study (NCT02824068) collected data from adult Pompe disease patients receiving ERT for at least 3 years. Demographics and baseline characteristics, muscle strength, lung function (FVC), walking capability (6MWT), and safety were assessed once a year. Evaluation was done on the group and individual levels, using quantitative linear models (t test) and general univariate linear models (ANOVA).

Findings: Sixty-eight adult Pompe disease patients from four countries (Spain, Taiwan, Italy, Germany (STIG)) participated. The mean follow-up was 7.03 years ± 2.98. At group level in all outcome measures, an initial improvement followed by a secondary decline was observed. After 10 years, the 6MWT showed the most sustained positive effect (p = 0.304). The MRC remained stable with a mild decline (p = 0.131), however, FVC deteriorated significantly (p < 0.001) by 14.93% over 10 years of ERT. The progression rate of FVC under ERT could be explained in most of the patients (83.5%) by the disease severity at baseline. Furthermore, our study shows a decline in the FVC combined with an increase in non-invasive and invasive ventilation requirements in adult Pompe disease patients over time.

Conclusions: The STIG real-world study confirms an initial efficacy of ERT in the first years with a secondary sustained decline in multiple outcome measures. Further efforts are required to establish a more valid long-term monitoring and improved therapies.
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http://dx.doi.org/10.1007/s00415-021-10409-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862044PMC
February 2021

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

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

Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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

The increasing role of muscle MRI to monitor changes over time in untreated and treated muscle diseases.

Curr Opin Neurol 2020 10;33(5):611-620

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

Purpose Of Review: This review aims to discuss the recent results of studies published applying quantitative MRI sequences to large cohorts of patients with neuromuscular diseases.

Recent Findings: Quantitative MRI sequences are now available to identify and quantify changes in muscle water and fat content. These two components have been associated with acute and chronic injuries, respectively. Studies show that the increase in muscle water is not only reversible if therapies are applied successfully but can also predict fat replacement in neurodegenerative diseases. Muscle fat fraction correlates with muscle function tests and increases gradually over time in parallel with the functional decline of patients with neuromuscular diseases. There are new spectrometry-based sequences to quantify other components, such as glycogen, electrolytes or the pH of the muscle fibre, extending the applicability of MRI to the study of several processes in neuromuscular diseases.

Summary: The latest results obtained from the study of long cohorts of patients with various neuromuscular diseases open the door to the use of this technology in clinical trials, which would make it possible to obtain a new measure for assessing the effectiveness of new treatments. The challenge is currently the popularization of these studies and their application to the monitoring of patients in the daily clinic.
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http://dx.doi.org/10.1097/WCO.0000000000000851DOI Listing
October 2020

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy.

Sci Rep 2020 06 22;10(1):10111. Epub 2020 Jun 22.

Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1-49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age.
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http://dx.doi.org/10.1038/s41598-020-66940-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308386PMC
June 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.
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http://dx.doi.org/10.3390/genes11050539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288461PMC
May 2020

Thrombospondin-1 mediates muscle damage in brachio-cervical inflammatory myopathy and systemic sclerosis.

Neurol Neuroimmunol Neuroinflamm 2020 05 6;7(3). Epub 2020 Mar 6.

From the Neuromuscular Diseases Unit (X.S.-C., J.A.-P., A.C.-R., E.F.-S., A.A.-J., R.R.-G., J.T., L.Q., N.d.L., E.C.-V., I.I., E.G., J.D.-M.), Neurology Department, Hospital de la Santa CreuiSant Pau and Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER) (X.S.-C., R.R.-G., L.Q., N.d.L., E.C.-V., I.I., E.G., J.D.-M.), Madrid; John Walton Muscular Dystrophy Research Center (J.D.-M), University of Newcastle, UK; Rheumatology Unit (I.C., A.M.-n.-M., H.C.), Hospital de la Santa Creu i Sant Pau; Laboratory of Experimental Immunology (C.Z.), Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau); Servei Immunologia (L.M.-M.), Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau); and Department of Respiratory Medicine (D.C.), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Objective: To describe the clinical, serologic and histologic features of a cohort of patients with brachio-cervical inflammatory myopathy (BCIM) associated with systemic sclerosis (SSc) and unravel disease-specific pathophysiologic mechanisms occurring in these patients.

Methods: We reviewed clinical, immunologic, muscle MRI, nailfold videocapillaroscopy, muscle biopsy, and response to treatment data from 8 patients with BCIM-SSc. We compared cytokine profiles between patients with BCIM-SSc and SSc without muscle involvement and controls. We analyzed the effect of the deregulated cytokines in vitro (fibroblasts, endothelial cells, and muscle cells) and in vivo.

