RESUMEN
La distrofia facioescapulohumeral es una miopatía progresiva de base genética, con gran variabilidad fenotípica. Se caracteriza por la progresión de cambios distróficos en la dirección cráneo-caudal con lesiones asimétricas de los músculos faciales, cintura escapular, hombros y piernas. Se expone este caso con el objetivo de demostrar la importancia de la rehabilitación en el manejo integral de pacientes con distrofia muscular y fractura de cadera. Se presenta el abordaje rehabilitador en una paciente con distrofia facioescapulohumeral y fractura de cadera tratada mediante artroplastia total de cadera. El tratamiento rehabilitador precoz contribuyó a mejorar el control del dolor y su recuperación funcional(AU)
Facioscapulohumeral dystrophy is a genetically based progressive myopathy (4q35), with great phenotypic variability. It is characterized by the progression of dystrophic changes in the craniocaudal direction with asymmetric lesions of the facial muscles, shoulder girdle, shoulders, and legs. We report the rehabilitation approach in a female patient with facioscapulohumeral dystrophy and hip fracture treated by total hip arthroplasty. A rehabilitation program was included and improvement in pain control and functionality was observed. Rehabilitation is a fundamental pillar in the comprehensive management of patients with muscular dystrophy and hip fracture(AU)
Asunto(s)
Humanos , Femenino , Anciano , Artroplastia de Reemplazo de Cadera/métodos , Distrofia Muscular Facioescapulohumeral/rehabilitación , Fracturas Óseas/cirugía , Terapia por Ejercicio/métodosRESUMEN
DUX4 is a transcription factor required during early embryonic development in placental mammals. In this work, we provide evidence that DUX4 is a co-repressor of nuclear receptors (NRs) of progesterone (PR) and glucocorticoids (GR). The DUX4 C-ter and N-ter regions, including the nuclear localization signals and homeodomain motifs, contribute to the co-repressor activity of DUX4 on PR and GR. Immunoprecipitation studies, using total protein extracts of cells expressing tagged versions of DUX4 and GR, support that these proteins are physically associated. Our studies suggest that DUX4 could modulate gene expression by co-regulating the activity of hormone NRs. This is the first report highlighting a potential endocrine role for DUX4.
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Distrofia Muscular Facioescapulohumeral , Femenino , Embarazo , Animales , Distrofia Muscular Facioescapulohumeral/genética , Distrofia Muscular Facioescapulohumeral/metabolismo , Glucocorticoides , Progesterona , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas Co-Represoras , Receptores de Glucocorticoides/genética , Señales de Localización Nuclear , Placenta/metabolismo , Factores de Transcripción , Receptores Citoplasmáticos y Nucleares , MamíferosRESUMEN
BACKGROUND: Although facial muscle weakness is common in patients with Facioscapulohumeral Muscular Dystrophy (FSHD), the literature is scarce on the speech and swallowing aspects. OBJECTIVE: To investigate speech and swallowing patterns in FSHD and assess the correlation with clinical data. METHODS: A cross-sectional study was conducted. Patients with clinical confirmation of FSHD and aged above 18 years were included and paired with healthy control individuals by age and gender. Individuals who had neurological conditions that could interfere with test results were excluded. The following assessments were applied: speech tests (acoustic and auditory-perceptual analysis); swallowing tests with the Northwestern Dysphagia Patient Check Sheet (NDPCS), the Eat Assessment Tool (EAT-10), the Speech Therapy Protocol for Dysphagia Risk (PARD), and the Functional Oral Intake Scale (FOIS); disease staging using the modified Gardner-Medwin-Walton scale (GMWS); and quality of life with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). The correlation between test results and clinical data was verified by non-parametric statistics. RESULTS: Thirteen individuals with FSHD and 10 healthy controls were evaluated. The groups presented significant differences in the motor bases of phonation and breathing. Regarding swallowing, two (15%) individuals presented mild dysphagia and seven (53.8%) showed reduced facial muscles strength. These results were not correlated with duration of the disease, age at symptoms onset, and quality of life. Dysphagia was related to worsening disease severity. CONCLUSIONS: FSHD patients presented mild dysarthria and dysphagia. Frequent monitoring of these symptoms could be an important way to provide early rehabilitation and better quality of life.
