Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 130
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Brain ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39045638

RESUMEN

Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.

2.
Am J Hum Genet ; 108(5): 840-856, 2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-33861953

RESUMEN

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.


Asunto(s)
Proteína Jagged-2/genética , Distrofias Musculares/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Línea Celular , Niño , Preescolar , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Femenino , Glucosiltransferasas/genética , Haplotipos/genética , Humanos , Proteína Jagged-1/genética , Proteína Jagged-2/química , Proteína Jagged-2/deficiencia , Proteína Jagged-2/metabolismo , Masculino , Proteínas de la Membrana/genética , Ratones , Persona de Mediana Edad , Modelos Moleculares , Músculos/metabolismo , Músculos/patología , Distrofias Musculares/patología , Mioblastos/metabolismo , Mioblastos/patología , Linaje , Fenotipo , Receptores Notch/metabolismo , Transducción de Señal , Secuenciación del Exoma , Adulto Joven
3.
Brain ; 146(9): 3800-3815, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36913258

RESUMEN

Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.


Asunto(s)
Enfermedades Musculares , Distrofia Muscular de Cinturas , Femenino , Masculino , Humanos , Mialgia/genética , Estudios Retrospectivos , Anoctaminas/genética , Mutación/genética , Enfermedades Musculares/epidemiología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/diagnóstico , Atrofia/patología
4.
Neurol Neurochir Pol ; 58(5): 498-502, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38935421

RESUMEN

INTRODUCTION: Lambert-Eaton myasthenic syndrome (LEMS) is an ultrarare neuromuscular disease with a triad of symptoms: muscle paresis, dysautonomy, and areflexia. Amifampridine is the symptomatic treatment of LEMS. AIM OF STUDY: To assess the effectiveness and safety of treatment in the real world. MATERIAL AND METHODS: 14 patients with non-neoplastic LEMS treated with amifampridine were enrolled in the study (female 42.9%, mean age 48.8 ± 11.4 years). The patients were assessed using the Quantitative Myasthenia Gravis (QMG) scale, QMG limb domain (LD) score, spirometry, Hand Grip Strength (GRIP) test, and repetitive nerve stimulation study (RNS) at baseline and at the end of follow-up. Diagnostic delay since first symptoms was from seven months up to 22 years. Treatment delay ranged from one to 26 years. The patients were treated and reevaluated after 21.1 ± 12.0 weeks (range 13-48). RESULTS: All of the patients improved in QMG score. Mean improvement was 5.1 ± 2.0 (range 1-8) points (p < 0.001) and this showed no correlation with the duration of the disease before treatment (p = 0.477). 85.7% of patients (N = 12) improved ≥ 3 points (clinically meaningful) in QMG. 78.6% of the patients improved in QMG LD (mean 2.2 ± 1.6 points (p < 0.001)). Also, forced vital capacity (FVC) improved after treatment (p = 0.031). Mean improvement in GRIP test was 7.0 ± 7.1 kg in the right hand and 5.2 ± 7.5 kg in the left hand (p < 0.001). In RNS before treatment, facilitation ( > 100%) was observed in 78.6% (N = 11) of patients, and was higher before treatment (p < 0.001). Compound muscle action potential (CMAP) amplitude was higher after treatment (p < 0.001). Mean increase of CMAP amplitude was 2.1 ± 1.6 times. In 64.3% (N = 9) of patients lowering of corticosteroid dose was achieved. CONCLUSIONS: Amifampridine is an effective treatment in non-neoplastic LEMS patients, regardless of disease duration. The treatment is well-tolerated and allows to reduce dose of corticosteroids in the majority of patients.


Asunto(s)
Amifampridina , Síndrome Miasténico de Lambert-Eaton , Humanos , Femenino , Síndrome Miasténico de Lambert-Eaton/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Adulto , Amifampridina/uso terapéutico , Resultado del Tratamiento , Fuerza de la Mano , Bloqueadores de los Canales de Potasio/uso terapéutico
5.
Eur J Neurol ; 30(1): 266-282, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36094738

