Structural Biochemistry/Genetic Diseases

Implications of Nucleic Acid Mutations
Before exploring genetic diseases, scientists must be familiar with possible types of DNA mutations(which include, but are not limited to frameshift, chromosomal translocation, insertion and deletions  Structural Biochemistry/DNA Mutation). Multiple genetic mutations can alter biochemical processes, causing different diseases. Understanding the mechanical pathways have led to tremendous discoveries that introduce potential cures for these diseases. Genetic tests improve patients quality of life: earlier diagnosis, fewer misdiagnoses and early medical intervention.

Details on specific disorders are available to the public from the National Institute of Health, Genetic Disorders: Basics and Research Rare Diseases

Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy is a genetic disease that causes the mutation of the Dystrophin protein, which is a rod- shaped protein found in muscle fibers and cardiac cells that function by connecting the muscle fiber cytoskeleton to extracellular matrix of cell membrane. The mutation is found in the DMD gene and is an x-linked recessive disease, which is passed from mother to son. Two thirds of the cases reported are inherited, however, one third of the cases arise from a new mutation that specific gene. The mutation causes the alteration of the shape and therefore function and a lack of production of the dystrophin protein causing symptoms such as, muscle weakness and heart problems, like, arrhythmias, cardiomyopathy and congestive heart failure. Approximately, 1 in 3,500 boys are affected and most of them do not live past their early twenties. Moreover, although females are not affected, they are at higher risk for developing heart problems in their lifetime.

Angelman Syndrome
Angelman Syndrome is a genomic imprinting disorder caused by a deletion or silencing of the genes inherited from the mother on the chromosome 15. This disorder is similar to the Prader- Willii syndromewhich affects the paternally inherited chromosome 15. Most people receive both genetic information from mother and father, however, because of this specific deletion of a segment of the chromosome, the maternal genetic information is silenced. This disorder can also be a result of a single gene mutation on the UBE3A gene. Some symptoms include, seizures, developmental delays, mental retardation, frequent laughter and smiling and jerky movement, such as hand flapping. This is not a degenerative disease; therefore, improvement in motor skills and living can be achieved through support and therapy.

Haemochromatosis Type 1
Haemochromatosis type 1 is a genetic disorder that causes the over absorption of dietary iron. Excess iron in the body aggregates in the tissues particularly in the liver, adrenal glands, heart and pancreas causing cirrhosis, diabetes, heart failure, and adrenal dysfunction. This disorder is caused by a mutation in the HFE gene, a gene that monitors and conducts the binding a transferrins which are protein that carrier iron in the blood. Typically these proteins are at low concentration in the bloodstream, however, when low iron levels are exhibited these proteins released to simulate the secretion of iron into the blood. Upon mutation, the intestines constantly signal for the release of these proteins causing an over secretion of iron.

Tay-Sachs Disease
Tay sachs is a autosomal genetic disorder characterized by loss of motor control, muscle strength and function, dementia and seizures, due to a defective gene on chromosome 15 caused by a deletion or base insertion. This disease is expressed when both copies inherited from both the mother and father are defective. This defective gene causes a decrease in the production of hexosaminidase A, which is a protein, specifically a lysosomal enzyme that functions in the chemical degradation a gangliosides, causing a build up in nerve cells in the brain. Most children afflicted with this disorder usually die before the age of five. Although the cure for this disorder is unknown, there is research conducted for possible therapies. Some of the therapies included: Enzyme replacement therapy, which would replace the defective enzyme with functioning enzymes similar to treatment of diabetes with insulin injections. In addition, Substrate Reduction Therapy which treats the build up of gangliosides by using other enzymes to catabolize it.

Polycystic Kidney Disease
Polycystic kidney disease is an autosomal dominant disease inherited from one parent, occurring in both children and adults. Symptoms included development of cysts in liver, kidneys and pancreas, diverticulitis of the colon and aortic and brain aneurysms. The pathophysiology of this disorder is currently unknown and treatment goal is to minimize symptoms by low salt diets, blood pressure medication and possible kidney transplants.

