Downs Syndrome: Structural and Physiological Changes - Research Paper Example

?Down’s syndrome. Down’s syndrome. Down’s syndrome. Down’s syndrome is a genetic disorder resulting from a chromosomal aberration. The affected childhas a facial dysmorphology with slanting eyes, flattening of the facial features, an enlarged tongue, short height and fingers which are stubby looking (Marieb and Hoehn, 2010). In addition some have mental retardation. Down’s syndrome (DS) patients suffer from cognitive deficits; they are also prone to Alzheimer’s disease at an early age (Down’s syndrome, NIH). The onset of Alzheimer’s disease is usually at around 65 years of age in normal people but DS patients could acquire it at an earlier age. Leukemia also has a greater incidence in Down’s syndrome (Down’s syndrome, NIH). The major risk factor is advanced age of either parent, especially the mother. The life expectancy of DS has now risen to above 50 years enhancing the cognitive deficits and posing threats to the societal burden (Down’s syndrome, NIH). Children with Down’s have hypotonia of the muscles as the neurological system is affected in DS (Allison et al, 2008)). Developmental delay was a significant feature of DS. These children had all their milestones of development delayed. The chromosomal abnormality Nondisjunction appeared to be the alteration at the chromosomal level. Non-disjunction was the “abnormal segregation of chromosomes during meiosis which resulted in gametes having 2 copies of a parental chromosome, the resulting complement having an abnormal chromosomal portion ” in 95% of Down’s syndrome (Marieb and Hoehn, 2010). Familial Down’s syndrome seen in 4% individuals was also possible when the third chromosome 21was translocated to another chromosome like the 14th (Marieb and Hoehn, 2010). A milder phenotype of Down’s occurred in 1% of individuals when non-disjunction occurred in mitosis after the formation of the xygote. Screening at pregnancy A pregnant woman could be screened by chorionic villus sampling or by amniocentesis for fetal chromosomes. The incidence of Down’s in pregnant women over the age of 40 was 1 in 100. A suspicion of Down’s syndrome had to be clarified through genetic tests. The extent of damage to the child could also be understood from the genetic tests (Allison et al, 2008). Supports could be provided by professionals and self-help groups when the diagnosis was confirmed to help the couple adjust. This couple should also be advised on future pregnancies. Genetic counseling needed to include implications of diagnosis. Cardiac abnormalities The twenty-first chromosome had an extra autosome and hence termed trisomy 21 (Marieb and Hoehn, 2010). It occurred in the incidence of 1 in 800 live births if screening had not been done in the first trimester (Dunlevy et al, 2010). Had screening been done then, many pregnancies would have been terminated and the incidence would have been less. Many phenotype features had been associated with this disorder. Congenital heart disorder had been found in 40-60% of the children affected with DS. The heart complications were varied and could be mere chamber separation to really complex problems like tetralogy of Fallot. The involvement of the atrio-ventricular junctions indicated that the cardiovascular system was involved early in the embryogenesis as the AV junction was formed in the first stages of embryogenesis (Dunlevy et al, 2010). The trisomy involved many genes which varied in severity in different people. Atrio-venous junction malformations constituted a major feature of the cardiac abnormalities. AV septal defect and the common AV junction occurring in cardiogenesis being retained as malformation were two defects. Septal defects which caused shunting problems also were associated (Dunlevy et al, 2010). The shunting caused the anatomical arrangement of the cusps of the mitral and tricuspid valves to be disturbed. The Ventricular septal defect was usually accompanied by a pansystolic murmur which had an associated thrill (a thrill is the pulsation of the murmur palpated on the chest wall). Doppler and echocardiogram could both evaluate the cardiac abnormalities in pregnancy. Eisenmenger’s syndrome was a possibility in Down’s syndrome if there were a left-to-right shunt of the cardiac circulation (Allison et al, 2008). Eisenmenger’s syndrome was caused by a reversal of the normal right-to-left shunt of the heart and occurred as follows. In some cardiac abnormalities, more blood than normal entered the pulmonary circulation leading to pulmonary hypertension. The pulmonary artery could be damaged due to further rise in pressure resulting in pulmonary vascular illness. As the pressure rose and exceeded the left ventricular pressure, there occurred a reversal of shunt from left to right. Deoxygenated blood moved