A DETAILED ASSIGNMENT ON GENETICS

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DEFINITION:

Alkaptonuria, also known as black urine disease, is a rare autosomal recessive disorder which occurs due to a mutation in the HGD gene. The HGD gene provides instructions for making an enzyme called homogentisic acid oxidase (HGAO), which is the enzyme that helps in the breakdown of the amino acids tyrosine and phenylalanine. Tyrosine is a non-essential amino acid with a polar side group and it has a special role by virtue of the phenol functionality. It occurs in proteins that are part of signal transduction processes. On the other hand, phenylalanine is an essential amino acid classified as non-polar because of the hydrophobic nature of the benzyl side chain. It is a precursor of tyrosine, and also a direct precursor to the neuromodulator phenylethylamine, commonly used as dietary supplement.

In patients with Alkaptonuria, there is deficiency of the enzyme homogentisic acid oxidase (HGAO), as a result, homogentisic acid, which is produced in the improper breakdown of tyrosine and phenylalanine accumulate in the body. Excess homogentisic acid accumulates in the blood and also in the connective tissues especially around joints. This leads to development of ochronosis,arthritis and many more complications seen in patients with Alkaptonuria. Therefore, Alkaptonuria is basically a disorder which results due to improper breakdown of tyrosine and phenylalanine owing to the deficiency of the enzyme HGAO.

Excess Homogentisic acid in blood leads to its excretion in the urine, and this makes the urine turn blue-black (dark) when exposed to air. A high urinary level of homogentisic acid is defined as greater than 4-8 grams in a 24 hour period. In children, dark staining of the diapers sometimes can indicate Alkaptonuria. It is important to note that most patients are not aware that they have the disease until they are about 30 to 40 years of age. There is tendency of males to have earlier onset of arthritic symptoms with higher severity than females, although the reason for this difference is unclear but to me, it may be because males do more of mechanical work than females, which might be a reason for them to have more severe arthritic symptoms.

Alkaptonuria, although has no currently known cure is not life threatening, maybe because it does not affect severely most of the vital organs in the body. That is to say that, if the disorder is known by any means to affect organ like the liver or the brain as well as other vital internal organ it may lead to many more complications like mental retardation or interfere with other metabolic processes which may or can lead to early death.

Typically, patients with Alkaptonuria require lifelong treatment to aid the management of the symptoms and complications of this disorder, but they are expected to live relatively normal and healthy lives.

Alkaptonuria, being an inherited disorder, has a risk factor of family history. It is known that it affects men and women in equal numbers. The prevalence is estimated to be about 1 in 250,000 people worldwide. Newborn screening for this disorder is NOT widely practiced, which may be because the disorder is not life threatening and can be managed very well for patients to live a normal life. But the effect of this has made it difficult to estimate the number of cases of Alkaptonuria . It is known that some people may have the mutation that causes this disorder but do not show the symptoms.

SUGGESTION

I believe every disorder can be treated or managed properly if it is detected and disgnosed early. Example is in the case of cancer. Cancer may start as benign tumor which grow from a single cancer cell. If detected and diagnosed early, it can be eradicated in a well fashioned way without any complication. But if it is diagnosed or detected late, when the cancer cells has spread through lymph nodes and blood vessels to other tissues, it can result to other serious complications and can lead to death. In order to avoid the complications of Alkaptonuria like arthritis, brittle heart valves etc, the newborn screening for this disorder will do a lot of good and benefit to people with this disorder because early diagnosis of the disorder can help reduce serious complications of the disease in later years.

RISK FACTORS:

AUTOSOMAL RECESSIVE INHERITANCE:

As said earlier, Alkaptonuria is an autosomal recessive disorder. This means that an individual must inherit two mutated alleles of the disease-causing gene one from the father and one from the mother in order to have the disease. Carriers of this disease are individual who possess only one mutated allele of the disease-causing gene and they do not show or experience the symptoms but they may pass the mutated gene to their offsprings.

