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3.
Rev Neurol ; 73(9): 337-338, 2021 11 01.
Article in Spanish | MEDLINE | ID: mdl-34676531

ABSTRACT

TITLE: Quince años de la terapia enzimática en la enfermedad de Pompe.


Subject(s)
Enzyme Replacement Therapy , Glycogen Storage Disease Type II/drug therapy , Humans , Time Factors
5.
Eur J Neurol ; 27(12): 2604-2615, 2020 12.
Article in English | MEDLINE | ID: mdl-32697863

ABSTRACT

BACKGROUND AND PURPOSE: The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data. METHODS: Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1-weighted and short-tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema. RESULTS: The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro-caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2. CONCLUSION: This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD-related disease spectrum.


Subject(s)
Muscular Dystrophy, Facioscapulohumeral , Humans , Lower Extremity , Magnetic Resonance Imaging , Muscle, Skeletal/diagnostic imaging , Muscular Dystrophy, Facioscapulohumeral/diagnostic imaging , Muscular Dystrophy, Facioscapulohumeral/genetics
6.
Eur J Neurol ; 27(8): 1364-1373, 2020 08.
Article in English | MEDLINE | ID: mdl-32320108

ABSTRACT

BACKGROUND AND PURPOSE: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMNs). A series of BSCL2 patients is presented and clinical, neurophysiological and muscle magnetic resonance imaging (MRI) findings are correlated. METHODS: Twenty-six patients from five families carrying the p.N88S mutation were identified. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth, spastic paraplegia), physical examination, disability measured as a modified Rankin Scale score and neurophysiological findings were collected. A whole body muscle MRI had been performed in 18 patients. The pattern of muscle involvement on T1-weighted and short time inversion recovery sequences was analysed. Hierarchical analysis using heatmaps and an MRI Composite Score were generated. Statistical analysis was carried out with STATA SE v.15 (TX, USA). RESULTS: The mean age was 51.54 ± 19.94 years and 14 patients were men. dHMN was the most common phenotype (50%) and five patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (modified Rankin Scale score 1.34 ± 1.13) although median time since onset of disease was 32 years (range 10-47). Charcot-Marie-Tooth-like patients were more disabled and disability correlated with age. On muscle MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI Composite Score was strongly correlated with disability. CONCLUSION: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials.


Subject(s)
Charcot-Marie-Tooth Disease , GTP-Binding Protein gamma Subunits/metabolism , Hereditary Sensory and Motor Neuropathy , Adult , Aged , Charcot-Marie-Tooth Disease/diagnostic imaging , Charcot-Marie-Tooth Disease/genetics , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Mutation , Phenotype
8.
Neurologia (Engl Ed) ; 35(3): 185-206, 2020 Apr.
Article in English, Spanish | MEDLINE | ID: mdl-31003788

ABSTRACT

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.


Subject(s)
Genetic Counseling , Myotonic Dystrophy/diagnosis , Myotonic Dystrophy/genetics , Practice Guidelines as Topic/standards , Deglutition Disorders , Follow-Up Studies , Humans , Myotonic Dystrophy/complications
9.
Rev Neurol ; 66(8): 268-270, 2018 Apr 16.
Article in Spanish | MEDLINE | ID: mdl-29645070

ABSTRACT

INTRODUCTION: The differential diagnosis of diseases that are accompanied by adult-onset girdle weakness is broad and includes motor neurone, neuromuscular junction or muscular diseases. The 8344A>G mutation of the MTTK gene of mitochondrial DNA usually presents with involvement of multiple organs associated (or not) with girdle weakness. To date no cases of isolated girdle weakness have been reported as the presenting symptom of this mutation. CASE REPORT: A 57-year-old male, with a four-year history of isolated clinical signs of progressive girdle weakness. He is the brother of a 59-year-old woman with the same clinical features. Muscular biopsy played a decisive role in the diagnosis and was characteristic of mitochondrial myopathy. The genetic analysis revealed the 8344A>G mutation of the MTTK gene of mitochondrial DNA. CONCLUSIONS: The 8344A>G mutation of mitochondrial DNA can be associated with clinical signs and symptoms of adult-onset girdle weakness, and must therefore be included as part of its differential diagnosis.


TITLE: Debilidad aislada de cinturas: ampliacion del espectro fenotipico de la mutacion MERRF 8344A>G del ADN mitocondrial.Introduccion. El diagnostico diferencial de los trastornos que cursan con debilidad de cinturas de inicio en la edad adulta es amplio e incluye enfermedades de neurona motora, union neuromuscular o musculo. La mutacion m.8344A>G del gen MTTK del ADN mitocondrial suele presentarse con afectacion de multiples organos asociada o no a una debilidad de cinturas. No se han descrito hasta el momento casos de debilidad de cinturas aislada como sintoma de presentacion de esta mutacion. Caso clinico. Varon de 57 años, con clinica aislada de debilidad progresiva de cinturas, de cuatro años de evolucion. Hermano de una mujer de 59 años con la misma sintomatologia. La biopsia muscular fue decisiva en el diagnostico y es caracteristica de una miopatia mitocondrial. El analisis genetico objetivo la mutacion m.8344A>G del gen MTTK del ADN mitocondrial. Conclusiones. La mutacion 8344A>G del ADN mitocondrial puede cursar con un cuadro aislado de debilidad de cinturas de inicio en el adulto, por lo que debe de formar parte del diagnostico diferencial de este.


Subject(s)
DNA, Mitochondrial/genetics , MERRF Syndrome/genetics , Muscle Weakness/genetics , Mutation, Missense , Point Mutation , RNA, Transfer, Lys/genetics , Age of Onset , Diagnosis, Differential , Genetic Association Studies , Humans , MERRF Syndrome/diagnosis , MERRF Syndrome/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Muscle Weakness/diagnosis , Muscle Weakness/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/ultrastructure , Phenotype
11.
Neuromuscul Disord ; 27(12): 1087-1098, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29054425

ABSTRACT

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.


Subject(s)
Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/physiopathology , Adolescent , Adult , Female , Humans , Male , Middle Aged , Myasthenic Syndromes, Congenital/classification , Myasthenic Syndromes, Congenital/epidemiology , Spain/epidemiology , Young Adult
12.
Neuromuscul Disord ; 25(7): 548-53, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25998610

ABSTRACT

We aimed to screen for Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) or asymptomatic hyperCKemia using dried blood spot (DBS) assays. Subsequently, we aimed to calculate the diagnostic delay between initial symptom presentation and the diagnosis. A prospective, multicenter, observational study was conducted in 348 patients: 146 with unclassified LGMD and 202 with asymptomatic or paucisymptomatic hyperCKemia. We quantified levels of acid alpha-glucosidase (GAA) from dried blood spots analyzed fluorometrically. The test was positive in 20 patients, and Pompe disease was confirmed by genetic testing in 16. Undiagnosed Pompe disease was detected in 7.5% of patients with LGMD and in 2.5% of patients with persistent, idiopathic elevation of serum creatine kinase. The c.-32-13 T > G mutation was found most commonly. The diagnostic delay was 15 years on average. In conclusion, DBS tests are useful and reliable screening tools for Pompe disease. We recommend the dried blood spot test to be included in the diagnostic work-up of patients with unclassified myopathies with proximal weakness and/or hyperCKemia of unknown cause and, when positive, to define the diagnosis, it will have to be confirmed by biochemical and/or molecular genetic analysis.


Subject(s)
Creatine Kinase/blood , Dried Blood Spot Testing , Glycogen Storage Disease Type II/blood , Glycogen Storage Disease Type II/diagnosis , Metabolic Diseases/blood , Muscular Dystrophies, Limb-Girdle/blood , Adolescent , Adult , Aged , Aged, 80 and over , Delayed Diagnosis , Female , Genetic Testing , Glycogen Storage Disease Type II/complications , Glycogen Storage Disease Type II/enzymology , Humans , Male , Metabolic Diseases/complications , Metabolic Diseases/genetics , Middle Aged , Muscular Dystrophies, Limb-Girdle/complications , Muscular Dystrophies, Limb-Girdle/enzymology , Mutation , Prospective Studies , Young Adult , alpha-Glucosidases/blood
15.
Neurology ; 78(3): 189-93, 2012 Jan 17.
Article in English | MEDLINE | ID: mdl-22218276