from left to right leading to a state of cyanosis (Allison et al, 2008). Surgery could correct the septal defect in DS and reinstate the right-to-left shunt of blood and also abolish the cyanosis. Other structural abnormalities Other structural abnormalities that could be associated with Down’s syndrome (DS) were duodenal atresia, congenital cataracts and atlanto-subluxation of which duodenal atresia was the commonest (Allison et al, 2008). At some stage in the lives of individuals with Down’s, osteoarthritis developed in 15%. “Oesophageal atresia, Meckel’s diverticulum, Hirchsprung’s disease and imperforate anus” were other possible problems of the gastro-intestinal system associated with Down’s (Allison et al, 2008). Neurological deficits The social intelligence levels of DS and cognitive deficits differed greatly from other retardations like Fragile X or Williams’s syndrome (Down’s syndrome, NIH). High levels of social intelligence existed in the DS but communication with expressions or explicit memory was poor. Sleep was an issue too and this further worsened memory. The prefrontal cortex, hippocampus, and cerebellum were structures which developed late and the deficit in cognitive functions had been attributed to these structures (DS, NIH). The brain in DS had shown several abnormalities. The dendritic spines were not normal; the spine density was decreased but the size of the spines varied. Similar abnormalities were detected in the mouse model of DS in research which indicated a spine strength increase in most parts of the brain except the hippocampus which showed a decrease (DS, NIH). Memory deficits were associated with these abnormalities. Synaptic plasticity was also seen in the mouse model. Normal spine development and synapse formation required specific synaptic proteins. In DS, these were changed. This was the reason for abnormal spines and poor synapse formation. There had been doubts as to whether the defects in the synaptic development could have been initiators of the DS phenotype (DS, NIH). Neuronal connections and the possible deficits The memory loss and cognitive deficits in DS were believed to occur due to alterations in the hippocampal connections to the frontal brain (Bearer et al, 2007). Imaging of the enhanced circuitry and the dynamic alterations in signals were possible with magnetic resonance imaging of high resolution. A mouse model of DS, Ts65Dn, had shown behavioral deficits in learning and memory issues. Histopathology of the brain was altered. Functional measures showed variations below normal (Roper ad Reeves, 2006 and Seregaza et al, 2006 both in Bearer et al, 2007). There had been indications that the cholinergic activity in the forebrain was suppressed (Bearer et al, 2007). Increased expression of genes in the excess segment of chromosome 21 had also been indicated (Seo and Icacson, 2005 in Bearer et al, 2007). The neurons in the forebrain and hippocampus were connected through reciprocal connections. They were connecting the cell bodies of various affinities (cholinergic, glutaminergic and GABAergic) of the fore-brain to the hippocampus (Colom, 2006 in Bearer et al, 2007). The processes within the brain were responsible for functioning and survival of the neurons. The mouse model showed an atrophy of the cholinergic neurons of the fore-brain in DS. It was found that the activity of these cells could be recovered with the Injection of nerve growth factor intracerebroventricularly (Tuyzinski et al, 2005 in Bearer et al, 2007). Direct imaging of the transport was not available then. The imaging was done by Bearer et al with Manganese enhanced Magnetic resonance Imaging. The transport dynamics was measured in vivo in the model mice which indicated alterations. Manganese as a tracer allowed the functional differences of the transport dynamics to be measured (Bearer et al, 2007). The significance of the Magnetic Resonance Imaging was established in allowing the physiological transport systems in the mammalian brain to be understood (Bearer et al, 2007). Memory loss was attributed to the changes in the hippocampal neuronal functions. Research had indicated the reduction of synapses, excitatory in nature, and the altered morphology of synaptic structure in the hippocampus (Hanson et al, 2007). New research had eliminated the concept of the long-term potentiation being the reason for memory loss. It had been established that long-term potentiation was intact but that the excitation-inhibition ratio of the synaptic transmission was impaired so that the inhibitory action was more displayed. This reduced the depolarization of the post-synaptic cells which in turn was insufficient to influence the long-term potentiation cells. The memory impairments could be attributed to the changed synaptic anatomy and circuitry changes (Hanson et al, 