GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

What is G6PD deficiency

• G6PD deficiency is a genetic disorder
• G6PD deficiency caused due to a deficiency of a chemical enzyme called glucose-6-phosphate dehydrogenase found in the RBC (red blood cells) causes red blood cells to break down prematurely.
• This syndrome is more common in males than females. Usually female became carrier.
• This deficiency did not show any symptom but after exposure to certain medicines, foods, and other infections, it causes severe injury to red blood cells by breaking the RBC's down
• Destruction of red blood cells is called hemolysis. If not properly treated, it will cause kernicterus.
• Once you get this disease, it can be either life long process or it could be cured.
• Typically,  easily curable with proper medicine

Symptoms of G6PD deficiency

• typically do not show any symptoms of the disorder until their red blood cells are exposed to certain triggers, which can be:

       Øillness, such as bacterial and viral infections

Øcertain painkillers and fever-reducing drugs

Øcertain antibiotics (especially those that have "sulf" in their names)

Øcertain antimalarial drugs (especially those that have "quine" in their names)

• In more serious cases
  Øpaleness (in darker-skinned children paleness is sometimes best seen in the mouth, especially on the lips or tongue)
  Øextreme tiredness
  ØRapid heartbeat
  ØRapid breathing and shortness of breath
  Øjaundice, or yellowing of the skin and eyes, particularly in newborns
  ØAn enlarged spleen
  Ødark, tea-colored urine

• Jaundice is one of the big side effects of G6PD deficiency. Newborn babies can have this disorder

ØThe main symptom of jaundice is a yellowish color of the eyes and mucous membrane.

ØG6PD causes jaundice by breaking down the red blood cells

Ø With jaundice, the baby's liver can not properly filter out toxins from the child's system, then lead to even more serious health problems

• For adult – if you get G6PD deficiency:

Ø You should avoiding eating beans – this food  increases the breakdown of red blood cells in this condition

Ø You should never use mothballs in your clothing or closets – these can exacerbate the disease

ØYou need proper medical treatment to make sure you have no lasting negative health effects 

Common affected of G6PD

• Distribution – most frequently in certain parts of Africa, Asia, and the Mediterranean
• An estimated 400 million people worldwide have glucose-6-phosphate dehydrogenase deficiency
• It affects about 1 in 10 African-American males in the United States

The gene related to G6PD

• G6PD is genetic disorder that related to mutations in the G6PD gene
• The G6PD gene provides instructions for making an enzyme called glucose-6-phosphate dehydrogenase.
• This enzyme functions as:

       Ø normal processing of carbohydrates

Øprotects red blood cells from the effects of potentially harmful molecules called reactive oxygen species - Reactive oxygen species are byproducts of normal cellular functions that building up to toxic levels within red blood cells

• If the G6PD deficiency by mutation, reactive oxygen species can accumulate and damage red blood cells
• Then, factor such as infections, certain drugs, or ingesting fava beans can increase the levels of reactive oxygen species causing red blood cells to be destroyed faster than the body can replace them. Afterward, it will cause hemolytic anemia
• carriers of a G6PD mutation may be partially protected against malaria, an infectious disease carried by a certain type of mosquito. Glucose-6-phosphate dehydrogenase deficiency occurs most frequently in areas of the world where malaria is common

How people inherit G6PD deficiency 

• This condition is inherited in an X-linked recessive pattern
• The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes
• In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition.
• In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder.
• Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females.
• A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons

Diagnosis and treating G6PD deficiency

• G6PD deficiency go undiagnosed until symptoms have been develop
• To confirm the diagnosis usually use blood tests and to rule out other possible causes of the anemia
• Treating the symptoms associated with G6PD deficiency is usually as simple such treating the illness or infection or stopping the use of a certain drug
• But, severe anemia may require treatment in the hospital to receive oxygen, fluids, and, if needed, a transfusion of healthy blood cells
• In rare cases, the deficiency can lead to other more serious health problems

HEMOPHILIA

OVERVIEW 

Hemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken.  

Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, occurring at about 1 in 5,000–10,000 male births. 

Haemophilia B (factor IX deficiency) occurs at about 1 in about 20,000–34,000 male births.

CAUSES

It's caused by a defect in one of the genes that determine how the body makes blood clotting factor VIII or IX. These genes are located on the X chromosomes. 

Chromosomes come in pairs. Females have two X chromosomes, while males have one X and one Y chromosome. Only the X chromosome carries the genes related to clotting factors.

A male who has the abnormal gene on his X chromosome will have hemophilia. A female must have the abnormal gene on both of her X chromosomes to have hemophilia; this is very rare.

A female is a "carrier" of hemophilia if she has the abnormal gene on one of her X chromosomes. Even though she doesn't have the condition, she can pass the gene on to her children.

Examples of how hemophilia is inherited

Example 1

• The father doesn't have hemophilia (that is, he has two normal chromosomes—X and Y). The mother is a carrier of hemophilia (that is, she has one abnormal X chromosome and one normal X chromosome). 
• Each daughter has a 50 percent chance of inheriting the abnormal gene from her mother and being a carrier. Each son has a 50 percent chance of inheriting the abnormal gene from his mother and having hemophilia. 

Example 2

• The father has hemophilia (his X chromosome is abnormal). The mother isn't a hemophilia carrier (she has two normal X chromosomes). 
• Each daughter will inherit the abnormal gene from her father and be a carrier. 
• None of the sons will inherit the abnormal gene from their father, and, therefore, none will have hemophilia. 
• Very rarely, a girl is born with hemophilia. This can happen if her father has hemophilia and her mother is a carrier. 

SYMPTOMS

- Excessive bleeding

Signs of excessive external bleeding include:

• Bleeding in the mouth from a cut or bite or from cutting or losing a tooth 
• Nosebleeds for no obvious reason 
• Heavy bleeding from a minor cut 
• Bleeding from a cut that resumes after stopping for a short time 

Signs of internal bleeding include blood in the urine (from bleeding in the kidneys or bladder) and blood in the stool (from bleeding in the intestines or stomach).

- Bleeding in joint

- Bleeding in the brain

The signs and symptoms of bleeding in the brain include:

• Long-lasting, painful headaches or neck pain or stiffness 
• Repeated vomiting 
• Sleepiness or changes in behavior 
• Sudden weakness or clumsiness of the arms or legs or problems walking 
• Double vision 
• Convulsions or seizures 

DIAGNOSIS

- Take personal and family medical histories

- Will have a physical exam and blood tests to diagnose hemophilia. 

Blood tests are used to find out:

• How long it takes for your blood to clot 
• Whether your blood has low levels of any of the clotting factors 
• Whether one of the clotting factors is completely missing from your blood 

The test results will show whether you have hemophilia, what type of hemophilia you have, and how severe it is.

Hemophilia A and B are classified as mild, moderate, or severe, depending on the amount of clotting factor VIII or IX in the blood.

• Mild hemophilia = 5–30 percent of normal clotting factor 
• Moderate hemophilia = 1–5 percent of normal clotting factor 
• Severe hemophilia = Less than 1 percent of normal clotting factor 

TREATMENTS

• Clotting factors concentrate

Plasma-derived clotting factor / recombinant clotting factor 

• Desmopressin (DDAVP)(for mild hemophilia A)   

Synthetic hormone which encourages the body to produce more of its own Factor VIII

• RICE (Rest, Ice, Compression, Elevation) 

Treatment many health care professionals recommend for joint bleeds

• Administering clotting factor concentrates 

Injected into a vein - generally in the back of the hand or at the crook of the elbow

THALASSEMIA

OVERVIEW

Thalassemia are inherited blood disorders.  It means that parents pass the genes for the disorder on to their children.

Thalassemia cause the body to make fewer healthy red blood cells and less hemoglobin than normal. Hemoglobin is an iron-rich protein in red blood cells. It carries oxygen to all parts of the body. Hemoglobin also carries carbon dioxide ( a waste gas) from the body to the lungs, where it’s exhaled.

People who have thalassemia can have mild or severe anemia. This condition is caused by a lower than normal number of red blood cells or not enough hemoglobin in the red blood cells.

Normal hemoglobin, also called hemoglobin A, has four protein chains (2 alpha globin and two beta globin). The two major types of thalassemia, alpha and beta, are    named after defects in these protein chains. 

Four genes (two from each parent) are needed to make enough alpha globin protein chains. Alpha thalassemia traits occur if one or two of the four genes are missing. If more than two genes are missing, moderate  to severe anemia occurs.

Two genes (one from each parent) are needed to make enough beta  globin protein chains. Beta thalassemia occurs if one or both genes are altered. 

Two major types of thalassemia 

vAlpha (α) Thalassemia

  
Defect in the rate of synthesis of the alpha chains

Inheritance Pattern for α–Thalassemia .

Picture shows one example of how α thalassemia  inherited.

The α globin genes are located on chromosome 16.

A child inherit 4 α globin – 2 from each parent.

Each child has 25% chance of inheriting either one of four possibility.

Alpha thalassemia occurs when one or more of the four genes needed for making the alpha globin chain of hemoglobin are missing. Moderate to severe  anemia results when more than two genes are affected. The most severe form of alpha thalassemia is known as alpha thalassemia major. It can result in miscariage.

q  One missing genes – Silent carrier

People with only one gene affected are called silent carriers and have no sign of illness. Deletion of one alpha gene, leaving three functional alpha genes. Borderline low of MCV (mean cell volume)  78 – 80 fL. No reliable way to diagnose silent carriers by hematologic methods. It must be done by genetic mapping. No hematologic abnormalities present.

q  Two missing genes – Alpha thalassemia trait ( also called thalassemia minor or mild anemia)

People with two genes affected called as alpha thalassemia or alpha thlassemia minor. This people have mild anemia and are considered carriers. Two missing alpha genes maybe homozygous (-a/-a) or hetero zygous (--/aa). Sometimes it may be confused with iron deficiency anemia.

q  Three missing genes – Hemoglobin H (moderate to severe anemia )

People with three genes affected have moderate to severe anemia or hemoglobin H disease. Usually caused by presence of only one  gene producing alpha chains (--/-a). This unstable form causing the red blood cells to break down more quickly. Result is fewer red blood cell, a condition called anemia.

People with hemoglobin H disease do not have serious health problem but offer them to be more tired. However, these are rare except for children with hemoglobin H –Constant Spring disease which is a more severe form of this disorder.

Diagnosis: red blood cells are microcytic, hypochromic with marked poikilocytosis. Numerous target cells.

q  Four missing genes – Bart’s Hydrops fetalis syndrome (alpha thalassemia major)

Babies with all four genes missing usually die before or shortly after birth. Most severe form and incompatible with life due to have no functioning alpha chain genes (--/--). Baby born with hydrops fetalis, which is edema and ascites caused by accumulation serous fluid in fetal tissues as result of severe anemia. Also see hepatosplenomegaly and cardiomegaly.

Hemoglobin Bart’s has high oxygen affinity so cannot carry oxygen to tissues. Fetus dies in uterus or shortly after birth. At birth, see severe hypochromic, microcytic anemia with numerous nucleated red blood cells. Pregnancies dangerous to mother. Increased risk of toxemia and severe postpartum hemorrhage.

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v  Beta (β) Thalassemia

  
Defect in the rate of synthesis of the beta chains 

Inheritance Pattern for Beta Thalassemia

The picture shows one example of how β – Thalassemia is inherited.

The β globin gene is located on chromosome 11.

A child inherits two beta globin genes – one from each parents.

   

Two genes (one from each parent) are needed to make enough beta  globin protein chains. If one or both of these genes are altered, you will have beta thalassemia. This means that you don’t  make enough beta globin protein.

If you have one altered gene, you’re carrier. This condition is called beta thalassemia trait or beta thalassemia minor. It cuases mild anemia.

v  Silent carrier state – the mildest form of beta thalassemia

Various heterogeneous beta mutations that produce only small decrease in production of beta chains. Patients have nearly normal beta chain ratio and no hematologic abnormalities.

v  Beta thalassemia minor – heterozygous disorder

If one gene is affected (one normal beta gene and other mutated), a person is a carrier and has mild anemia. This condition is called beta thalassemia trait or beta thalassemia minor. Caused by heterogenous mutations that affect beta globin synthesis.

Diagnosis:

• Hemoglobin level in 10 – 13 g/dL range with normal or slightly elevated RBC count. 
• Anemia usually with hypochromic and microcytic with slight anisocytosis and poikilocytosis. 
• Rarely see hepatomegaly or splenomegaly. 
• Normally required no treatment. 
• Make sure are not diagnosed with iron deficiency anemia.

v  Beta thalassemia intermedia – severity lies between minor and major

v  Beta thalassemia major – homozygous disorder

Cooley’s anemia or beta thalassemia major is a rare condition. Most of these persons had the severe forms of illness, but there may be more who are not diagnosed. Characterized by severe microcytic, hypochromic anemia.

Detected early in childhood:

• Infants fail to thrive
• Have pallor, variable degree of jaundice, abdominal enlargement and hepatosplenomegaly.
• Severe anemia causes marked bone changes due to expansion of marrow space for increased erythropoiesis.
• Characteristic changes in skull, long bones, and hand bones.
• Have protrusion upper teeth and Mongoloid facial features.
• Physical growth and development  delayed.
• Peripheral blood shows markedly hypochromic, microcytic erythrocytes with extreme poikilocytosis. 

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Laboratory Diagnosis

Complete Blood Count (CBC) with Differential

• Decrease in hemoglobin, hematocrit, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).

• Normal to slightly decreased mean corpuscular hemoglobin concentration (MCHC).

• Normal or elevated RBC count with a normal red cell volume distribution (RDW).

• Elevated RBC count with markedly decreased MCV differentiates thalassemia from iron deficiency anemia. 

•On differential, see microcytic, hypochromic RBCs (except in carrier states). See mild to moderate poikilocytosis.

• In more severe cases, see marked number of target cells and elliptocytes. Will see polychromasia, basophilic stippling and nucleated RBCs.

Brilliant Cresyl Blue Stain 

• Incubation with brilliant cresyl blue stain causes Hemoglobin H to precipitate.

• Results in characteristic appearance of multiple discrete inclusions – golf ball appearance of RBcs.

• Inclusions smaller than Heinz bodies and are evenly distributed throughout cell.

Acid Elution Stain

• Based on Kleihauer – Betke  procedure.

• Acid pH will dissolve Hemoglobin A from red cell. Hemoglobin F is resistant to denaturation and remains in cell.

• Stain slide with eosin. Normal adult cells appear as “ghost” cells while cells with Hb F stain varying shades of pink.

• Useful way to differentiate between pancellular HPFH and heterocellular HPFH.

Routine Chemistry Tests

• Indirect bilirubin elevated in thalassemia major and intermedia

• Assessment of iron status, total iron binding capacity and ferritin level important in differentiating thalassemia from iron deficiency anemia.