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Human genotype is the most prominent determinant of human pathogenesis. Thus the role of human gene on the progression and development of human disease can never be neglected. A hereditary disorder might be monogenetic which occurs due to mutation in a single particular gene. For instance sickle cell disease, thalassemia, Cystic fibrosis are the examples of monogenetic disorder which are caused due to defect in a particular genetic mutation. In contrast, in some genetic disorders, mutation occurs in more than one gene causing the same disease. Thus Alzheimer's disease and Parkinson's disease which are caused due to involvement of more than one gene can be termed as multigenic diseases.
Sickle Cell Disease (SCD)
Sickle Cell Disease is a monogenetic disorder in haemoglobin causing the Red Blood Cells(RBC) to form an abnormal sickle shape. This process is called sickling which ultimately results in the loss of flexibility in RBC and other pathogenic consequences. The factor involved behind the sickling of RBC is the mutation of Beta Globin gene located in chromosome 11. This disorder is prevalent in people originated from tropical and sub tropical regions where malariaÂ is /was common. Nearly one third indigenous people of Sub- Saharan Africa bear this mutated Beta globin gene. Sickle cell disease results into reduced life expectancy with average life of male and female being 42 years and 48 years in affected males and females respectively. (Platt OS,Â et al, 1994)
A point mutationÂ in the Î²-globin gene of chromosome 11 , which results in the substitution of hydrophilic glutamic acidÂ to by hydrophobic Â valineÂ at the sixth position gives rise to mutated beta globin sub unit.When two mutated beta globin subunits bind to two wild type alpha sub units, formation of a an abberent haemoglobin called HbS takes place. Being benign in nature, this mutation does not causeÂ any apparent effects on theÂ secondary,Â tertiary, or quaternary structureÂ of haemoglobin in conditions of normalÂ oxygenÂ concentration. However, this HbS has a tendency to polymerize in low-oxygen tension and causes polymerisation of the haemoglobin. In this process, the hydrophobic residues of the valine at position 6 of the beta chain of HbS associates with the hydrophobic patch, making the haemoglobin molecules to aggregate and form fibrous precipitates. The repeated episodes of polymerization and sickling causes permanent deformity on the shape of RBC and decreased elasticity. When these deformed and rigid RBCs pass through the capillaries, they get occluded there due to reduced elasticity. Thus the adhesion of abnormal red bloodÂ cellÂ (RBC)Â toÂ the endothelium has been proposed as the probable initiatingÂ event of vasoocclusion, nevertheless the variations in the endothelium activationÂ state may modulate the unpredictable occurrence of the major complications. (Â Hebbel RP, 1997)Inflammation is the major catalytic agent for this process.(Kaul DK, Hebbel RP,2000). This process ultimately results in ischaemia.
The anemia in sickle cell disease is caused byÂ hemolysis due to the destruction of the RBCs inside the spleen. The rapid destruction rate of RBC exceeds the rate of replenishment rate of bone marrow. Unlike Â healthy red blood cells typically sickle cells survive only for 10-20 days.Though the peripheral destruction of sickled RBCs have been considered to be prominent feature of sickle cell disease, potential contribution of ineffective erythropoiesis toÂ the pathophysiology of this hemoglobinopathy is also point to be considered. (Catherine J. Wu et al,2005).
Dietary cyanate or derivatives can be used on the treatment of sickle cell disease. Painful crisis due to vaso-occlusion can be managed by analgesics, opoid administration.Children born with sicle cell disease are given 1 mg dose of folic acid per day throughout the life. As a supplement they are accompanied by a dose of penicillin too, till the age of five years in order to safe guard from infections. In adults patients with acute chest pain due to vaso-occlusion, oxygen supplementation, and blood transfusion can give relief. Bone marrow transplantation has been found to be effective in children. (Walters MC, Patience M, Leisenring W,Â et al., 1996)
Hydroxyurea is the first approved drug for the treatment of sickle cell anemia which had successfully decreased the severity of attacks in a study done by Charache et al in 1995. "ToÂ date,Â hydroxyurea (HU) is the only drug knownÂ toÂ reduce the frequencyÂ of vasoocclusive crises, acute chest syndromes (ACSs), and transfusionÂ requirements". (Malika Benkerrou et al, 2002). The possible mechanism of action of hydroxyurea has been believed to be the reactivation of fetal heamoglobin in place of HbS. Neverthless the long term use of this drug as a chemotheraupetic agent has shown some risks. (Â Platt OS, 2008).
Gene therapy is the most novel and most promising technique for treatment of monogenetic disorder like sickle cell disease.
Alzheimer's disease (AD)
Alzheimer's diseaseÂ (AD), was named after German psychiatrist Alois Alzheimer who first described it in 1906 as a incurable , neurodegenerative disease generally diagnosed in people more than 65 years of age.( Brookmeyer R, Gray S, Kawas C, 1998). The survey of September 2009 shows that number of patients suffering from Alzheimer's disease worldwide is more than 35 million. This prevalence has been expected to reach up to 107 million by 2050.( Brookmeyer, R et al ,2007).
Alzheimer's disease is a type of aÂ protein misfoldingÂ disease (proteopathy), caused by accumulation of abnormally folded amyloid-beta and tau proteins in the brain. Hence it is also called aÂ tauopathyÂ due to abnormal aggregation of theÂ tau protein in brain.
