Down Syndrome
Down syndrome (DS) or trisomy of chromosome 21 is the most prevalent cause of genetic intellectual disability affecting approximately 1 in 700 live births. Most DS cases are caused by full triplication of chromosome 21, and a small number of cases arise f
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Introduction to Down Syndrome Down syndrome (DS) or trisomy of chromosome 21 is the most prevalent cause of genetic intellectual disability affecting approximately 1 in 700 live births. Most DS cases are caused by full triplication of chromosome 21, and a small number of cases arise from mosaicism or chromosomal translocations, resulting in multiple medical and physical manifestations. Common characteristics of individuals with DS include skeletal anomalies, craniofacial alterations, hypotonia, increased incidence of congenital heart disease and seizures, abnormalities of the gastrointestinal tract, thyroid dysfunction, and premature aging [1]. Additional clinical features include altered folate metabolism and hormone imbalances [2, 3]. Neurological changes include reduced brain mass, impaired neuronal differentiation, aberrant dendritic spine morphology, and defects in synaptic plasticity [4]. Most middle-aged individuals with DS develop Alzheimer’s disease (see chapter “Alzheimer’s disease”) due to increased expression of the amyloid precursor protein gene located on chromosome 21 [5]. Alterations
M.D. Torres • J. Busciglio (*) Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders (iMIND), Center for the Neurobiology of learning and Memory (CNLM), University of California – Irvine, 3216 Biological Sciences III, Irvine, CA 92697-4545, USA e-mail: [email protected]; [email protected]
in reactive oxygen species (ROS) and energy metabolism have long been associated with the development and progression of DS neuropathology [6]. This section focuses on the role of oxidative stress, mitochondrial dysfunction, and hypothyroidism in DS.
Pathophysiology of Down Syndrome and Metabolic Alterations Altered Oxidative Stress and Energy Metabolism in DS Oxidative stress is a prominent feature associated with DS [7]. Enhanced lipid peroxidation (which can cause DNA damage) has been documented [8], as well as differential expression of oxidative stress-related genes [9]. Similarly, DS cortical neurons exhibit intracellular accumulation of ROS, increased lipid peroxidation, and reduced neuronal survival [10]. Another feature of DS pathology closely related to oxidative stress is mitochondrial dysfunction (Fig. 1). DS cells exhibit reduced mitochondrial transmembrane potential, ATP production, and oxidoreductase activity [9]. These energy deficits lead to an abnormal pattern of protein processing and secretion in DS including intracellular accumulation of Aβ [11]. Mitochondria are not only the main intracellular source of ROS and free radicals but also play a critical role in apoptotic pathways. Increased levels of ROS and mutations in
E. Lammert, M. Zeeb (eds.), Metabolism of Human Diseases, DOI 10.1007/978-3-7091-0715-7_10, © Springer-Verlag Wien 2014
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M.D. Torres and J. Busciglio
54 Fig. 1 Schematic representation of the proposed pathological cascade leading to Alzheimer’s disease in Down syndrome. Down syndrome is caused by triplication, mosaicism, or translocation of chromo
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