AL Bio notes Health and diseases_non-communicable diseases_genetic diseases P.1

Genetic diseases--Inborn ‘Errors’ of Metabolism

A.Defects in genes

1.G6PD- an enzyme deficiency

(G6PD)Glucose-6-Phosphate Dehydrogenasedeficiency is the most common human enzyme deficiency; an estimated 400 million people worldwide are affected. One benefit of having G6PD deficiency is that it confers a resistance to malaria. G6PD deficiency is also referred to as favism since some G6PD deficient individuals are also allergic to favabeans.Reduced G6PD activity are potentially serious (even causing death) if they are not properly treated.

A.GENETICS OF G6PD DEFICIENCY

The gene for the G6PD enzyme is located on theX-chromosome.

Q. What can you infer from this information?

G6PD deficiency is known to have over400 variant alleles. A mutant G6PD enzyme may be different from person to person; mutations can be in the form of point mutations or can range from one to several base pair deletions as well as replacements in the DNA.

Q. What is the meaning of ‘variant alleles’

African Americans and some isolated tribes inAfricaandSoutheast Asia exhibit the highest frequency of incidence. The incidence in HK is 4.5 in 100 newborn babies.

B.PHYSIOLOGY OF G6PD

The G6PD enzyme catalyzes an oxidation/reduction reaction. G6PD enzyme functions in catalyzing the oxidation of glucose-6-phosphate to 6-phosphogluconate, while concomitantly reducing nicotinamide adenine dinucleotide phosphate (NADP+ to NADPH).

This is the first step in the pentose phosphate pathway. This pathway produces the 5-carbon sugar, ribose, which is an essential component of both DNA and RNA. There are other metabolic pathways, however, that can produce ribose if there is a deficiency in G6PD.

In addition to producing the 5-carbon sugar ribose, G6PD is also responsible for maintaining adequate levels of NADPH inside the cell. NADPH is a required cofactor in many biosynthetic reactions. NADPH is also used to keep glutathione, a tri-peptide, in its reduced form:

Reducedglutathione acts as a scavenger for dangerous oxidative metabolites in the cell; it converts harmful hydrogen peroxide to water. There are other metabolic pathways that can generate NADPH in all cells, except in red blood cells where other NADPH-producing enzymes are lacking. This has a profound effect on the stability of red blood cells since they have only one NADPH-producing enzyme to remove these harmful oxidants.

This is why G6PD deficient individuals are not prescribed oxidativedrugs, because the red blood cells in these individuals are not able to handle this stress and consequently haemolysis ensues.

  1. What are the importance of G6PD to body cells?

Q. Why are red blood cells particularly susceptible to damage by oxidative drugs or metabolites?

Q. What are the possible consequences of haemolysis on the body?

C.ASPECTS OF G6PD DEFICIENCY

i)NEONATAL JAUNDICE
One of the problems experienced by G6PD deficient individuals presents itself immediately after birth. Neonatal jaundice is a common condition in all newborns, but when it persists, G6PD deficiency is suspected. Neonatal jaundice is a yellowish discoloration of the whites of the eyes, skin, and mucous membranes caused by deposition of bile salts in these tissues. This is a direct result of insufficient activity of the G6PD enzyme in the liver. In some cases, the neonatal jaundice is severe enough to cause death or permanent neurologic damage.

ii)HAEMOLYTIC ANAEMIA
An anaemic response can be induced in affected individuals bycertain oxidative drugs including naphthalene, fava beans, or infections. Death ensues if the haemolytic episode is not properly treated. In order to prevent a severe reaction or even death, G6PD deficient individuals are prohibited from taking certain drugs. The common theme shared among all of these drugs is thatthey areoxidizingagents. In G6PD deficient individuals, oxidative stress may result in the denaturation, or unfolding, of the haemoglobinmolecule. This results in the loss of biological function with respect to haemoglobin and leads to the inability of the red blood cell to effectively transport oxygen throughout the body. A physician should always be consulted before any medications are taken.

Primaquine, one of the first anti-malarial drugs, was the first drug to be implicated in inducing an anaemic response. It is interesting to note that a deficiency in G6PD has been shown to sometimes confer a resistance to the malaria-causing parasite, Plasmodium falciparum. This resistance is due to the fact that the parasite selectively infects red blood cells. In G6PD deficient red blood cells, an essential metabolite for the survival of the parasite is present in insufficient quantities. This is due to decreased activity of G6PD within these cells which ultimately leads to the death of the parasite.

Fava beans were the first, and only food product, to be implicated in inducing an anaemic response in G6PD deficient individuals. Inhaling the pollen of the fava bean plant can also induce haemolysis in favic individuals. Since some G6PD deficient individuals are allergicto fava beans, the deficiency is therefore sometimes referred to as favism.

Outside the areas where favism is prevalent, infection is probably the most common cause of haemolysis in subjects with G6PD deficiency. Oxidative metabolites produced by numerous bacterial and viralhave been identified as the cause of the anaemic response. Particularly important infections that can precipitate a haemolytic episode are viral hepatitis, pneumonia, and typhoid fever.

Q. What are the three major factors that can trigger hemolytic anaemia for G6PD deficient persons?

D.TREATMENT
Treatments for neonatal jaundice and haemolytic anaemia have existed for many years. These treatments insure that the body tissues will be provided with enough oxygen by the red blood cells. Infants with prolonged neonatal jaundice are placed under special lights, called bili-lights, which alleviate the jaundice. When an anaemic episode occurs, individuals are treated with nasal oxygen and are placed on bed rest, which may afford symptomatic relief. Anaemic individuals sometimes need bloodtransfusions.

  1. Genetic engineering is offering a hope to remove the worry of favism from G6PD, suggest how?

  • 日常生活方面要注意：
  • 避免吃蠶豆
  • 避免接觸樟腦丸
  • 不要使用龍膽紫 (紫藥水)
  • 有病應找醫生診療，不可亂服成藥(包括中藥和西藥)，避免使用很多，主要有：
  • 解熱及止痛劑：如Aspirin亞氏匹寧, Acetanilide, Acetophenetidin(Phenacetin), Antipyrine, Aminopyrine, p-Aminosalicylic acid
  • 抗生素：磺胺劑Sulfonamides, choramphenicol, sulphones, Nitrofurantoin, Furazolidone, PAS
  • 維他命C (ascorbic acid), 維他命K1
  • 抗瘧藥物，如Choroquine, Primaquine, Mepacrine, Pamaquine, Pentaquine, Plasmoquine
  • 其他Quinidine, Dimercaprol, NaphthaleneMethylene blue, 龍膽紫, Phenylhydrazine, Probenecid
  • 中藥包括川蓮，蠟梅花，牛黃...(可能還些未研究清楚)
  • 細菌或病毒感染亦可引起溶血，尤其是年紀小的。

2.Haemophilia

Haemophilia is a lifelong bleedingdisorder that prevents blood from clotting properly. Blood contains many proteins, called clottingfactors, which work to stop bleeding. In people with bleeding disorders, these clotting factors are missing or do not work as they should. The severity of a person’s haemophilia depends on the amount of clotting factor that is missing.

A person with haemophilia does not bleed faster than anyone else, but bleeding may lastlonger. The main danger is uncontrolledinternalbleeding that starts spontaneously or results from injury. Bleeding into jointsandmuscles can cause stiffness, pain, severe joint damage, disability, and sometimes death.

A.The Genetics Disorder Passing from Mother to Son

i)X-linked inheritance

Haemophilia is usually inherited and about one in every 5,000 males is born with the disorder. Worldwide, an estimated 500,000 people live with some form of haemophilia.

The haemophilia gene is carried on the X chromosome. As women have two X chromosomes (XX), the mutatedgene would have to be present on both chromosomes to cause the disease, and this is exceedingly rare. Since men have only one X chromosome (XY), one copy of the mutated haemophilia gene is enough to cause the disease, so males who inherit the gene will be affected.

ii)Haemophilia and Families
Haemophilia runs in families; it is passed on from parents to their children. Complete the following chart to show a person's chances of developing haemophilia:

Mother / Father / Descendents
Carrier (possesses haemophilia gene) / Normal clotting factor genes / Fifty percent chance son will have haemophilia.
Fifty percent chance daughter will be a "carrier."
Normal clotting factor genes / Haemophilia / Son possesses "normal" clotting factor gene.
Daughter will be a "carrier."
Carrier / Haemophilia / Fifty percent chance son will have haemophilia.
Daughter may develop haemophilia (rare occurrence).

iii)Spontaneous genetic mutation

Although a family history of blood clotting factor difficulties is important, it should also be noted that no family history can be traced in one third of haemophilia A cases. In these cases, a spontaneousgeneticmutation is assumed to be the cause.

B.Types of Haemophilia
Two main varieties of haemophilia exist. HaemophiliaA is responsible for 80% of all cases. The genetic disorders responsible for haemophilia A result in low levels or abnormal production of the clotting protein factor VIII. HaemophiliaB, the second most common form of haemophilia, affects factor IX proteins and accounts for almost 20% of haemophilia cases.

B.What are the signs of haemophilia?

bigbruises;

bleeding into muscles and joints, especially the knees, elbows and ankles;

suddenbleeding inside the body for no clear reason;

prolongedbleeding after a cut, tooth removal, surgery or an accident.

Haemophiliasymptoms may be mild, moderate, or severe, depending on the amount of clotting factors produced.

Levels of Haemophilia / clottingfactor levels
(% of normal level) / Symptoms
mild, / 6-30% percent / a concern only when surgery or dentalwork is required.
moderate / 1-5% percent / easybruising and bleeding.
severe / less than 1% percent / Spontaneous jointbleeding can cause severe pain and physical deformity as cartilage and surrounding bones are damaged. Further, gastrointestinal, urinarytract, or intracranial bleeding can occur and require immediate medical attention. Even mild physical trauma to the head may result in intracranialbleeding, a very serious condition.

D.How is haemophilia treated?

Replacing Blood Factors

Haemophilia is treated by supplementing low levels of bloodfactorproteins with healthy replacement clotting proteins. These proteins are most often administered intravenously so that the clotting factors enter the bloodstream directly and are spread quickly throughout the body.
The frequency of treatment depends on the severity of the haemophilia symptoms. Mild haemophilia may only require blood factor replacement beforesurgery or dentalwork. Severe haemophilia may require prophylactic (preventive) treatment: blood factors are replaced several times a week to prevent bleeding incidents.
Q.One problem of replacement clotting proteins is that they can be inhibited by the immune system. Suggest a possible explanation.


Q.What can be done to the adverse effect of the inhibitor problem?


Q.Are there effective treatments for haemophilia? Is there a cure at the moment?

E.AVOIDINGcomplications of haemophilia

i)Helpful advices

Decide whether the following are correct advice for people with haemophilia? Explain

·Advice / Explanation
Check with a physician before taking any form of medication.
Avoid medications specifically designed to thin the blood e.g. some painkiller such as aspirin. /
Good dentalhygiene /
Avoid exercises

ii)Hepatitis C and HIV
During the 1980s, haemophilia was treated by replacing low levels of clotting factors with blood plasma pooled from thousands of donors. This strategy, although an effective treatment for haemophilia, proved to have serious safety issues. Viralagents, especially hepatitis C and HIV, were passed on to people with haemophilia through the pooled plasma. By the time the health risk was discovered, almost 70% percent of people treated with pooledplasma or infected blood products had contracted HIV and almost 100% of people were infected with hepatitis C in the 1980s.


Q. What was introduced later to reduce the incidence of HIV and hepatitis C infections?

F.Researching New treatment methods-gene therapy

The future of Haemophilia Treatment may be Gene Therapy
Haemophilia could be cured if clinical trials discover a way to replace or "repair" the defective gene.
Haemophilia gene therapy research seeks to replace the defective gene with a normal, fully functional, gene. Researchers have been successful in developing healthy replacement genes for use in haemophilia clinicaltrials. These genes will be carried into the body using a vector.

Most vectors are harmless viruses that are able to insert the new DNA into cells. The virus "infects" cells with the healthy gene, overriding the mutated haemophilia gene. In clinical trials, gene vectors have been used to cure labanimals of haemophilia A and B. The body's immune system does not appear to release antibody inhibitors when gene therapy is used.

  1. Why is haemophilia a good candidate for gene therapy research?
  1. What are the problems facing researchers in haemophilia gene therapy research?

Haemophiliacs in vCJD scare January 30, 2001

LONDON, England (CNN) -- Haemophiliacs in the UK who fear they have been exposed to plasma derived from a blood donor later found to have the humanformofmad cow disease are being urged to contact their doctors.
The blood plasma is said to have been distributed only in "tiny amounts" only after the donor was found to have the new variant Creutzfeldt-Jakob disease (vCJD).
No simple test exists for vCJD and it has not been proven that the ailment can be transmitted through blood or blood products. Health experts do not know how many UK haemophiliacs could be at risk from the vCJD infected blood, which was used before tightercontrols were introduced in 1998.
This has come as a devastating shock to the haemophiliac community who have already been stricken by HIV and Hepatitis C infection. The best advice from experts is that any link between blood, blood products and the transmission of vCJD is purely theoretical.

3.Sickle cell anaemia

Sickle cell anaemia is a genetic disease which, under certain circumstances, causes thered blood cells of a sufferer to be shaped like sickles, instead of the normal rounded shape. This causes the cells to become stuck in capillaries which deprives affected tissues of oxygen.
Sickle cell anaemia is caused by amutation in the β-globin chains of haemoglobin, replacing glutamic acid with less polar valine at the sixthamino acid position. /

The mutant haemoglobin S polymerises under low oxygen conditions causing distortion of red blood cells.

The disease usually occurs in periodic painful attacks, eventually leading to damage of some internal organs, stroke, or anaemia, and usually resulting in decreased lifespan. It is common in countries with a high incidence of malaria, and especially inWest Africa.

A.Genetics

Theallele responsible for sickle cell anaemia isincompletely (autosomal) recessive.
A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as acarrier.
If two parents who are carriers have a child, there is a 1-in-4 chance of their child developing the illness and a 1-in-2 chance of their child just being a carrier. /

C.Consequences

The gene defect is a knownmutation of a single nucleotide (U to A) of the β-globin gene, which results in glutamic acid to be substituted for valine at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure of hemoglobin. What it does allow for, under conditions of low oxygen concentration, is thepolymerization of the HbS itself.

In people heterozygous for HbS (carriers), the polymerization problems are minor. In people homozygousfor HbS, the presence of long chain polymers of HbS distort the shape of the red blood cell. Carriers only have symptoms if they are deprived of oxygen (for example, climbing a mountain) will they develop symptoms.

D.The evolution of Sickle cell anaemia

The sufferers of the illness usually die young and yet the disease is not eliminated from the gene pool by natural selection. This is because carriers are relatively resistant to malaria. Carriers of the allele have an unsymptomatic condition called sickle cell trait. Since the gene is incompletely recessive, carriers have a few sickle red blood cells at all times, not enough to cause symptoms, but enough to give resistance to malaria. Because of this, heterozygotes have a higher fitness than either of the homozyogotes. This is known asheterozygote advantage.

  1. What does it mean by an ‘unsymptomatic’ trait? Explain in term of the situation in sickle cell anaemia.

In areas where malaria is a problem, people's chances of survival actually increase if they carry sickle cell anaemia. Due to the above phenomenon, the illness is still prevalent, especially among people with recent ancestry in malaria-striken areas, such as Africa, the Mediterranean, India and the Middle East. In fact, sickle-cell anaemia is the most common genetic disorder among African Americans; about 1 in every 12 is a carrier.

Q.In the USA, where there is no endemic malaria, what would you predict about the incidence of sickle cell anaemia amongst people of African descent compared to those in West Africa?

E.Complications

Sickle cell anaemia can lead to various complications, including:

complications / explanations
Stroke / progressive vascular narrowing (occlusion) can prevent oxygen from reaching the brain, leading to stroke
Anemia / sickling due to hemoglobin S polymerisation leads to hemolysis and a decreased red blood cell count
gallstones / prolonged hemolysis may lead to excessive bile pigment production and precipitation

F.Treatment

Painful sickle crises are treated symptomatically with painkillers; in cases of severe hemolysis, exchange transfusion may be required; this is the removal of the patient's blood and replacing it with non-sickle donor blood.

One interesting treatment is the use of a drug (hydroxyurea) that reactivating foetal haemoglobinproduction in place of the haemoglobin S that causes sickle cell anaemia. There is some concern that long-term use may be harmful, but it is likely that the benefits outweigh the risks.

4.Alcohol sensitivity and Isozymes (polymorphism)

Isozymes are different molecular forms of enzyme catalyzing the same reaction, usually with differentactivity. The alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exist in a number of isozymes. The racial differences in their isozyme pattern may account for the racial differences(variants) concerning alcohol sensitivity.