Eficacia en la vida real del fingolimod en pacientes con esclerosis múltiple en Bulgaria / Real-world effectiveness of fingolimod in patients with multiple sclerosis in Bulgaria

Introducción El fingolimod es un agonista del receptor de esfingosina-1-fosfato utilizado para el tratamiento de la esclerosis múltiple (EM). Nuestro objetivo era evaluar los resultados del fingolimod en la calidad de vida de los pacientes con EM recurrente-remitente tras dos años de tratamiento en este estudio de la vida real. Pacientes y métodos Se trata de un estudio observacional prospectivo de dos años de duración realizado en Bulgaria en pacientes con EM recurrente-remitente tratados con fingolimod. Se evaluó la calidad de vida mediante la versión en búlgaro de la escala Multiple Sclerosis Quality of Life-54 (MSQoL-54). El criterio de valoración principal fue el cambio respecto al valor inicial en la puntuación en la MSQoL-54 tras dos años de tratamiento. Los criterios de valoración secundarios fueron el cambio respecto al valor inicial en la puntuación en la MSQoL-54 tras un año de tratamiento, además de la evaluación del nivel de depresión mediante la puntuación de la escala de puntuación de la depresión de Hamilton (HAM-D17). Resultados En el estudio se incluyó a 87 pacientes elegibles con una edad media de 38,7 ± 8,45 años. La mediana de la puntuación en la Expanded Disability Status Scale (EDSS) fue de 3,5 puntos. Se halló una mejora estadísticamente significativa en 10 subescalas en el mes 12 y en siete subescalas en el mes 24. La puntuación combinada de salud mental aumentó de 64 ± 16,69 puntos a 67,5 ± 15,94 puntos en el mes 24 (p = 0,012). La puntuación combinada de salud física aumentó de 61,7 ± 17,61 a 66,3 ± 16,7 (p = 0,001). El nivel de depresión medido por la HAM-D17 disminuyó considerablemente en el mes 12 y en el mes 24. La puntuación de la EDSS disminuyó o se mantuvo estable en más de la mitad de los pacientes (61,6%). Detectamos una mejor calidad de vida en los pacientes con una puntuación más baja en la EDSS. Conclusiones Las puntuaciones de calidad de vida y el nivel de depresión mejoraron ... (AU)

INTRODUCTION Fingolimod, a sphingosine-1-phosphate receptor agonist used for the treatment of multiple sclerosis (MS). Our goal was to assess the impact of fingolimod on quality of life in patients with relapsing-remitting multiple sclerosis (RRMS) after 2 years of treatment in this real-world study. PATIENTS AND METHODS This was a 2-year, prospective, observational study conducted in Bulgaria in RRMS patients treated with fingolimod. Quality of life was assessed using the Bulgarian-language version of the MSQoL-54 scale. The primary endpoint was the change from baseline in the MSQoL-54 score after 2 years of treatment. Secondary endpoints included the change from baseline in the MSQoL-54 score after one year of treatment, furthermore the assessment of depression level using the Hamilton D-17 score. RESULTS A total of 87 eligible patients were included in the study with a mean age of 38.7 ± 8.45 years. The median Expanded Disability Status Scale (EDSS) score was 3.5 points. We found statistically significant improvement in 10 subscales at month 12 and in seven subscales at month 24. The mental health composite score increased from 64.0 ± 16.69 points to 67.5 ± 15.94 points at month 24 (p = 0.012). The physical health composite score increased from 61.7 ± 17.61 to 66.3 ± 16.70 (p = 0.001). Depression level measured by the HAM-D17 decreased significantly by month 12 and month 24. The EDSS score decreased or remained stable in more than half of the patients (61.6%). We detected better quality of life in patients with a lower EDSS score. CONCLUSIONS Quality of life scores and the depression level are improved in RRMS patients treated with fingolimod over 2 years in real-life setting. (AU)

Real-world effectiveness of fingolimod in patients with multiple sclerosis in Bulgaria. / Eficacia en la vida real del fingolimod en pacientes con esclerosis múltiple en Bulgaria.

INTRODUCTION: Fingolimod, a sphingosine-1-phosphate receptor agonist used for the treatment of multiple sclerosis (MS). Our goal was to assess the impact of fingolimod on quality of life in patients with relapsing-remitting multiple sclerosis (RRMS) after 2 years of treatment in this real-world study. PATIENTS AND METHODS: This was a 2-year, prospective, observational study conducted in Bulgaria in RRMS patients treated with fingolimod. Quality of life was assessed using the Bulgarian-language version of the MSQoL-54 scale. The primary endpoint was the change from baseline in the MSQoL-54 score after 2 years of treatment. Secondary endpoints included the change from baseline in the MSQoL-54 score after one year of treatment, furthermore the assessment of depression level using the Hamilton D-17 score. RESULTS: A total of 87 eligible patients were included in the study with a mean age of 38.7 ± 8.45 years. The median Expanded Disability Status Scale (EDSS) score was 3.5 points. We found statistically significant improvement in 10 subscales at month 12 and in seven subscales at month 24. The mental health composite score increased from 64.0 ± 16.69 points to 67.5 ± 15.94 points at month 24 (p = 0.012). The physical health composite score increased from 61.7 ± 17.61 to 66.3 ± 16.70 (p = 0.001). Depression level measured by the HAM-D17 decreased significantly by month 12 and month 24. The EDSS score decreased or remained stable in more than half of the patients (61.6%). We detected better quality of life in patients with a lower EDSS score. CONCLUSIONS: Quality of life scores and the depression level are improved in RRMS patients treated with fingolimod over 2 years in real-life setting.

TITLE: Eficacia en la vida real del fingolimod en pacientes con esclerosis múltiple en Bulgaria.Introducción. El fingolimod es un agonista del receptor de esfingosina-1-fosfato utilizado para el tratamiento de la esclerosis múltiple (EM). Nuestro objetivo era evaluar los resultados del fingolimod en la calidad de vida de los pacientes con EM recurrente-remitente tras dos años de tratamiento en este estudio de la vida real. Pacientes y métodos. Se trata de un estudio observacional prospectivo de dos años de duración realizado en Bulgaria en pacientes con EM recurrente-remitente tratados con fingolimod. Se evaluó la calidad de vida mediante la versión en búlgaro de la escala Multiple Sclerosis Quality of Life-54 (MSQoL-54). El criterio de valoración principal fue el cambio respecto al valor inicial en la puntuación en la MSQoL-54 tras dos años de tratamiento. Los criterios de valoración secundarios fueron el cambio respecto al valor inicial en la puntuación en la MSQoL-54 tras un año de tratamiento, además de la evaluación del nivel de depresión mediante la puntuación de la escala de puntuación de la depresión de Hamilton (HAM-D17). Resultados. En el estudio se incluyó a 87 pacientes elegibles con una edad media de 38,7 ± 8,45 años. La mediana de la puntuación en la Expanded Disability Status Scale (EDSS) fue de 3,5 puntos. Se halló una mejora estadísticamente significativa en 10 subescalas en el mes 12 y en siete subescalas en el mes 24. La puntuación combinada de salud mental aumentó de 64 ± 16,69 puntos a 67,5 ± 15,94 puntos en el mes 24 (p = 0,012). La puntuación combinada de salud física aumentó de 61,7 ± 17,61 a 66,3 ± 16,7 (p = 0,001). El nivel de depresión medido por la HAM-D17 disminuyó considerablemente en el mes 12 y en el mes 24. La puntuación de la EDSS disminuyó o se mantuvo estable en más de la mitad de los pacientes (61,6%). Detectamos una mejor calidad de vida en los pacientes con una puntuación más baja en la EDSS. Conclusiones. Las puntuaciones de calidad de vida y el nivel de depresión mejoraron en los pacientes con EM recurrente-remitente tratados con fingolimod durante dos años en un entorno real.

POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

Association between loss of dp140 and cognitive impairment in duchenne and becker dystrophies.

The presence of variable degrees of non progressive cognitive impairment is recognized as a clinical feature of patients with Duchenne and Becker muscular dystrophies (DMD and BMD), but its pathogenesis still remains a matter of debate. A number of findings have proved that rearrangements located in the second part of the dystrophin ( DMD ) gene seem to be preferentially associated with cognitive impairment. Dp140 is a distal dystrophin isoform, mainly expressed during fetal brain development, whose role for neuropsychological functioning was suggested. The aims of the current study were to explore the possible association between cognitive impairment and DNA mutations affecting the regulatory regions of Dp140, as well as to compare the neuropsychological functioning of patients affected with DMD and Intermediate muscular dystrophy (IMD) with those affected by Becker muscular dystrophy (BMD). Fiftythree patients genetically diagnosed with DMD, IMD and BMD, subdivided according to sites of mutations along the DMD gene, underwent a neuropsychological assessment, evaluating their general cognitive abilities, verbal memory, attention and executive functions. Twenty patients with mutations, terminating in exon 44 or starting at exon 45 were tested by polymerase chain reaction (PCR) amplification of microsatellites STR44, SK12, SK21 and P20 DXS269, in order to evaluate the integrity of the Dp140 promoter region. According to our statistical results, there was not a significant difference in terms of general intelligence between the allelic forms of the disease, a higher frequency of mental retardation was observed in DMD patients. The patients with BMD had better results on tests, measuring long-term verbal learning memory and executive functions. We found that patients lacking Dp140 performed more poorly on all neuropsychological tests compared to those with preserved Dp140. Overall, our findings suggest that the loss of Dp140 is associated with a higher risk of intellectual impairment among patients with dystrophinopathies and highlights the possible role of this distal isoform in normal cognitive development.

Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency.

OBJECTIVE: In this study, we investigated the detailed clinical findings and underlying genetic defect in 3 presumably related Bulgarian families displaying dominantly transmitted adult onset distal myopathy with upper limb predominance. METHODS: We performed neurologic, electrophysiologic, radiologic, and histopathologic analyses of 13 patients and 13 at-risk but asymptomatic individuals from 3 generations. Genome-wide parametric linkage analysis was followed by bidirectional sequencing of the filamin C (FLNC) gene. We characterized the identified nonsense mutation at cDNA and protein level. RESULTS: Based on clinical findings, no known myopathy subtype was implicated in our distal myopathy patients. Light microscopic analysis of affected muscle tissue showed no specific hallmarks; however, the electron microscopy revealed changes compatible with myofibrillar myopathy. Linkage studies delineated a 9.76 Mb region on chromosome 7q22.1-q35 containing filamin C (FLNC), a gene previously associated with myofibrillar myopathy. Mutation analysis revealed a novel c.5160delC frameshift deletion in all patients of the 3 families. The mutation results in a premature stop codon (p.Phe1720LeufsX63) that triggers nonsense-mediated mRNA decay. FLNC transcript levels were reduced in muscle and lymphoblast cells from affected subjects and partial loss of FLNC in muscle tissue was confirmed by protein analysis. CONCLUSIONS: The FLNC mutation that we identified is distinct in terms of the associated phenotype, muscle morphology, and underlying molecular mechanism, thus extending the currently recognized clinical and genetic spectrum of filaminopathies. We conclude that filamin C is a dosage-sensitive gene and that FLNC haploinsufficiency can cause a specific type of myopathy in humans.