Genetic Disorders and Mechanisms Quiz
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Questions and Answers

What enzyme is absent in Lesch-Nyhan syndrome, and what is the consequence of this absence?

HGPRT is absent, leading to de novo purine synthesis impairment and increased uric acid production.

Describe the genetic mechanism that leads to β-thalassemia.

It involves mutations at splice sites or promoter sequences, which can result in retained introns in mRNA.

What leads to microsatellite instability in Lynch syndrome?

Failure of mismatch repair during the S phase of the cell cycle causes microsatellite instability.

What is the effect of the defect in N-acetylglucosaminyl-1-phosphotransferase in I-cell disease?

<p>It leads to failure in mannose residues phosphorylation in the Golgi, resulting in cellular debris accumulation in lysosomes.</p> Signup and view all the answers

What mutation is responsible for Marfan syndrome and its effects on the body?

<p>A mutation in the FBN1 gene on chromosome 15 causes defective fibrillin, which normally forms a sheath around elastin.</p> Signup and view all the answers

What is the primary defect in X-linked (Bruton) agammaglobulinemia?

<p>A defect in the BTK gene prevents B-cell maturation, resulting in absent B cells in peripheral blood.</p> Signup and view all the answers

Describe the mechanism that leads to Graft-versus-host disease.

<p>Graft-versus-host disease occurs due to a type IV hypersensitivity reaction where donor T cells attack host cells due to HLA mismatch.</p> Signup and view all the answers

What is the relationship between CD4+ T cells and cytokine release?

<p>CD4+ T cells are responsible for releasing cytokines that facilitate various immune responses, including activating other immune cells.</p> Signup and view all the answers

What characterizes Chronic Granulomatous Disease (CGD) in terms of neutrophil function?

<p>CGD is characterized by a defect in NADPH oxidase, leading to reduced reactive oxygen species and impaired respiratory burst in neutrophils.</p> Signup and view all the answers

How does Tetanospasmin affect neurotransmission?

<p>Tetanospasmin prevents the release of inhibitory neurotransmitters like GABA and glycine from Renshaw cells, leading to muscle spasms.</p> Signup and view all the answers

Explain the importance of the LFA-1 integrin in leukocyte adhesion deficiency.

<p>The LFA-1 integrin (CD18) is crucial for phagocyte migration and chemotaxis, and its defect leads to impaired immune responses.</p> Signup and view all the answers

What happens during a hemolytic transfusion reaction?

<p>Hemolytic transfusion reactions occur due to a type II hypersensitivity reaction against donor RBCs, typically involving ABO antigens.</p> Signup and view all the answers

What causes the pulmonary hypertension associated with Eisenmenger syndrome?

<p>Eisenmenger syndrome occurs due to an uncorrected left-to-right shunt that results in increased pulmonary blood flow, remodeling of vasculature, and eventual right-to-left shunting.</p> Signup and view all the answers

How does the C. difficile toxin contribute to pseudomembranous colitis?

<p>Toxins A and B released by C. difficile damage enterocytes, leading to inflammation and watery diarrhea, characteristic of pseudomembranous colitis.</p> Signup and view all the answers

What is the mechanism by which botulism toxin affects the neuromuscular junction?

<p>Botulism toxin cleaves SNARE proteins, inhibiting the release of the neurotransmitter acetylcholine at the neuromuscular junction.</p> Signup and view all the answers

What genetic mutation is associated with Angelman syndrome?

<p>A deletion or mutation of the paternal allele affecting the UBE3A gene on chromosome 15.</p> Signup and view all the answers

Describe the genetic cause of cystic fibrosis.

<p>Cystic fibrosis is caused by an autosomal recessive ΔF508 deletion in the CFTR gene on chromosome 7.</p> Signup and view all the answers

What is the main consequence of a dystrophin gene mutation in Duchenne muscular dystrophy?

<p>The main consequence is myonecrosis due to loss of the anchoring protein dystrophin to the extracellular matrix.</p> Signup and view all the answers

How does the CTG trinucleotide repeat expansion affect patients with myotonic dystrophy?

<p>It leads to abnormal expression of the myotonin protein kinase, causing myotonia.</p> Signup and view all the answers

What is the pathological mechanism behind fragile X syndrome?

<p>Fragile X syndrome is caused by CGG trinucleotide repeat expansion in the FMR1 gene leading to hypermethylation.</p> Signup and view all the answers

What nutritional deficiency leads to Bitot spots in vitamin A deficiency?

<p>Bitot spots are caused by a deficiency in vitamin A, resulting in squamous metaplasia of conjunctival epithelial cells.</p> Signup and view all the answers

Explain the effect of thiamine deficiency in Wernicke encephalopathy.

<p>Thiamine deficiency results in impaired glucose breakdown, leading to ATP depletion worsened by glucose infusion.</p> Signup and view all the answers

What is the primary consequence of hereditary fructose intolerance?

<p>The primary consequence is accumulation of fructose-1-phosphate due to aldolase B deficiency, leading to phosphate depletion.</p> Signup and view all the answers

Describe the primary feature of classic galactosemia.

