patho 5

Genetic and Congenital Disorders

Terminology of Genetic and Congenital Disorders

Understanding the terminology is essential for interpreting genetic and congenital disorders. These terms describe the genetic basis and observable traits of inherited conditions.

• Congenital: Condition present at birth.

• Allele: Variant form of a gene.

• Gene locus: Position of a gene on a chromosome.

• Gene mutation: Permanent change in the DNA sequence of a gene.

• Genotype: Genetic makeup of an organism.

• Phenotype: Observable characteristics or traits of an organism.

• Homozygous: Two identical alleles of a particular gene.

• Heterozygous: Two different alleles of a particular gene.

• Polymorphism: Presence of two or more variant forms of a specific DNA sequence.

• Gene penetrance: Likelihood a specific genotype will result in an observable trait.

• Gene expression: Process by which information encoded in a gene is used to create a functional product (usually a protein).

Causes of Birth Defects

Birth defects arise from genetic, environmental, or intrauterine factors, each contributing to abnormal development.

• Genetic Factors: Single-gene or multifactorial inheritance, chromosomal aberrations.

• Environmental Factors: Maternal disease, infections, or drugs taken during pregnancy.

• Intrauterine Factors (rare): Fetal crowding, positioning, or entanglement of fetal parts with the amnion.

Single-Gene Disorders

Characteristics of Single-Gene Disorders

Single-gene disorders are caused by mutations in one gene and follow Mendelian inheritance patterns.

• May be present on autosomes or the X chromosome.

• May affect one or both members of an autosomal gene pair.

• Inheritance patterns can be predicted using a Punnett square.

• Transmission patterns are often determined through family genetic history.

Result of Single-Gene Disorders

Mutations in single genes can disrupt normal protein function, leading to disease.

• Formation of abnormal proteins or decreased production of gene products.

• Defective or decreased amounts of enzymes.

• Defects in receptor proteins and their function.

• Alterations in nonenzyme proteins.

• Mutations resulting in unusual reactions to drugs.

Disorders of Single-Gene Inheritance (Mendelian)

Single-gene disorders are classified by their inheritance pattern.

• Autosomal Dominant: A single mutant allele from an affected parent is transmitted to offspring regardless of sex.

• Autosomal Recessive: Manifested only when both members of the gene pair are affected (parents are usually carriers).

• X-linked Recessive: Associated with the X chromosome; inheritance is predominantly recessive and affects males more frequently.

Autosomal Dominant Disorders

• Marfan Syndrome: Connective tissue disorder affecting skeleton, eyes, and cardiovascular system.

• Neurofibromatosis (NF): Condition involving neurogenic tumors from Schwann cells and other elements of the peripheral nervous system.

Autosomal Recessive Disorders

• Phenylketonuria (PKU): Metabolic disorder due to deficiency of liver enzyme phenylalanine hydroxylase; can cause brain damage if untreated. Newborns are routinely screened for PKU.

• Tay-Sachs Disease: Lysosomal storage disease (gangliosidosis) causing accumulation of gangliosides in neurons and retina, leading to destruction of nerve cells.

X-Linked Disorders

• Fragile X Syndrome: Most common inherited form of intellectual disability after Down syndrome. Associated with a fragile site on the X chromosome where chromatin fails to condense during mitosis. Affects males more than females (approx. 1 in 1000 male infants). May cause connective tissue issues such as mitral valve prolapse.

Punnett Square Example: Fragile X Inheritance

The Punnett square is a tool to predict the probability of inheriting specific alleles.

	X (Father)	Y (Father)
X (Mother)	XX (Healthy Girl)	XY (Healthy Boy)
Xa (Mother)	XaX (Carrier Girl)	XaY (Affected Boy)

• 25% chance: Healthy daughter (XX)

• 25% chance: Carrier daughter (XaX)

• 25% chance: Healthy son (XY)

• 25% chance: Affected son (XaY)

• Each child has a 50% chance of inheriting the affected X chromosome.

• Daughters who inherit it: carriers (may or may not show symptoms).

