Literatura académica sobre el tema "Brody syndrome"

INTRODUCCIÓN La aparición del síndrome de Meigs o pseudomeigs caracterizado por presencia de tumor ovárico, ascitis, derrame pleural es menos frecuente en este grupo de edad por lo que es infradiagnosticado retrasando el tratamiento oportuno. Debido a eso es detectado hasta en estadios avanzados ocasionando disfuncionalidad en poco tiempo. CASO CLÍNICO Mujer de 91 años conocida con hipertensión arterial sistémica, Diabetes Mellitus, uso de bastón monopodálico, con valoración geriátrica inicial: Katz A-B-G, Lawton y Brody 7-3-1, Barthel 85-75-35, pre frágil, sin queja de memoria. Acudió por hiporexia de 1 mes de evolución, evacuaciones diarreicas asociados a episodios de incontinencia fecal, disnea que progreso a pequeños esfuerzos, ascitis y edema de miembros inferiores. CONCLUSIÓN Es importante considerar estos síndromes como diagnóstico diferencial en pacientes que presenten súbitamente derrame pleural, ascitis o ambos con el fin de no retrasar el tratamiento oportuno y preservar la funcionalidad en el mayor grado posible. Background The appearance of Meigs syndrome or pseudomeigs characterized by the presence of an ovarian tumor, ascites, pleural effusion is less frequent in this age group, which is why it is underdiagnosed, delaying timely treatment. Because of this, it is detected even in advanced stages, causing dysfunction in a short time. Clinical Case A 91-year-old woman with systemic arterial hypertension, Diabetes Mellitus, use of monopodal with initial geriatric assessment: Katz A-B-G, Lawton and Brody 7-3-1, Barthel 85-75-35, pre-frail, without complaint of memory. He came due to hyporexia of 1 month evolution, diarrhea associated with episodes of fecal incontinence, dyspnea that progressed with small efforts, ascites and edema of the lower limbs. Conclusión It is important to consider these syndromes as a differential diagnosis in patients who suddenly present with pleural effusion, ascites, or both in order not to delay timely treatment and to preserve functionality to the greatest possible degree.

OBJECTIVE: To determine the demographic and health factors related to the frailty syndrome in older adults. METHODS: This is a longitudinal quantitative study carried out with 262 older adults aged 65 years and older, of both sexes, living at home. Data collection was carried out in Period 1 between October 2007 and February 2008, and in Period 2 between July and December 2013. For data collection, we used the sociodemographic profile instrument, the Edmonton Frail Scale, the Mini-Mental State Examination, the number of falls in the last 12 months, the number of self-reported diseases and used drugs, the Functional Independence Measure, and the Lawton and Brody Scale. We used descriptive statistics for data analysis, in the comparison of the means between periods, the nonparametric Wilcoxon test, and the method of Generalized Estimating Equations, which is considered an extension of the Generalized Linear Models with p ≤ 0.05. RESULTS: Of the 515 participants, 262 completed the follow-up, with a predominance of females, older individuals, and those who had no partner; there was an increase in frail older adults. In the Generalized Estimating Equations analysis, frailty score was related to sociodemographic (increase in age, no partner, and low education level) and health variables (more diseases, drugs, falls, and decrease in functional capacity). There was an association between the variables of age (older), marital status (no partner), and loss of functional capacity. CONCLUSIONS: Frailty syndrome was associated with increasing age, having no partner, and decreased functional capacity over time, and investments are required to prevent this syndrome and promote quality in aging.