If only one parent is a carrier, there is a 50% chance with each birth that the child will become a carrier but 0% chance of actually inheriting the disease.

If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that the child will be a carrier, and a 25% chance that each child will not inherit either mutated allele.

If both parents have the disease, there is 100% chance that their offspring will have the disease.

ETHNICITY

The frequency of Alkaptonuria is higher in certain population. In certain areas of Slovakia,Alkaptonuria affects approximately 1 in 19,000 people. It has been noted to be common also in the Dominican republic in which the prevalence is not known.

Ethnicity is known to play some variable roles in certain diseases, just like the case of sickle cell anemia which affects more of the African American population than the white population.

GENERAL: Because Alkaptonuria is inherited in an autosomal recessive fashion, theonly risk factor is a family history of the disorder. Men and women are affected in equal numbers,and the prevalence is known to be 1 in 250,000 people worldwide. It is difficult to estimate the number of cases of Alkaptonuria because newborn screening for this disorder is not widely practiced and some people that have the mutation that causes the disorder do not show the symptoms.

CAUSES:

Alkaptonuria is caused by a defect, or mutation in the HGD gene which provides information for making an enzyme known as homogentisic acid oxidase (HGAO) as mentioned earlier. More than 80 different mutations associated with Alkaptonuria have been identified in the HGD gene.

The normal function of the enzyme HGAO is to help in the breakdown of the amino acids phenylalanine and tyrosine. Deficiency of this enzyme will result in the accumulation of homogentisic acid which is produced in the improper breakdown of phenylalanine and tyrosine. Excess homogentisc acid in the blood and also in the connective tissue lead to ochronosis,blue-black urine etc.

Also as an inherited disorder, the genes are inherited on alleles or genetic variants of a specific gene.

SIGNS AND SYMPTOMS:

BLACK URINE: Urine from patients with Alkaptonuria turn blue-black when exposed to air. This is because of the buildup of homogentisic acid in the urine.

HEART: The aortic and mitral valves, which control blood flow to the body are most affected by the accumulation of homogentisic acid which causes calcification of the valves around age 60. Deposits of homogentisic acid can lead to the formation of atherosclerotic plaque, which can lead to coronary artery disease. This complication may result to death if not properly treated or managed as it is known that atherosclerosis id the leading cause of myocardial infarction which can result to death if not properly treated.

JOINTS: The buildup of homogentisic acid in the joints especially the spine, hips, shoulders and knees is the cause of the arthritic symptoms seen in patients with Alkaptonuria. Pateints may also develop osteoarthritis, which is a degenerative joint disease associated with painful joints and arthropathy, or diseased joints.

OCHRONOSIS: This is the build up of dark pigments caused by the accumulation of homogentisic acid in connective tissues such as cartilage and skin.

SKIN: Patients with Alkaptonuria have blue-black speckled discoloration of the skin. This is most noticeable in areas where the body is exposed to sun and where sweat glands are located. The ear and sclera of the eye may appear grayish blue. However,vision is not usually affected.

OTHER: In men, the prostate is often affected. The deposits of homogentisic acid can form stones in the prostate and kidney. Ear wax exposed to air turns black depending on the amount of tyrosine and phenylalanine in the diet after several hours. This is a distinctive characteristic of Alkaptonuria.

DIAGNOSIS

GENERAL: Alkaptonuria can be diagnosed based on symptoms of skin coloration, joint discomforts and urine samples. The diagnosis can be confirmed by verifying family history of the disease, microscopic examination of the skin cells. In testing, a high urinary level of homogentisic acid is defined as greater than 4-8 grams in a 24 hour period. It is necessary to note that homogentisic acid is not normally excreted in the urine of healthy individuals.

CHROMATOGRAPHY: Paper chromatography and thin layer chromatography can be used in the diagnostic testing performed on blood sample to detect high levels of homogentisic acid.