The clinical picture of AD is variable , however the common feature is progressive breakdown of memory and cognitive functions like reasoning.(Nussbaum et al 2004). Confusion, irritability , language breakdown, aggression and long term memory loss are some of the symptoms that appear as the disease becomes more severe.( Waldemar G,Â et al.Â 2007)( Tabert MH et al 2005).This ultimately leads to loss of body functions and death. Most of the AD sufferers, are expected to survive for around seven years after getting diagnosed..( Mölsä PK, Marttila RJ, Rinne UK , 1986.).However, less than 3%sufferers remain alive even after fourteen years of diagnosis. (Mölsä PK, Marttila RJ, Rinne UK 1995)
AD is mainly a sporadic disease and only 0.1 percent cases are familial which onst before the age of 65. Neverthless there are some genes that act as a risk factor. (Blennow K, de Leon MJ, Zetterberg H ,2006). Most of the familial autosomal dominant AD are due to mutation in one of the following genes: 1)APP (Amyloid precursor protein) gene 2)presenilin1 and 3)Presinilin 2 (Waring SC, Rosenberg RN , 2008). Most of the mutation in APP or Presenilin gives rise to the production of AB42(Amyloid beta 42) which is the major part of senile plaques that are seen in AD.
Apolipoprotein E(APOE) another genetic factor associated with AD. APOE is actually a common aminoacid involved in cholesterol transport. However it is also detected in both plaques and neurofibraillary tangles associated with AD.Studies have shown that at least 40 to 80 percent individuals with AD possess at least one APOE 4 allele.( Mahley RW, Weisgraber KH, Huang Y, 2006).
Though the exact cause of onset of AD has not yet been revealed, some theories has been put forward. They are : i)Cholinergic hypothesis ii)Amyloid Hypothesis and iii)Tau Hypothesis.
The cholinergic hypothesis says that impaired synthesis of a neurotransmitter called acetylcholine is responsible for the onset of AD.( Francis PT, Palmer AM, Snape M, Wilcock GK, 1999). However this hypothesis was refuted by the evidence that medications intended to treat acetylcholine deficiency could not produce promising results.
Amyloid hypothesis holds the notion that deposition of amyloid beta protein (ABP) derived from amyloid beta precursor protein(APP) is the main basis of the AD.( Hardy J, Allsop D ,1991 )( Mudher A, Lovestone S , 2002). This APP is encoded by APP gene located on chromosome 21.
According to this hypothesis, the plaques of AD are made up of smallÂ peptides calledÂ beta-amyloidÂ . Beta-amyloid is derived from a larger protein calledÂ amyloid precursor proteinÂ (APP), which penetrates through the neuron's membrane. APP has significant role on neuron growth, survival and post-injury repair.Â In Alzheimer's disease, APP is divided into smaller fragments byÂ enzymesÂ through proteolysis. Fibrils of beta-amyloid are derived from one of these fragments of APP. These fibrils then form clumps .These clump deposits outside neurons are known asÂ senile plaques. The fibrils thus formed disrupt the cell's calcioum ion homeostasis . This process ultimately results in programmed cell death or apoptosis.( Yankner BA, Duffy LK, Kirschner DA,1990)
In 2004, Tau hypothsis for AD emerged when amyloid hypothesis was challenged by the fact that amyloid plaques do not correlate with the neuron loss. (Schmitz C, Rutten BP, Pielen A,Â et al., 2004). Tau hypothesis emphasize that when hyperphosphorylated Tau pairs with other thread of Tau, formation of a neurofibrillary tangle takes place inside the nerve cell bodies. (Goedert M, Spillantini MG, Crowther RA , 1991)..
As we know every neuron has aÂ cytoskeleton, partly made up ofÂ microtubules which help in guiding different molecules from the body of the cell to the ends of theÂ axon. The Tau hypothesis says that Â tauÂ protein stabilizes the microtubules whenÂ phosphorylated and undergoes chemical changes, becomingÂ hyperphosphorylated. After that tau protein pairs with other threads and creates neurofibrillary tangles. This process disintegrate the neuron's transport system. ( Hernández F, Avila J , 2007). As a result, biochemical communication stops between theneurons leading to death of cell.
Since Alzheimer's disease does not have any cure so far, only symptomatic treatment can be given to the sufferers. AD can be managed by following aspects :
Acetylcholinesterase inhibitorsÂ are used to reduce the rate ofÂ acetylcholineÂ broken down.
GlutamateÂ which is a useful excitatoryÂ neurotransmitterÂ of theÂ nervous system.
MemantineÂ (brand namesÂ Akatinol,Â Axura,Â Ebixa/Abixa,Â MemoxÂ andÂ Namenda),Â is a noncompetitiveÂ NMDA receptor antagonistÂ
AntipsychoticÂ drugs can be used to reduceÂ aggressionÂ andÂ psychosisÂ in Alzheimer's patients with behavioural problems
Psychosocial intervention is complementary to pharmaceutical treatment in AD patients. Especially dementia is managed by psychosocial intervention.
Since AD renders people incapable of fulfilling their own needs, caregiving is very essential.