Trinucleotide Repeats
Long arrays of repeating sequences of three nucleotides are particularly prone to errors, which can cause serious diseases. Trinucleotide repeats tend to expand when repeats "loop out" of the double helix, such that one strand of the helix contains additional sequences than the other strand. (See Fig. 9 Bissler,1998

Huntington Disease Huntington disease is an autosomal dominant neurological disorder, due to a mutated gene that expresses the protein huntingtin. This protein is expressed in the brain. Huntingtin contains a repetition of glutamine residues encoded in the array of CAG sequences. People affected by this mutation have the CAG array from 36-82 (or longer) repeats while healthy individual have an array between 6-31 repeats. The array becomes longer as it is passed from one generation to the next, a phenomenon known as anticipation. Anticipation causes the children of an affected parent to have an earlier onset of the disease than the parent.

Bloom Syndrome
People with Bloom syndrome causes short physique, infertile males, and can be known to cause many types of cancers. It is an autosomal recessive disease that has a mutation in the locus for a gene that encodes a DNA helicase enzyme. With a mutated form of the BLM locus, people can have a higher risk of cancer if they are homozygous for the mutation. Those who are heterozygous are not as affected, but they have a greater risk of contracting colorectal cancer.

Noonan Syndrome
Noonan Syndrome is a genetic disorder caused by mutations in the PTPN11, SOS1, or KRAS genes. Approximately half of the people affected by Noonan syndrome have a PTPN11 mutation, and those with mutations in the other genes have a more severe, atypical form of the syndrome. Mutations in these genes cause certain proteins involved with growth and development to become overactive. However, the absence of a mutation in these genes does not exclude a possible diagnosis because there are still some unidentified genes that contribute to the syndrome under mutations. For this reason, genetic testing mainly provides a basis to examine a patient for all the physical symptoms possible and to know what to expect with regards to their health, and the diagnosis of Noonan syndrome is made primarily by clinical features. A physical examination alone can also be the basis for a diagnosis if the majority of symptoms are present. Most common symptoms include:

▪	Heart defects, especially pulmonary stenosis

▪	Delayed puberty

▪	Down-slanting or wide-set eyes ▪	Low-set or abnormally shaped ears

▪	Sagging eyelids

▪	Short stature ▪	Undescended testicles ▪	Unusual sunken chest shape ▪	Webbed and short-appearing neck ▪	Mild mental retardation in 25% of cases

Noonan syndrome can be inherited from a parent or can occur as a random mutation with no family history involved. Noonan syndrome affects males and females equally, and is seen between approximately 1 in 1000 to 1 in 2500 children born worldwide. It is one of the most prevalent genetic syndromes associated with congenital heart disease, very close in frequency to Down syndrome. The symptoms associated with Noonan syndrome can very widely in severity so a diagnosis is not always made at an early age.

A person with NS has up to a 50% chance of transmitting it to a child. However, there is not always and identified affected parent of children with Noonan syndrome. This shows that the manifestations of the syndrome could possibly be subtle enough as to not be identified in some patients (variable expressivity). This could also mean that a random mutation has occurred to cause the condition. Therefore, Noonan syndrome is heterogeneous, where multiple origins cause the disorder in different individuals, whether by inheritance with one or multiple mutations of different genes, or random mutation of one or all of the genes involved.

Triplo-X Syndrome
This syndrome occurs when a female has more than two X chromosomes and are usually tall and thin and few cases of mental retardation have occurred although most have normal intelligence. Females that have this condition do not have many phenotypic differences; some may be infertile, but they are usually able to bear children and menstruate regularly. The more X chromosomes a female, the greater chance they will experience more severe effects such as mental retardation and other physical problems.