<p>Classic galactosemia results from a deficiency in galactose-1-phosphate uridyltransferase, causing accumulation of toxic substances.</p> Signup and view all the answers

What are the mechanisms involved in type I hypersensitivity reactions?

<p>Type I hypersensitivity involves antigen cross-linking with IgE on mast cells, causing degranulation and release of histamine.</p> Signup and view all the answers

What is the impact of the mutation in COL1A1 and COL1A2 genes in osteogenesis imperfecta?

<p>It leads to a defect in type 1 collagen formation, affecting the stability and strength of bones.</p> Signup and view all the answers

What are the consequences of impaired copper absorption and transport in Menkes disease?

<p>It results in reduced lysyl oxidase activity, which impairs collagen cross-linking.</p> Signup and view all the answers

Explain the genetic basis of Prader-Willi syndrome.

<p>It is caused by uniparental disomy or imprinting that silences the paternal gene.</p> Signup and view all the answers

How does the defect in N-acetylglucosaminyl-1-phosphotransferase affect lysosomal function in I-cell disease?

<p>It leads to a failure in the phosphorylation of mannose residues, causing cellular debris accumulation in lysosomes.</p> Signup and view all the answers

What role does the FBN1 gene play in Marfan syndrome?

<p>The FBN1 gene mutation leads to defective fibrillin, which normally provides elasticity to connective tissues.</p> Signup and view all the answers

What gene mutation is associated with the loss of dystrophin in Duchenne muscular dystrophy?

<p>Dystrophin gene frameshift mutations.</p> Signup and view all the answers

In myotonic dystrophy, what genetic alteration is responsible for the condition?

<p>CTG trinucleotide repeat expansion in the DMPK gene.</p> Signup and view all the answers

What is the primary cause of cataracts and peripheral neuropathy in diabetes mellitus?

<p>Intracellular sorbitol accumulation due to lack of sorbitol dehydrogenase.</p> Signup and view all the answers

What deficiency leads to Pellagra in malignant carcinoid syndrome?

<p>Tryptophan diversion towards serotonin synthesis.</p> Signup and view all the answers

What is the major consequence of C1 esterase inhibitor deficiency in hereditary angioedema?

<p>Unregulated activation of kallikrein and increased bradykinin levels.</p> Signup and view all the answers

What leads to recurrent Neisseria bacteremia in patients?

<p>Terminal complement deficiencies affecting C5–C9.</p> Signup and view all the answers

What cellular process is disrupted in Wernicke encephalopathy following thiamine deficiency?

<p>Impaired glucose breakdown leads to ATP depletion.</p> Signup and view all the answers

What triggers histamine release in type I hypersensitivity reactions?

<p>Antigen cross-links IgE on mast cells.</p> Signup and view all the answers

What metabolic defect is associated with hereditary fructose intolerance?

<p>Aldolase B deficiency leading to fructose-1-phosphate accumulation.</p> Signup and view all the answers

What is the consequence of hypermethylation in fragile X syndrome?

<p>Reduced expression of the FMR1 gene.</p> Signup and view all the answers

What is the primary defect in Hyper-IgM syndrome?

<p>Defective CD40L on T helper cells leads to a class switching defect.</p> Signup and view all the answers

What causes the neutrophils' impaired function in Chronic Granulomatous Disease?

<p>A defect in NADPH oxidase results in reduced reactive oxygen species production.</p> Signup and view all the answers

How does the α toxin from gas gangrene contribute to tissue damage?

<p>The α toxin degrades phospholipids, leading to myonecrosis.</p> Signup and view all the answers

What is the mechanism behind the tissue damage caused by Shiga toxin in hemolytic uremic syndrome?

<p>Shiga toxin inactivates the 60S ribosome, leading to decreased protein synthesis and cytokine release.</p> Signup and view all the answers

In DiGeorge syndrome, what is primarily affected due to the 22q11 microdeletion?

<p>The development of the 3rd and 4th branchial pouches is impaired.</p> Signup and view all the answers

How does a lack of effective vaccine for N. gonorrhoeae relate to antigenic variation?

<p>N. gonorrhoeae undergoes antigenic variation of pilus proteins, preventing effective immune response.</p> Signup and view all the answers

What is the primary immune response in tuberculoid leprosy, and what symptoms does it cause?

<p>A Th1 immune response leads to mild symptoms and effective granuloma formation.</p> Signup and view all the answers

What is the consequence of E-cadherin dysfunction in cancer invasion?

<p>Dysfunction of E-cadherin leads to loss of intercellular junctions, facilitating tumor invasion.</p> Signup and view all the answers

What characterizes the immune response in graft-versus-host disease?

<p>Donor T cells attack host cells due to HLA mismatch, indicating a type IV hypersensitivity reaction.</p> Signup and view all the answers

What occurs due to the retrograde transport of rabies virus in neuronal cells?

