Human genetics..........................pptx

Pedigree analysis, nail patella syndrome, sickle cell anemia, phenylketonuria, familial hypercholesterolemia, huntington's disease, albinism, ADA deficiency etc.

1. HUMAN GENETICS MERIN ALICE GEORGE

2. Human genetics is the study of the inheritance of characteristics by children from parents. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counselling.

3. INHERITANCE OF TRAITS IN HUMANS An inherited trait is one that is genetically determined. Inherited traits are passed from parent to offspring. EX. In humans- eye color, hair color, skin color, freckles, dimples, etc. are all examples of inherited traits EX. In animals- eye color, fur color and texture, facial shape, etc. are examples of inherited traits.

4. PEDIGREE ANALYSIS A very important tool for studying human inherited diseases These diagrams make it easier to visualize relationships with in families, particularly large extended families. Pedigrees are often used to determine the mode of inheritance (dominant, recessive, etc.) of genetic diseases. Pedigrees are diagrams that show the relationship among the members of the family.

5. In pedigree problems plain : Unaffected Shaded: Affected.

6. CATEGORIES OF INHERITANCE Humans have 23 pairs of chromosomes--22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y. 1.Autosomal Recessive: To have an autosomal recessive disorder, you inherit two mutated genes, one from each parent.(mm-both genes must be mutated for the progeny) These disorders are usually passed on by two carriers. Their health is rarely affected, but they have one mutated gene (recessive gene) and one normal gene (dominant gene) for the condition(For Carriers). Examples: Cystic fibrosis, sickle cell anemia, and Tay-Sachs disease.

7. You inherit two mutated genes, one from each parent

8. 2. Autosomal Dominant: "Dominant" means that a single copy of the disease-associated mutation is enough to cause the disease. (m+) Some autosomal dominant traits are neurofibromatosis Type I, Huntington disease, and Marfan syndrome.

9. 3. X-linked recessive: X-linked recessive inheritance refers to genetic conditions associated with mutations in genes on the X chromosome. A male carrying such a mutation will be affected, because he carries only one X chromosome. A female carrying a mutation in one gene, with a normal gene on the other X chromosome, is generally unaffected.( XX - rr affected, X X -Rr unaffected, X Y-rR affected) Example : Color -blindness, hemophilia

10. 4. X linked dominant: X-linked dominant inheritance refers to genetic conditions associated with mutations in genes on the X chromosome. A single copy of the mutation is enough to cause the disease in both males (who have one X chromosome) and females (who have two X chromosomes). Ex, Hypophosphatemia. 5 . Y-linked (meaning the allele is found on the Y chromosome and can only be in males.

11. NAIL PATELLA SYNDROME Nail patella syndrome (NPS) is an autosomal dominant condition affecting the nails, skeletal system, kidneys and eyes. Nail patella syndrome (NPS) also known as hereditary osteoonychodysplasia (HOOD), Fong disease, Turner- Kieser syndrome, and Österreicher -Turner syndrome, is a pleiotropic condition with a classical clinical tetrad involving the nails, knees, elbows. It mainly results in small, poorly developed nails, knee caps, elbows ,chest and hips. The name ‘nail patella’ is very misleading because this affects many other areas of body not only nails including the production of certain proteins.

12. Symptoms Knees are unstable and patella are smaller. Limited motion of elbows. Radial head subluxation Erythrodysplasia of elbow. Exostoses from iliac bones. Scoliosis. Scapular hypoplasia. Loss of peripheral vision. Blind spots. Blurred vision. Severe headache. Nausea. Eye pain in rare cases. Osteoporosis

13. Nail-patella syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the LMX1B gene. These cases occur in people with no history of the disorder in their family. When a person who has a genetic change in the LMX1B gene has children, for each child there is a: 50% chance to inherit the changed copy of the LMX1B gene, meaning he or she will have nail-patella syndrome 50% chance to inherit the working copy of the LMX1B gene, meaning he or she will not have nail-patella syndrome

14. About 88% of people with nail-patella syndrome have a genetic change in the LMX1B gene that is inherited from a parent. In about 12% of people with nail-patella syndrome, the genetic change in the LMX1B gene was not inherited from either parent. The genetic change was new in the person diagnosed with nail-patella syndrome.

15. Q. Study the pedigree and answer the question for nail patella syndrome.

16. Nail-patella syndrome is an autosomal disorder affecting the shape of nails on fingers and toes, as well as the structure of kneecaps. The pedigree shows the transmission of nail-patella syndrome in a family along with ABO blood type. Is nail-patella syndrome a dominant or a recessive condition? Does this family give evidence of genetic linkage between nail-patella syndrome and ABO blood group ?

17. By looking at the pedigree, we can see that in almost all cases, individuals with nail-patella syndrome also posses the A allele. This strongly suggests that the nail-patella and blood type genes are linked, and that the dominant allele responsible for the disease is in coupling with the A allele at the blood type locus as given in the example above.(Detecting and Measuring Linkage in Humans)

18. AUTOSOMAL RECESSIVE DISORDERS ( mm-both genes must be mutated for the progeny )

19. ADA DEFICIENCY Adenosine deaminase (also known as adenosine aminhydrolase or ADA) is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. In all mammalian cells, its primary function in humans is the development and maintenance of the immune system.

20. Adenosine deaminase deficiency (ADA deficiency) is an inherited condition that damages the immune system. Common cause of severe combined immunodeficiency (SCID). People with SCID due to ADA deficiency are unable to fight off most types of infections, including bacterial, viral and fungal infections. INHERITANCE The enzyme adenosine deaminase is encoded by a gene on chromosome 20;q12-q13 . ADA deficiency is inherited in an autosomal recessive manner . This means the defective gene responsible for the disorder is located on an autosome (chromosome 20 is an autosome). Two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder.

21. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

22. IMMUNE DEFECTS Adenosine deaminase deficiency SCID, commonly called ADA SCID. It is caused by a mutation in the gene that encodes a protein called adenosine deaminase (ADA). This ADA protein is an essential enzyme needed by all body cells to produce new DNA. This enzyme also breaks down toxic metabolites that otherwise accumulate to harmful levels that kill lymphocytes. People afflicted with this disease often have to take antibiotics and supplemental infusions of antibodies to protect themselves from serious infections. They can also receive adenosine deaminase injections given once or twice a week. ADA SCID is lethal without treatment.

23. What Is Severe Combined Immunodeficiency It is a type of primary immune deficiency. SCID is a "combined" immunodeficiency because it affects both of T cells and B cells infection-fighting white blood cells. In SCID, the child's body has too few lymphocytes or lymphocytes that don't work properly. Because the immune system doesn't work as it should, it can be difficult or impossible for it to battle the germs — viruses , bacteria , and fungi — that cause infections.

24. It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. The most common treatment for SCID is bone marrow transplantation. A treatment for patients with ADA-SCID is enzyme replacement therapy, in which the patient is injected with polyethyleneglycol -coupled adenosine deaminase (PEG-ADA) which metabolizes the toxic substrates of the ADA enzyme and prevents their accumulation.

25. SICKLE CELL ANEMIA

26. Is an inherited form of anemia — a condition in which there aren't enough healthy red blood cells to carry adequate oxygen throughout your body. In sickle cell anemia, the red blood cells become rigid and sticky and are shaped like sickles or crescent moons. These irregularly shaped cells can get stuck in small blood vessels, which can slow or block blood flow and oxygen to parts of the body.

27. Sickle cell anemia is inherited in an autosomal recessive pattern, which means that both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In regards to sickle cell anemia, a person who carries one copy of the mutated gene is said to be a carrier for the condition, or to have sickle cell trait. When two people who are carriers of an autosomal recessive condition have a child, there is a 25% (1 in 4) chance that the child will have the condition, a 50% (1 in 2) chance that the child will be a carrier like each of the parents, and a 25% (1 in 4) chance that the child will not have the condition and not be a carrier.

28. GENETICS The change in cell structure arises from a change in the structure of hemoglobin. A single change in an amino acid causes hemoglobin to aggregate. Sickle cell disease is caused by a mutation in the hemoglobin-Beta gene found on chromosome 11.

29. RBCs containing HbS have a shorter lifespan Normally 20 days Chronic state of anemia Symptoms: They vary from person to person and change over time, include: Anemia. Sickle cells break apart easily and die, leaving you without enough red blood cells. Red blood cells usually live for about 120 days before they need to be replaced. But sickle cells usually die in 10 to 20days, leaving a shortage of red blood cells (anemia) causing fatigue.

30. 2. Episodes of pain . Periodic episodes of pain, called crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. 3. Stroke, Acute chest syndrome, Pulmonary hypertension, organ damage, blindness. Treatments might include medications to reduce pain and prevent complications, and blood transfusions, as well as a bone marrow transplant.

31. AUTOSOMAL DOMINANT (m+)

32. Huntington's disease is caused by an inherited defect in a single gene. Huntington's disease is an autosomal dominant disorder , which means that a person needs only one copy of the defective gene to develop the disorder. With the exception of genes on the sex chromosomes, a person inherits two copies of every gene — one copy from each parent. A parent with a defective gene could pass along the defective copy of the gene or the healthy copy. Each child in the family, therefore, has a 50% chance of inheriting the gene that causes the genetic disorder

33. CAUSE The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row . Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease.

34. The disease causes progressive degeneration of neurons in the brain. Signs and symptoms usually develop between ages 35 to 44 years and may include uncontrolled movements, loss of intellectual abilities, and various emotional and psychiatric problems. People with HD usually live for about 15 to 20 years after the condition begins. It is caused by changes (mutations) in the HTT gene and is inherited in an autosomal dominant manner.

35. Symptoms: Behavioral disturbances, Clumsiness, Moodiness, Irritability, Paranoia, Apathy, Anxiety Hallucinations, Abnormal eye movements, Depression, Involuntary movements Trouble with balance and walking Chorea with twisting and writhing motions Slow reaction time General weakness Weight loss Speech difficulties Stubbornness etc.

36. Familial hypercholesterolemia Familial hypercholesterolemia is a disorder that is passed down through families. It causes LDL (bad) cholesterol level to be very high. Familial hypercholesterolemia is a genetic disorder. It is caused by a defect on chromosome 19. The defect makes the body unable to remove low density lipoprotein (LDL, or bad) cholesterol from the blood. As a result, cholesterol accumulates in the bloodstream and can ultimately build up in the walls of the arteries. Cholesterol build up in the artery wall is called hardening of the arteries, or atherosclerosis, and can lead to problems such as heart attacks and strokes in young adults and even children. The condition is typically passed down through families in an autosomal dominant manner.

37. INBORN ERRORS

38. DEFECTS IN METABOLISM OF AMINO ACIDS : PHENYLKETONURIA (PKU) Phenylalanine is an essential amino acid. Dietary phenylalanine not utilized for protein synthesis is normally degraded by way of the Tyrosine pathway. (PKU) is an autosomal recessive metabolic genetic disorder characterized by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). This enzyme is necessary to metabolize the phenylalanine ( Phe ) to the tyrosine.

39. When PAH isdeficient , phenylalanine accumulates and is converted into phenylpyruvate, which is detected in the urine. It can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. Optimal treatment involves lowering blood ( Phe ) levels to a safe range and monitoring diet and cognitive development. The brain is the main organ affected by hyperphenylalaninemia.

40. Alkaptonuria Alkaptonuria is inherited as an autosomal recessive trait. Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. This blue-black pigmentation usually appears after age 30. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood. Mutations in the HGD gene ( homogentisate 1,2-dioxygenasegene )cause alkaptonuria. The HGD gene provides instructions for making an enzyme called homogentisate oxidase.

41. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Mutations in the HGD gene impair the enzyme's role in this process . As a result phenylalanine and tyrosine accumulates in the body. Although homogentisic acid is rapidly cleared from the body by the kidneys, it also slowly accumulates in the various tissues of the body, especially connective tissue such as cartilage. Long-term, chronic accumulation of homogentisic acid eventually weakens and damages affected tissue and leads to many of the characteristic symptoms of alkaptonuria.

42. ALBINISM Albinism is a group of inherited disorders that results in little or no production of the pigment melanin. Melanin also plays a role in the development of certain optical nerves, so all forms of albinism cause problems with the development and function of the eyes . People with albinism often have white or very light blonde hair, although some have brown or ginger hair. The exact colour depends on how much melanin their body produces.

43. Albinism is caused by mutations and most types are inherited in an autosomal recessive manner. Eye problems The reduced amount of melanin can cause eye problems. This is because melanin is involved in the development of the retina, the thin layer of cells at the back of the eye. Possible eye problems linked to albinism include: Poor eyesight – either short-sightedness or long-sightedness, and low vision (sight loss that cannot be corrected) Astigmatism – where the cornea (clear layer at the front of the eye) is not perfectly curved or the lens is an abnormal shape, causing blurred vision Potophobia – where the eyes are sensitive to light Squint – where the eyes point in different directions

44. Shaun Ross: The first African-American male model with albinism: