Transcript 血红蛋白病 血红蛋白
Birth Defects Shun Zhu, Department of Cellular and Genetic Medicine A Boy with Down Syndrome Outline Introduction Genetic Defects Neural Tube Defect Mouth/facial defects Limb defects Congenital Heart Defects Summary Introduction What are birth defects? Birth defects ARE abnormalities of structure or function of the body that are present at birth Structural birth defects Functional birth defects Birth defects ARE NOT impairment of body function or structure due to adverse influences to which the infant has been subjected at birth – birth injuries Structural Birth Defects related to how a body part/structure looks Cleft lip/palate Heart defects, e.g. misshaped valves Abnormal limbs, e.g. clubfoot Neural tube defects, e.g. spina bifida Functional Birth Defects related to how a body part/structure works Central Nervous System problems, e.g. Down syndrome Sensory problems, e.g. blindness Metabolic disorders, e.g., phenylketonuria (PKU) Degenerative disorders, e.g. muscular dystrophy A Collection of Birth Defects How common are they? In the US/world, ~3% babies born with a birth defect http://www.cdc.gov/ Top 6 Common Birth Defects Genetic defects (e.g. Down syndrome): 6,916 babies per year Mouth/facial defects (cleft lip): 6,776 babies per year Heart defects: 6,527 babies per year Musculoskeletal defects (including arm/leg defects): 5,799 babies per year Stomach/intestinal defects: 2,883 babies per year Eye defects: 834 babies per year CDC, Morbidity and Mortality Weekly Report, Jan. 6, 2006; vol 54: pp 1301-1305. Causes-Misconceptions In ancient times, birth defects were seen as warnings or punishments from the gods In some parts of the world, it was believed that unsatisfied wish of a pregnant woman will cause a birth mark Causes-The Truth Faulty genes can cause birth defects Gene mutations, Chromosome aberration Adverse environment Exposure to chemical, physical and biological factors Interactions between genes and environment Unknown Example of ExposuresThalidomide Perhaps the most notorious case of a drug that caused defects It was brought on to the market first in West Germany by the company Grünenthal after inadequate testing Treat pregnancy reaction like sickness but cause limb defects Other Examples Tetracycline may affect the long bones and teeth Anticonvulsant medicines for epilepsy may cause hare lip, limbs defects, and CHDs Moderate alcohol use in pregnancy may cause subtle brain damage to the developing fetus Smoking during pregnancy may cause events like premature delivery and low birth weight The rubella virus, Cytomegalovirus which causes German measles, can cross the placenta and cause a range of defects Cytomegalovirus can also causes birth defects Herpes simplex causes heart defects and deafness (4weeks 61%, 5-8weeks 26%, 9-10weeks 6%) Bacteria such as salmonella, present in undercooked meat (especially chicken), and listeria (found in some cheeses), can cause problems for the continuation of the pregnancy Parasite Toxoplasma can cross the placenta, leading to hydrocephalus or chorioretinitis X-rays and radiation may affect the baby’s central nervous system Vulnerabilities At Various Development Stages Genetic Defects Down Syndrome 1 in 1000 babies Down Syndrome-John Langdon Down1828-1896 The first to describe down syndrome Originally named as mongolian idiocy About Down Syndrome Also know as Down’s syndrome or Trisomy 21 A genetic disorder caused by the presence of all of, or part of chromosome 21 The most common chromosome abnormality, 1 in 1000 babies Mechanisms of TrisomyNondisjunction Symptoms http://www.mun.ca/biology/scarr/MGA2-11-17_Down.html Symptoms Tests and Diagnosis Screening tests can indicate the likelihood a mother is carrying a baby with Down syndrome Diagnostic tests can identify whether your baby has Down syndrome Pregnancy Timeline Screening Tests The first trimester combined test Blood test: measures the levels of pregnancyassociated plasma protein-A (PAPP-A) and the pregnancy hormone known as human chorionic gonadotropin (HCG). Abnormal levels of PAPP-A and HCG may indicate a problem with the baby. Ultrasound: measure a specific area on the back of your baby's neck. This is known as a nuchal translucency screening test. When abnormalities are present, more fluid than usual tends to collect in this neck tissue. Integrated screening test First trimester: includes a blood test to measure PAPP-A and an ultrasound to measure nuchal translucency. Second trimester: the quad screen measures your blood level of four pregnancy-associated substances: alpha