Genetic Disorders

Review of Genetic Control

Chromosomes

• Autosomes: Chromosomes that impact genotype and phenotypic functions are exempt from sexual function.

• Karyotype: Visual representation of an individual’s chromosomes.

• XY Chromosomes: Sexual chromosomes of an individual; they determine secondary sex characteristics.

• Allele: a location at a specific point on paired chromosomes which encored for a function.

  • Genotype: The genetic constitution of an individual, represented by the alleles inherited from both parents.

  • Gene penetration: Frequency of expression amongst individuals with a specific genotype.

Congenital Anomalies

• Can be inflicted by single-gene traits, chromosomal defects, or can be multi-factorial.

• Single-gene disorders: A change in one gene within reproductive cells, which are transmitted to subsequent generations.

  • Due to mutations or dysfunctions that affect expression (phenotype), they can vary in severity.

• Chromosomal anomalies: Typically result from error(s) during meiosis in cell division, leading to altered genetic information.

  • Translocation → a segment of one chromosome breaks off and attaches to another chromosome.

  • Deletion → a segment of the chromosome is missing.

  • Insertion and inversion/

• General congenital and developmental disorders: Result from external factors such as premature birth, teratogens, and environmental influences.

• Multifactoral disorders (10% of the population) → can be polygenic or an inherited tendency that is expressed after an exposure.

Genetic Disorders

Single-Gene Disorders

• Occurs in every 1:200 live births.. some present, some not.

  • 50% chance roughly on inheritance.

• Minor impact on limited functions typically

  • Color Blindness

Systemic Impacts

• Cystic Fibrosis: A genetic disorder that affects the lungs and digestive system, leading to severe respiratory and nutritional complications.

• Marfan Syndrome: A genetic disorder that affects the connective tissue, leading to features such as tall stature, long limbs, and an increased risk of cardiovascular complications.

Autosomal Recessive Disorders

• Autosomal genotype must be recessive for phenotype expression.

  • 75% child will be carrier (RR or Rr/ Heterozygous or Homozygous Dominant)

  • 25% child will be affected and be an carrier (rr / Homozygous Recessive)

• The majority of these disorders involve enzyme defects that cause toxic metabolites to accumulate and cause cell dysfunction or death.

Example Disorders

• PKU (Phenylketonuria): A genetic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase.

  • Leads to the buildup of phenylalanine in the body, which can result in serious neurological damage if not managed through dietary restrictions.

• Cystic Fibrosis: A hereditary disorder affecting the respiratory and digestive systems, caused by mutations in the CFTR gene.

  • CFTR → Cystic Fibrosis Transmembrane Conductance Regulator protein, which is responsible for the transport of chloride ions across epithelial cells, leading to the production of thick, sticky mucus.

  • Build-up of mucus systemically causes systemic issues, especially with the respiratory and digestive systems.

• Incomplete Dominance → Genetic phenomenon in which heterozygotes express partial clinical signs.

  • Sickle Cell → Disorder caused by a mutation in the hemoglobin gene, resulting in the production of abnormal hemoglobin (HbS), which distorts red blood cells into a sickle shape, leading to various health complications, including anemia, pain crises, and increased risk of infections.

Autosomal Dominant Disorders

• Only one defect in alleles is required to express a disordered condition.

  • Heterozygous or Homozygous dominant → 50% chance of affected and carrier.

  • No carriers are present, so unaffected individuals are normal.

• Some of these conditions are late-onset disorders that become evident later in life.

  • Huntingon Disease: A genetic disorder caused by a mutation in the HTT gene, leading to progressive neurodegeneration and usually manifests in mid-adulthood.

X-Linked Dominant Disorders

• Inherited as a dominant allele carried on the X chromosome, affecting both sexes. Males always pass on their Y chromosome, which means they can only contribute to the inheritance of X-linked traits through their daughters.

• Fragile X syndrome → 1/4000 males affected, with 1/8000 females affected. Mental retardation is present in a significant proportion of cases, with varying levels of severity, alongside behavioral challenges and developmental delays.