RESUMEN

BACKGROUND AND PURPOSE: Although myasthenia gravis (MG) is recognized as an immunoglobulin G autoantibody-mediated disease, the relationship between autoantibody levels and disease activity in MG is unclear. We sought to evaluate this landscape through systematically assessing the evidence, testing the impact of predefined variables on any relationship, and augmenting with expert opinion. METHODS: In October 2020, a forum of leading clinicians and researchers in neurology from across Europe (Expert Forum for Rare Autoantibodies in Neurology in Myasthenia Gravis) participated in a series of virtual meetings that took place alongside the conduct of a systematic literature review (SLR). RESULTS: Forty-two studies were identified meeting inclusion criteria. Of these, 10 reported some correlation between a patient's autoantibody level and disease severity. Generally, decreased autoantibody levels (acetylcholine receptor, muscle-specific kinase, and titin) were positively and significantly correlated with improvements in disease severity (Quantitative Myasthenia Gravis score, Myasthenia Gravis Composite score, Myasthenia Gravis Activities of Daily Living score, Myasthenia Gravis Foundation of America classification). Given the limited evidence, testing the impact of predefined variables was not feasible. CONCLUSIONS: This first SLR to assess whether a correlation exists between autoantibody levels and disease activity in patients with MG has indicated a potential positive correlation, which could have clinical implications in guiding treatment decisions. However, in light of the limited and variable evidence, we cannot currently recommend routine clinical use of autoantibody level testing in this context. For now, patient's characteristics, clinical disease course, and laboratory data (e.g., autoantibody status, thymus histology) should inform management, alongside patient-reported outcomes. We highlight the need for future studies to reach more definitive conclusions on this relationship.


Asunto(s)
Actividades Cotidianas , Miastenia Gravis , Humanos , Miastenia Gravis/terapia , Miastenia Gravis/tratamiento farmacológico , Autoanticuerpos , Inmunoglobulina G , Biomarcadores
6.
J Stroke Cerebrovasc Dis ; 32(3): 106951, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36565520

RESUMEN

BACKGROUND: Transient global amnesia is a benign syndrome characterized by a sudden onset loss of anterograde amnesia with full recovery. Magnetic resonance of the brain including diffusion-weighted imaging of patients with transient global amnesia revealed the presence of punctate hyperintense signal abnormalities in the hippocampus. OBJECTIVE: Analysis of the presence of hippocampal lesions in brain magnetic resonance imaging in patients with transient global amnesia and the possible influence of additional factors on their appearance. METHODS: In this retrospective, an observational study we assessed brain magnetic resonance imaging in 38 consecutive patients with transient global amnesia. The incidence of brain magnetic resonance imaging lesions was analyzed for the coexisting cardiovascular risk factors and precipitating events. RESULTS: Hippocampal brain magnetic resonance imaging lesions were detected in 47% of patients with transient global amnesia. Of those, 65% had unilateral lesions, 82% were left-sided, and 28% were right-sided. Most lesions were located in the CA1 subfield. The incidence of hypertension in patients with transient global amnesia was higher than in the general population. Stress and exercise preceded the onset of transient global amnesia only in 13% and 16% of patients, respectively. There was no higher incidence of migraine in transient global amnesia patients (13%). CONCLUSIONS: We found that nearly 50% of patients with transient global amnesia had hyperintense hippocampal brain magnetic resonance imaging lesions. In addition to hypertension, individuals with transient global amnesia had similar cardiovascular risk factors as the general population. We did not identify any precipitating events prior to the onset of transient global amnesia.


Asunto(s)
Amnesia Global Transitoria , Hipertensión , Humanos , Amnesia Global Transitoria/diagnóstico por imagen , Amnesia Global Transitoria/epidemiología , Amnesia Global Transitoria/etiología , Estudios Retrospectivos , Imagen por Resonancia Magnética/efectos adversos , Imagen de Difusión por Resonancia Magnética/métodos , Hipocampo/patología , Hipertensión/complicaciones , Amnesia/complicaciones , Amnesia/patología
7.
Neurol Neurochir Pol ; 57(2): 143-150, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36478346

RESUMEN

INTRODUCTION: Pompe disease is a rare, autosomal recessive, lysosomal disorder caused by deficiency of alpha glucosidase (GAA). It leads to the accumulation of glycogen in body tissues, with severe myopathy and cardiomegaly as a hallmark of the classic infantile form. Non-classical, or late onset, Pompe disease (LOPD) manifests after 12 months of age or in adulthood. MATERIAL AND METHODS: The clinical heterogeneity of LOPD causes delay in diagnosis and pharmacological treatment. In the Polish population, it is still underdiagnosed, and the time from onset to diagnosis remains a cause for concern. CLINICAL IMPLICATIONS: Although typically patients present with proximal muscle weakness, high CK or early respiratory insufficiency, they can also suffer from multiple symptoms from other organs. Patients may present with arrhythmias, vascular abnormalities including aneurysms or dilative arteriopathy, gastric or urinary symptoms, or musculoskeletal pathologies. RESULTS: A high index of suspicion among neurologists consulting internal medicine wards would aid early diagnosis of LOPD, while a multidisciplinary approach with the involvement of other specialists can reduce the risk of complications and improve the prognosis for LOPD patients. Patients who manifest with musculoskeletal and respiratory symptoms are prone to be diagnosed sooner than individuals with non-muscular symptoms, and therefore it is important to raise awareness of other manifestations of this disease.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Neurólogos , Edad de Inicio , alfa-Glucosidasas
8.
Neurol Neurochir Pol ; 57(5): 430-437, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37706668