Asunto(s)
Trastornos de Deglución , Distrofia Muscular Facioescapulohumeral , Anciano , Estudios Transversales , Deglución , Trastornos de Deglución/etiología , Humanos , Distrofia Muscular Facioescapulohumeral/complicaciones , Distrofia Muscular Facioescapulohumeral/diagnóstico , Calidad de Vida , HablaRESUMEN
Objective To evaluate the reliability of the motor function measure (MFM) scale in the assessment of disease severity and progression when administered at home and clinic and assess its correlation with the Paediatric Outcomes Data Collection Instrument (PODCI). Methods In this prospective study, two assessors rated children with hereditary neuromuscular diseases (HNMDs) using the MFM at the clinic and then 2 weeks later at the patients' home. Intraclass correlation coefficient (ICC) was calculated for the reliability of the MFM and its domains. The reliability of each item was assessed and the correlation between MFM and three domains of PODCI was evaluated. Results A total of 48 children (5-17 years of age) were assessed in both locations and the MFM scale demonstrated excellent inter-rater reliability (ICC, 0.98). Weighted kappa ranged from excellent to poor. Correlation of the home-based MFM with the PODCI domain 'basic mobility and transfers' was excellent, with the 'upper extremity' domain was moderate, but there was no correlation with the 'happiness' domain. Conclusion The MFM is a reliable tool for assessing patients with HNMD when used in a home-based setting.
Asunto(s)
Enfermedades Genéticas Congénitas/diagnóstico , Servicios de Atención de Salud a Domicilio , Actividad Motora , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular Facioescapulohumeral/diagnóstico , Polineuropatías/diagnóstico , Adolescente , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Enfermedades Genéticas Congénitas/fisiopatología , Humanos , Masculino , Distrofia Muscular de Cinturas/fisiopatología , Distrofia Muscular de Duchenne/fisiopatología , Distrofia Muscular Facioescapulohumeral/fisiopatología , Polineuropatías/fisiopatología , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD), a prevalent inherited human myopathy, develops following a complex interplay of genetic and epigenetic events. FSHD1, the more frequent genetic form, is associated with: (1) deletion of an integral number of 3.3 Kb (D4Z4) repeated elements at the chromosomal region 4q35, (2) a specific 4q35 subtelomeric haplotype denominated 4qA, and (3) decreased methylation of cytosines at the 4q35-linked D4Z4 units. FSHD2 is most often caused by mutations at the SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1) gene, on chromosome 18p11.32. FSHD2 individuals also carry the 4qA haplotype and decreased methylation of D4Z4 cytosines. Each D4Z4 unit contains a copy of the retrotransposed gene DUX4 (double homeobox containing protein 4). DUX4 gene functionality was questioned in the past because of its pseudogene-like structure, its location on repetitive telomeric DNA sequences (i.e. junk DNA), and the elusive nature of both the DUX4 transcript and the encoded protein, DUX4. It is now known that DUX4 is a nuclear-located transcription factor, which is normally expressed in germinal tissues. Aberrant DUX4 expression triggers a deregulation cascade inhibiting muscle differentiation, sensitizing cells to oxidative stress, and inducing muscle atrophy. A unifying pathogenic model for FSHD emerged with the recognition that the FSHD-permissive 4qA haplotype corresponds to a polyadenylation signal that stabilizes the DUX4 mRNA, allowing the toxic protein DUX4 to be expressed. This working hypothesis for FSHD pathogenesis highlights the intrinsic epigenetic nature of the molecular mechanism underlying FSHD as well as the pathogenic pathway connecting FSHD1 and FSHD2. Pharmacological control of either DUX4 gene expression or the activity of the DUX4 protein constitutes current potential rational therapeutic approaches to treat FSHD.