Progeria
Progeria meaning “prematurely old” in Greek, this rare disease is formally known as Hutchinson-Gilford progeria syndrome, this disease was noticed by Jonathan Hutchinson and Hastings Gilford. When babies are first born they seem healthy, but a couple years later they begin to display an unusual accelerated aging process and will experience hair loss, aged skin, stiff joints, heart disease and osteoporosis. Most cases die when they first reach their teenage years. The mutation for this disease is found on a gene called lamin A (LMNA) on chromosome 1.

Williams Syndrome
Williams Syndrome is caused by a deletion in chromosome 7, which includes at least 25 genes. This gives rise to a broad range of effects. This is not inherited, but rather due to a random mutation in chromosome 7 of a sperm or egg cell. Yet, it is considered an autosomal dominant condition, because just one abnormal chromosome is needed to cause the disorder. This developmental disorder is characterized by moderate intellectual disabilities, distinct facial and personality features, visual problems and cardiovascular problems. CLIP2, ELN, GTF2I, GTF2IRD1, and LIMK1 are among the genes that are typically deleted in people with Williams syndrome (Williams Syndrome, 2008). The prevalence of Williams Syndrome in the United States is estimated to be about 1 in 7,500-20,000.

Hermansky-Pudlak Syndrome
Hermansky-Pudlak Syndrome is anautosomal recessive genetic disorder that causes albinism or the loss of pigment due to the lack of production a melanin and accumulation of ceroids in lungs and kidneys. There are several different types of this disorder caused by mutations of different genes. Type 1, 3, 4, 5,6 are caused by several gene mutations, type 2 caused by a mutation on the AP3B1 gene and type 7 caused by a mutation in the gene expressing the information for the production of the dysbindin protein used in muscle fibers. Symptoms included easy bruising and bleeding, loss of pigmentation in hair, eyes and skin and colitis.

Neurofibromatosis type 1
Neurofibromatosis Type 1 is an autosomal dominant genetic disorder caused by a mutation on the NF1 gene, a gene that codes for the production of many different nerve cells, including schwann cells and oligodentrocytes and a protein called Neurofibromin that functions as a tumor suppressor. This disorder is characterized an over production of nerve cells due to the defective neurofibromin resulting in tumors to form. Some symptoms of this disorder include change in skin pigmentations and development of tumors in skin, nerves and brain. Half the cases are due to an inheritance of dominant allele from one parent and most of these cases developed other mutations on other genes due to unchecked cell growth. The other half is due to a new mutation developed on the NF1 gene.

Cystic Fibrosis
Cystic fibrosis is a recessive genetic disorder that is more common in the Caucasian population. It is a type of disorder where a thick, sticky mucus plugs up the airways in and out of the lungs as well as clogs the pathways that lead away from the pancreas and into the intestine. This can cause respiratory infections and digestive problems. This disorder can be life-threatening in some cases, depending on how much of the genetic disorder is expressed. Cystic fibrosis is a gene that has a codominance gene expression. The gene that causes cystic fibrosis can be found on chromosome 7. The gene codes a protein called cystic fibrosis transmembrane conductance regulator and people with cystic fibrosis have a mutated form of this protein. The regular protein functions as a gate into the cell membrane and controls the chloride ions in and out of the cell; people with the mutated protein have a closed channel and the chloride ions eventually build up and forming thick mucus. People who suffer this disease usually do not live past their 30s as their lungs become more susceptible to infection and other lung diseases such as pneumonia. Other medical problems include malnutrition and inefficient nutrient absorption within the digestive system.