fetoprotein, estriol, HCG and inhibin A. The results are combined to estimate the risk that your baby has Down syndrome with the same level of detection as the first trimester combined test but with a lower false-positive rate Cell free fetal DNA test Circulating freely in the maternal blood stream Can be sampled by venipuncture as a non-invasive prenatal diagnosis http://www.gelab.com.tr/ Diagnostic Tests Amniocentesis A sample of the amniotic fluid surrounding the fetus is withdrawn through a needle inserted into the mother's uterus This sample is used to analyze the chromosomes of the fetus Usually performed in the second trimester, after 15 weeks of pregnancy A slight risk of miscarriage, and risk increases if done before 15 weeks Chorionic Villus Sampling Cells are taken from the placenta to analyze the fetal chromosomes Typically performed in the first trimester, after 10 weeks of pregnancy Appears to carry a somewhat higher risk of miscarriage than second trimester amniocentesis Cordocentesis Fetal blood is taken from a vein in the umbilical cord for chromosomal defects exam Performed between 18 and 22 weeks of pregnancy Carries a significantly greater risk of miscarriage than does amniocentesis or CVS Marfan Syndrome 1 in 5000 babies About Marfan Syndrome A genetic disorder that affects connective tissue, which holds other tissues together Can affect many body systems, including the heart, blood vessels, bones, eyes, lungs and skin but not intelligence Can be mild or severe. May be present at birth or become apparent in childhood or in adult life Marfan Syndrome-Symptoms Affected individuals are tall, slender and loosejointed Arms, legs, fingers and toes often are unusually long Usually have long, narrow faces, and their teeth are generally crowded Marfan Syndrome-Causes Mutations in the FBN1 gene encoding fibrillin-1 on chr15, which form thread like filaments called microfibrils Microfibrils become part of the fibers that provide strength and flexibility to connective tissue. Microfibrils store molecules called growth factors Mutations in FBN1 reduce the amount of functional fibrillin-1 that is available to form microfibrils or store growth factors, leading to instability of tissues and overgrowth Isogai et al., Journal of Biological Chemistry, 278, 2750-2757, 2003 Cri du chat Syndrome 1 in 50,000 Cri du chat Syndrome Its name is a French term (call of the cat) referring to the characteristic cat-like cry of affected children Also known as chromosome 5p deletion syndrome A rare genetic disorder due to a missing part (deletion) of chromosome 5 Autism 1 in 68 babies About Autism A neurodevelopmental disorder characterized by impaired social interaction, verbal and non-verbal communication, and restricted and repetitive behavior The rate of autism are estimated at about 1-2 per 1,000 people worldwide Autism-Causes A complex disorder whose core aspects have distinct causes that often co-occur Has a strong genetic basis, although the genetics of autism are complex: it is unclear whether Autism is explained more by rare mutations with major effects, or by rare multigene interactions of common genetic variants Environmental factors are also contributors to Autism Neural Tube Defect Neural Tube Defect (NTD) Spina Bifida 1 in 1000 babies Spina Bifida A condition that affects the spine and a type of neural tube defect (NTD) Can happen anywhere along the spine if the neural tube does not close all the way Might cause physical and intelectual disabilities that range from mild to severe Three Types of Spina Bifida Spina Bifida Occulta: is a small gap in the spine, no opening or sac Meningocele: a sac of fluid without spinal cord Myelomeningocele: a sac of fluid with spinal cord (most serious) http://www.cdc.gov/ncbddd/spinabifida/facts.html Causes of Spina Bifida Largely unknonwn, generally caused by the interaction of multiple genetic and environmental factors Could be related to the genetic variations of MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase Tests and Diagnosis Blood test: tests how much alpha-fetoprotein (AFP ) has passed into the mother’s bloodstream from the baby. A high level of AFP might indicate spina bifida Ultrasound: a type of image for the unborn baby, which may indicate whether the baby has spina bifida in a straightforward way Amniocentesis: takes a small sample of the amniotic fluid surrounding the baby. Higher than average levels of AFP in the fluid might indicate spina bifida Anencephaly 1 in 10,000 babies Anencephaly As the neural tube forms and closes, it helps form the baby’s brain and skull, spinal