Asunto(s)
Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Distrofia Muscular Facioescapulohumeral/genética , Distrofia Muscular Facioescapulohumeral/metabolismo , Animales , Epigénesis Genética , Expresión Génica/genética , Expresión Génica/fisiología , HumanosRESUMEN
BACKGROUND: Facioscapulohumeral muscular dystrophy is the third most common muscular dystrophy with an estimated prevalence of 1 per 20.000 and a normal life expectancy in the majority of patients. However, approximately 15% of patients become wheelchair bound in the course of their life. It is a hereditary autosomal dominant disease with high (95%) penetrance by the age of 20, but with variable degree of phenotypic expression even in the same family group. Symptoms frequently start in the second decade of life, with facial and scapular weakness. AIM: To report the clinical features of seven patients with the disease, seen at a public hospital. MATERIAL AND METHODS: Analysis of seven patients with genetic study seen in a public Hospital in Santiago. RESULTS: The age of patients fluctuated from 18 to 61 years and four were females. The mean age at onset of symptoms was 29 years and four had a family history of the disease. The usual presenting complaint was arm or shoulder asymmetric weakness. Four patients had bone pain. Facial involvement was present in four. A genetic study was done in five patients, the other two patients were relatives, confirming the contraction or lower number of repetitions in D4Z4 region. After 12 years of follow up only 2 patients older than 60 years cannot work and one female patients is in a semi dependent state at the age of 30. CONCLUSIONS: The clinical workup in the diagnosis and the timely indication of genetic studies are highlighted, to avoid unnecessary and invasive procedures. The variability in the phenotypic expression in a similar genetic defect is discussed and the genetic or epigenetic mechanisms of this muscular dystrophy are described.
Asunto(s)
Cromosomas Humanos Par 4/genética , Distrofia Muscular Facioescapulohumeral/genética , Fenotipo , Adolescente , Adulto , Biopsia , Creatina Quinasa/sangre , Diagnóstico Diferencial , Electromiografía , Asimetría Facial/etiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/etiología , Distrofia Muscular Facioescapulohumeral/complicaciones , Distrofia Muscular Facioescapulohumeral/diagnóstico , Distrofia Muscular Facioescapulohumeral/patología , Mutación/genética , Dolor de Hombro/etiología , Centros de Atención Terciaria , Adulto JovenRESUMEN
Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P = 0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R(2) = 0.503; P = 0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1 ± 1.9 vs. 3.2 ± 1.2; P <0.0001) and body mass index (26.9 ± 6.0 vs. 22.9 ± 4.0 kg/m(2); P = 0.003) and a smaller number of D4Z4 allele repeats (4.8 ± 1.6 vs. 5.7 ± 1.8; P = 0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index.
Asunto(s)
Distrofia Muscular Facioescapulohumeral/complicaciones , Insuficiencia Respiratoria/complicaciones , Músculos Respiratorios/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Espiración , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular , Insuficiencia Respiratoria/fisiopatología , Capacidad Vital , Adulto JovenRESUMEN
DUX4 (Double Homeobox Protein 4) is a nuclear transcription factor encoded at each D4Z4 unit of a tandem-repeat array at human chromosome 4q35. DUX4 constitutes a major candidate pathogenic protein for facioscapulohumeral muscular dystrophy (FSHD), the third most common form of inherited myopathy. A low-level expression of DUX4 compromises cell differentiation in myoblasts and its overexpression induces apoptosis in cultured cells and living organisms. In this work we explore potential molecular determinants of DUX4 mediating nuclear import and cell toxicity. Deletion of the hypothetical monopartite nuclear localization sequences RRRR(23), RRKR(98) and RRAR(148) (i.e. NLS1, NLS2 and NLS3, respectively) only partially delocalizes DUX4 from the cell nuclei. Nuclear entrance guided by NLS1, NLS2 and NLS3 does not follow the classical nuclear import pathway mediated by α/ß importins. NLS and homeodomain mutants from DUX4 are dramatically less cell-toxic than the wild type molecule, independently of their subcellular localization. A triple ΔNLS1-2-3 deletion mutant is still partially localized in the nuclei, indicating that additional sequences in DUX4 contribute to nuclear import. Deletion of ≥111 amino acids from the C-terminal of DUX4, on a ΔNLS1-2-3 background, almost completely re-localizes DUX4 to the cytoplasm, indicating that the C-ter tail contributes to subcellular trafficking of DUX4. Also, C-terminal deletion mutants of DUX4 on a NLS wild type background are less toxic than wild type DUX4. Results reported here indicate that DUX4 possesses redundant mechanisms to assure nuclear entrance and that its various transcription-factor associated domains play an essential role in cell toxicity.