Abstract Introduction: MDS is a disease of the elderly; yet, the impact of clinical frailty (an age-related vulnerability state created by a multidimensional loss of reserves) and patient-reported outcomes on overall survival (OS) are unknown. Rockwood et al. have developed a simple 9-point clinical frailty scale (CFS) that correlated highly with the risk of death, institutionalization, worsening health and hospital use (Rockwood K., CMAJ 2005). In a prospective, national MDS registry, participants have undergone annual evaluations with the following: (a) 3 geriatric physical performance tests, (b) Charlson (CCI) and Della Porta comorbidity index (DP-CCI) scores, (c) graded frailty using the Rockwood CFS, (d) disability assessments with the Lawton Brody SIADL, and (e) QOL using the EORTC QLQ C-30 and the EQ-5D. The results of these frailty assessments and the effects of these patient-related factors and reported outcomes on OS, in addition to the IPSS/revised IPSS, will be presented. Methods: Overall survival was measured from time to enrollment. Results from physical performance tests were divided into quintiles with higher scores indicating better performance. We used univariate and multivariable Cox proportional hazard model to determine significant predictive factors of overall survival (OS). The variables considered included age, IPSS, R-IPSS, ferritin, LDH, transfusion dependence, hemoglobin (hgb), ECOG, frailty, CCI and DP-CCI, grip strength, 4 M walk test, stand-sit test, modified short physical performance battery (SPPB), Lawton Brody SIADL, time from diagnosis and selected QOL domains including the EQ-5D summary score, EORTC physical functioning, dyspnea and fatigue scores. Results: 453 MDS patients (pts) have been consented and enrolled locally since January 2008 (n=231) and nationally since January 2012 (n=222). Median time from diagnosis was 5.8 mos (IQR 1.4-21). Median age was 73 y (range, 26-95 y), 65% were male and the R-IPSS scores were very low (14%), low (46%), intermediate (24%), high (10%) and very high (6%). Thirty-three % of pts were transfusion dependent at enrollment. Median CCI and DP-CCI scores were 1 (0-12) and 0 (0-6) respectively with 18% and 24% falling into the highest category scores. Median frailty scale score (n=346) was 3 (1-9) with 25% having scores indicating moderate (4-5) or severe (6-9) frailty. The CCI and DP-CCI strongly correlated (r=0.6; p< .0001) with each other, while frailty significantly but modestly correlated with them (r=0.3-0.35, p<.0001). With a median follow up (from enrollment) of 15 mos (95% CI: 13-16), 159 (35%) pts have died and 28 pts lost to follow up. Actuarial survival was 41.0 mos (range, 33.6 - 48.5 mos). When considering patient related factors - age, frailty, comorbidity (both indices), sex, ECOG, the 10 x stand sit test, the SPPB, Lawton Brody SIADL, and all QOL domains considered above were significantly predictive of OS. The multivariable model with the highest R2 included R-IPSS (p=.0004), frailty (1-3 vs 4-9, p= .004), CCI (0-1 vs >2, p=.03) and EORTC fatigue (p=.01) as summarized in Table 1 below. A frailty score > 3 predicted for worse survival (figure 1: 2 year OS 68.5% vs. 83.8%) and further refined survival within the R-IPSS categories (Figure 2). Frailty was also the single most predictive factor for OS from the start of azacitidine therapy (not shown). Conclusions: Patient-related factors such as frailty and comorbidity (that evaluate physiologic reserve and global fitness) should be considered in addition to traditional MDS prognostic indices. Abstract 165. Table. Independent Covariate Predictive factors at baseline Coefficient SE p -value HR 95% CI of HR R2 (%) Time from diagnosis (months) * 0.0335 0.1076 0.7557 1.034 0.837 1.277 17.29% R-IPSS (5 categories) <.0001 Very high vs. very low 2.5701 0.7289 0.0004 13.066 3.131 54.524 High vs. very low 2.1156 0.6437 0.0010 8.294 2.349 29.285 Intermediate vs. very low 1.0466 0.6430 0.1036 2.848 0.808 10.043 Low vs. very low 0.6346 0.6181 0.3045 1.886 0.562 6.334 Frailty (1-3 vs. 4-9) -0.8323 0.2905 0.0042 0.435 0.246 0.769 Comorbidity Charlson (0-1 vs. ³2) -0.5915 0.2749 0.0314 0.553 0.323 0.949 EORTC fatigue * 0.3671 0.1546 0.0176 1.443 1.066 1.954 natural log-transformation was applied for normalizing distribution Figure 1 Overall survival by Frailty (n=346) Figure 1. Overall survival by Frailty (n=346) Figure 2 Overall Survival by Frailty and R-IPSS Figure 2. Overall Survival by Frailty and R-IPSS Disclosures Buckstein: Celgene Canada: Research Funding. Wells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Leitch:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Educational Grant Other, Honoraria, Research Funding. Shamy:Celgene: Honoraria, Other.