<p>The rabies virus binds to ACh receptors, utilizing retrograde transport to invade the CNS.</p> Signup and view all the answers

Study Notes

Lesch-Nyhan Syndrome

  • Deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
  • Increased de novo purine synthesis and uric acid production

β-Thalassemia

  • Mutations in splice sites or promoter sequences within the β-globin gene
  • Result in retained introns in mRNA

Lynch Syndrome

  • Failure of mismatch repair during the S phase of the cell cycle
  • Leads to microsatellite instability

I-Cell Disease

  • Deficiency in N-acetylglucosaminyl-1-phosphotransferase
  • This enzyme is responsible for phosphorylating mannose residues in the Golgi apparatus
  • Results in failure of lysosomal enzymes to be properly targeted to lysosomes
  • Leads to accumulation of cellular debris in lysosomes

Osteogenesis Imperfecta

  • Defect in type 1 collagen
  • This defect results from mutations in the COL1A1 and COL1A2 genes
  • Leads to an inability to form triple helices

Menkes Disease

  • Defective ATP7A protein
  • This protein is responsible for copper absorption and transport
  • Leads to impaired lysyl oxidase activity
  • Decreased collagen cross-linking

Marfan Syndrome

  • Mutation in the FBN1 gene on chromosome 15
  • This gene encodes fibrillin which forms a sheath around elastin
  • Results in defective fibrillin

Prader-Willi Syndrome

  • Caused by uniparental disomy or imprinting
  • This leads to silencing of the maternal gene
  • Disease is expressed when the paternal allele is deleted or mutated

Angelman Syndrome

  • Silenced paternal gene
  • Leads to mutation, lack of expression, or deletion of UBE3A on the maternal chromosome 15

Cystic Fibrosis

  • Autosomal recessive disorder
  • Caused by a ΔF508 deletion in the CFTR gene on chromosome 7
  • This gene encodes an ATP-gated chloride channel
  • Results in impaired chloride transport in the lungs, gastrointestinal tract, and sweat glands

Duchenne Muscular Dystrophy

  • Caused by frameshift mutations in the dystrophin gene
  • This gene encodes a protein that anchors the cytoskeleton to the extracellular matrix
  • Leads to loss of dystrophin and myonecrosis

Myotonic Dystrophy

  • Caused by a CTG trinucleotide repeat expansion in the DMPK gene
  • This gene encodes a myotonin protein kinase
  • Results in abnormal expression of myotonin protein kinase and myotonia

Fragile X Syndrome

  • Caused by a CGG trinucleotide repeat expansion in the FMR1 gene
  • This gene encodes a protein involved in mRNA translation
  • Results in hypermethylation and silencing of the FMR1 gene

Bitot Spots in Vitamin A Deficiency

  • Deficiency in vitamin A leads to impaired epithelial cell differentiation
  • This results in squamous metaplasia

Wernicke Encephalopathy in Alcoholic Patient Given Glucose

  • Thiamine deficiency in alcoholic patients
  • This impairs glucose breakdown and ATP depletion
  • Glucose infusion worsens the situation

Pellagra in Malignant Carcinoid Syndrome

  • Tryptophan is diverted towards serotonin synthesis by the tumor.
  • This results in a deficiency of B3, which is derived from tryptophan

Kwashiorkor

  • Protein malnutrition
  • Leads to decreased oncotic pressure and edema
  • Impaired apolipoprotein synthesis and fatty liver changes

Lactic Acidosis, Fasting Hypoglycemia, Hepatic Steatosis in Alcoholism

  • Ethanol metabolism increases the NADH/NAD+ ratio
  • This disrupts normal metabolic pathways

Aspirin-Induced Hyperthermia

  • Aspirin increases the permeability of the mitochondrial membrane
  • This uncouples oxidative phosphorylation and decreases ATP production

Hereditary Fructose Intolerance

  • Deficiency in aldolase B
  • This enzyme is necessary for fructose metabolism
  • Results in accumulation of fructose-1-phosphate which inhibits glycogenolysis and gluconeogenesis

Classic Galactosemia

  • Deficiency in galactose-1-phosphate uridyltransferase
  • This enzyme is involved in galactose metabolism
  • Results in accumulation of toxic metabolites such as galactitol

Cataracts, Retinopathy, Peripheral Neuropathy in Diabetes Mellitus

  • Lens, retina, and Schwann cells lack sorbitol dehydrogenase
  • This leads to accumulation of sorbitol within these cells
  • Sorbitol is a sugar alcohol that is osmotic
  • This accumulation causes osmotic damage to these tissues

Recurrent Neisseria Bacteremia

  • Deficiency in terminal complement components (C5-C9)
  • This leads to failure of the membrane attack complex (MAC) formation
  • MAC is required for lysis of bacteria

Hereditary Angioedema

  • Deficiency in C1 esterase inhibitor
  • This inhibitor prevents the uncontrolled activation of the kallikrein-kinin system
  • Results in unregulated activation of kallikrein and the release of bradykinin
  • Bradykinin is a potent vasodilator that causes edema

Paroxysmal Nocturnal Hemoglobinuria

  • Mutation in the PIGA gene
  • This gene is required for the formation of glycosylphosphatidylinositol (GPI) anchors
  • GPI anchors are necessary for complement inhibitors (DAF/CD55, MIRL/CD59) to attach to red blood cells
  • Absence of these inhibitors leads to complement-mediated intravascular hemolysis

Type I Hypersensitivity

  • Immediate reaction: antigen cross-links IgE on mast cells, leading to degranulation and release of histamine and tryptase
  • Late reaction: mast cells secrete chemokines and leukotrienes, attracting eosinophils and causing inflammation and tissue damage