• Sons who inherit it: affected (more likely to show symptoms because they have only one X).

Multifactorial Inheritance Disorders

Characteristics

These disorders result from the combined effects of multiple genes and environmental factors.

• Exact number of genes involved is unknown.

• Traits do not follow a clear-cut pattern of inheritance.

• Disorders may be present at birth or expressed later in life.

Examples

• Cleft lip or palate

• Clubfoot

• Congenital dislocation of the hip

• Congenital heart disease

• Pyloric stenosis

• Urinary tract malformation

Chromosomal Disorders

Results of Chromosomal Disorders

Chromosomal abnormalities can have severe developmental consequences.

• Early gestational loss

• Congenital malformations

• Intellectual disability

• Linked to more than 60 identifiable syndromes present at birth

Types of Chromosomal Disorders

• Alterations in chromosome duplication

• Alterations in chromosome number:

  • Trisomy 21 (Down syndrome)

  • Monosomy X (Turner syndrome)

  • Polysomy X (Klinefelter syndrome)

• Alterations in chromosome structure

Mitochondrial DNA Disorders

Mitochondrial DNA is inherited maternally and is more prone to mutations due to lack of repair mechanisms.

• Subject to mutations at a higher rate than nuclear DNA.

• No repair mechanisms.

• Disorders interfere with cellular energy production, may lead to increased reactive oxygen species or disrupt apoptosis signaling.

• Commonly associated with neuromuscular disorders.

Disorders Caused by Environmental Influences

Teratogenic Agents

Teratogens are substances or agents that cause structural or functional abnormalities in a developing fetus or embryo, especially during organogenesis.

• Radiation

• Chemicals and drugs:

  • Fetal alcohol syndrome

  • Cocaine exposure

  • Folic acid deficiency

• Infectious agents

Criteria for Defining Fetal Alcohol Syndrome

• Prenatal or postnatal growth retardation: Weight or length below the 10th percentile.

• Central nervous system involvement:

  • Neurologic abnormalities

  • Developmental delays

  • Behavioral dysfunction

  • Intellectual impairment

  • Skull and brain malformation

• Characteristic facial features:

  • Short palpebral fissures (eye openings)

  • Thin upper lip

  • Elongated, flattened midface, and philtrum

Effects of Cocaine Use During Pregnancy

• Decrease in uteroplacental blood flow

• Maternal hypertension

• Stimulation of uterine contractions

• Fetal vasoconstriction

Other Medications During Pregnancy

• Possibilities of cytotoxic (cell-killing), antimetabolic, or growth-inhibiting activities

• Vitamin A derivatives

• Folic acid deficiency

Infectious Agents During Pregnancy

Several infectious agents can cause congenital abnormalities if contracted during pregnancy.

• TORCH infections:

  • Toxoplasmosis

  • Other (Listeriosis, Leptospirosis, Epstein-Barr virus infection, Tuberculosis, Syphilis)

  • Rubella

  • Cytomegalovirus

  • Herpes

• Varicella-zoster virus infection

• Human immunodeficiency virus (HIV)

• Human parvovirus (B19)

Genetic Assessment and Prenatal Diagnosis

Components of a Genetic Assessment

The purpose of genetic assessment is to evaluate and identify inherited conditions.

• Assessment of genetic risk and prognosis

• Detailed family history

• Pregnancy history

• Detailed accounts of birth process

• Accounts of postnatal health and development

• Physical examination of the affected child and family

• Laboratory tests

Purposes of a Prenatal Diagnosis

• Provide parents with information needed to make informed choices about having a child with abnormality.

• Provide reassurance and reduce anxiety among high-risk groups.

• Allow parents at risk to begin pregnancy with assurance that knowledge about the presence or absence of a disorder can be confirmed with testing.

Methods Used for Fetal Diagnosis

• Maternal blood screening

• Ultrasonography

• Amniocentesis

• Chorionic villus sampling

• Percutaneous umbilical cord blood sampling

• Fetal biopsy

• Cytogenetic and biochemical analyses