Asunto(s)
Transporte Activo de Núcleo Celular/genética , Proteínas de Homeodominio/metabolismo , Distrofia Muscular Facioescapulohumeral/metabolismo , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patología , Proteínas de Homeodominio/genética , Humanos , Distrofia Muscular Facioescapulohumeral/genética , Distrofia Muscular Facioescapulohumeral/patología , Mutagénesis Sitio-DirigidaRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.
Asunto(s)
Haplotipos/genética , Distrofia Muscular Facioescapulohumeral/diagnóstico , Distrofia Muscular Facioescapulohumeral/genética , Secuencias Repetidas en Tándem/genética , Adulto , Anciano , Brasil/epidemiología , Cromosomas Humanos Par 4/genética , Femenino , Pruebas Genéticas , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder that has been associated with a contraction of 3.3-kb repeats on chromosome 4q35. FSHD is characterized by a wide clinical inter- and intrafamilial variability, ranging from wheelchair-bound patients to asymptomatic carriers. Our study is unique in comparing the gene expression profiles from related affected, asymptomatic carrier, and control individuals. Our results suggest that the expression of genes on chromosome 4q is altered in affected and asymptomatic individuals. Remarkably, the changes seen in asymptomatic samples are largely in products of genes encoding several chemokines, whereas the changes seen in affected samples are largely in genes governing the synthesis of GPI-linked proteins and histone acetylation. Besides this, the affected patient and related asymptomatic carrier share the 4qA161 haplotype. Thus, these polymorphisms by themselves do not explain the pathogenicity of the contracted allele. Interestingly, our results also suggest that the miRNAs might mediate the regulatory network in FSHD. Together, our results support the previous evidence that FSHD may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, and suggest some factors potentially important for FSHD pathogenesis. The study of the gene expression profiles from asymptomatic carriers and related affected patients is a unique approach to try to enhance our understanding of the missing link between the contraction in D4Z4 repeats and muscle disease, while minimizing the effects of differences resulting from genetic background.
Asunto(s)
Regulación de la Expresión Génica/genética , Heterocigoto , Distrofia Muscular Facioescapulohumeral/genética , Transcripción Genética/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 4/genética , Perfilación de la Expresión Génica , Humanos , Polimorfismo Genético/genéticaRESUMEN
OBJETIVO: Avaliar a técnica cirúrgica da artrodese escapulotorácica na distrofia fascioescapulumeral (DFEU), analisando os resultados e as complicações pós-operatórias. MÉTODOS: No período de fevereiro de 1992 a fevereiro de 2006 foram realizadas oito artrodeses escapulotorácicas em cinco pacientes no Departamento de Ortopedia e Traumatologia da Faculdade de Ciências Médicas da Santa Casa de São Paulo (DOT-FCM-SCSP). Os critérios para indicação cirúrgica foram: dor, déficit funcional do membro acometido, fadiga muscular e deformidade estética. Na técnica cirúrgica empregada para a artrodese foi realizada a fixação da escápula à parede torácica por meio de amarrilho com fios de poliéster n° 5, uma placa metálica estreita e fina, além de colocação de enxerto esponjoso autólogo. RESULTADOS: O seguimento médio dos pacientes foi de 124 meses. Na comparação da amplitude de movimentos pré e pós-operatórios, notou-se melhora na elevação, mantida a rotação lateral, com o UCLA no período pré-operatório variando de 7 a 11 e pós-operatório de 29 a 33. Dentre as complicações, encontraram-se dois casos de pneumotórax, um caso de soltura do material de síntese e um caso de ausência de consolidação óssea. COMENTÁRIO: Obtida consolidação da artrodese em seis casos, além da melhora da dor e elevação. Dois casos foram reoperados, sendo um devido à quebra do material e o outro, à não consolidação. Todos evoluíram para consolidação.