RESUMEN

INTRODUCTION: The main aim of our study was to compare diffusion tensor imaging (DTI) parameters in patients with myotonic dystrophy types 1 and 2 (DM1 and DM2). CLINICAL RATIONALE FOR THE STUDY: To ascertain whether DTI could be used to assess the integrity of white matter tracts in the brain and identify any abnormalities or disruptions in connectivity between different brain regions in patients with DM. By providing a more detailed understanding of the structural changes in the brain associated with DM, could DTI potentially be used to develop more effective treatments for the cognitive and neurological symptoms of the disorder? MATERIAL AND METHODS: We retrospectively compared MRI scans of 19 patients with DM1 to those of 23 healthy, matched controls, and of 16 patients with DM2 to those of 20 healthy, matched controls, and finally compared the DM1 and DM2 samples. Fraction anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were assessed using Tract Based Spatial Statistics (TBSS). RESULTS: In patients with DM1, a statistically significant decrease in the values of the FA parameter was revealed in 45/48 white matter tracts compared to patients with DM2. There was no statistically significant decrease in the values of the FA parameter in patients with DM2 compared to DM1. The values of MD and RD were significantly higher in 47 tracts in DM1 patients compared to DM2 patients. AD values were significantly higher in all 48 tracts in DM1 patients compared to DM2 patients. There were no tracts with increased MD, AD, or RD values in DM2 patients compared to DM1. CONCLUSIONS: Our results indicate diffuse disintegration of white matter pathways in DM patients, especially in the DM1 group. The damage to all types of fibres (association, commissural, and projection) may explain the diversity of clinical symptoms, which were more severe in the DM1 group of patients than in the DM2 group. CLINICAL IMPLICATIONS: DTI in patients with DM may help us to understand the neural mechanisms underlying brain involvement during the disease. In future, it may help to identify biomarkers for disease progression and treatment response.


Asunto(s)
Distrofia Miotónica , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Distrofia Miotónica/diagnóstico por imagen , Estudios Retrospectivos , Encéfalo/diagnóstico por imagen
9.
Acta Neuropathol ; 144(4): 707-731, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35948834

RESUMEN

Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.R1671Q, p.R1698P and p.L1664P mutations in the LG2 domain of agrin. Overexpression in primary motoneurons cultures in vitro and in chick spinal motoneurons in vivo revealed that the mutations modified agrin trafficking, leading to its accumulation in the soma and/or in the axon. Expression of mutant agrins in cultured cells demonstrated accumulation of agrin in the endoplasmic reticulum associated with induction of unfolded protein response (UPR) and impaired secretion in the culture medium. Interestingly, evaluation of the specific activity of individual agrins on AChR cluster formation indicated that when secreted, mutant agrins retained a normal capacity to trigger the formation of AChR clusters. To confirm agrin accumulation and secretion defect, iPS cells were derived from a patient and differentiated into motoneurons. Patient iPS-derived motoneurons accumulated mutant agrin in the soma and increased XBP1 mRNA splicing, suggesting UPR activation. Moreover, co-cultures of patient iPS-derived motoneurons with myotubes confirmed the deficit in agrin secretion and revealed a reduction in motoneuron survival. Altogether, we report the first mutations in AGRN gene that specifically affect agrin secretion by motoneurons. Interestingly, the three patients carrying these mutations were initially suspected of spinal muscular atrophy (SMA). Therefore, in the presence of patients with a clinical presentation of SMA but without mutation in the SMN1 gene, it can be worth to look for mutations in AGRN.