cord, and back bones Anencephaly happens if the upper part of the neural tube does not close all the way A serious type of neural tube defect in which a baby is born without parts of the brain and skull Usually happens during the first month of pregnancy Almost all babies with Anencephaly will die shortly after birth Anencephaly Encephalocele 1 in 5000 babies Encephalocele A sac-like protrusion or projection of the brain and the membranes that cover it through an opening in the skull Happens when the neural tube does not close completely The result is an opening in the midline of the upper part of the skull, the area between the forehead and nose, or the back of the skull How to prevent NTD? Causes of most NTDs are largely unknown But there are ways for women to reduce the risk of having a baby with spina bifida. Take folic acid every day. Folic acid prevents most cases of spina bifida Others, like vitamins, and dietary or herbal supplements Avoid overheating your body. Treat any fever About Folic Acid Mouth/facial defects Facial Development A baby’s head forms early during pregnancy. To make the face, body tissue and special cells from each side of the head grow toward the center of the face and join together. This joining of tissue forms the facial features, like the lips and mouth. Cleft Lip / Cleft Palate 1 in 700 babies Cleft Lip / Cleft Palate Cleft Lip: The lip forms between the fourth and seventh weeks of pregnancy. A cleft lip happens if the tissue that makes up the lip does not join completely before birth. Cleft Palate: The roof of the mouth (palate) is formed between the sixth and ninth weeks of pregnancy. A cleft palate happens if the tissue that makes up the roof of the mouth does not join together completely. Limb defects Club Foot 1 in 1000 babies About Club Foot Also called congenital talipes equinovarus (CTEV) The affected foot appears to have been rotated internally at the ankle Causes are largely unknown, but may be related to PITX1-TBX4 transcription pathways With treatment, the vast majority of patients recover completely during early childhood Dobbs and Gurnett J Pediatr Orthop B. 21, 7-9, 2012 Treatments Ponseti method: stretching and casting French method: stretching, taping and splinting Surgery: in severe conditions when stretching treatments don’t work, clubfoot can be treated with surgery Polydactyly 1 in 500 babies About Polydactyly Polydactyly means “many” “fingers” It may occur in three places of the hand on the small finger side most common (ulnar) on the thumb side - less common (radial) in the middle of the hand - least common (central) Potentail Genetic Causes Mutations in Sonic hedgehog (shh) genes Shh genes plays a key role in regulating vertebrate organogenesis Lettice et al., Dev. Cell, 22, 459-467, 2012 Congenital Heart Defect (CHD) 1 in 100 babies Congenital Heart Defect CHDs are present at birth and can affect the structure of a baby’s heart and the way it works Affect how blood flows through the heart and out to the rest of the body Vary from mild (such as a small hole in the heart) to severe (such as missing or poorly formed parts of the heart) Causes are largely unknown http://www.cdc.gov/ncbddd/heartdefects/facts.html Major Types of CHD Atrial Septal Defect Atrioventricular Septal Defect Coarctation of the Aorta Hypoplastic Left Heart Syndrome Pulmonary Atresia Tetralogy of Fallot Total Anomalous Pulmonary Venous Return Transposition of the Great Arteries Tricuspid Atresia Truncus Arteriosus Ventricular Septal Defect http://www.cdc.gov/ncbddd/heartdefects/facts.html Coarctation of the Aorta Part of the aorta narrower than usual is A critical congenital heart defect, the baby may need surgery or other procedures soon after birth Pulmonary Atresia Missing pulmonary valve, which is the valve that controls blood flow from the right ventricle (lower right chamber of the heart) to the main pulmonary artery (the blood vessel that carries blood from the heart to the lungs) In babies with this defect, blood has trouble flowing to the lungs to pick up oxygen for the body Ventricular Septal Defect A ventricular septal defect (VSD) is a birth defect of the heart in which there is a hole in the wall (septum) that separates the two lower chambers (ventricles) of the heart Summary Birth defects have various forms affecting nearly every part of the body Birth defects have complex causes, including both genetic and environmental factors The risks of having babies with birth defects can be minimized with proper measures Final Exam When: 1PM, Jan. 19 (Monday) Where: F2305 Thank You!