OBJECTIVE: To evaluate the surgical scapulothoracic arthrodesis technique in facioscapulohumeral dystrophy (FSHD) by analyzing post-op results and complications. METHODS: from February 1992 to February 2006, eight scapulothoracic arthrodesis procedures were performed in five patients at the Orthopedics and Traumatology Department of the Medical Sciences School at the Santa Casa Hospital of São Paulo (DOT-FCM-SCSP). The criteria for surgical indication were pain, functional deficit of the limb involved, muscular fatigue, and esthetic deformity. The surgical technique used for the arthrodesis fixated the scapula to the thoracic wall by tying a narrow, slim plate with No. 5 polyester threads and placing an autologous cancellous bone graft. RESULTS: Mean follow-up of the patients was of 124 months. Comparing the range of movement before and after surgery, the authors observed an improvement in raising, lateral rotation being kept, with the pre-op UCLA ranging from 7 to 11, and the post-op UCLA ranging from 29 to 33. Complications included two cases of pneumothorax; one case of the detachment of synthesis material, and one case of lack of bone fusion. COMMENT: Arthrodesis fusion was achieved in six cases, besides improvement in pain and raising. Two cases were reoperated on, one of them due to breakage of the material and another one due to lack of fusion. All cases evolved on to fusion.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Artrodesis , Estudio de Evaluación , Distrofias Musculares , Distrofia Muscular Facioescapulohumeral , EscápulaRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) patients carry contractions of the D4Z4-tandem repeat array on chromosome 4q35. Decrease in D4Z4 copy number is thought to alter a chromatin structure and activate expression of neighboring genes. D4Z4 contains a putative double-homeobox gene called DUX4. We identified DUX4 mRNAs in cells transfected with genomic fragments containing the DUX4 gene. Using RT-PCR we also recognized expressed DUX4 mRNAs in primary FSHD myoblasts. Polyclonal antibodies raised against specific DUX4 peptides detected the DUX4 protein in cells transfected with D4Z4 elements. DUX4 localizes in the nucleus of cells transfected with CMV-DUX4 expression vectors. A DUX4-related protein is endogenously expressed in nuclei of adult and fetal human rhabdomyosarcoma cell lines. Overexpression of DUX4 induces cell death, induces caspase 3/7 activity and alters emerin distribution at the nuclear envelope. We propose that DUX4-mediated cell death contributes to the pathogenic pathway in FSHD.
Asunto(s)
Apoptosis/fisiología , Proteínas de Homeodominio/genética , Células Musculares/fisiología , Distrofia Muscular Facioescapulohumeral/genética , Distrofia Muscular Facioescapulohumeral/patología , Secuencia de Aminoácidos , Línea Celular Tumoral , Expresión Génica/fisiología , Proteínas de Homeodominio/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Células Musculares/citología , Distrofia Muscular Facioescapulohumeral/fisiopatología , Membrana Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Músculo Cuádriceps/citología , ARN Mensajero/metabolismo , Rabdomiosarcoma , Transcripción Genética/fisiologíaRESUMEN
Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with contractions of D4Z4 repeat on 4q35. It displays a remarkable inter- and intra-familial clinical variability ranging from severe phenotype to asymptomatic carriers. Mosaicism for the contracted FSHD-sized allele is a recurrent finding, but only DNA from lymphocytes had been studied. It is currently not known if mosaicism is unequally distributed between different tissues and if muscle is relatively spared for the presence of the disease allele in mosaic asymptomatic carriers of a disease allele. Here we compare DNA extracted from peripheral blood lymphocytes (PBL), fibroblasts and muscle from a mosaic asymptomatic female carrier and mother of a FSHD patient. PFGE analysis showed a complex allelic segregation: two independent mitotic rearrangement episodes occurred, resulting in mosaicism for a contracted D4Z4 repeat on 4q35 in the mother and mosaicism for an expanded D4Z4 repeat on 10q26 in the affected daughter. The results show that the proportion of mosaicism in PBL and muscle were comparable, while in fibroblasts there was some variation in the mosaicism, which might be caused by culturing artefacts. This finding supports the hypothesis that a mitotic contraction of D4Z4 is an early embryonic event and indicates that the degree of mosaicism in PBL is representative for that of muscle.