LECTURE 6.2: Notes on Mitochondrial Disorders and Teratogens

Mitochondrial Gene Disorders

Mitochondria in cells contain their own DNA, consisting of $37$ genes. Of these, $13$ provide instructions for making enzymes involved in oxidative phosphorylation, an important step in cellular respiration that produces adenosine triphosphate (ATP). The remaining genes encode transfer RNA (tRNA) and ribosomal RNA (rRNA). Disorders of mtDNA are inherited by the mother because ova contain numerous mitochondria while sperm have few to none.

Examples include:

• Kearns-Sayre Syndrome: caused by a single, large deletion of mitochondrial DNA. Deletions range from $1000$ to $10000$ nucleotides, and the most common deletion is $4997$ nucleotides. Primarily affects the eyes, causing weakness of the eye muscles (ophthalmoplegia) and degeneration of the light-sensing tissue at the back of the eye (retinopathy).

• Leigh disease: a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing. It is rare for people with early onset to survive into their teens, and rare for it to develop in adults.

• Leber hereditary optic neuropathy: caused by mutations in one of four genes; affects the optic nerve that relays visual information from the eye to the brain. It is unclear why it specifically affects the optic nerve.

Key point: Mitochondrial DNA is separate from nuclear chromosomes and is not on chromosomes 1–23.

Disorders Due to Environmental Influence

Teratology is the study of factors that contribute to birth defects. Teratogens are environmental factors that can contribute to birth defects.

Examples of Teratogens

• Radiation: There is no evidence that diagnostic levels of radiation (e.g., chest X-rays) cause congenital abnormalities.

• Alcohol: Alcohol use during pregnancy is the leading preventable cause of intellectual disabilities in children in the United States. Alcohol consumption—particularly during the second month of prenatal development—may lead to neurocognitive and behavioral difficulties that can last a lifetime. Alcohol is lipid-soluble and has low molecular weight, so it crosses the placenta easily and fetal concentrations can be as high as the mother’s. This reflects environmental exposure rather than genetic factors.

• Chemicals/Drugs

  • Tobacco: Smoking exposes the fetus to nicotine, carbon monoxide and tar, reducing the amount of oxygen available to the fetus.

  • Prescription/OTC drugs: Some can cause birth defects and developmental problems in the fetus. In 1983, the FDA established a system classifying drugs by probable risk to the fetus. Drugs are categorized into five groups: A, B, C, D, and X, where A is the least dangerous and X is a proven teratogen.

  • Illicit drugs: Cocaine, ecstasy, heroin, marijuana, etc. It is difficult to determine the effects of a particular illicit drug because many pregnant women take more than one substance and may have other unhealthy behaviors such as smoking and drinking alcohol.

Infectious Agents: TORCH

TORCH is an acronym for several infectious agents that can cause fetal anomalies and neonatal problems. The most common infectious agents listed are:

• Toxoplasmosis

• “Other”: rubella (German measles), cytomegalovirus, herpes

• “Others”: varicella-zoster, listeriosis, leptospirosis, Epstein–Barr, TB, and syphilis

• Modern texts add HIV and HPV to the list of “others.”

Neonatal herpes (congenital herpes)

Infected during vaginal birth; less commonly in the womb. Usually occurs if the mother has a primary infection. Can become infected even if the mother has not had a primary infection. Symptoms include skin infection or systemic infection, and may include brain damage, seizures, blindness, and respiratory issues.

Toxoplasmosis

Caused by a single-celled parasite, Toxoplasma gondii. More than $40{,}000{,}000$ people in the United States may be infected; many infections are asymptomatic but can persist long-term in the body. Pregnant women must avoid exposure, particularly from cat feces because cats can shed the parasite.

Other teratogens within TORCH

• Mercurials can cause neurologic defects, blindness, and hearing problems. Certain fish and water sources can be contaminated; pregnant women are advised about fish consumption.

• Bisphenol A (BPA): used in plastics and food/beverage containers and may disrupt the action of certain genes contributing to birth defects (March of Dimes, 2016).

• Pesticides: can cause miscarriage or premature birth and birth defects or learning problems.

• Lead poisoning: can cause neurological defects.

Factors Influencing Prenatal Risk from Teratogens

• Timing of exposure: Structures are most vulnerable when they are forming. For example, the ears and arms reach their critical periods at about $6\,\text{weeks}$ after conception; exposure during this period can cause malformations.

• Amount of exposure: The harmful threshold depends on maternal size and metabolism.

• Number of teratogens: Fetuses exposed to multiple teratogens have more problems than those exposed to a single teratogen.

• Genetics: Studies show fraternal twins can share prenatal exposure but not experience the same teratogenic effects, suggesting a genetic influence.

• Being male or female: Males are more likely to experience damage due to teratogens; the reason may relate to the Y chromosome having fewer genes than the X chromosome.

Birth Defects Connected to Nutrition

• Folic acid deficiency is linked to neural tube defects (NTDs).

• The most common neural tube defect occurs in about $1/2500$ births in the United States.

• The neural tube closes between $21-28\,\text{days}$ after conception.

• Long-term folate supplementation decreases NTDs. Therefore, it is recommended that women of child-bearing age receive $400\,\mu g$ of folic acid daily and continue during pregnancy.

• A folic acid food chart is widely referenced for dietary guidance.

Folic Acid Fortification and Declines in Neural Tube Defects

• In $1998$, the FDA mandated fortification of refined cereals and grains with $140\,\mu g / 100\,\text{g}$ of folic acid. Spina bifida prevalence declined after fortification began. See the FDA report: Folic-Acid Fortification—Fact and Folly.

• The fortification program is cited as a factor in reducing neural tube defect rates, illustrating a population-level nutrition intervention.