Abstract OBJECTIVES Frailty syndrome predicts adverse outcomes after surgical aortic valve replacement. However, disability or comorbidity is frequently associated with preoperative frailty evaluation. The effects of these domains on early and late outcomes were analysed. METHODS A prospective study including patients aged ≥75 years with symptomatic severe aortic stenosis who received aortic valve replacement with or without coronary artery bypass grafting was conducted. We used the Cardiovascular Health Study Frailty Phenotype to assess frailty, the Lawton–Brody index to define disability and the Charlson comorbidity index (CCI) to evaluate comorbidity. RESULTS Frailty was identified in 57 (31%), dependence in 18 (9.9%) and advanced comorbidity (CCI ≥ 4) in 67 (36.6%) of the 183 enrolled patients. Operative mortality (1.6%), transfusion rate and duration of stay increased in patients with CCI ≥4 (P < 0.005). There was a non-significant trend for these adverse outcomes among the frail patients. Follow-up was achieved in all patients (median/interquartile range 869/699–1099 days). Kaplan–Meier univariable analysis showed a reduced survival rate for frail and dependent patients and for those with multiple comorbidities (P < 0.05). According to multivariable analysis, frailty and comorbidity were independent risk factors for 1-year mortality, while disability and comorbidity, but not frailty, were risk factors for 3-year mortality (P < 0.05). CONCLUSIONS Surgical aortic valve replacement in patients aged ≥75 years is a safe procedure with low mortality rates. Operative outcomes are mainly affected by comorbidities. The main influence of survival occurs throughout the first year, and an improved functional status prevents any progression towards disabilities, which could potentially benefit long-term outcomes. Clinical trial registration number NCT02745314

La malattia di Brody è una rara patologia muscolare che può essere trasmessa come carattere autosomico recessivo o dominante. L'ereditarietà recessiva è associata a mutazione del gene ATP2A1 che codifica la proteina del reticolo sarcoplasmico/endoplasmico calcio ATPasi 1 (SERCA1), la quale catalizza il riassorbimento ATP-dipendente del Ca2+ dal citosol al lume del reticolo sarcoplasmatico. Tuttavia, mutazioni nel gene ATP2A1 non sono state identificate in alcuni pazienti con ereditarietà recessiva ed in tutti i casi che presentano la forma autosomica dominante, suggerendo l'eterogeneità genetica della malattia. Il termine “sindrome di Brody” è stato recentemente proposto per designare pazienti con ridotta attività SR Ca2+-ATPasica ma senza mutazioni del gene ATP2A1. La principale caratteristica clinica è il ritardo nel rilassamento muscolare a seguito dell’ esercizio con conseguente rigidità muscolare in assenza di dolore. La creatina chinasi (CK) sierica è normale o leggermente aumentata, l'elettromiografia (EMG) registra scariche pseudo-miotoniche durante gli episodi di rigidità muscolare indotta da esercizio ("silent cramps") ed il fenomeno miotonico non è presente. Una ridotta attività SR Ca2+-ATPasica è stata riportata in tutti i casi descritti, indipendentemente dall’associazione con mutazioni di ATP2A1. Al contrario, i dati sull’ espressione della proteina SERCA1 sono ancora oggetto di dibattito. Infatti, nei muscoli dei pazienti con BD, mediante immunoistochimica è stata riportata una normale o ridotta espressione di SERCA1, mentre l’immunoblot, effettuato solo in pochi casi, ha documentato una significativa riduzione dei livelli di espressione di SERCA1. Nella prima parte di questo studio sono stati caratterizzati 13 pazienti con miopatia di Brody tramite analisi molecolare e biochimica condotte sul muscolo scheletrico. Mediante immunofluorescenza, SERCA1 ha mostrato una distribuzione ed un’ intensità di segnale simili nel muscolo dei controlli e dei pazienti con e senza mutazione di ATP2A1 mentre, inaspettatamente, l’immunoblot dopo SDS-PAGE e 2D-PAGE ha mostrato una significativa riduzione di espressione di SERCA1 nei muscoli dei pazienti con BD rispetto ai muscoli dei pazienti con BS e dei soggetti di controllo. Pertanto è stato ipotizzato che la proteina mutata potesse avere una diversa solubilità di quella wild type. Tuttavia, la resa di estrazione di SERCA1 mutata era inferiore a quello della proteina wild-type, indipendentemente dal tampone di lisi utilizzato, suggerendo che le mutazioni identificate non influenzino le proprietà di solubilità della proteina SERCA1 nei tamponi usati per omogenare il muscolo. Lo studio dello stato di oligomerizzazione della proteina ha mostrato uno spostamento dalle forme monometrica/dimerica allo stato oligomerico ad alto peso molecolare di SERCA1 nel muscolo dei pazienti con mutazione di ATP2A1, fornendo una possibile spiegazione della riduzione del livello di SERCA1 allo stato monomerico riscontrato all’immunoblot dopo SDS-PAGE. Questi dati evidenziano inoltre come l’immunoblot, contrariamente all’immunoistochimica, possa essere utile per la diagnosi della malattia di Brody in pazienti con ridotta attività SR Ca2+-ATPasica. In questo studio è stata anche riportata la caratterizzazione clinica ed istologica di un nuovo paziente con sindrome di Brody e sono state documentate due nuove mutazioni nel gene ATP2A1 in un nuovo paziente e in un caso di malattia Brody precedentemente descritto. Lo studio di localizzazione di SERCA1 nel reticolo sarcoplasmatico non ha mostrato differenze tra il muscolo dei pazienti con BD e quelli con BS. Nella seconda parte dello studio è stata valutata l'espressione delle isoforme di SERCA1 e saggiata l’attività SR Ca2+-ATPasica nei muscoli dei pazienti con distrofia miotonica (tipo 1 e 2) e dei pazienti con miopatia ipotiroidea. Infatti, i dati di letteratura supportavano l’ipotesi di un’ alterata espressione di SERCA1 e di una ridotta attività del SR Ca2+-ATPasica nel muscolo nei pazienti con distrofia miotonica e nei modelli murini di ipotiroidismo. In questo studio non sono stati osservate nè una riduzione dell’attività SR Ca2+-ATPasica nè una ridotta espressione di SERCA1 e SERCA2 nei muscoli dei pazienti affetti da distrofia miotonica e di quelli con miopatia ipotiroidea. Nel muscolo di pazienti affetti da distrofia miotonica è stata documentata la presenza dell’isoforma neonatale SERCA1b, i cui livelli di espressione sono risultati essere maggiori nel muscolo dei pazienti con distrofia miotonica di tipo 2 rispetto ai pazienti affetti da distrofia miotonica di tipo 1. Inoltre, in questo studio è stata analizzata l’espressione di SERCA1 e SERCA2 nel muscolo di neonati a diversi stadi di sviluppo (10, 20 giorni, uno e quattro mesi dopo la nascita). In tutti gli stadi di sviluppo neonatale analizzati, l’espressione di SERCA1 era presente solo in alcune fibre, mentre la quasi totalità delle fibre muscolari esprimeva SERCA2 fino ad 1 mese dopo la nascita. Nel muscolo dei neonati di 10 e 20 giorni, solo poche fibre presentavano SERCA1b. Infine, è stato dimostrato che SERCA1b è la principale isoforma di SERCA1 espressa, insieme con SERCA2, in colture primarie di muscolo scheletrico umano le quali rappresentano quindi un buon modello per lo studio del muscolo nelle prime fasi dello sviluppo neonatale. Nella terza e ultima parte di questo studio sono state identificate nuove proteine che interagiscono in condizioni fisiologiche con SERCA1 e che potrebbero pertanto rappresentare geni candidati responsabili della sindrome di Brody. Infatti, la mutazione in un gene codificante una proteina che, interagendo con SERCA1 è in grado di regolarne la funzione potrebbe spiegare la riduzione dell’attività SR Ca2+-ATPasica nei pazienti senza mutazione in ATP2A1. Due diversi approcci sono stati usati per identificare nuovi partners di legame di SERCA1. La purificazione mediante affinità accoppiata a spettrometria di massa ha portato ad identificare la proteina del reticolo sarcoplasmico/endoplasmico calcio ATPasi 3 (SERCA3) come proteina di legame di SERCA1. L'espressione delle isoforme di SERCA3 nel muscolo scheletrico ha mostrato che SERCA3b è presente nelle fibre muscolari di tipo 2, le stesse che esprimono SERCA1. Inoltre, esperimenti di elettroforesi nativa/SDS-PAGE e di co-immunoprecipitazione hanno confermato la possibile interazione tra SERCA1 e SERCA3b nel muscolo scheletrico in condizioni fisiologiche. Il secondo approccio è stato quello di isolare i complessi SERCA1-proteina allo stato nativo dal muscolo scheletrico e di identificare le proteine di legame di SERCA1 mediante spettrometria di massa. Questa strategia ha portato all’identificazione di sarcalumenina, di reticulone-2, di Nogo/reticulone-4 e di mioadenilato deaminasi come possibili proteine che interagiscono con SERCA1. Una riduzione dell'espressione di sarcalumenina è stata osservata nel muscolo di quattro pazienti con sindrome di Brody, suggerendo SLN come un gene candidato per la malattia.
Brody disease is a rare skeletal muscle disorder transmitted as an autosomal recessive or dominant trait. The recessive inheritance is associated to mutation of ATP2A1 gene encoding the sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1), a protein that catalyzes the ATP dependent Ca2+ uptake from the cytosol to the lumen of sarcoplasmic reticulum. However, mutations in the ATP2A1 gene are missed in some patients with recessive inheritance and have never been found in patients with an autosomal dominant pattern suggesting the genetic heterogeneity of the disease. The term Brody syndrome has been recently proposed to designate patients with decreased SR Ca2+ATPase activity but without ATP2A1 mutation. The main clinical feature is the exercise-induced delay in muscle relaxation which causes painless muscle stiffness following contraction. Serum creatine kinase (CK) is normal or slightly increased, needle electromyography (EMG) records no myotonic and pseudomyotonic discharges during the exercise-induced muscle stiffness (“silent cramps”) and percussion myotonia is absent. Reduction of SR Ca2+ ATPase activity has been reported in all described cases, independently from the association with ATP2A1 mutation. Conversely, data on SERCA1 protein expression are still under debate. Indeed, in muscle of patients with BD, immunostaining for SERCA1 has been reported to be normal or reduced while immunoblot analysis,performed in just a few cases, documented a significant reduction in protein amount. In the first part of the study we performed molecular and biochemical analysis on muscle from 13 patients with Brody myopathy. Immunofluorescence studies of SERCA1 revealed similar staining pattern and intensity in muscle of controls and of patients with and without ATP2A1 mutation whereas, contrary to the expectations, immunoblot analysis after SDS-PAGE and 2D gel electrophoresis showed a significant reduction of SERCA1 protein in muscle of patients with BD as compared to muscle of patients with BS and of control subjects. Therefore, we hypothesized that the mutated protein could have different solubility features of the wild type one. However, the recovery of mutated SERCA1 was lower than that of the wild type protein, irrespectively the lysis buffer, suggesting that mutations detected in ATP2A1 gene did not affect the solubility properties of SERCA1 in the buffers we used for muscle homogenization The study of SERCA1 oligomerization revealed the shift from monomeric/dimeric forms to the high-oligomeric status of SERCA1 in muscle from patients with ATP2A1 mutation, providing a possible explanation of the reduced detection of SERCA1 monomer after denaturing electrophoresis. The present data provide also evidence that immunoblotting, in contrast to the immunohistochemistry, could be a useful tool for confirming the diagnosis of BD in patients with reduced SR Ca2+ ATPase activity. In this study we reported also the clinical and histological characterization of a new patient with Brody syndrome and document novel mutations in the ATP2A1 gene of a new patient and in a previously described case of Brody disease. Moreover, we study SERCA1 distribution within the sarcoplasmic reticulum revealing no remarkable changes in the localization of the protein in muscle from patients with BD and BS. In the second part of the study we analyzed the expression of SERCA1 isoforms and investigated SR Ca2+ ATPase activity in muscle of patients with myotonic dystrophy (type 1 and 2) and in hypothyroid myopathy. Indeed, data from the literature seem to support the alteration of SERCA1 expression and SR Ca2+ ATPase activity in patients with myotonic dystrophies and in hypothyroid mice. We observed no significant changes in SR Ca2+ ATPase activity, SERCA1 and SERCA2 expression in muscle from patients with myotonic dystrophies and with hypothyroid myopathy. Interestingly, we observed that the neonatal isoform SERCA1b is expressed in myotonic dystrophies, in particular at higher levels in type 2 than type 1 disease. Moreover, we provide data on SERCA1 and SERCA2 expression in neonatal muscle at different developmental stages (10, 20 days, one and four months after birth) revealing that, at all analyzed time of neonatal development, SERCA1 is expressed only in some fibers whereas nearly all fibers express SERCA2 up to 1 month after birth. In muscle from 10 and 20 days after birth, only a few fibers express SERCA1b. Finally, we showed that SERCA1b is the main SERCA1 isoforms expressed, together with SERCA2, in cultured human muscle fibers which therefore represent a good model to study neonatal muscle at early stages after birth. In the third, and last part of this study we focused on the identification of novel physiological interacting partners of SERCA1 that could be candidate genes responsible for Brody syndrome. Indeed, mutation in a gene encoding a protein which, by interacting with SERCA1, is able to regulate its function could account for the decreased SR Ca2+ ATPase activity in patients without ATP2A1 mutations. Two different approaches were used to identify novel SERCA1 binding partners. Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 (SERCA3) has been identified as a reliable SERCA1-binding protein by affinity purification couple to mass spectrometry. The analysis of SERCA3 isoforms expression in skeletal muscle tissue led to identify SERCA3b as strongly expressed in type 2 muscle fibers, where SERCA1 is also located. Moreover, native/SDS-PAGE and co-immunoprecipitation experiments seem to support the existence of an interaction between SERCA1 and SERCA3b in skeletal muscle in physiological conditions. The second approach consisted in isolating SERCA1-protein complexes in native state from skeletal muscle and in protein identification by mass spectrometry. This strategy led to the identification of sarcalumenin, reticulon-2, Nogo/reticulon-4 and myoadenylate deaminase as putative SERCA1 interacting partners. A reduction of sarcalumenin expression was observed in muscle from four patients with Brody syndrome suggesting SLN gene as a candidate gene the disease.

A good way to come up with a list of causes is to visualize the anatomy of the affected area and think of what could go wrong. Thus, in chest pain, there may be pathology of the heart, aorta, lungs, pulmonary vessels, oesophagus, stomach, thoracic nerves, thoracic muscles, or ribs. The main causes of acute chest pain in an individual aged over 60 include are listed in Figure 9.1. A younger patient is less likely to be suffering from diseases of old age, such as: • Acute coronary syndrome • Stable angina • Myopericarditis (usually post-infarction) • Thoracic aortic dissection • Thoracic aortic aneurysm A younger female patient on the combined oral contraceptive pill is more likely to be suffering from: • PE (the combined oral contraceptive pill is thrombogenic) • Pneumothorax (especially if tall and thin) • Cocaine-induced coronary spasm (still rare, but particularly unusual in older people). The following diagnoses require immediate management and should be kept in mind: • Acute coronary syndrome (unstable angina, or myocardial infarction (MI)) • Aortic dissection • Pneumothorax • PE • Boerhaave’s perforation The key features of each are listed below. 1 Features of acute coronary syndrome ■ History of sudden-onset, central, crushing chest pain radiating to either/both arms, neck or jaw, usually lasting a few minutes to half an hour (longer if there is ongoing infarction). Have a higher index of suspicion in those with a previous history of angina on exertion or MI and/or cardiovascular risk factors (smoking, hypertension, hypercholesterolaemia, diabetes mellitus, family history). ■ Signs of hypercholesterolaemia: cholesterol deposits in small skin lumps on the back of the hand or bony prominences like elbows (xanthomata), in creamy spots around the eyelids (xanthelasma), or a creamy ring around the cornea (arcus). Note that arcus is a normal finding in older people. ■ Signs of peripheral (atherosclerotic) vascular disease: weak pulses, peripheral cyanosis, cool peripheries, atrophic skin, ulcers, bruits on auscultation of carotids. ■ Signs of brady- or tachyarrhythmia. An arrhythmia is relevant for two reasons.