GENETIC TESTING: Knowing the specific mutation that cause the disorder within a particular family can help in the test of DNA of an individual to look for the presence of the specific mutation. This is done byblood sample analysis.

BLACK URINE: Urine from patients with Alkaptonuria turn blue-black when exposed to air

PRENATAL DIAGNOSIS: This type of testing is done by chorionic villus sampling, amniocentesis or blood collected from the umbilical cord.

X-RAYS: X-ray can help identify complications such as degenerative fussion of vertebrae.

COMPLICATIONS:

ARTHRITIS: Alkaptonuria patients eventually experiences worsening arthritis especially in the shoulder, hip and spine

BREATHING: Accumulation of homogentisic acid in the cartilage of treachea, larynx and bronchi causes weakness of these tissues. This may interfere with speech and breathing.

HEART: Weakness of heart valve and risk of coronary heart disease are seen as complications of Alkaptonuria.

OTHER: The central nervous system and the endocrine organs may be affected. In men, the prostate is often affected leading to prostate stones.

TREATMENT:

GENERAL: There is currently no known cure for Alkaptonuria, but treatment can help to reduce symptoms and for proper management.

DIET: Low protein diet especially in the amino acids tyrosine and phenylalanine help to reduce homogentisic acid, thereby reducing the amount deposited in body tissues.

MEDICATION: Patients with Arthritis may take non-steroidal anti-inflammatory drugs (NSAIDs) or Acetaminophen to relieve pain and inflammation. There has been research of limited use of nitisinone, which is an inhibitor of homogentisic acid oxidase (HGAO) which plays a role in the formation of homogentisic acid. Nitisinone shuts down the enzyme entirely preventing formation of homogentisic acid. Eye irritation may be a side effect.

SURGERY: Older patients may require surgery to correct fusion of vertebrae and joint replacement.

VITAMIN C (ascorbic acid): Some patients benefit from high doses of vitamin c which has been shown to reduce the buildup of homogentisic acid in the cartilage of the ears, which may indicate that there is less homogentisic acid in the rest of the body and may show the progression of arthritis.

PREVENTION:

There are currently no known method of preventing this disorder. Individuals with genetic predisposition for this disorder can take steps to slow the disease progression, such as by eating healthy food free from proteins and also by exercising regularly. People with family history of this disease should visit the doctor on regular bases.

GENETIC COUNSELING: This will help individuals. Families and couples affected or at risk of the disease to plan and manage the disease in a better way.

PRENATAL TESTING: Prenatal testing is necessary in order to reduce serious complication that may come up as a result of this disorder in later years. It can also help in proper management of the disease if a newborn is known to inherit the disease.

CASE STUDY

A male infant of 7months old, son of a non-consaguineous couple, noted by the parents to have darkening of his clothes and diapers moistened with urine when left unwashed for some hours. He has a 4 year old sister with the same complaint, other of his siblings (two brothers) were normal. There was no medical problem in the family. Growth and development of the elder case was normal. Physical examination revealed no abnormality. There was no pigmentation of the sclera and the ear lobe cartilage. Joint examination was normal. The urine of both the cases appeared normal on collection but turned blue-black on prolonged exposure to the atmosphere. Routine laboratory investigations were normal and radiological examination showed no degenerative changes in the joints (hip, shoulder and spine). The paper and thin layer chromatography revealed the presence of high amounts of homogentisic acid in the urine. Both of them were prescribed ascorbic acid (vitamin C) 500mg BD and low protein diet. Currently both of them are asymptomatic.

CONCLUSION:

This case study suggests an autosomal recessive type of inheritance already established in Alkaptonuria although there is no consanguinity. My suggestion earlier in this text comes into play here as early detection being very important for the prevention and treatment of multiple systems disorders and the complications of Alkaptonuria. The parents being able to detect the stains in diapers helped in the early diagnosis of this disorder which helped in the proper management and reduce the risk of other complications. These children being asymptomatic can live a normal life without any complicated in linked to Alkaptonuria in later years.

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