ABSTRACT

OBJECTIVE: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients. METHODS: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied. RESULTS: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3. CONCLUSION: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Autoantibodies/blood , Myasthenia Gravis/blood , Myasthenia Gravis/drug therapy , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Adult , Female , Humans , Immunologic Factors/therapeutic use , Longitudinal Studies , Male , Myasthenia Gravis/diagnosis , Rituximab , Treatment Outcome
17.
Neurology ; 75(4): 316-23, 2010 Jul 27.
Article in English | MEDLINE | ID: mdl-20574037

ABSTRACT

BACKGROUND: The most frequent phenotypes of dysferlin myopathy are limb-girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy (MM). Our objective was to find clinical or MRI markers to differentiate phenotypes of dysferlin myopathy regardless of initial symptoms. METHODS: This retrospective study included 29 patients with confirmed mutations in the DYSF gene (14 MM, 12 LGMD2B, 1 asymptomatic hyperCKemia, and 2 symptomatic carriers). All underwent an annual clinical examination (Medical Research Council scale), functional status assessment, and creatine kinase, pulmonary, and cardiac testing. For research purposes, we performed lower limb MRI studies in all 29 patients to identify the pattern of muscle impairment and to quantify involvement. Statistical correlations between MRI findings and phenotype, disease duration, and functional status were determined. RESULTS: The mean clinical follow-up was 6.4 +/- 5.7 years. No significant differences were found in the rate of progression, functional prognosis, or mutations between patients with MM and patients with LGMD2B. The MRI pattern of muscle involvement was the same for patients with MM and patients with LGMD2B. The adductor magnus and gastrocnemius medialis were the first to be impaired in both phenotypes. The progression of muscle involvement correlated with clinical status. CONCLUSIONS: Splitting dysferlin myopathy into separate phenotypes does not reveal significant differences in terms of rate of progression, prognosis, genotype, or MRI pattern. The finding that proximal and distal muscles are already impaired in the MRI at onset in both MM and LGMD2B favors grouping all phenotypes under the term dysferlin myopathy.


Subject(s)
Magnetic Resonance Imaging , Membrane Proteins/genetics , Muscle Proteins/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/pathology , Activities of Daily Living , Adolescent , Adult , Aged , Child , Cohort Studies , Disease Progression , Dysferlin , Follow-Up Studies , Genotype , Humans , Infant , Leg/pathology , Middle Aged , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/physiopathology , Phenotype , Prognosis , Retrospective Studies , Severity of Illness Index , Young Adult
18.
Cell Death Dis ; 1: e61, 2010 Aug 05.
Article in English | MEDLINE | ID: mdl-21364666

ABSTRACT

Dysferlin deficiency leads to a peculiar form of muscular dystrophy due to a defect in sarcolemma repair and currently lacks a therapy. We developed a cell therapy protocol with wild-type adult murine mesoangioblasts. These cells differentiate with high efficiency into skeletal muscle in vitro but differ from satellite cells because they do not express Pax7. After intramuscular or intra-arterial administration to SCID/BlAJ mice, a novel model of dysferlinopathy, wild-type mesoangioblasts efficiently colonized dystrophic muscles and partially restored dysferlin expression. Nevertheless, functional assays performed on isolated single fibers from transplanted muscles showed a normal repairing ability of the membrane after laser-induced lesions; this result, which reflects gene correction of an enzymatic rather than a structural deficit, suggests that this myopathy may be easier to treat with cell or gene therapy than other forms of muscular dystrophies.


Subject(s)
Aging/pathology , Blood Vessels/metabolism , Blood Vessels/pathology , Membrane Proteins/metabolism , Muscular Dystrophies, Limb-Girdle/physiopathology , Recovery of Function/physiology , Animals , Biological Assay , Blood Vessels/transplantation , Disease Models, Animal , Dysferlin , Inflammation/pathology , Mice , Mice, Inbred C57BL , Mice, SCID , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/metabolism , Muscular Dystrophies, Limb-Girdle/pathology
19.
Eur J Neurol ; 15(10): 1085-90, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18717722

ABSTRACT

BACKGROUND AND PURPOSE: We performed an observational study that compared baseline and subsequent blood pressure (BP) measurements and its association with haematoma enlargement (HE) in patients with intracerebral haemorrhage (ICH). METHODS: We prospectively studied consecutive patients with supratentorial spontaneous ICH within the first 6 h after the onset of symptoms. HE was defined as an increase >or=33% in the volume of haematoma on the CT obtained 24-48 h after the onset of symptoms as compared with the CT at admission. We recorded systolic BP (SBP), diastolic BP (DBP) and mean BP (MBP) at admission and at 6, 12, 18 and 24 h after onset; the maximum SBP, DBP and MBP during the study period; the maximum SBP and DBP within intervals; the mean of all BP readings; administration of antihypertensive agents. RESULTS: We studied 60 patients whose mean age was 72.1 +/- 11.3 years. HE was observed in 27 (45%) patients. No statistically significant differences were observed in any of the analyses that compared BP parameters between the HE and non-HE groups (two-way anova). CONCLUSIONS: In an exploratory analysis, we did not find an association between BP and HE within the first 24 h after an acute ICH.


Subject(s)
Blood Pressure/physiology , Cerebral Hemorrhage/physiopathology , Cerebrovascular Circulation/physiology , Hematoma/physiopathology , Acute Disease , Aged , Aged, 80 and over , Antihypertensive Agents/therapeutic use , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/diagnostic imaging , Disease Progression , Female , Hematoma/diagnostic imaging , Hematoma/etiology , Homeostasis , Humans , Hypertension/complications , Hypertension/physiopathology , Male , Middle Aged , Prospective Studies , Tomography, X-Ray Computed
20.
Neurology ; 65(3): 366-70, 2005 Aug 09.
Article in English | MEDLINE | ID: mdl-16087899

ABSTRACT

OBJECTIVE: To determine whether pretreatment markers of coagulation and fibrinolysis are related to recanalization and functional outcome. METHODS: The authors included patients treated with IV rt-PA with occlusion on baseline transcranial Doppler (Thrombolysis in Brain Ischemia [TIBI] criteria) in whom recanalization within 6 hours was monitored. At baseline, the authors recorded data about demographics, vascular risk factors, the NIH Stroke Scale (NIHSS) score, early CT signs, etiology, blood glucose, and time to rt-PA. The authors also measured plasmatic markers of coagulation (fibrinogen, prothrombin fragments 1 + 2, Factor XIII, Factor VII) and fibrinolysis (alpha2-antiplasmin, Plasminogen Activator Inhibitor, Functional Thrombin Activatable Fibrinolysis Inhibitor [fTAFI]). A favorable outcome was defined as a modified Rankin score < 2 at 3 months. RESULTS: The authors studied 63 patients with a mean age of 67.3 +/- 12.5 years. The median NIHSS score was 16. Patients who recanalized had lower concentrations of alpha2-antiplasmin (87.5 +/- 18% vs 96.5 +/- 12.5%, p = 0.023) and fTAFI (91.7 +/- 26.7% vs 104.4 +/- 21%, p = 0.039). A multivariant logistic regression analysis showed that the level of alpha2-antiplasmin was the only predictive variable of recanalization (OR 0.95, 95% CI 0.91, 0.99, p = 0.038), while the NIHSS score was the only predictive variable of functional outcome (OR 0.81, 95% CI 0.72, 0.92, p = 0.001). CONCLUSION: Baseline levels of alpha2-antiplasmin were predictive of recanalization but were not related to the long-term outcome in patients treated with rt-PA within the first 3 hours.


Subject(s)
Brain Ischemia/drug therapy , Intracranial Thrombosis/drug therapy , Tissue Plasminogen Activator/administration & dosage , Aged , Biomarkers/blood , Blood Coagulation/drug effects , Blood Coagulation/physiology , Brain Ischemia/diagnostic imaging , Brain Ischemia/physiopathology , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/drug effects , Cerebral Arteries/physiopathology , Female , Fibrinolysis/drug effects , Fibrinolysis/physiology , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/therapeutic use , Humans , Injections, Intravenous , Intracranial Thrombosis/diagnostic imaging , Intracranial Thrombosis/physiopathology , Male , Middle Aged , Patient Selection , Prognosis , Prospective Studies , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/therapeutic use , Risk Factors , Time Factors , Tissue Plasminogen Activator/therapeutic use , Treatment Outcome , Ultrasonography, Doppler, Transcranial , alpha-2-Antiplasmin/metabolism
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