Type II Hypersensitivity

  • Antibodies bind to cell-surface antigens
  • This leads to cell destruction, inflammation, and cellular dysfunction

Type III Hypersensitivity

  • Antigen-antibody complexes activate complement and attract neutrophils

Type IV Hypersensitivity

  • Cell-mediated response
  • No antibodies are involved
  • CD8+ T cells directly kill target cells
  • CD+ T cells release cytokines

Acute Hemolytic Transfusion Reaction

  • Type II hypersensitivity reaction against donor red blood cells
  • Typically due to ABO blood group incompatibility

X-Linked (Bruton) Agammaglobulinemia

  • Defect in the BTK gene
  • This gene encodes a tyrosine kinase critical for B-cell development
  • Results in a lack of B-cell maturation and absent B cells in peripheral blood
  • All immunoglobulin classes are absent

DiGeorge Syndrome

  • 22q11 microdeletion
  • This microdeletion leads to failure of the 3rd and 4th branchial pouches to develop
  • These pouches contribute to the development of the thymus and parathyroid glands

Hyper-IgM Syndrome

  • Defect in CD40L on Th cells
  • This defect prevents class switching of immunoglobulins

Leukocyte Adhesion Deficiency (Type 1)

  • Defect in LFA-1 integrin (CD18)
  • This integrin is essential for leukocyte adhesion and migration
  • Leads to impaired phagocyte migration and chemotaxis

Chédiak-Higashi Syndrome

  • LYST mutation
  • This mutation affects microtubule function
  • Leads to defective phagosome-lysosome fusion

Chronic Granulomatous Disease

  • NADPH oxidase defect
  • This enzyme is responsible for producing reactive oxygen species (ROS) during the respiratory burst in neutrophils
  • Leads to impaired bacterial killing

Candida Infection in Immunodeficiency

  • Candida infections are often seen in patients with impaired T cell or granulocyte function
  • Impaired T cell function leads to local candidiasis
  • Impaired granulocyte function leads to systemic candidiasis

Graft-versus-Host Disease

  • Type IV hypersensitivity reaction
  • Occurs when donor T cells attack host cells
  • This is typically due to HLA mismatch between the donor and recipient

Recurrent Staphylococcus aureus, Serratia, and Burkholderia cepacia Infections in CGD

  • Catalase + organisms can degrade hydrogen peroxide (H2O2)
  • H2O2 is essential for the myeloperoxidase system to produce microbicidal products
  • Patients with chronic granulomatous disease cannot produce H2O2
  • This allows catalase + organisms to survive and cause recurrent infections

Hemolytic Uremic Syndrome

  • Caused by Shiga or Shiga-like toxins
  • These toxins inactivate the 60S ribosomal subunit
  • This leads to inhibition of protein synthesis and cell death
  • Also leads to cytokine release and inflammation

Tetanus

  • Caused by tetanus toxin (tetanospasmin)
  • This toxin blocks the release of inhibitory neurotransmitters (GABA and glycine) from Renshaw cells
  • Leads to uncontrolled muscle contraction

Botulism

  • Caused by botulinum toxin
  • This toxin is a protease that cleaves SNARE proteins
  • SNARE proteins are essential for neurotransmitter release
  • Results in paralysis

Gas Gangrene

  • Caused by Clostridium perfringens
  • This bacteria produces alpha toxin
  • Alpha toxin is a phospholipase/lecithinase that degrades phospholipids in cell membranes
  • Leads to myonecrosis

Toxic Shock Syndrome, Scarlet Fever

  • Both caused by toxins produced by Staphylococcus aureus and Streptococcus pyogenes
  • These toxins bind to the beta region of the T cell receptor (TCR) outside of antigen binding site
  • This activates T cells and promotes the release of pro-inflammatory cytokines like IL-1, IL-2, IFN-gamma, and TNF-alpha

Shock and Disseminated Intravascular Coagulation (DIC) by Gram-Negative Bacteria

  • Gram-negative bacterial lipopolysaccharide (LPS) activates macrophages through TLR4/CD14 complex
  • LPS also activates the complement system
  • This leads to the release of tissue factor, which promotes coagulation

Prosthetic Device Infection by Staphylococcus epidermidis

  • Staphylococcus epidermidis produces biofilms
  • Biofilms are a protective layer of bacteria that can resist antibiotics and host defenses
  • These biofilms can form on prosthetic devices and cause infections

Endocarditis Secondary to Streptococcus sanguinis

  • Streptococcus sanguinis produces dextrans, which bind to fibrin-platelet aggregates
  • These aggregates often form on damaged heart valves
  • Streptococcus sanguinis can then colonize these aggregates and cause endocarditis

Pseudomembranous Colitis Secondary to Clostridium difficile

  • Clostridium difficile produces Toxins A and B
  • These toxins damage enterocytes leading to watery diarrhea
  • This can lead to pseudomembranous colitis

Diphtheria

  • Caused by Corynebacterium diphtheriae
  • This bacterium produces diphtheria toxin
  • Diphtheria toxin inhibits protein synthesis by ADP-ribosylating elongation factor 2 (EF-2)