Results: All patients with BCIM-SSc presented with muscle weakness involving cervical and proximal muscles of the upper limbs plus Raynaud syndrome, telangiectasia and/or sclerodactilia, hypotonia of the esophagus, and interstitial lung disease. Immunosuppressive treatment stopped the progression of the disease. Muscle biopsy showed pathologic changes including the presence of necrotic fibers, fibrosis, and reduced capillary number and size. Cytokines involved in inflammation, angiogenesis, and fibrosis were deregulated. Thrombospondin-1 (TSP-1), which participates in all these 3 processes, was upregulated in patients with BCIM-SSc. In vitro, TSP-1 and serum of patients with BCIM-SSc promoted proliferation and upregulation of collagen, fibronectin, and transforming growth factor beta in fibroblasts. TSP-1 disrupted vascular network, decreased muscle differentiation, and promoted hypotrophic myotubes. In vivo, TSP-1 increased fibrotic tissue and profibrotic macrophage infiltration in the muscle.

Conclusions: Patients with SSc may present with a clinically and pathologically distinct myopathy. A prompt and correct diagnosis has important implications for treatment. Finally, TSP-1 may participate in the pathologic changes observed in muscle.
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http://dx.doi.org/10.1212/NXI.0000000000000694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136050PMC
May 2020

Follow-up of late-onset Pompe disease patients with muscle magnetic resonance imaging reveals increase in fat replacement in skeletal muscles.

J Cachexia Sarcopenia Muscle 2020 08 4;11(4):1032-1046. Epub 2020 Mar 4.

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

Background: Late-onset Pompe disease (LOPD) is a genetic disorder characterized by progressive degeneration of the skeletal muscles produced by a deficiency of the enzyme acid alpha-glucosidase. Enzymatic replacement therapy with recombinant human alpha-glucosidase seems to reduce the progression of the disease; although at the moment, it is not completely clear to what extent. Quantitative muscle magnetic resonance imaging (qMRI) is a good biomarker for the follow-up of fat replacement in neuromuscular disorders. The aim of this study was to describe the changes observed in fat replacement in skeletal muscles using qMRI in a cohort of LOPD patients followed prospectively.

Methods: A total of 36 LOPD patients were seen once every year for 4 years. qMRI, several muscle function tests, spirometry, activities of daily living scales, and quality-of-life scales were performed on each visit. Muscle MRI consisted of two-point Dixon studies of the trunk and thigh muscles. Computer analysis of the images provided the percentage of muscle degenerated and replaced by fat in every muscle (known as fat fraction). Longitudinal analysis of the measures was performed using linear mixed models applying the Greenhouse-Geisser test.

Results: We detected a statistically significant and continuous increase in mean thigh fat fraction both in treated (+5.8% in 3 years) and in pre-symptomatic patients (+2.6% in 3years) (Greenhouse-Geisser p < 0.05). As an average, fat fraction increased by 1.9% per year in treated patients, compared with 0.8% in pre-symptomatic patients. Fat fraction significantly increased in every muscle of the thighs. We observed a significant correlation between changes observed in fat fraction in qMRI and changes observed in the results of the muscle function tests performed. Moreover, we identified that muscle performance and mean thigh fat fraction at baseline visit were independent parameters influencing fat fraction progression over 4 years (analysis of covariance, p < 0.05).

Conclusions: Our study identifies that skeletal muscle fat fraction continues to increase in patients with LOPD despite the treatment with enzymatic replacement therapy. These results suggest that the process of muscle degeneration is not stopped by the treatment and could impact muscle function over the years. Hereby, we show that fat fraction along with muscle function tests can be considered a good outcome measures for clinical trials in LOPD patients.
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http://dx.doi.org/10.1002/jcsm.12555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432562PMC
August 2020

Accuracy of a machine learning muscle MRI-based tool for the diagnosis of muscular dystrophies.

Neurology 2020 03 6;94(10):e1094-e1102. Epub 2020 Feb 6.

From the Neuromuscular Disorders Unit, Neurology Department (J.V.-D., J.A.-P., I.I., J.D.-M.), and Radiology Department (C.N.-P., J.L.), Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; UOC di Neurologia (G.T.), Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Copenhagen Neuromuscular Center, Department of Neurology (J.V.), Rigshospitalet, University of Copenhagen, Denmark; John Walton Muscular Dystrophy Research Centre (V.S., J.D.-M.), University of Newcastle, Newcastle Upon Tyne, UK; Hospital Universitario Donostia (R.F.-T.); and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (I.I., J.D.-M.), Madrid, Spain.

