Congenital And Genetic Diseases

Congenital & Genetic Diseases

OBJECTIVES

❚ Differentiate among the terms congenital, genetic, chromosomal, environmental, and multifactorial defects. ❚ Describe the inheritance pattern: ❙ Autosomal recessive disorders ❙ Autosomal dominant disorders ❙ X-linked recessive disorders

❚ Explain the common causes of developmental disorders and their relationship to fetal development

OBJECTIVES ❚ Describe the benefits and risks of genetic screening programs and prenatal testing. ❚ Discuss the purposes of genetic engineering and current concerns. ❚ Describe the genetic defect in a child with Down syndrome and the effects on the child.

Origins of Modern Genetics ❚ Gregor Mendel ❚ Studied inheritance of characteristics in garden peas

Mendel’s First Experiment

Mendel’s Conclusions ❚ Hereditary characters are determined by discrete factors (GENES) ❚ Genes appear in pairs, one from each parent ❚ Genes can occur in different forms (ALLELE) ❚ If members of gene pair are different (heterozygous), one allele will express itself (dominant allele) and the other will not (recessive allele)

Chromosomes ❚ Genetic information for each cell is stored ❚ 23 pairs in each human cell ❚ 22 pairs are AUTOSOMES => shaped in karyotype ❚ 23rd pair => pair of sex chromosomes ❙ XY => male ❙ XX => female

PAIRING OF CHROMOSOMES: Gender Identification MALE X

X

FEMALE X

Y

X

X

X

Y

Chromosomes

Chromosomes: Carriers of Genes

Meiosis  Each sperm and ovum receive only 23 chromosomes Zygote = 46 chromosomes (23 pairs containing an assortment of genetic information inherited from the parents)

Mitosis

Deoxyribonucleic Acid (DNA) “file” that contains information about protein synthesis in the cell

DNA Structure

DNA Replication

Genes and DNA

Ribonucleic Acid  Provides communication link with DNA during the actual synthesis of proteins and helps to maintain control of cell activity.

Protein Synthesis

Protein Synthesis

Protein Structure determines Protein Function

Molecular Biology’s Central Dogma DNA RNA PROTEIN

FUNCTION

STRUCTURE

CONGENITAL DEFECTS ❚ disorders present at birth ❙ GENETIC – may result from single-gene trait or from chromosomal defect; may be multifactorial. ❙ CHROMOSOMAL – usually result from an error during meiosis, when the DNA fragments are displaced or lost, thus altering genetic information ❙ DEVELOPMENTAL – may result from premature death, difficult labor & delivery or exposure to teratogens

Mendelian Inheritance ❚ Autosomal Recessive ❚ Autosomal Dominant ❚ X-linked Recessive ❚ X-linked Dominant ❚ Y-linked

❚ GENETIC DISODERS ❙ Single-gene disorders

HOMOZYGOUS HETEROZYGOUS

Autosomal Recessive ❚ Either sex gets disease ❚ Siblings are usually affected, but not parents ❚ Heterozygotes of both sexes normal ❚ Heterozygote parents have diseased kids in ratio of 1:3 ❚ If defect involves a rare gene parents may be related

PROBABILITY:

 25% Normal  50% Carrier  25% Affected

A.K.A: Storage disease or Inborn Errors of Metabolism

PROBILITY

 50% NONCARRIERS  50% CARRIERS

Autosomal Recessive ❚ ❚ ❚ ❚ ❚ ❚

Galactosemia Tay-Sachs Disease Cystic Fibrosis Albinism Phenylketonuria (PKU) Sickle Cell Anemia

TAY-SACH’S DISEASE ❚ aka, Sphingolipidosis ❚ deficiency of hexosaminidase A, resulting in apathy and regression in motor & social development and decreased vision. ❚ Prognosis: poor (4y.o.)

CYSTIC FIBROSIS ❚ affects exocrine glands, primarily the lungs and pancreas resulting in altered viscosity of mucus-secreting glands throughout the body.

SICKLE CELL DISEASE ❚ involves a defective hemoglobin (sickleshape) resulting to joint pains and swelling.

PHENYLKETONURIA (PKU) ❚ metabolic (liver) enzyme (phenylalanine hydroxylase) w/c metabolizes the amino acid phenylalanine. {toxic to brain cells}

ALBINISM ❚ caused by the absence of an enzyme that produces melanin ❚ results in a complete lack of pigmentation in skin, hair, or eyes

GALACTOSEMIA ❚ the inability to metabolize lactose

Autosomal Dominant ❚ Affects males, females equally ❚ If you have the gene, you have the disease ❚ Every affected individual has an affected parent ❚ Normal siblings of affected individuals do not transmit disease (no unaffected “carriers”)

PROBABILITY

50% AFFECTED CHILD 

PROBABILITY

 75% AFFECTED  25% NORMAL

Marfan’s Syndrome ❚ Marfan patients are tall, with very long extremities. ❚ The arm span exceeds the height. ❚ Joints are hyperextensible

Huntington’s Disease ❚ Neurodegenarative disorder ❚ pattern of repetitive abnormal movements called chorea

ACHOO Syndrome:

Autosomal dominant Compelling Heliopthalmic Outburst

❚ sneeze excessively, approximately 30 to 40 times, in the presence of brightness.

Polydactyly ❚ More than the number of digits.