Virulence of Mycobacterium tuberculosis

  • Cord factor activates macrophages and promotes granuloma formation
  • It also induces the release of TNF-alpha
  • Sulfatides on the bacterial surface inhibit phagolysosomal fusion

Tuberculoid Leprosy

  • Characterized by a Th1 immune response
  • Leads to milder symptoms

No Effective Vaccine for Neisseria gonorrhoeae

  • Neisseria gonorrhoeae exhibits antigenic variation of its pilus proteins
  • This makes it difficult to develop a vaccine that can target a variety of strains

Cystitis and Pyelonephritis by Escherichia coli

  • Escherichia coli expresses fimbriae (P pili), which allow the bacteria to attach to the urinary tract

Pneumonia and Neonatal Meningitis by Escherichia coli

  • Escherichia coli expresses a K capsule, which helps the bacteria evade the host's immune system

Chlamydiae Resistance to Beta-Lactam Antibiotics

  • Chlamydiae lack classic peptidoglycan
  • This is because they have reduced muramic acid content
  • This makes them resistant to beta-lactam antibiotics, which target peptidoglycan synthesis

Influenza Pandemics

  • Caused by RNA segment reassortment
  • This leads to antigenic shift
  • Reassortment occurs when two different influenza viruses infect the same cell
  • The resulting virus may have a new combination of genes, leading to a new pandemic strain

Influenza Epidemics

  • Caused by mutations in the hemagglutinin and neuraminidase genes
  • This leads to antigenic drift
  • These mutations occur gradually over time and cause smaller-scale epidemics

CNS Invasion by Rabies Virus

  • Rabies binds to acetylcholine receptors (AChRs)
  • It then travels retrogradely to the central nervous system
  • It does this by using the motor protein dynein

HIV Infection

  • HIV binds to CD4 receptors on macrophages
  • It also binds to CCR5 on macrophages (early infection) or CXCR4 on T cells (late infection)
  • Binding of HIV to these receptors allows the virus to enter and infect these cells

Granuloma Formation

  • Macrophages present antigens to CD4+ T cells
  • This leads to secretion of IL-12 by macrophages
  • This stimulates the differentiation of CD4+ T cells into Th1 cells
  • Th1 cells secrete interferon-gamma (IFN-gamma), which activates macrophages
  • Macrophages then form granulomas to contain the infection

Limitless Replicative Potential of Cancer Cells

  • Cancer cells reactivate telomerase
  • This allows them to maintain and lengthen their telomeres
  • Telomeres are protective caps at the ends of chromosomes
  • They prevent chromosome shortening and aging
  • The reactivation of telomerase allows cancer cells to divide indefinitely

Tissue Invasion by Cancer Cells

  • Cancer cells downregulate E-cadherin function
  • This disrupts intercellular junctions
  • This allows cancer cells to move away from the primary tumor
  • Cancer cells also secrete metalloproteinases
  • These enzymes degrade the basement membrane and extracellular matrix proteins
  • This allows cancer cells to invade surrounding tissues and metastasize

Persistent Truncus Arteriosus

  • Failure of the aorticopulmonary septum to form
  • This results in a single great artery that arises from the heart

D-Transposition of the Great Arteries

  • Failure of the aorticopulmonary septum to spiral
  • This results in the aorta arising from the right ventricle and the pulmonary artery arising from the left ventricle

Tet Spells in Tetralogy of Fallot

  • Tetralogy of Fallot is a heart defect that includes a ventricular septal defect (VSD), pulmonary stenosis, overriding aorta, and right ventricular hypertrophy
  • Crying, fever, or exercise can worsen the pulmonary stenosis
  • This leads to right-to-left shunting across the VSD
  • Squatting increases systemic vascular resistance (SVR)
  • This decreases right-to-left shunting and improves cyanosis

Eisenmenger Syndrome

  • Uncorrected left-to-right shunting
  • This leads to increased pulmonary blood flow
  • This causes remodeling of the pulmonary vasculature, resulting in pulmonary hypertension
  • Pulmonary hypertension leads to right ventricular hypertrophy (RVH)
  • This causes a reversal of the shunt, leading to right-to-left shunting and cyanosis

Atherosclerosis

  • Begins with endothelial cell dysfunction
  • This leads to accumulation of macrophages and LDL in the arterial wall
  • Macrophages engulf LDL, resulting in foam cell formation
  • This causes fatty streaks
  • Smooth muscle cell migration and extracellular matrix deposition leads to fibrous plaque formation
  • This ultimately leads to complex atheromas

Thoracic Aortic Aneurysm

  • Caused by cystic medial degeneration
  • This is a weakening of the aortic media
  • This can lead to dilation and aneurysm formation

Myocardial Infarction

  • Caused by a rupture of a coronary artery atherosclerotic plaque
  • This results in acute thrombosis, blocking blood flow to the heart
  • This can lead to myocardial cell death and infarction

Lesch-Nyhan Syndrome

  • Absent HGPRT, leading to de novo purine synthesis and uric acid overproduction

Beta-Thalassemia

  • Mutations at splice sites or promoter sequences, leading to retained introns in mRNA