Objective: Genetic diagnosis of muscular dystrophies (MDs) has classically been guided by clinical presentation, muscle biopsy, and muscle MRI data. Muscle MRI suggests diagnosis based on the pattern of muscle fatty replacement. However, patterns overlap between different disorders and knowledge about disease-specific patterns is limited. Our aim was to develop a software-based tool that can recognize muscle MRI patterns and thus aid diagnosis of MDs.

Methods: We collected 976 pelvic and lower limbs T1-weighted muscle MRIs from 10 different MDs. Fatty replacement was quantified using Mercuri score and files containing the numeric data were generated. Random forest supervised machine learning was applied to develop a model useful to identify the correct diagnosis. Two thousand different models were generated and the one with highest accuracy was selected. A new set of 20 MRIs was used to test the accuracy of the model, and the results were compared with diagnoses proposed by 4 specialists in the field.

Results: A total of 976 lower limbs MRIs from 10 different MDs were used. The best model obtained had 95.7% accuracy, with 92.1% sensitivity and 99.4% specificity. When compared with experts on the field, the diagnostic accuracy of the model generated was significantly higher in a new set of 20 MRIs.

Conclusion: Machine learning can help doctors in the diagnosis of muscle dystrophies by analyzing patterns of muscle fatty replacement in muscle MRI. This tool can be helpful in daily clinics and in the interpretation of the results of next-generation sequencing tests.

Classification Of Evidence: This study provides Class II evidence that a muscle MRI-based artificial intelligence tool accurately diagnoses muscular dystrophies.
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http://dx.doi.org/10.1212/WNL.0000000000009068DOI Listing
March 2020

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

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

Hospital Gregorio Marañón, Madrid, Spain.

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

Spanish Pompe registry: Baseline characteristics of first 49 patients with adult onset of Pompe disease.

Med Clin (Barc) 2020 02 26;154(3):80-85. Epub 2019 Jun 26.

Unidad de Patología Neuromuscular, Departamento de Neurología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Electronic address:

Introduction And Objectives: Pompe disease is a rare autosomal recessive disorder produced by a deficiency of acid maltase. This deficit produces an accumulation of glycogen in tissues. Clinically it is mainly characterized by limb girdle and respiratory muscle weakness. In 2013, we developed the Spanish Pompe Registry. The objective of this article was to analyse the characteristics of the first 49 patients and disclose the existence of this registry within the medical community.

Material And Methods: An observational retrospective study was undertaken. We analysed the 49 patients included in the Spanish Registry of Pompe Disease from May 2013 to October 2018.

Results: Patients were visited at 7 different Spanish hospitals. Twenty-six patients were women and 23 were men. The average age at the time of the analysis was 47.2 years. Ten patients were asymptomatic. The mean age of onset of symptoms was 29, and low limb girdle weakness was the most frequent initial symptom. Of the patients, 49% had respiratory involvement, and 70.8% of them required non-invasive mechanical ventilation. The most common mutation found was IVS1-13T>G in 85.3% of the patients. All symptomatic patients received treatment with ERT.

Conclusions: This registry allows us to know the clinical and genetic characteristics of adult patients with Pompe disease in Spain. Moreover, it can be the basis for future studies of natural history to understand the impact of ERT in the course of the disease.
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http://dx.doi.org/10.1016/j.medcli.2019.03.036DOI Listing
February 2020

PDGF-BB serum levels are decreased in adult onset Pompe patients.

Sci Rep 2019 02 14;9(1):2139. Epub 2019 Feb 14.

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

Adult onset Pompe disease is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzymatic replacement therapy with human recombinant alfa glucosidase. Motor functional tests and spirometry are commonly used to follow patients up. However, a serological biomarker that correlates with the progression of the disease could improve follow-up. We studied serum concentrations of TGFβ, PDGF-BB, PDGF-AA and CTGF growth factors in 37 adult onset Pompe patients and 45 controls. Moreover, all patients performed several muscle function tests, conventional spirometry, and quantitative muscle MRI using 3-point Dixon. We observed a statistically significant change in the serum concentration of each growth factor in patients compared to controls. However, only PDGF-BB levels were able to differentiate between asymptomatic and symptomatic patients, suggesting its potential role in the follow-up of asymptomatic patients. Moreover, our results point to a dysregulation of muscle regeneration as an additional pathomechanism of Pompe disease.
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http://dx.doi.org/10.1038/s41598-018-38025-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375999PMC
February 2019