CLASE TEÓRICA 3 - TRASTORNOS GENÉTICOS
Introduction to Genetic Disorders
Overview of Genetics
- Dr. Carolina Luque introduces the topic of genetic disorders, emphasizing the importance of understanding basic genetics.
- Cells divide through mitosis, with chromosomes reaching maximum compaction during metaphase, consisting of two chromatids.
- A gene is defined as a sequence of DNA that encodes for protein synthesis, crucial for passing genetic traits to offspring.
Chromosomal Behavior and Inheritance
- Discussion on homologous chromosomes and alleles; alleles are alternative forms of a gene affecting a single trait.
- Example given: brown (dominant allele A) vs. blue (recessive allele a) eye color inheritance in offspring from parents.
- The likelihood of inheriting dominant versus recessive traits is explained; 50% chance for brown eyes if one parent has a dominant allele.
Types of Hereditary Diseases
Classification of Genetic Disorders
- Introduction to hereditary diseases including Mendelian disorders, multifactorial disorders influenced by environment, and cytogenetic disorders.
- Mendelian disorders can affect autosomes or sex chromosomes; those linked to sex are characterized by their association with X or Y chromosomes.
Autosomal Dominant and Recessive Disorders
- Autosomal dominant conditions include familial hypercholesterolemia, Marfan syndrome, neurofibromatosis, and others.
- Recessive conditions require homozygosity for expression; examples include cystic fibrosis and albinism.
Specific Genetic Conditions
Notable Genetic Disorders
- Sex-linked diseases mentioned include Duchenne muscular dystrophy, hemophilia A & B, gamma globulinemias, diabetes insipidus, and fragile X syndrome.
Familial Hypercholesterolemia
- Familial hypercholesterolemia is highlighted as an important autosomal dominant disorder associated with high cholesterol levels unrelated to diet.
Marfan Syndrome Characteristics
Aneurysms and Genetic Disorders
Aortic Aneurysm and Its Consequences
- The thoracic aortic aneurysm can lead to rupture, resulting in patient mortality. The media layer of the aorta is composed of elastic fibers, which show degeneration and fragmentation, contributing to hematoma formation.
- This dissection separates the layers of the aorta, weakening its structural integrity and function.
Neurofibromatosis Overview
- Neurofibromatosis is characterized by two types: Type 1 presents with neurofibromas at various locations, optic nerve neuromas, café-au-lait spots on skin, and iris nodules known as Lisch nodules.
- Type 1 neurofibromas can be plexiform or solid; plexiform variants may progress to malignant tumors necessitating lifelong medical follow-up. The affected gene is located on chromosome 17q.
- Type 2 neurofibromatosis is less common but involves multiple meningiomas and affects chromosome 22q12. Patients often require continuous monitoring due to potential complications.
Cystic Fibrosis Insights
- Cystic fibrosis (mucoviscidosis), an autosomal recessive disorder affecting ion transport in exocrine glands primarily involving chloride ions, leads to severe health issues.
- For autosomal recessive diseases like cystic fibrosis to manifest clinically, both homologous chromosomes must exhibit homozygosity for the recessive allele; carriers do not express symptoms.
- The respiratory system is significantly impacted by cystic fibrosis leading to malnutrition, cirrhosis, infertility in males, and intestinal obstructions in newborns due to meconium ileus.
Lysosomal Storage Diseases
- Autosomal recessive lysosomal storage diseases result from enzyme degradation failures leading to substance accumulation; examples include Gaucher's disease and Pompe disease.
- Histopathological examination reveals macrophages filled with eosinophilic amorphous substances within enlarged cells indicative of these disorders.
Pompe Disease Characteristics
- In Pompe disease histology shows macrophages laden with glycogen deposits; electron microscopy confirms lysosomal vacuoles filled with material characteristic of this condition.
- Comparison between normal cardiac muscle tissue versus that affected by Pompe disease highlights significant glycogen accumulation within cardiac cells impacting heart function negatively.
Mendelian Disorders Linked to X Chromosome
Duchenne Muscular Dystrophy (DMD)
- DMD primarily affects skeletal muscle systems and follows an X-linked recessive inheritance pattern where carrier mothers pass the gene directly to male offspring who will develop the condition but cannot transmit it further.
- Affected males experience progressive muscle weakness without a definitive cure; however, treatments such as physiotherapy and corticosteroids are available for management.
Multifactorial Disorders Examples
- Multifactorial disorders involve genetic predispositions combined with environmental factors; examples include diabetes mellitus, hypertension, gout, pyloric stenosis, and congenital heart disease.
Hypertensive Heart Disease Features
- Hypertensive heart disease manifests through structural changes such as left ventricular hypertrophy observed via imaging techniques indicating over 1.5 cm wall thickness associated with hypertension.
Gout and Genetic Disorders
Understanding Gout
- Gout is characterized by the abnormal precipitation of monosodium urate crystals in joints and soft tissues. It can be classified into two types:
- Primary gout, with an unknown origin due to an unidentified enzymatic defect.
- Secondary gout, which occurs in about 10% of cases, often linked to conditions like hyperparathyroidism.
Clinical Presentation of Gout
- The primary clinical manifestation includes acute arthritis, particularly noticeable at the metatarsophalangeal joint. Symptoms include:
- Celso's tetrad: inflammation (calor), swelling (tumor), redness (rubor), pain (dolor), and functional impairment.
- Chronic gout may lead to ankylosis, where joints become immobile due to crystal deposits forming tophi in soft tissues.
Histopathological Features
- A characteristic histopathological finding in gout is the presence of foreign body granulomas surrounding precipitated crystals. This reaction involves:
- Type IV hypersensitivity with epithelioid cells and multinucleated giant cells.
Cytogenetic Disorders Overview
- Cytogenetic disorders arise from numerical or structural alterations in homologous chromosomes. Key points include:
- Numerical alterations can affect sex chromosomes or autosomes.
- Structural changes include reciprocal translocations and Robertsonian translocations that increase genetic load on certain chromosome pairs.
Specific Genetic Conditions
- Notable examples of chromosomal abnormalities include:
- Down syndrome (Trisomy 21): caused by nondisjunction during meiosis or Robertsonian translocation.
- Phenotypic features: epicanthic folds, simian lines on palms, hypotonia, and congenital heart defects.
- Edwards syndrome (Trisomy 18): presents with low-set ears, short neck, hip adduction limitations; also associated with severe congenital heart defects.
Turner Syndrome Insights
- Turner syndrome results from the absence of one X chromosome in females leading to various physical characteristics such as:
- Short stature, webbed neck, underdeveloped breasts, ovarian dysgenesis resulting in amenorrhea.
- While missing a sex chromosome can be compatible with life, losing a somatic chromosome typically is not due to significant genetic information loss.
Congenital Disorders Not Inherited
- Non-hereditary congenital disorders can arise from environmental factors such as viral infections (e.g., rubella), folic acid deficiency during pregnancy, radiation exposure, or medications. Examples include:
- Syndactyly: fusion of fingers/toes.
- Polydactyly: presence of extra digits.
Deficiencies and Neurological Development
Impact of Folic Acid Deficiency on Nervous System Development
- The deficiency of folic acid can lead to incomplete development of the central nervous system, particularly affecting the brain.
- A condition known as anencephaly occurs when there is a failure in the complete development of the brain.
- When neither the brain nor spinal cord develops properly, resulting in exposed vertebrae, this condition is referred to as craniorachischisis.