Lynch Syndrome

  • Failure of mismatch repair during the S phase, resulting in microsatellite instability

I-cell Disease

  • Defect in N-acetylglucosaminyl-1-phosphotransferase, a key enzyme in Golgi-mediated mannose-6-phosphate phosphorylation
  • This results in the failure of lysosomal enzymes to be targeted to lysosomes, leading to the accumulation of cellular debris within lysosomes

Osteogenesis Imperfecta

  • Defect in Type 1 collagen due to an inability to form triple helices
  • Commonly caused by mutations in either COL1A1 or COL1A2 genes

Menkes Disease

  • Defective ATP7A protein, impairing copper absorption and transport
  • This leads to decreased lysyl oxidase activity, resulting in impaired collagen cross-linking

Marfan Syndrome

  • FBN1 mutation on chromosome 15 leads to a defective fibrillin protein
  • Fibrillin normally forms a sheath around elastin, so its deficiency leads to connective tissue abnormalities

Prader-Willi Syndrome

  • Characterized by the silencing of the maternal gene due to uniparental disomy or imprinting.
  • The condition is expressed when the paternal allele is deleted or mutated.

Angelman Syndrome

  • The paternal gene is silenced, leading to mutation, lack of expression, or deletion of the UBE3A gene on the maternal chromosome 15

Cystic Fibrosis

  • Autosomal recessive disease caused by a ΔF508 deletion in the CFTR gene on chromosome 7
  • This deletion impairs the function of the ATP-gated Cl- channel, which is responsible for secreting Cl- in the lungs and GI tract and reabsorbing Cl- in sweat glands

Duchenne Muscular Dystrophy

  • Caused by frameshift mutations in the dystrophin gene, leading to the loss of the anchoring protein dystrophin, which connects the cytoskeleton to the extracellular matrix (ECM)
  • The loss of dystrophin results in myonecrosis, leading to progressive muscle weakness and degeneration.

Myotonic Dystrophy

  • Caused by a CTG trinucleotide repeat expansion in the DMPK gene, leading to abnormal expression of myotonin protein kinase
  • This excess of myotonin protein kinase leads to myotonia, or difficulty relaxing muscles after contraction.

Fragile X Syndrome

  • Caused by a CGG trinucleotide repeat expansion in the FMR1 gene, leading to hypermethylation and silencing of the gene
  • Silencing of the FMR1 gene leads to impaired synthesis of the FMR1 protein, which is essential for normal brain development

Bitot Spots in Vitamin A Deficiency

  • Vitamin A deficiency impairs the differentiation of epithelial cells into specialized tissues, leading to squamous metaplasia
  • Bitot spots are accumulations of keratin in the conjunctiva of the eye, a sign of vitamin A deficiency

Wernicke Encephalopathy in Alcoholic Patients Given Glucose

  • Thiamine deficiency results in impaired glucose breakdown, leading to ATP depletion
  • Glucose infusion worsens this ATP depletion by increasing the demand for glucose metabolism without the necessary thiamine coenzyme

Pellagra in Malignant Carcinoid Syndrome

  • Tryptophan is diverted towards serotonin synthesis by the tumor, leading to a deficiency of B3, which is derived from tryptophan
  • Pellagra is the clinical manifestation of niacin (B3) deficiency, characterized by diarrhea, dermatitis, and dementia

Kwashiorkor

  • Protein malnutrition leads to decreased oncotic pressure, resulting in edema
  • It also impairs apolipoprotein synthesis, contributing to liver fatty change

Lactic Acidosis, Fasting Hypoglycemia, and Hepatic Steatosis in Alcoholism

  • Ethanol metabolism leads to an increased NADH/NAD+ ratio, impairing gluconeogenesis and leading to lactic acidosis, fasting hypoglycemia, and hepatic steatosis

Aspirin-Induced Hyperthermia

  • Aspirin increases the permeability of the mitochondrial membrane, disrupting the proton gradient and uncoupling oxidative phosphorylation
  • This leads to decreased oxygen consumption and increased heat production, resulting in hyperthermia

Hereditary Fructose Intolerance

  • Aldolase B deficiency leads to the accumulation of fructose-1-phosphate
  • Fructose-1-phosphate depletes available phosphate, inhibiting glycogenolysis and gluconeogenesis, leading to hypoglycemia and liver damage

Classic Galactosemia

  • Galactose-1-phosphate uridyltransferase deficiency leads to the accumulation of toxic substances, such as galactitol in the eyes
  • Galactitol accumulates due to its inability to be metabolized, leading to osmotic damage to tissues

Cataracts, Retinopathy, and Peripheral Neuropathy in Diabetes Mellitus

  • Lens, retina, and Schwann cells lack sorbitol dehydrogenase, resulting in intracellular sorbitol accumulation
  • Sorbitol accumulates due to an inability to be metabolized, leading to osmotic damage to tissues and contributing to diabetic complications

Recurrent Neisseria Bacteremia

  • Terminal complement deficiencies (C5-C9) result in the failure of membrane attack complex (MAC) formation, leaving individuals susceptible to recurrent Neisseria bacteremia

Hereditary Angioedema

  • C1 esterase inhibitor deficiency leads to unregulated activation of kallikrein, the enzyme that generates bradykinin
  • Bradykinin is a potent vasodilator and increases vascular permeability, leading to angioedema (swelling) particularly in the face, larynx, and gastrointestinal tract

Paroxysmal Nocturnal Hemoglobinuria

  • PIGA gene mutation impairs the synthesis of glycosylphosphatidylinositol (GPI) anchors, which are essential for attaching certain proteins to cell membranes
  • GPI anchors for complement inhibitors (DAF/CD55, MIRL/CD59) are absent, resulting in complement-mediated intravascular hemolysis

Type I Hypersensitivity

  • Immediate reaction (minutes): antigen cross-links IgE on mast cells, triggering degranulation and the release of histamine and tryptase
  • Late reaction (hours): mast cells secrete chemokines (attract eosinophils) and leukotrienes, contributing to inflammation and tissue damage

Type II Hypersensitivity

  • Antibodies bind to cell-surface antigens, leading to direct cellular destruction, inflammation, and cellular dysfunction

Type III Hypersensitivity

  • Antigen-antibody complexes activate complement, attracting neutrophils and leading to tissue damage

Type IV Hypersensitivity

  • T cell-mediated (no antibodies involved): CD8+ cytotoxic T cells directly kill target cells, while CD4+ helper T cells release cytokines leading to inflammation

Acute Hemolytic Transfusion Reaction

  • Type II hypersensitivity reaction against donor red blood cells (usually ABO antigens) resulting in hemolysis and potential transfusion reaction

X-linked (Bruton) Agammaglobulinemia

  • Defect in the BTK gene (tyrosine kinase) impairs B-cell maturation, leading to the absence of B cells in peripheral blood and a deficiency in immunoglobulins of all classes

DiGeorge Syndrome

  • 22q11 microdeletion leads to the failure of the 3rd and 4th pharyngeal pouches to develop, resulting in the absence of thymus and parathyroid glands

Hyper-IgM Syndrome

  • Defective CD40 ligand (CD40L) on T helper (Th) cells leads to a class switching defect, resulting in elevated levels of IgM but deficiencies in other immunoglobulin classes

Leukocyte Adhesion Deficiency (Type 1)

  • LFA-1 integrin (CD18) defect impairs phagocyte migration and chemotaxis, leading to recurrent infections with bacterial and fungal organisms

Chédiak-Higashi Syndrome

  • LYST mutation disrupts microtubule function, resulting in a defective phagocytotic process where phagosomes fail to fuse with lysosomes
  • This leads to impaired killing of engulfed pathogens

Chronic Granulomatous Disease

  • NADPH oxidase deficiency results in a decreased ability of neutrophils to produce reactive oxygen species (ROS) and execute a respiratory burst for killing pathogens

Candida Infection In Immunodeficiency

  • Candida infections are common in individuals with immunodeficiency, particularly involving granulocyte defects (systemic infections) and T cell defects (local infections)

Graft-versus-Host Disease

  • Type IV hypersensitivity reaction: HLA mismatch between donor and recipient leads to donor T cells attacking host cells, causing graft-versus-host disease

Recurrent Staphylococcus aureus, Serratia, and Burkholderia cepacia infections in Chronic Granulomatous Disease

  • Catalase-positive organisms can degrade hydrogen peroxide (H2O2), a key molecule in the killing of bacteria by neutrophils
  • This resistance to oxidative killing contributes to persistence and recurrent infections in patients with Chronic Granulomatous Disease

Hemolytic Uremic Syndrome

  • Shiga/Shiga-like toxins inactivate the 60S ribosome, inducing cytokine release and leading to hemolytic uremic syndrome, a condition characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury

Tetanus

  • The tetanus toxin (tetanospasmin) prevents the release of inhibitory neurotransmitters, GABA and glycine, from Renshaw cells.
  • This disruption of the nervous system leads to muscle spasms, rigidity, and potentially fatal respiratory failure.

Botulism

  • Botulism toxin (protease) cleaves SNARE proteins, which are essential for the release of acetylcholine (ACh) at neuromuscular junctions.
  • This blockade of neurotransmitter release results in flaccid paralysis and respiratory failure.

Gas Gangrene

  • The alpha toxin produced by Clostridium perfringens acts as a phospholipase (lecithinase), degrading phospholipids in cell membranes, leading to myonecrosis, and tissue damage

Toxic Shock Syndrome, Scarlet Fever

  • Toxic shock syndrome toxin-1 (TSST-1) and erythrogenic toxin A (scarlet) bind to the β region of T cell receptors, activating T cells and cytokine release.
  • This activation leads to widespread inflammation and organ dysfunction, characteristic of toxic shock syndrome and scarlet fever

Shock and Disseminated Intravascular Coagulation (DIC) by Gram Negative Bacteria

  • Lipid A of LPS triggers macrophage activation via TLR4/CD14, complement activation, and tissue factor activation.
  • This leads to a cascade of events that result in widespread inflammation, hypotension, and disseminated intravascular coagulation (DIC).