Sickle Cell Disease
Sickle Cell Disease is a recessive genetic disorder that is caused by an error in the hemoglobin gene. Hemoglobin is the protein that carries oxygen in red blood cells. The incorrect amino acid mutation at one position distorts the normal circular, disc-like shape of red blood cells. Instead, the red blood cells are in an abnormal crescent shape. Their distorted shape often results in blood cells jamming together or break into pieces due to their inability to travel through small blood vessels. Consequently, those with sickle cell disease suffer from unpredictable pain in various organs and joints. The pain can either last for hours to up to several days. The blood vessel blockages prevent red blood cells from transferring oxygen to tissues and organs. Symptoms include abdominal pain, poor eyesight/blindness, ulcers and strokes. The disease is commonly found in those of African and Mediterranean descent. In fact, 1 in every 500 African Americans are affected by sickle cell disease. To increase the blood cell count, folic acid supplements can be taken. Treatment options include blood transfusions, pain medications and Hydroxyurea that can be used to reduce pain episodes. Those with the sickle cell trait only get it from one parent and thus do not suffer from the symptoms. However, those with sickle cell anemia inherit it from both parents and they are the ones who suffer from the sickle cell disease. Some people who are carriers or have sickle cell anemia are immune to the contraction of Malaria which is a disease propagated by a parasite. It is believed that due to a large proportion of sickle cell cases occur in the Africa and India, where malaria outbreaks are prevalent this immunity came to be, however, the link between the two pathogens are still unknown. One theory regarding the pathophysiology of the link could be that the malaria parasite is killed by the misshapen red blood cell due to the shorter life cycle of the cell because of its sickled shape halting in replication of this parasite and propagation of disease.

Turner Syndrome
/Turner syndrome/ is a genetic disorder that occurs in about 1 in 5,000 births. It is a genetic abnormality that affects the development in only females. Girls born with Turner syndrome show certain physical attributes in which the levels of severity differ greatly between individuals. Most cases of Turner syndrome are not inherited. It is a genetic abnormality in which the female does have the usual pair of two X chromosomes. It is characterized as a chromosomal abnormality when one normal X chromosome is present in a female's cells and the other sex chromosome is missing or structurally altered.

Phenylketonuria
Phenylketonuria (also known as PKU) is a autosomal recessive genetic disorder with a mutation in the gene coding for the enzyme phenylalanine hydroxylase (PAH), making it nonfunctional. PAH metabolizes the amino acid phenylalanine into tyrosine. With absence of PAH activity, phenylketonuria patients have a buildup of Phe in their body. Excess Phe in blood levels lead to decreased levels of other large neutral amino acids in the brain, thus hindering the development of brain and causing severe consequences such as mental retardation.

Early Treatment and Prevention of PKU
Approximately 1 in 14,000 individuals are affected by PKU. During pregnancy, chorionic villus sampling can be done to screen the unborn baby for PKU. Furthermore, newborns can be tested for the disorder so that they can be treated early if they are diagnosed. Under laboratory analysis, a blood sample taken from a newborn can be tested and screened for PKU. This genetic disorder can be treated by controlling the levels of Phe in the body. Some treatments include certain restrictive diets. For example, people with PKU cannot eat foods that contain aspartame, an artificial sweetener. They can consume a new sugar-substitute called neotame which is similar to aspartame except that it combines the two amino acids differently. The effect is that it is 30 times as sweet as aspartame, so less is needed and thus less phenylalanine is produced when it is metabolized. People are advised to follow the diet throughout their lives. Moreover, foods such as milk and diet drinks contain large amounts of Phe. One who has PKU would be advised to avoid heavy intake of these foods. Another example would be to take supplements and vitamins to ensure a healthy balance of essential amino acids. Another possibility in treating PKU would be treating one with the enzyme PAL. This enzyme facilitates the disposal of excess Phe. Further clinical trials will determine if PAL is safe for human intake.

Further Treatment of PKU
For further controlled and treatment of PKU, children and adults should undergo timely cognitive, neurophysical, and social-emotional testings and evaluations. For infants and children up four-years old, annual evaluations should be taken. Children during their elementary school years should undergo evaluations under a psychologist to evaluate any metabolic disorders twice a year. For individuals in and beyond high school, psychological examinations should be taken to evaluate signs of decreased metabolic control or lack of social acceptance.