2007). Area CA3 was the place in the hippocampus with the most excitatory synaptic connections. This area was associated with pattern completion and separation of memory storage. Hanson et al investigated the functional synaptic connectivity in CA3 in the mouse model, Ts65Dn, using high resolution (Hanson et al, 2007). Silent synapses were differentiated from active synapses which had functional AMPA (? amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors. Lesser synapses were made in the CA3 region of pyramidal neurons. However the inter-neuronal associations between the pyramidal neurons were plentiful. Alterations in the functional inter-neuronal connections could probably answer for the learning and memory issues in DS (Hanson et al, 2007). The mechanisms for impairment in spatial learning and memory in DS had not been definite yet when Harashima et al had investigated the GIRK2 gene (G-protein-activated inwardly rectifying potassium channel 2) which was found in the hippocampus (2006). It was found in abundance in the hippocampus of the mouse model with DS, Ts65Dn. Increased levels of GIRK 2 in hippocampus and frontal cortex were found associated with high levels of GIRK 1. Harashima et al found that elevated levels of mRNA caused similar high levels of GIRK 2 and GIRK 1 in the hippocampus and the frontal brain (2006). A simultaneous increase of both GIRK 2 and 1 in the hippocampus and fontal cortex could reduce the excitatory input, regulate the spike frequency and synaptic kinetics (Harashima, 2006) thereby answering for the impairments of spatial learning and memory. Hewitt et al indicated that trisomy affected neurogenesis (2010). It could provoke a pathogenesis of neuronal deficits which progressively worsened. This study allowed for the development of therapies which could either slow the progression or even remove the neuronal deficits (Hewitt et al, 2010). Trisomy 21 was shown to include the APP gene which encoded the Alzheimer’s disease. The APP gene led to the accumulation of Amyloid-beta peptides in the cerebrum causing an early onset of Alzheimer’s in the DS. The neuropathology and cognitive sequelae were the results of the accumulation of amyloid-beta peptides in the brain (Moncaster et al, 2010). Conclusion Down’s syndrome is a genetic disorder resulting from a chromosomal aberration of the twenty first chromosome of human beings causing an extra autosome to be incorporated. Down’s syndrome produced many structural and physiological changes in the affected. The major risk factor was advanced age of the mother. Structural and physiological changes affected the cardiovascular system and the neurological system mostly. These could account for the cardiovascular abnormalities, developmental delay, mental retardation, memory loss, cognitive decline and early onset of Alzheimer’s disease. Researchers had been able to do exhaustive investigations which had revealed certain positive results regarding how embryogenesis was affected and possible areas of correction with therapy so that the pathological progression could be delayed or stopped or even cured in the future. References: Allison, M.E.M., McDonald, S. and Allison, M. (2008). Core clinical cases: self-assessment for medical students. Anatomy and physiology, PasTest Ltd, 2008 Bearer, E.L., Zhang, X.,and Jacobs, R.E. (2007). Live Imaging of Neuronal Connections by Magnetic Resonance: Robust Transport in the Hippocampal-Septal Memory Circuit in a Mouse Model of Down Syndrome. Neuroimage. 2007 August 1; 37(1): 230–242. Dunlevy, L., Bennett M., Slender, A., Lana-Elola, E., Tybulewicz, V.L., Fisher, E.M.C., and Mohun, T. (2010). Down’s syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse. Cardiovascular Research (2010) 88, 287–295 doi:10.1093/cvr/cvq193 Hanson, J.E., Blank, M., Valenzuela, R.A., Garner, C.C. and Madison, D.V. (2007). The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down’s syndrome. J Physiol 579.1 (2007) pp 53–67 Harashima, C., Jacobowitz, D.M., Witta, J., Borke, R.C., Best, T.K., Siarey, R.J. and Galdzicki, Z. (2006). Abnormal Expression of the GIRK2 Potassium Channel in Hippocampus, Frontal Cortex and Substantia Nigra of Ts65Dn Mouse: A Model of Down Syndrome. J Comp Neurol. 2006 February 10; 494(5): 815–833. doi:10.1002/cne.20844. Hewitt1, C.A., Ling, K-H, Merson, T.D., Simpson, K.M., Ritchie, M.E., King, S.L. et al.(2010). Gene Network Disruptions and Neurogenesis Defects in the Adult Ts1Cje Mouse Model of Down Syndrome. PLoS One, 5(7): e11561. doi:10.1371/journal.pone.0011561 Marieb, E.N. and Hoehn, K. (2010). Human anatomy and physiology. Pearson Education India, 2010 Moncaster JA, Pineda R, Moir RD, Lu S, Burton MA, et al. (2010) Alzheimer’s Disease Amyloid-b Links Lens and Brain Pathology in Down Syndrome. PLoS ONE 5(5): e10659. doi:10.1371/journal.pone.0010659 Read More