Prosthetic Device Infection by Staphylococcus epidermidis

  • Staphylococcus epidermidis can form biofilms on prosthetic devices, shielding them from host defenses and increasing susceptibility to infection

Endocarditis Secondary to Streptococcus sanguinis

  • Streptococcus sanguinis produces dextrans, which bind to fibrin-platelet aggregates on damaged heart valves, contributing to the development of endocarditis

Pseudomembranous Colitis Secondary to Clostridium difficile

  • Clostridium difficile toxins A and B damage enterocytes, leading to watery diarrhea and pseudomembranous colitis.

Diphtheria

  • Diphtheria toxin inhibits protein synthesis by ADP-ribosylating elongation factor 2 (EF-2)
  • This blockade of protein synthesis leads to cell death and severe symptoms, including respiratory distress and cardiac complications

Virulence of Mycobacterium tuberculosis

  • Cord factor activates macrophages, contributing to granuloma formation and TNF-α release
  • Sulfatides on the surface of Mycobacterium tuberculosis inhibit phagolysosomal fusion, promoting survival within macrophages.

Tuberculoid Leprosy

  • Characterized by a Th1 immune response, leading to milder symptoms of leprosy

No Effective Vaccine for Neisseria gonorrhoeae

  • Neisseria gonorrhoeae exhibits antigenic variation in its pilus proteins, which serve as key adhesion factors, hindering vaccine development

Cystitis and Pyelonephritis by Escherichia coli

  • Escherichia coli possesses fimbriae (P pili) that help adhere to the urinary tract epithelium, contributing to cystitis and pyelonephritis.

Pneumonia and Neonatal Meningitis by Escherichia coli

  • Escherichia coli can produce a capsular polysaccharide (K capsule), which protects the bacteria from phagocytosis and contributes to its virulence in causing pneumonia and neonatal meningitis.

Chlamydiae Resistance to Beta-lactam Antibiotics

  • Chlamydiae lack a classic peptidoglycan due to reduced muramic acid, rendering them resistant to beta-lactam antibiotics.

Influenza Pandemics

  • RNA segment reassortment (antigenic shift) between different strains of influenza viruses leads to the emergence of novel strains with potentially pandemic potential

Influenza Epidemics

  • Mutations in hemagglutinin and neuraminidase (antigenic drift) can generate new influenza strains causing seasonal epidemics

CNS Invasion by Rabies

  • Rabies virus binds to acetylcholine receptors at neuromuscular junctions and then undergoes retrograde transport (dynein) to the central nervous system.

HIV Infection

  • HIV binds to CD4 and CCR5 on macrophages in the early stages and CXCR4 on T cells in the later stages of infection, leading to immune suppression and disease progression.

Granuloma Formation in Tuberculosis

  • Macrophages present antigens to CD4+ T cells and secrete IL-12, driving CD4+ T cell differentiation to Th1 cells.
  • Th1 cells secrete IFN-γ, activating macrophages to contain and control Mycobacterium tuberculosis infection.

Cancer Cell Replicative Potential

  • Reactivation of telomerase prevents chromosome shortening and aging, allowing cancer cells to replicate indefinitely.

Tissue Invasion by Cancer

  • Loss of E-cadherin function disrupts intercellular junctions and allows cancer cells to invade surrounding tissues
  • Degradation of the basement membrane and ECM by metalloproteinases promotes cell attachment to ECM proteins and enhances cell migration, facilitating vascular dissemination.

Persistent Truncus Arteriosus

  • Characterized by the failure of the aorticopulmonary septum to form, resulting in a single great artery that supplies blood to both the pulmonary and systemic circulations

D-Transposition of the Great Arteries

  • Failure of the aorticopulmonary septum to spiral properly , leading to the aorta arising from the right ventricle and the pulmonary artery from the left ventricle

Tet Spells in Tetralogy of Fallot

  • Crying, fever, or exercise can increase right ventricular outflow obstruction, leading to right-to-left shunting across the ventricular septal defect, resulting in cyanosis
  • Squatting increases systemic vascular resistance (SVR), reducing right-to-left shunting and improving oxygen saturation

Eisenmenger Syndrome

  • Uncorrected left-to-right shunts over time lead to pulmonary blood flow overload, resulting in pulmonary hypertension.
  • Pulmonary hypertension leads to right ventricular hypertrophy and eventual right-to-left shunting, causing cyanosis.

Atherosclerosis

  • Endothelial cell dysfunction leads to the accumulation of macrophages and LDL, forming foam cells.
  • Foam cells contribute to fatty streaks, which progress to fibrous plaques and complex atheromas, ultimately narrowing arteries and increasing the risk of cardiovascular events.

Thoracic Aortic Aneurysm

  • Results from cystic medial degeneration, a weakening of the aortic wall due to a loss of elastic fibers and smooth muscle cells

Myocardial Infarction

  • Rupture of a coronary artery atherosclerotic plaque leads to acute thrombosis, occluding blood flow to the myocardium and causing cell death.

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Test your knowledge on various genetic disorders such as Lesch-Nyhan syndrome, β-thalassemia, Lynch syndrome, I-cell disease, and Marfan syndrome. This quiz covers the absent enzymes, genetic mechanisms, and the effects of specific mutations related to these conditions.

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