  • Mutation is responsible causes X chromosome to be constricted or broken.

X-Linked Recessive Disorders

• Alleles for sex-linked recessive disorders are typically carried by the X chromosome, as the Y chromosome does not carry the same genes.

  • As well, Y is automatically dominant due to a lack of a Y-matching X allele, meaning that any allele present on the Y chromosome will express its phenotype regardless of the X chromosome's contribution.

• Females are carriers (without clinical signs) when heterozygous.

• Affected males always inherit from their mother and always pass it to their daughters. Males are unaffected by inheritance.

  • 50% chance of producing an affected male or a carrier female.

Example Disorders

• Hemophilia A → a genetic disorder caused by a deficiency of clotting factor VIII, leading to prolonged bleeding episodes.

• Duchenne Muscular Dystrophy → a severe type of muscular dystrophy characterized by rapid progression of muscle degeneration, ultimately leading to loss of ambulation and premature death.

Chromosomal Disorders

• Trisomy → three chromosomes present rather than two at the gene position. Down syndrome is an example at position 21.

• Monosomy → One chromosome present rather than two at the gene position.

  • Turner Syndrome (Monosomy X) → a condition resulting from the absence of one X chromosome in females, leading to developmental and reproductive issues.

    • Lack of ovaries and underdeveloped secondary sexual characteristics are common.

  • Klinefelter Syndrome (XXY) → a condition where males have an extra X chromosome, often resulting in physical and cognitive challenges.

    • Males surprisingly don’t get affected much. Lack of testes size and sperm production is present.

Multifactorial Disorders

• Multiple genetic and environmental factors come together to affect the likelihood of developing these disorders.

• Same defect is likely to recur in siblings due to the shared genetic background and potential environmental influences within the family.

• Documentation of family history important to allow prevention measures and early detection of potential genetic disorders.

Example Disorders

• Cleft palate → a congenital defect where a fissure forms in the roof of the mouth due to incomplete fusion of palatine structures.

• Congenital hip dislocation → a condition where the hip joint does not properly form in babies and young children, leading to the femur being improperly positioned in the hip socket, which can cause joint problems or arthritis later in life.

• Congenital heart disease → a range of problems that affect the structure and function of the heart, which can occur due to genetic factors or environmental influences during fetal development, potentially leading to heart failure, arrhythmias, or other serious complications.

• Type 2 diabetes → a metabolic disorder characterized by high blood sugar levels due to insulin resistance, which can lead to various health complications such as cardiovascular disease, nerve damage, and kidney problems if not managed effectively.

• anencephaly → a severe congenital condition in which a major portion of the brain, skull, and scalp is absent at birth, often resulting in stillbirth or death shortly after delivery, as affected infants typically lack the structures necessary for basic bodily functions.

• Hydrocephalus → a condition characterized by an accumulation of cerebrospinal fluid within the ventricles of the brain, leading to increased intracranial pressure and potentially causing brain damage, developmental delays, or other neurological issues.

Developmental Disorders

• Exposure to negative environmental influences prior or during pregrenancy can induce changes in ova or sperm.

• Fetal alcohol syndrome, cigarette smoking (low birthweight and increased still birth), radiaton, pharmaceuticals, cocaine abuse, and maternal infections.

  • TORCH → an acronym for a group of infections that can have serious effects on fetal development, including Toxoplasmosis, Other infections (like syphilis), Rubella, Cytomegalovirus (CMV), and Herpes simplex virus (HSV).

  • Cerebral palsy → a group of disorders affecting movement and muscle tone, often caused by brain damage that occurs during pregnancy, childbirth, or shortly after birth.

• Damage during organogenesis (first two months) is most damaging as stem cells are dividing rapdily and differentiating into fundamental structures.

• Anomalies or developmental abnormalities are signs of exposure to teratogens, which are substances or factors that can cause malformation or functional changes in an embryo or fetus.