Asunto(s)
Agrina , Síndromes Miasténicos Congénitos , Agrina/genética , Humanos , Neuronas Motoras/metabolismo , Mutación , Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/metabolismo , Unión Neuromuscular/metabolismo
10.
Artículo en Inglés | MEDLINE | ID: mdl-35896379

RESUMEN

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

11.
Acta Neurol Scand ; 145(4): 471-478, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34981830

RESUMEN

INTRODUCTION: Myasthenia gravis (MG) is a rare autoimmune disorder of neuromuscular junction. MG healthcare burden has not been studied in Poland before. METHODS: Data were drawn from the National Health Fund database; MG patient was defined as a person who received at least once medical service with ICD-10 code MG (G70) and at least two reimbursed prescriptions for pyridostigmine bromide or ambenonium chloride in two consecutive years. We have analyzed treatment: immunosuppression, intravenous immunoglobulins (IVIg), plasma exchange (PE), the number and length of hospitalizations (LOS), intensive care unit (ICU) care, and deaths between 2013 and 2018. RESULTS: In 2018, there were 9012 MG patients (F:M 1.62:1), and 30.6% had early -onset MG (<50 years). 66.3% received symptomatic treatment only, 33.7%-glucocorticoids (CS) and/or other immunosuppressants (IS), 64.6%-CS only, 17.5%-azathioprine plus CS, 11%-azathioprine only, 4.6%-CS plus other IS (methotrexate, mycophenolate mofetil, cyclosporine, or tacrolimus), and 2%-other IS only. In 2018, 42.3% of patients were hospitalized at least once (mean 2.05/year), 13.7% due to MG (1.47/year). In 2018, 1.63% patients received PE, 2.33% IVIg. In 2013-2018, 2.7%-3.2% of MG patients required hospitalization in ICU. ICU mean LOS 2013-2018 was 11.5-15.0 days/per patient/year. 2.1% of all MG patients had myasthenic crisis. Mean age at death was 75.7 years for MG and 73.9 for general population (p = .006). All-cause mortality was higher for men (4.1%-5.1%) than for women (2.5%-3.1%), p < .01. CONCLUSIONS: Our findings confirm significant healthcare burden of MG, comprising a tool to plan resources needed for MG patients.


Asunto(s)
Miastenia Gravis , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/epidemiología , Intercambio Plasmático , Bromuro de Piridostigmina
12.
Neurol Neurochir Pol ; 56(5): 399-403, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35792560

RESUMEN

INTRODUCTION: In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis. MATERIAL AND METHODS: We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC. RESULTS: Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.


Asunto(s)
Miotonía Congénita , Femenino , Humanos , Masculino , Miotonía Congénita/diagnóstico , Miotonía Congénita/genética , Caracteres Sexuales , Electromiografía , Potenciales de Acción/fisiología , Mutación
13.
Am J Hum Genet ; 103(5): 817-825, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30401461

RESUMEN

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.


Asunto(s)
Ataxia Cerebelosa/genética , Discapacidades del Desarrollo/genética , Glicósido Hidrolasas/genética , Mutación/genética , Enfermedades Neurodegenerativas/genética , ADP-Ribosilación/genética , Adenosina Difosfato Ribosa/genética , Adolescente , Alelos , Niño , Preescolar , Exoma/genética , Femenino , Humanos , Lactante , Masculino , Malformaciones del Sistema Nervioso/genética , Procesamiento Proteico-Postraduccional/genética
14.
Neuroepidemiology ; : 1-8, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33611318

RESUMEN

INTRODUCTION: Myasthenia gravis (MG) is a rare autoimmune disorder of the neuromuscular junction. MG epidemiology has not been studied in Poland in a nationwide study before. METHODS: Our epidemiological data were drawn from the National Health Fund (Narodowy Fundusz Zdrowia, NFZ) database; an MG patient was defined as a person who received at least once medical service coded in ICD-10 as MG (G70) and at least 2 reimbursed prescriptions for pyridostigmine bromide (Mestinon®) or ambenonium chloride (Mytelase®) in 2 consecutive years. RESULTS: On 1st of January 2019, 8,702 patients with MG were receiving symptomatic treatment (female:male ratio: 1.65:1). MG incidence was 2.36/100,000. The mean age of incident cases in 2018 was 61.37 years, 59.17 years for women and 64.12 years for men. Incidence of early-onset MG (<50 years) was 0.80/100,000 and 4.98/100,000 for late-onset MG (LOMG), with male predominance in LOMG. Prevalence was 22.65/100,000. In women, there was a constant increase in prevalence of symptomatic MG from the first decade of life up to 80-89 years. In men, an increase in prevalence appeared in the 6th decade. The highest prevalence was observed in the age group of 80-89 years: 59.65/100,000 in women and 96.25/100,000 in men. CONCLUSIONS: Our findings provide information on epidemiology of MG in Poland and can serve as a tool to evaluate healthcare resources needed for MG patients.