Achondroplastic Dwarfism ❚ short stature, usually reaching a full adult height of around 4'0" (1.2 meters). ❚ mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation

X-linked Recessive ❚ Females ❙ 25% genetic carrier ❙ 25% normal

❚ Males ❙ 25% affected ❙ 25% normal

X-linked Recessive ❚ More frequent in males ❚ Passed from affected males through their daughters ❚ No transmission directly from father to son ❚ Female carriers can express phenotype at variable levels

X-linked Recessive ❚ Red/Green Colorblindness

Duchenne Muscular Dystrophy ❚ weakens the muscles that assist the body's movements. ❚ have either missing or mutated genes that don't produce the proteins needed for the muscles

Hemophilia A:caused by a deficiency of active ❚ Hemophilia B (Christmas disease): clotting factor (8).active clotting factor caused by a VIII lack of IX

X-linked Dominant ❚ Females ❙ 50% carrier

❚ Males ❙ 50% normal

X-linked Dominant ❚ Affected males with normal spouses have normal sons and all affected daughters ❚ All offspring have 50% chance of being affected

Y-linked Father’s Gametes

Mother’s Gametes

X

Y

X

XX

XY

X

XX

XY

Y-linked ❚ Hairy ears

Non-Mendelian Inheritance ❚ Mitochondrial Traits ❙ Mitochondria contain multiple copies of a single DNA strand ❙ All mitochondria transmit through ova ❙ Mitochondrial traits pass from mother to child ❙ Disorders involve combinations of CNS, eye, and muscle tissue abnormalities

Non-Mendelian Inheritance ❚ Multifactorial Inheritance ❙ Do not involve single genes ❙ Pedigrees do not exhibit Mendelian patterns ❙ Frequently involve interaction between host, environmental factors

Multifactorial Disorders ❚ Congenital ❙ Neural tube disorders ❙ Cleft lip, palette ❙ Congenital heart disease

Multifactorial Disorders ❚ Adult ❙ Coronary artery disease ❙ Type I diabetes ❙ Type II diabetes ❙ Breast cancer ❙ Colon cancer ❙ Lung cancer ❙ Rheumatic heart disease ❙ Alcoholism

❙ Asthma, allergies ❙ Autoimmune disorders ❙ Bipolar disorder ❙ Schizophrenia ❙ Kidney stones ❙ Gallstones ❙ Obesity ❙ Peptic ulcer disease ❙ Gout

Coronary Artery Disease Blood pressure Cholesterol Triglycerides HDL Weight Glucose

Hypercholesterolemia Diabetes mellitus Major Genes Background Genes

Environmental Factors

Smoking Stress Inactivity Diet Oral Contraceptives

Chromosomal Abnormalities

Trisomy-21

Down’s Syndrome 1 in 600 births Short, broad nose Epicanthal fold Small oral cavity Large, furrowed tongue ❚ Large, irregular teeth ❚ IQs from 20 to 50 ❚ ❚ ❚ ❚ ❚

 Slanting

palpebral fissures and epicanthic folds ("mongolism")  Open mouth, big tongue with no central crease

BRUSHFIELD'S SPOTS

PALMAR (Simian) CREASE

Trisomy 13: Patau's syndrome

Patau’s Syndrome 1 in 20,000 births Sloping forehead Small head, eyes Cleft lip, palate Heart defects 75% die in first year ❚ 100% by age 6 ❚ ❚ ❚ ❚ ❚ ❚

Trisomy 18

Edwards’ Syndrome ❚ 1 in 11,000 births ❚ Small mouth, jaw ❚ Low-set, malformed ears ❚ Clinched fist, index finger overlapping 3rd, 4th fingers ❚ Rocker-bottom feet ❚ Heart defects ❚ Hearing loss ❚ 90% die by age 1

Kleinfelter’s Syndrome

Kleinfelter’s Syndrome ❚ 1 in 500 males ❚ Taller than average ❚ Partial breast development ❚ Small testicles, highpitched voice, female hair distribution ❚ Altered body proportions, hips slightly larger than normal

Turner’s Syndrome

Turner’s Syndrome 1 in 2500 females Grow slowly Shield chest when young Low hair line Widely spaced nipples Fail to menstruate, no ova ❚ Normal IQ; weakness in math, spatial perception ❚ “cubitus valgus” (elbows ❚ ❚ ❚ ❚ ❚ ❚

Small uterus flanked by two streak ovaries

Streak ovary histology (right, no eggs), normal for comparison (left, eggs)

Jacob’s Syndrome (XYY) ❚ ❚ ❚ ❚ ❚ ❚

“Super Male” 1 in 1000 males 1 in 50 in prison populations Excessively tall (2/3s > 6 feet) IQs around 80 Low threshold for control of aggression

X-Polysomy (XXX, XXXX) ❚ XXX, 1 in 1400 females ❚ Cannot be distinguished from XX females ❚ Problems with spontaneous abortions ❚ XXX have normal IQs, increasing numbers cause mental deficiency

DEVELOPMENTAL DISORDERS ❚ Exposure to harmful influences in the first 2 wks of life => DEATH OF THE EMBRYO ❚ Critical time = first 2 months of development

❚ Alcohol = FETAL ALCOHOL SYNDROME ❚ Cigarette smoking = LOW BIRTHWEIGHT ❚ Radiation ❚ Drugs (e.g. thalidomide) ❚ Maternal infections (German measles) ❚ Mercury

TORCH ❚ routine prenatal screening test for high risk maternal infections ❚ Toxoplasmosis, Other (Hep. B, Mumps, Rubeola, Varicella, Gonorrhea, Syphillis), Rubella, Cytomegalovirus, and Herpes

SCREENING ❚ ❚ ❚ ❚ ❚

Family pedigree UTZ – gross defects Newborn Screening Test Amniocentesis Maternal blood screens ❙ Triple screen: AFP, beta unit hCG, unconjugated estriol (uE3) ❙ Quadruple screen : + inhibin-A (Spina bifida or Down syndrome)