Developmental & Genetic Diseases

Zygote

1-4 weeks

Embryo

5-10 weeks

Fetal

11-40 weeks

1st trimester

0-13 weeks

2nd semester

14-27 weeks

3rd trimester

28-40 weeks

Ectoderm

Skin, nervous system

Mesoderm

Bones, muscles

Endoderm

Intestines

Homeobox genes

Master regulators of organogenesis

Critical periods

• First trimester is most sensitive

• Brain remains vulnerable postnatally

Developmental malformations

• Idiopathic (~75%)

• Genetic factors

  • Lethal mutations > spontaneous abortion

  • Multifactorial, autosomal dominant or recessive, X-linked

• Exogenous teratogens

  • Physical, chemical, microbial

Teratogens

Anything that can disrupt the development of zygote/embryo/fetus resulting in spontaneous abortion, birth defects, structural abnormalities or functional impairments

Factors that influence risk of teratogen exposure

• Timing of exposure

• Dose and duration

• Genetics

• Multiple exposures

Physical teratogens

• Radiation

• Extreme

Chemical teratogens

• Alcohol

• Drugs (prescription & illicit)

• Tobacco

• Toxic chemicals (pesticides, solvents, PCBs, phthalates)

Microbial teratogens

TORCH [toxoplasma; others (varicella, zika, epstein-barr, listeria); rubella; CMV/cytomegalovirus; herpes virus]

Maternal factor teratogens

• Uncontrolled diabetes

• Obesity

• Genetic conditions

Structural chromosomal abnormality

Genes are deleted from chromosomes or they are located incorrectly on chromosomes

Numerical chromosomal abnormality

Aneuploidy: missing or additional chromosomes

Down’s Syndrom

• Trisomy 21

• Flattened facial profile, small nose, upward-slanting eyes, short neck, single palm crease, wide gap b/w first 2 toes, poor muscle tone, macroglossia

• Intellectual disability, learning delays, speech/motor skill delays

• Congenital heart defects, vision/hearing problems, thyroid issues, celiac disease, increased leukemia risk, early-onset Alzheimer’s

Edward’s Syndrome

Trisomy 18

Turner Syndrome

• (45, X_)

• Females

• High arched palate, low set ears, low hairline, broad chest, cubitus valgus, horse-shoe kidney

Klinefelter Syndrome

• (47, XXY)

• Males

• Tall stature, reduced muscle tone, weaker bones, lack of facial & body hair, enlarged breast tissues, infertility, structural genitourinary, developmental & behavioral abnormalities

• Later risks: type 2 DM, autoimmune disorders, breast cancer, heart & vascular problems

Trisomies

Extra chromosome; 47 chromosomes instead of 46

Sexual Chromosome Abnormalities

Too few/many of X or Y chromosomes

Autosomal Dominant (AD)

• Marfan Syndrome

• Familial hypercholesterolemia

Autosomal Recessive (AR)

• Cystic fibrosis

• Lysosomal storage diseases

• Phenylketonuria

X-linked recessive

• Hemophilia A & B

• Duchenne/Becker Muscular Dystrophy

• Fragile X Syndrome

Marfan Syndrome

Familial Hypercholesterolemia

Cystic Fibrosis

CFTR mutation > Thick mucus, lung infections, pancreatic insufficiency, salty sweat

Lysosomal Storage Diseases

Tay-Sachs, Gaucher, Hurler > enzyme deficiencies, metabolite accumulation

• Don’t clear metabolic products/wastes efficiently

Phylketonuria

PAH deficiency > increased phenylalanine > intellectual disability if untreated

• Do not process phenylalanine, so it builds up in tissues

• Sensitive to protein

Hemophilia A/B

• Problem with clotting factors

• Hemophilia A: mild, moderate or severe bleeding disorder

• Hemophilia B: severe bleeding disorder

Fragile X Syndrome

• Intellectual disability

• Anticipation phenomenon

  • Symptoms get worse with each generation

Duchenne/Becker Muscular Dystrophy

Muscle wasting

Anencephaly

• Combo of genetics & environmental influences

• Neural tube defect (dysraphism)

• Folic acid before/during pregnancy

• Increased risk w/ each pregnancy

Type 2 DM

• Combo of genetics & environmental influences

• Predisposed to metabolic issues > hyperglycemia

• Lifestyle factors (diet, obesity, sedentary lifestyle)