15.
Neuroradiology ; 63(4): 539-545, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33512541

RESUMEN

PURPOSE: Intrathecal injection of nusinersen is an approved treatment of spinal muscular atrophy (SMA). CT-guided injection is a method of nusinersen administration in patients with severe scoliosis, in whom standard lumbar puncture is not feasible. The injections are repeated every 4 months for life, and accumulated radiation doses absorbed by the patient can increase the risk of cancer. In this study, we present the results of CT-guided intrathecal nusinersen injections with an ultra-low radiation dose protocol. METHODS: Eighteen patients (15 adults and three children) in whom standard lumbar puncture was not feasible due to severe scoliosis or spinal stabilization were included in this retrospective study. The first 23 injections were performed with a standard radiation dose protocol and the next 42 injections with an ultra-low-dose protocol. The radiation doses, measured as total dose length product (DLP), were acquired and compared between the protocols. RESULTS: Injections were successful in 100% of patients with both ultra-low-dose and standard protocols. The radiation dose, measured as DLP, was 111.2-1100.7 (Me = 248.1) mGy*cm for the standard protocol. For the ultra-low-dose protocol, the dose range was 5.0-54.4 (Me = 26.7) mGy*cm, which was significantly lower than with the standard protocol (p < 0.001, η2 = 0.67). CONCLUSION: Radiation doses can be significantly decreased in the CT-guided injection of nusinersen. The proposed protocol allows for effective CT-guided intrathecal nusinersen administration in patients with SMA and severe scoliosis.


Asunto(s)
Atrofia Muscular Espinal , Escoliosis , Adulto , Niño , Humanos , Inyecciones Espinales , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos , Dosis de Radiación , Estudios Retrospectivos , Escoliosis/diagnóstico por imagen , Escoliosis/tratamiento farmacológico , Tomografía Computarizada por Rayos X
16.
J Electrocardiol ; 65: 136-142, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33618294

RESUMEN

BACKGROUND: There is limited data on cardiac arrhythmias and ventricular repolarization and dispersion abnormalities in patients with mitochondrial diseases (MitD). METHODS: Consecutive 40 patients with genetically proven MitD and 35 healthy controls were studied. Among other examinations all subjects underwent 24-h Holter recording and 12­lead electrocardiography (ECG) with corrected QT (QTc), QT dispersion (QTd), Tp-e and Tp-e/QT ratio assessment. RESULTS: Patients with MitD were 55.4 ± 15.7 years old, the disease duration was 18.5 ± 10.3 years, presented 6 clinical syndromes while mitochondrial and nuclear DNA type of mutation was present in 40 and 60% of cases, respectively. In MitD more frequently 1st degree atrioventricular block and intraventricular conduction defects were observed and also QRS complex duration was increased. Mean values of QTc (p = 0.001), QTd (p = 0.02), Tp-e (p < 0.00001) and Tp-e/QT (p < 0.00001) were significantly higher in MitD than in controls. Correlations between disease duration and PR interval duration (p = 0.003) and Creatine Kinase MB isoenzyme activity (p = 0.02) were found. No differences in depolarization and dispersion parameters were observed according to type of mutation or dominant clinical syndromes. In addition to supraventricular extrasystoles, nonsustained supraventricular tachycardias occurred more frequently in MitD (in 45.0 vs 14.3%, p = 0.0004). Ventricular arrhythmias were rare and observed almost exclusively in subjects with mitochondrial DNA mutation. CONCLUSIONS: In contrast to healthy controls, in MitD patients intraventricular, repolarization and dispersion disturbances were more frequently observed. In addition to bradyarrhythmias observed in some defined MitD syndromes, supraventricular rather than ventricular arrhythmias are more common.


Asunto(s)
Electrocardiografía , Enfermedades Mitocondriales , Adulto , Anciano , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Humanos , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética
17.
Neurol Neurochir Pol ; 55(5): 479-484, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34664710