Diagnostic Tools

• Screening programs → identify at-risk populations by testing for specific genetic disorders, allowing for early interventions and appropriate management.

  • Example is Ashkenazi Jews and Tay-Sachs disease.

• Blood testing → detect specific genetic mutations associated with inherited conditions, facilitating timely diagnosis and treatment strategies.

  • Example would be sickle cell disease.

• Prenatal diagnosis → screening procedures such as amniocentesis or chorionic villus sampling (CVS) to identify genetic abnormalities in the fetus before birth.

  • Birth defects present in 1:28 births, this allows for early intervention.

  • Ultrasonography → a non-invasive imaging technique used during pregnancy to visualize the fetus and assess its development.

  • Maternal blood testing → a method that analyzes biomarkers in the mother's blood to detect potential genetic disorders in the fetus, providing results earlier in pregnancy than traditional invasive tests.

    • triple screen → performed at 16-18 weeks, it measures levels of alpha-fetoprotein (AFP), the beta subunit of human chorionic gonadotropin (β-hCG), and estriol (uE3).

      • Elevated or abnormal levels are indicative of spinda bifida or down syndrome.

    • quad screen → an extension of the triple screen, performed around 15-20 weeks, which adds the measurement of inhibin A to the biomarkers, improving the detection rates for Down syndrome and other chromosomal abnormalities.

  • Amniocentesis → Extraction of amniotic fluid from uterus, and extraction of a sample of chorionic villus to examine feta tissue.

    • Allows for the analysis of fetal DNA, enabling the identification of genetic disorders with high accuracy and providing critical information for prenatal care.

• Neonate testing → Can be done ~48 hours aftr birth using a heel prick. Testing includes PKU, hyperthyroidism, sickle cell disease, and cystic fibrosis, allowing for early intervention and management of these conditions.

  • Some wait might be necessary due to maternal organs keeping neonate disorders hidden.

Genetic Technology

Gene Engineering and Gene Therapy

• Genetic engineering → laboratory practices of manipulating genes to produce desired traits or to correct genetic disorders.

• Gene therapy → a technique that modifies a person's genes to treat or prevent disease, often by adding or removing genetic material in order to correct defects.

  • Particularly effective in single-gene disorders.

Genetic Diagnosis and DNA testing

• DNA testing for genetic disorders has been used to identify conditions in embryos and newborns.

• In vitro fertilization → this process allows for preimplantation genetic diagnosis (PGD), which can screen embryos for specific genetic conditions before they are implanted.

• DNA finger-printing → this technique analyzes an individual's unique DNA patterns, allowing for the identification of genetic disorders and assisting in paternity testing.

Proteomic Research / Designer Drugs

• Proteomics → the large-scale study of proteins, particularly their functions and interactions, which can aid in understanding genetic disorders by highlighting how protein variations can influence disease mechanisms.

• Designer Drugs → these are customized pharmaceuticals designed to target specific genetic disorders at the molecular/protein level, potentially improving treatment efficacy and minimizing side effects.

Down Syndrome

• Down syndrome or Trisomy 21 → a genetic disorder caused by an extra copy of chromosome 21, leading to developmental differences and a range of physical and intellectual disabilities.

  • Formely called Down’s syndrome or mongolism.

• Risk of bearing children with down syndrome increases with maternal age (35+). Hypothesis is oocyte aging and environmental factors.

Characteristics

• Head is small and has flat facial profile.

• Eyes are slanted, and irises contain Brushfield spots.

• Mouth tends to hang open, revealing large protruding tongue with high-arched palate.

• Hands are small and have a single palmar crease.

• Muscles tend to be hypotonic, joints are loose and structural abnormalities may occur, leading to a higher risk of dislocations and difficulty with motor skills.

• Cognitive impariment is always present, however severity varies per individual.

• Development and sexual development is delayed or incomplete.

• Assortment of other problems including visual, hearing, digestive, heart, immune, and cancer problems.