Secondary Muscle Pathology and Metabolic Dysregulation in Adults with Cerebral Palsy.
ABSTRACT Cerebral palsy (CP) is caused by an insult to, or malformation of the developing brain which affects motor control centers, and causes alterations in growth, development, and overall health throughout the lifespan. In addition to the disruption in development caused by the primary neurologic insult, CP is associated with exaggerated sedentary behaviors and a hallmark accelerated progression of muscle pathology compared to typically developing children and adults. Factors such as excess adipose tissue deposition and altered partitioning, insulin resistance, and chronic inflammation may increase the severity of muscle pathology throughout adulthood, and lead to cardiometabolic disease risk and/or early mortality. We describe a model of exaggerated health risk represented in adults with CP, and discuss the mechanisms and secondary consequences associated with chronic sedentary behavior, obesity, aging, and muscle spasticity. Moreover, we highlight novel evidence that implicates aberrant inflammation in CP as a potential mechanism linking both metabolic and cognitive dysregulation in a cyclical pattern.
SourceAvailable from: Olaf Verschuren[Show abstract] [Hide abstract]
ABSTRACT: Low levels of physical activity are a global health concern for all children. Children with cerebral palsy have even lower physical activity levels than their typically developing peers. Low levels of physical activity, and thus an increased risk for related chronic diseases, are associated with deficits in health-related physical fitness. Recent research has provided therapists with the resources to effectively perform physical fitness testing and physical activity training in clinical settings with children who have cerebral palsy, although most testing and training data to date pertains to those who walk. Nevertheless, on the basis of the present evidence, all children with cerebral palsy should engage, to the extent they are able, in aerobic, anaerobic, and muscle-strengthening activities. Future research is required to determine the best ways to evaluate health-related physical fitness in nonambulatory children with cerebral palsy and foster long-term changes in physical activity behavior in all children with this condition.Journal of child neurology 05/2014; 29(8). DOI:10.1177/0883073814533152 · 1.67 Impact Factor
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ABSTRACT: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT: Fanconi anemia (FA) is known as an inherited bone marrow failure syndrome associated with cancer predisposition and susceptibility to a number of DNA damaging stimuli, along with a number of clinical features such as upper limb malformations, increased diabetes incidence and typical anomalies in skin pigmentation. The proteins encoded by FA-defective genes (FANC proteins) display well-established roles in DNA damage and repair pathways. Moreover, some independent studies have revealed that mitochondrial dysfunction (MDF) is also involved in FA phenotype. Unconfined to FA, we have shown that other syndromes featuring DNA damage and repair (such as ataxia-telangiectasia, AT, and Werner syndrome, WS) display MDF-related phenotypes, along with oxidative stress (OS) that, altogether, may play major roles in these diseases. Experimental and clinical studies are warranted in the prospect of future therapies to be focused on compounds scavenging reactive oxygen species (ROS) as well as protecting mitochondrial functions. Independent studies have identified MDF in FA [1-6], an inherited bone marrow failure (BMF) syndrome associated with DNA damage and repair (DDR) pathways, along with susceptibility to non-lymphocytic leukemias and other malignancies, and other clinical complications such as diabetes and malformations [7,8]. FA represents a unique model disorder that raised general attention in the last decade since it was discovered that one of the encoded proteins by the FA subgroup D1 (FANCD1) was identical with the breast cancer-related BRCA2 gene . The current state of knowledge on FA pathway relies on at least 16 genes corresponding to the FA genetic subgroups FA- and -Q [8,10]. When any of those genes is biallelically mutated, except for the X-linked FANCB, the FA disease occurs. The FA pathway is recognized to protect and regulate DNA from interstrand crosslinks [10-12]. Most of the mutations in the FA pathway inactivate a nuclear FA core complex, consisting of proteins FANCA, -B, -C, -E, -F, -G, -L, and -M and at least four FA-associated proteins, FAAP16, FAAP20, FAAP24, and FAAP100. The main known function of the FA core complex is to monoubiquitinate chromatin complex of two other FA proteins, FANCD2 and FANCI upon DNA damage [13-15]. Inactivation of the FA core complex does not allow monoubiquitination of FANCD2-FANCI, leading to a defect in downstream DNA repair signaling, consisting of FANCD1/BRCA2, FANCJ/BRIP1/BACH1, FANCN/ PALB2, FANCO/SLX4, and FANCP/RAD51C. The ubiquitinated FANCD2 recruits ubiquitin zinc finger domain-containing DNA repair proteins such as FAN1, FANCP (SLX4), TLS polymerases eta and finally mediates DNA homologous recombination together with RAD51 and BRCA1 [16-24]. Another line of studies, dating back to 1980's, has provided consistent evidence for a role of OS in FA phenotype, such as excess oxygen sensitivity [25-27], in vitro and in vivo accumulation of oxidative DNA damage [28,29], and other anomalies of redox endpoints . Most notably, direct implications of FANC proteins in
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ABSTRACT: Abstract OBJECTIVE: To examine the feasibility and potential benefits of using recumbent cross-training for nonambulatory adults with cerebral palsy (CP). DESIGN: Observational. SETTING: Clinical center for CP treatment and rehabilitation. PARTICIPANTS: Significantly motor-impaired adults with CP (N=11) with a mean age ± SD of 36.3±13.2 years and Gross Motor Function Classification System (GMFCS) levels III and IV. INTERVENTIONS: Participants completed a 40-minute session of aerobic exercise using the NuStep Recumbent Cross Trainer, in which resistance was progressively increased at 5-minute intervals. MAIN OUTCOME MEASURES: Every 5 minutes during the exercise session, heart rate, blood pressure, oxygen consumption (VO(2)), energy expenditure, and respiratory exchange ratios (RERs) were recorded along with rating of perceived exertion. Immediately after, and 24 hours postexercise, participants received a standard survey to assess levels of pain and discomfort. RESULTS: All participants were able to complete the 40-minute exercise protocol. Five of the 11 participants achieved a heart rate of at least 60% maximum throughout the duration, 10 participants had a significant elevation in VO(2) from baseline, and all participants had elevated RER values. Six participants reported pain during exercise, but only 2 reported pain after exercise was over. CONCLUSIONS: The NuStep Recumbent Cross Trainer is a feasible exercise modality for significantly motor-impaired adults with CP, GMFCS III and IV. Moreover, this mode was sufficient to stimulate a significant cardiorespiratory response in all participants, and thus it and similar devices may serve as a viable option for aerobic exercise interventions in this population, to prevent obesity and related cardiometabolic consequences. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.Archives of Physical Medicine and Rehabilitation 01/2013; 94(2):401-7. DOI:10.1016/j.apmr.2012.09.027. · 2.44 Impact Factor