RESUMEN

INTRODUCTION: Spinal muscular atrophy (SMA) is one of the most frequent autosomal recessive neuromuscular disorders. It leads to progressive muscle weakness, premature death or permanent ventilation. Significant disability, scoliosis, severe pulmonary infections and other problems require in- and outpatient medical care. Various approaches have been used to evaluate SMA epidemiology, healthcare burden and adherence to standard of care. The recent introduction of pharmacological treatment in a large SMA population will change the course of the disease and the healthcare requirements of patients. MATERIAL AND METHODS: We have used the National Health Fund database to identify children with SMA and the healthcare service they received in the pre-pharmacological treatment era. Pivotal phase II and III medical trials for nusinersen were conducted between 2013 and 2015. The National Treatment Programme of SMA patients with nusinersen in our country was started in January 2019. The year 2014 was used to evaluate incident cases. RESULTS: 51 new SMA cases (incidence 1:7,356) and 518 SMA patients younger than 18 were identified in 2014. 32 (6.2%) deaths were recorded, half in the first two years of life. 35 (6.8%) patients received palliative and 115 (22.2%) long-term care (including assisted ventilation). A total number of 3,057 days of hospital stay were reported. Only 65/518 (12.6%) patients did not receive publicly-funded healthcare service other than specialist or general practitioner's consultation. CONCLUSIONS: SMA caused significant mortality and morbidity in children. The National Health Fund database can be used to reliably record incident cases and track the care provided to paediatric SMA patients.


Asunto(s)
Atrofia Muscular Espinal , Niño , Atención a la Salud , Humanos , Incidencia , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/epidemiología , Polonia/epidemiología , Respiración Artificial
18.
Neurol Neurochir Pol ; 54(1): 8-13, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31922583

RESUMEN

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease with an autosomal recessive trait of inheritance and great variability of its clinical course - from the lethal congenital type (SMA0) to the adult-onset form (SMA4). The disease is associated with a deficiency of SMN protein, which is encoded by two genes SMN1 and SMN2. Clinical symptoms depend on mutations in the SMN1 gene. The number of copies of twin similar SMN2 gene, which produces small amounts of SMN protein, is the main phenotype modifier, which determines the clinical severity of the disease. Until recently, it was considered that spinal cord motoneurons undergo selective loss. Recent studies have shown the role of SMN protein in various cellular processes and the multisystemic character of SMA. The aim of the therapeutic strategies developed so far has been to increase the expression of SMN protein by modifying the splicing of SMN2 gene (intrathecally administered antisense oligonucleotide - nusinersen; orally available small molecules: RG7916 and LMI070 or SMN1 gene replacement therapy (AAV9-SMN). The first SMN2-directed antisense oligonucleotide (nusinersen) has demonstrated in clinical trials high efficiency, and it has now been registered. The best effects were obtained in patients who were introduced to the drug in the pre symptomatic period. Studies on other substances are ongoing. The great advances in SMA therapy and increased understanding of the pathogenesis of the disease raise hopes for changes to the natural history of the disease. Simultaneously, it increases awareness of the need to improve the standard of patient care and early diagnosis (newborn screening). Many questions (e.g. emerging phenotypes, combined therapies, systemic vs. intrathecal administration, long-term consequences, and complications of the therapy) will require further studies and observations.


Asunto(s)
Atrofia Muscular Espinal , Humanos , Recién Nacido , Mutación , Fenotipo
19.
Neurol Neurochir Pol ; 54(6): 552-560, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33373035

RESUMEN

BACKGROUND: Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) is a rare, progressive, hereditary, highly disabling multisystem disorder. ATTR-FAP phenotypes differ according to the type of TTR mutation, geographic region and other as yet unidentified factors. The aim of this study was to establish the clinical and genetic characteristics of Polish patients. METHODS AND PATIENTS: Clinical data and necessary examinations were collected from patients diagnosed with ATTR-FAP at the Department of Neurology of Medical University of Warsaw between 1970 and 2019. RESULTS: 16 patients from eight unrelated families with five different TTR mutations were identified. The family with Val71Ala TTR mutation presented with early onset severe progressive polyneuropathy, with marked visual symptoms in a few patients. The next family with Ile73Val TTR mutation developed symptoms in middle age, and presented with mixed neuropathic and cardiologic phenotype. Four unrelated families were found to have the Phe33Leu TTR mutation with mixed neuropathic and cardiologic phenotype and late onset of symptoms. Other TTR mutations identified were: Val30Met and Asp38Val, both with late onset sensory, motor and autonomic neuropathy. CONCLUSION: Polish ATTR-FAP cases presented with heterogeneity typical for non-endemic areas. Phe33Leu TTR mutation was the most common, found in four unrelated families.


Asunto(s)
Neuropatías Amiloides Familiares , Prealbúmina , Neuropatías Amiloides Familiares/genética , Humanos , Persona de Mediana Edad , Mutación , Fenotipo , Polonia , Prealbúmina/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA