BIOCHEMSTRY Flashcards
What are the main components of the TCA cycle?
Acetyl CoA
Citrate
Isocitrate
a-Ketoglutarate
Succinyl-CoA
Succinate
Fumarate
Malate
Oxaloacetate
What are the enzymes of the TCA cycle?
Citrate synthase
Aconitase
Isocitrate dehydrogenase
a-Ketoglutarate dehydrogenase
Succinyl-CoA Synthetase
Succinato dehydrogenase
Fumarase
Malate dehydrogenase
What are the products of one turn of the TCA cycle?
3 NADH
1 FADH2
1 GTP (or ATP)
2 CO2
What are the regulatory points of the TCA cycle?
The key regulatory points of the TCA cycle:
* Citrate synthase (Inhibited by ATP)
* Isocitrate dehydrogenase (Inhibited by NADH and ATP)
(Activated by ADP and CA)
* α-ketoglutarate dehydrogenase.
(Inhibited by NADH and Succinyl-CoA)
(Activated by CA)
What are the two major products of the TCA cycle that are used in the electron transport chain?
NADH
FADH2
What are the regulatory roles of citrate beyond TCA cycle?
Inhibit phosphofructokinase-1 (PFK-1) –> Glycolysis
Activate Acetyl-CoA carboxylase –> fatty acid synthesis
How does oxaloacetate function in the TCA cycle during the fasting state?
During fasting, the levels of oxaloacetate in the liver can be reduced due to increased gluconeogenesis, which uses oxaloacetate to produce glucose. This reduction can impact the TCA cycle’s efficiency, potentially leading to a shift in metabolism towards ketogenesis to provide energy.
Which enzyme Arsenic poisoning inhibit?
a-ketoglutarate dehydrogenase
What accumulates in the body due to the deficiency of homogentisate oxidase in alkaptonuria?
Homogentisic acid.
What enzyme is deficient in alkaptonuria?
Homogentisate oxidase
How does alkaptonuria affect the urine?
The urine turns dark upon standing due to the oxidation of homogentisic acid.
What is the inheritance pattern of alkaptonuria?
Autosomal recessive.
What is ochronosis?
A condition where homogentisic acid deposits in connective tissues, causing a blue-black discoloration of tissues, including cartilage and sclera.
What genetic mutation causes alkaptonuria?
Mutations in the HGD gene.
What joint problems are associated with alkaptonuria?
Arthritis, particularly in large joints.
What potential cardiac issue can occur in alkaptonuria?
Aortic stenosis (though less commonly emphasized).
How is alkaptonuria diagnosed?
By detecting elevated levels of homogentisic acid in the urine.
What are the primary management strategies for alkaptonuria?
Symptomatic treatment and potentially reducing intake of tyrosine and phenylalanine.
What is the name of the condition that causes urine to turn black upon standing in contact with air, and what is its underlying cause?
Alkaptonuria.
Deficiency: homogentisate oxidase
Accumulation: homogentisic acid, which darkens the urine when exposed to air.
A patient presents with a history of urine that darkens to a deep brown or black color after being left in a container for a few hours. Additionally, the patient reports persistent joint pain and has noted a bluish-black discoloration in their cartilage and sclera. Laboratory tests reveal elevated levels of homogentisic acid in the urine. Based on these findings, what is the most likely diagnosis?
Alkaptonuria
This test involves isolating a DNA sample and using a DNA polymerase enzyme along with specific primers . The process consists of repeated cycles of heating and cooling . What test is ? What is the purpose of this test?
Polymerase Chain Reaction (PCR)
Purporse: Amplify a target DNA sequence
DNA is first digested with restriction enzymes that cut it into fragments. These fragments are then separated by gel electrophoresis and transferred onto a membrane. A labeled probe that is complementary to a specific DNA sequence is used to bind to the target sequence on the membrane. The bound probe is detected, revealing the presence of the target sequence.
What test is ?
Southern Blotting
RNA is isolated and separated by gel electrophoresis. The separated RNA is then transferred to a membrane, and a labeled probe complementary to a specific RNA sequence is added. This probe binds to the target RNA, and the bound probe is detected, indicating the presence and size of the target RNA. What test is this?
Northern Blotting
Proteins are first separated by gel electrophoresis and then transferred to a membrane. The membrane is incubated with a primary antibody that specifically binds to the target protein. A secondary antibody, which is linked to an enzyme or fluorophore, is then added to bind to the primary antibody. The enzyme or fluorophore produces a detectable signal, indicating the presence of the protein.
Which test is this?
Western Blotting
Antigens or antibodies are immobilized on a microtiter plate. A sample containing the target antigen or antibody is added, and it binds to the immobilized counterpart. An enzyme-linked secondary antibody that binds to the target is then added. A substrate for the enzyme is used to produce a colorimetric or fluorescent signal, which is measured to determine the amount of target present. What test is this?
ELISA (Enzyme-Linked Immunosorbent Assay)
What is the primary mechanism of action of statins?
Statins inhibit HMG-CoA reductase, an enzyme involved in the biosynthesis of cholesterol. This leads to decreased cholesterol levels in the liver and increased uptake of LDL cholesterol from the bloodstream.
Which statin is most commonly used and has a high potency for lowering LDL cholesterol?
Atorvastatin (Lipitor).
What are some common side effects of statins?
Muscle-related issues (myalgia, myopathy, and rhabdomyolysis), liver enzyme elevation, and gastrointestinal symptoms.
What is a serious but rare side effect of statins that involves severe muscle damage?
Rhabdomyolysis, characterized by the breakdown of muscle tissue, which can lead to acute kidney injury.
How do statins affect cardiovascular risk?
Statins reduce the risk of cardiovascular events (such as heart attacks and strokes) by lowering LDL cholesterol levels and stabilizing atherosclerotic plaques.
Which statin is known for having the longest half-life, allowing for flexible dosing?
Rosuvastatin (Crestor).
What should be monitored periodically in patients on statins?
Liver function tests (LFTs) to monitor for liver enzyme elevations and creatine kinase (CK) levels to check for muscle-related side effects.
What drug interactions should be considered when prescribing statins?
Statins can interact with drugs that inhibit CYP3A4 (e.g., certain antibiotics and antifungals), which can increase statin levels and the risk of side effects. Examples include clarithromycin and ketoconazole.
Which statin is considered to have the lowest risk of drug interactions and is less affected by CYP3A4 inhibitors?
Pravastatin.
What lifestyle changes should be recommended in addition to statin therapy to manage hyperlipidemia?
- Diet modification (low saturated fat and cholesterol)
- Regular exercise
- Weight management
- Smoking cessation.
What is the key spirometric finding in COPD?
A reduced FEV1/FVC ratio, typically less than 0.70 (70%).
How does the post-bronchodilator response differ in COPD compared to asthma?
In COPD, the improvement in FEV1 post-bronchodilator is typically less than 12% and 200 mL from baseline.
Define Chronic Obstructive Pulmonary Disease (COPD).
Group of progressive lung diseases characterized by chronic airflow limitation, including chronic bronchitis and emphysema. It is primarily caused by long-term exposure to irritants, such as smoking.
What are the main pathophysiological changes in COPD?
COPD involves chronic inflammation, increased mucus production, and destruction of lung tissue (emphysema), leading to airflow limitation and impaired gas exchange.
Define Asthma.
Asthma is a chronic inflammatory disease of the airways characterized by reversible airflow obstruction, bronchial hyperreactivity, and increased mucus production, leading to wheezing, breathlessness, and cough.
What are the primary risk factors for developing COPD?
Smoking, occupational exposure to dust or chemicals, alpha-1 antitrypsin deficiency, and environmental pollutants.
What are common triggers for asthma exacerbations?
Allergens (e.g., pollen, dust mites), respiratory infections, exercise, cold air, and irritants such as smoke and pollution.
What spirometric changes are indicative of asthma?
A reversible decrease in FEV1/FVC ratio with significant improvement (≥12% and 200 mL increase) after bronchodilator administration.
What is the key spirometric finding in COPD?
A reduced FEV1/FVC ratio (<0.70) indicating persistent airflow limitation.
How is the severity of COPD classified based on FEV1?
Mild: FEV1 ≥ 80% of predicted
Moderate: FEV1 50-79% of predicted
Severe: FEV1 30-49% of predicted
Very Severe: FEV1 < 30% of predicted or FEV1 < 50% with respiratory failure
How is asthma typically diagnosed?
Diagnosis is based on clinical symptoms and spirometry:
* Reversible airflow obstruction (significant response to bronchodilators)
* Peak flow variability.
What are the cornerstone treatments for COPD?
- Corticoesteroid
- Oxygen (advanced cases)
- Pause smoking
- Dialator (Bronchodilators:beta-agonists, anticholinergics)
What are key treatments for managing asthma?
Inhaled corticosteroids
Beta-agonists for acute relief
Leukotriene receptor antagonists
Avoiding triggers.
What is the primary storage site for calcium within the cell?
The endoplasmic reticulum (ER) and mitochondria.
Which cellular mechanisms maintain low cytosolic calcium levels?
Calcium pumps (ATPases) actively transport calcium out of the cytosol into the ER, mitochondria, or extracellular space, and calcium channels regulate its flow across cell membranes.
Name two major causes of increased intracellular calcium.
Ischemia (reduced blood flow) or hypoxia (low oxygen levels) and cellular damage due to toxins or trauma.
What are the three main types of enzymes activated by increased intracellular calcium that cause cell damage?
Proteases, phospholipases, and endonucleases.
How does increased intracellular calcium lead to mitochondrial damage?
It causes the loss of mitochondrial membrane potential, disrupts ATP production, and leads to the release of cytochrome c, triggering apoptosis.
What role does calcium play in oxidative stress?
Elevated calcium can enhance the generation of reactive oxygen species (ROS), causing oxidative damage to lipids, proteins, and DNA.
What are the two main types of cell death caused by increased intracellular calcium?
Necrosis (unregulated cell death) and apoptosis (programmed cell death).
How does increased intracellular calcium contribute to reperfusion injury?
Sudden increases in calcium after restoring blood flow lead to ROS generation and enzyme activation, causing further cell damage.
Which clinical conditions often involve disrupted calcium homeostasis and subsequent cell damage?
Myocardial infarction, stroke, traumatic brain injury, and neurodegenerative diseases.
What is the difference between necrosis and apoptosis in terms of calcium’s role?
In necrosis, unregulated calcium influx causes cell swelling and membrane rupture; in apoptosis, calcium triggers mitochondrial damage and programmed cell death pathways.
What does affinity mean in the context of receptor-ligand interactions?
Affinity refers to the strength with which a ligand (such as a drug or agonist) binds to its receptor. Higher affinity means stronger binding and often lower concentrations needed to achieve an effect.
What is an agonist?
An agonist is a substance that binds to a receptor and activates it to produce a biological response.
What is a G-protein-coupled receptor (GPCR)?
A GPCR is a cell surface receptor that, when activated by an agonist, interacts with G-proteins to trigger intracellular signaling pathways.
How does activation of the 5-HT1B receptor lead to intracellular signaling?
Activation of the 5-HT1B receptor, a GPCR, triggers the exchange of GDP for GTP on the G-protein, initiating downstream signaling cascades.
What does the Km (Michaelis constant) represent in pharmacology?
Km represents the concentration of a ligand needed to achieve half of the maximum receptor activity. A lower Km indicates a higher affinity of the ligand for the receptor.
What is the significance of a lower Km for a drug’s action?
A lower Km means that the drug has a higher affinity for the receptor, requiring a lower concentration to achieve half-maximal activation.
What does Vmax (Maximum Reaction Rate) represent in the context of receptor-ligand interactions?
Vmax is the maximum rate of a reaction when the receptor is fully saturated with a ligand. It reflects the total receptor concentration and the intrinsic activity of the receptor-ligand complex.
Does a higher affinity agonist always result in a higher Vmax?
No, Vmax depends on the total number of receptors and their intrinsic activity, not directly on the ligand’s affinity.
How can understanding Km and Vmax help in clinical pharmacology?
Knowing Km and Vmax helps predict how drugs will behave in the body, determine dosing, understand therapeutic effects, and anticipate potential side effects.
What type of receptor is the 5-HT1B receptor, and what is its physiological role?
The 5-HT1B receptor is a serotonin GPCR involved in neurotransmission, affecting mood, vasoconstriction, and other physiological functions.
What are porphyrias?
Porphyrias are metabolic disorders caused by enzyme deficiencies in the heme biosynthesis pathway, leading to the accumulation of porphyrins or their precursors and resulting in clinical symptoms such as photosensitivity or neurovisceral symptoms.
What are the two main types of porphyrias?
The two main types are:
* Acute porphyrias (neurovisceral symptoms)
* Cutaneous porphyrias (photosensitivity and skin lesions).
What enzyme deficiency causes Acute Intermittent Porphyria (AIP)?
Porphobilinogen deaminase.
What are the clinical features of Acute Intermittent Porphyria (AIP)?
- Severe abdominal pain
- Neuropsychiatric disturbances (e.g., anxiety, depression, psychosis)
- Peripheral neuropathy.
(Patients do not have photosensitivity)
Which laboratory findings are characteristic of Acute Intermittent Porphyria (AIP)?
Increased levels of porphobilinogen and δ-aminolevulinic acid (ALA) in the urine.
What enzyme deficiency causes Porphyria Cutanea Tarda (PCT)?
Uroporphyrinogen decarboxylase.
What are the clinical features of Porphyria Cutanea Tarda (PCT)?
- Photosensitivity
- Blistering skin lesions on sun-exposed areas
- Hyperpigmentation
- Increased skin fragility.
P hotosensitivity
🌞 expousured blistering
R ise of skin fragility
P igmenttation
Which laboratory findings are characteristic of Porphyria Cutanea Tarda (PCT)?
Elevated levels of uroporphyrin in the urine.
What enzyme deficiency causes Hereditary Coproporphyria (HCP)?
Coproporphyrinogen oxidase.
What are common triggers for Porphyria Cutanea Tarda (PCT)?
- Alcohol consumption
- Hepatitis C infection
- Estrogen use
What are the clinical features of Hereditary Coproporphyria (HCP)?
- Neurovisceral symptoms (similar to AIP)
- Cutaneous photosensitivity.
Which laboratory findings are characteristic of Hereditary Coproporphyria (HCP)?
Increased levels of coproporphyrin in urine and feces
What enzyme deficiency causes Erythropoietic Protoporphyria (EPP)?
Ferrochelatase
What are the clinical features of Erythropoietic Protoporphyria (EPP)?
- Photosensitivity with non-blistering
- Painful erythema
- Swelling after sun exposure
Which laboratory findings are characteristic of Erythropoietic Protoporphyria (EPP)?
Elevated levels of protoporphyrin in erythrocytes, plasma, and feces.
How are cutaneous porphyrias managed?
- Avoiding sun exposure
- Using sunscreens
- Hydroxychloroquine or
- Phlebotomy to reduce porphyrin levels
How are acute porphyrias managed?
- Avoiding triggers (e.g., certain drugs, alcohol, fasting)
- Providing glucose to suppress heme synthesis
- Hemin infusions to inhibit ALA synthase.
What is the significance of urine color changes in diagnosing porphyrias?
- Pink/red urine (“tea colored”): PCT (⬆︎uroporphyrin)
- Dark urine (“Port-wine colored”): AIP (⬆︎porphobilinogen)
How does lead poisoning affect heme synthesis?
Inhibits:
* Ferrochelatase
* δ-aminolevulinic acid dehydratase (ALA dehydratase),
⬆︎ ALA and protoporphyrin
= Anemia and Neurological symptoms.
What is the purpose of hemin infusions in acute porphyrias?
Provides a negative feedback mechanism to inhibit ALA synthase.
⬇︎ production of toxic porphyrin precursors.
What distinguishes cutaneous porphyrias from acute porphyrias in terms of clinical presentation?
- Cutaneous porphyrias - photosensitivity and skin lesions.
- Acute porphyrias - neurovisceral symptoms (e.g., abdominal pain, psychiatric symptoms, and neuropathy).
What is the role of genetic testing in the diagnosis of porphyrias?
Genetic testing can confirm specific enzyme deficiencies and help identify asymptomatic carriers or individuals at risk for developing symptoms.
A 32-year-old woman presents to the emergency department with severe abdominal pain, confusion, and weakness in her extremities. Her symptoms started a few days after a crash diet and increased alcohol intake. Physical examination reveals mild tachycardia, but no skin lesions or rashes. Laboratory tests show increased levels of porphobilinogen in her urine. Which of the following enzymes is most likely deficient in this patient?
(A) Uroporphyrinogen decarboxylase
(B) Porphobilinogen deaminase
(C) Coproporphyrinogen oxidase
(D) Ferrochelatase
(E) δ-Aminolevulinic acid synthase
(B) Porphobilinogen deaminase
This deficiency causes Acute Intermittent Porphyria (AIP), characterized by severe abdominal pain, neurological symptoms, and increased porphobilinogen levels without photosensitivity.
A 45-year-old man with a history of hepatitis C infection presents with blistering lesions on his hands and forearms, which appear after sun exposure. He has noticed increased skin fragility and hyperpigmentation over the last several months. His urine is reddish in color and shows increased uroporphyrin levels on spectrophotometric analysis. Which of the following is the most likely diagnosis?
(A) Acute Intermittent Porphyria
(B) Hereditary Coproporphyria
(C) Porphyria Cutanea Tarda
(D) Erythropoietic Protoporphyria
(E) Lead poisoning
(C) Porphyria Cutanea Tarda
Porphyria Cutanea Tarda (PCT) is associated with photosensitivity, blistering skin lesions, and increased uroporphyrin in urine, often triggered by hepatitis C, alcohol, or estrogen.
A 5-year-old boy is brought to the pediatrician by his parents due to recurrent episodes of painful, burning erythema on his face and hands after brief sun exposure. He has no blisters, but his skin becomes red and swollen. Laboratory studies reveal increased protoporphyrin levels in erythrocytes. Which of the following is the most likely underlying enzyme deficiency?
(A) Porphobilinogen deaminase
(B) Uroporphyrinogen decarboxylase
(C) Coproporphyrinogen oxidase
(D) Ferrochelatase
(E) δ-Aminolevulinic acid dehydrase
(D) Ferrochelatase
Deficiency in ferrochelatase causes Erythropoietic Protoporphyria (EPP), presenting with painful erythema and swelling after sun exposure and increased protoporphyrin levels in erythrocytes.
A 28-year-old woman presents with recurrent episodes of severe abdominal pain, anxiety, and muscle weakness. Her symptoms worsen with stress and during her menstrual periods. Her urine darkens when left standing. Laboratory tests show elevated δ-aminolevulinic acid (ALA) and porphobilinogen. Which of the following triggers is most likely to precipitate her condition?
(A) Sun exposure
(B) Phlebotomy
(C) Carbohydrate loading
(D) Barbiturate use
(E) Hydroxychloroquine use
(D) Barbiturate use
Barbiturates can induce cytochrome P450 enzymes, increasing heme demand and triggering acute attacks in Acute Intermittent Porphyria (AIP) patients.
A 40-year-old male presents with fatigue, weight loss, and abdominal pain. Physical examination reveals a pale complexion and mild hepatomegaly. Blood tests show anemia, and his urine has an elevated level of coproporphyrin. A fecal porphyrin analysis also reveals elevated coproporphyrin levels. Which enzyme is most likely deficient in this patient?
(A) Uroporphyrinogen decarboxylase
(B) Porphobilinogen deaminase
(C) Ferrochelatase
(D) Coproporphyrinogen oxidase
(E) δ-Aminolevulinic acid synthase
(D) Coproporphyrinogen oxidase
Deficiency of coproporphyrinogen oxidase causes Hereditary Coproporphyria (HCP), which can present with both abdominal pain and increased levels of coproporphyrin in the urine and feces.
What enzyme converts glucose to sorbitol in the polyol pathway?
Aldose reductase converts glucose to sorbitol in the polyol pathway.
Why is sorbitol accumulation harmful in diabetic patients?
Sorbitol is osmotically active and poorly permeable to cell membranes, leading to
* osmotic stress
* oxidative damage
in tissues, such as the lens of the eye, nerves, and kidneys.
What diabetic complication is associated with sorbitol accumulation in the lens of the eye?
Cataracts are associated with sorbitol accumulation in the lens, leading to lens opacity and vision changes.
How does the polyol pathway contribute to oxidative stress in diabetes?
The polyol pathway depletes NADPH, which is necessary for regenerating reduced glutathione, an important antioxidant. This increases susceptibility to oxidative damage.
What is the role of aldose reductase inhibitors in diabetes management?
Aldose reductase inhibitors aim to reduce sorbitol accumulation and prevent complications like neuropathy and cataracts, but their clinical use is limited.
Which tissues are most affected by sorbitol accumulation due to hyperglycemia?
Tissues with insulin-independent glucose uptake:
* lens of the eye
* nerves
* kidneys
.
What are the four major mechanisms of tissue damage in diabetes?
The four major mechanisms are:
* Polyol pathway flux
* Advanced glycation end products (AGEs) formation
* Protein kinase C (PKC) activation
* Hexosamine pathway flux
What is the significance of protein kinase C (PKC) activation in diabetes?
- Increase vascular permeability
- Promote inflammation
- Enhance the production of extracellular matrix (ECM) proteins
- Reduce nitric oxide (NO) production
Leading to endothelial dysfunction.
Contributes to:
* Retinopathy
* Nephropathy
* Atherosclerosis
How does hyperglycemia affect the hexosamine pathway in diabetes?
- Production of UDP-N-acetylglucosamine (UDP-GlcNAc) that modify proteins involved to signaling, transcription and metabolism
- Impairming insulin signaling
- Altering gene expression involved in inflammation and fibrosis
- Insulin resistance
- Vascular and tissue damage leading to cardiovascular disease and nephropathy
What is the relationship between NADPH depletion and diabetic complications?
Polyol pathway deplet NADPH ⇢ ⬇︎availability of NADPH to regenerate reduced glutathione (GSH) (antioxidant) ⇢ ⬆︎oxidative stress, contributing to complications such as neuropathy and cataracts.
How does the polyol pathway specifically contribute to diabetic neuropathy?
Sorbitol accumulation in nerves:
* osmotic stress
* oxidative stress
Why is cataract formation more common in diabetic patients?
Diabetic patients have elevated blood glucose levels, which increases sorbitol production by aldose reductase in the lens, leading to osmotic stress and lens opacity (cataracts).
What is the role of hexokinase in normal glucose metabolism, and how is it different from aldose reductase?
Hexokinase converts glucose to glucose-6-phosphate in glycolysis; it has a low Km (high affinity for glucose) and functions efficiently at normal glucose levels, whereas aldose reductase is primarily active in hyperglycemic states.
Which pathway becomes more active in hyperglycemia and leads to the formation of fructose from glucose?
The polyol pathway becomes more active, converting glucose to sorbitol (via aldose reductase) and then to fructose (via sorbitol dehydrogenase).
A 58-year-old woman with a 15-year history of poorly controlled type 2 diabetes mellitus presents with blurry vision that has progressively worsened over the past year. She reports difficulty reading and increased glare while driving at night. Fundoscopic examination reveals lens opacities. Which of the following best explains the pathophysiological mechanism behind her symptoms?
(A) Increased production of advanced glycation end products (AGEs) in the lens
(B) Oxidative damage due to elevated sorbitol levels
(C) Retinal microaneurysms and hemorrhages due to microvascular damage
(D) Activation of protein kinase C leading to increased vascular permeability
(E) Increased hexosamine pathway activity causing glycosylation of lens proteins
Answer: (B) Oxidative damage due to elevated sorbitol levels
In diabetic cataracts, hyperglycemia leads to excess glucose conversion to sorbitol by aldose reductase. Sorbitol accumulation causes osmotic and oxidative stress, resulting in lens opacities.
A 46-year-old man with uncontrolled type 1 diabetes mellitus presents to the clinic with numbness and tingling in his feet, particularly noticeable at night. His symptoms have progressively worsened over the past six months. Physical examination reveals decreased sensation to light touch and pinprick in a stocking-glove distribution. Which enzyme’s activity is most directly responsible for this patient’s neurological symptoms?
(A) Sorbitol dehydrogenase
(B) Aldose reductase
(C) Hexokinase
(D) Protein kinase C
(E) Glucose-6-phosphatase
Answer: (B) Aldose reductase
Aldose reductase converts glucose to sorbitol in hyperglycemic states. Sorbitol accumulation in peripheral nerves causes osmotic stress and contributes to diabetic neuropathy, presenting with numbness and tingling.
A 50-year-old male with long-standing poorly controlled diabetes is found to have proteinuria and decreased renal function. His nephrologist suspects diabetic nephropathy. Which of the following mechanisms involving aldose reductase contributes to the development of this patient’s renal complication?
(A) Increased production of advanced glycation end products (AGEs)
(B) Sorbitol accumulation causing osmotic stress in renal cells
(C) Activation of protein kinase C leading to increased glomerular basement membrane thickness
(D) Increased diacylglycerol production stimulating mesangial cell proliferation
(E) Enhanced collagen cross-linking in the glomerulus
Answer: (B) Sorbitol accumulation causing osmotic stress in renal cells
Aldose reductase converts excess glucose to sorbitol in hyperglycemic conditions. Sorbitol accumulates in renal cells, causing osmotic damage and contributing to diabetic nephropathy.
A 65-year-old woman with type 2 diabetes mellitus reports worsening vision and recent cataract surgery in both eyes. She has been on metformin and insulin for several years, but her hemoglobin A1c remains elevated at 9.8%. Which of the following is a potential therapeutic target to prevent further vision complications in this patient?
(A) Inhibition of hexokinase
(B) Inhibition of aldose reductase
(C) Inhibition of insulin-like growth factor (IGF)
(D) Activation of sorbitol dehydrogenase
(E) Stimulation of protein kinase C
Answer: (B) Inhibition of aldose reductase
Aldose reductase inhibitors could prevent further sorbitol accumulation in the lens and reduce the risk of developing cataracts and other microvascular complications in diabetes.
A 72-year-old man with a history of type 2 diabetes presents with new-onset bilateral foot pain, described as burning and tingling. His blood glucose has been poorly controlled, with a recent HbA1c of 10.5%. Which of the following biochemical processes most likely contributes to his symptoms?
(A) Increased oxidative stress from sorbitol accumulation in Schwann cells
(B) Decreased glycolysis in peripheral nerves
(C) Enhanced production of advanced glycation end products in nerve axons
(D) Hyperglycemia-induced activation of hexokinase
(E) Reduced activation of sorbitol dehydrogenase in nerve cells
Answer: (A) Increased oxidative stress from sorbitol accumulation in Schwann cells
Sorbitol accumulation in Schwann cells due to aldose reductase activity causes osmotic and oxidative stress, leading to diabetic peripheral neuropathy.
What is the primary function of the p53 protein?
Transcription factor that regulates the expression of genes involved:
* Cell cycle arrest
* DNA repair
* Apoptosis
Prevent tumor development
Why is p53 often called the “guardian of the genome”?
Prevents the accumulation of mutations
by
* arresting the cell cycle
* promoting DNA repair
* inducing apoptosis
in response to cellular stress.
What type of mutation in the p53 gene is most commonly found in human cancers?
Acquired mutations that lead to loss of function of the p53 protein are the most common mutations in human cancers, occurring in more than 50% of all cases.
What is Li-Fraumeni syndrome?
Autosomal dominant familial cancer syndrome caused by a germline mutation in the p53 gene, resulting in a high risk of multiple cancers at a young age.
What cellular processes are activated by p53 in response to DNA damage?
- Cell cycle arrest (via p21)
- DNA repair (via GADD45)
- Apoptosis (via BAX, PUMA, NOXA)
How does p53 induce cell cycle arrest?
Upregulation of p21⇢ Inhibition of CDK ⇢ Inhibition of phosphorilation of Rb protein ⇢ inhibition of release of E2F
E2F is essential to entering into S phase
What role does MDM2 play in regulating p53?
Controlling p53 levels under normal condition:
MDM2 is an E3 ubiquitin ligase that binds to p53 and targets it for degradation via the ubiquitin-proteasome pathway
What are the consequences of a loss of function mutation in the p53 gene?
- Failure to regulate the cell cycle
- Impaired DNA repair
- Reduced apoptosis
Increased risk of tumor formation due to unchecked cell proliferation.
Which cellular stressors can activate p53?
- DNA damage (e.g., radiation, UV light)
- Oncogene activation (e.g., Ras, Myc)
- Hypoxia
- Telomere shortening
What is loss of heterozygosity (LOH) in the context of p53 mutations?
Loss of heterozygosity (LOH) occurs when one allele of the p53 gene is deleted and the other is mutated, resulting in a complete loss of p53 function in many tumors.
How does p53 contribute to apoptosis?
Upregulating pro-apoptotic genes like BAX, PUMA, and NOXA, which lead to mitochondrial membrane permeabilization and activation of the apoptotic cascade.
.
What is the clinical significance of p53 in cancer diagnosis and prognosis?
- Poor prognosis
- Guide therapeutic decisions, such as the use of specific chemotherapies or targeted therapies.
Which checkpoint does p53 primarily control in the cell cycle?
p53 primarily controls the G1/S checkpoint to prevent the replication of damaged DNA.
What is the role of p53 in preventing the formation of tumors?
p53 prevents tumor formation by ensuring that cells with damaged DNA do not proliferate, either by arresting the cell cycle for repair or by inducing apoptosis if the damage is irreparable.
A 35-year-old woman is diagnosed with breast cancer, and genetic testing reveals a germline mutation in the p53 gene. Her family history is significant for multiple cancers, including brain tumors, sarcomas, and adrenocortical carcinoma in first-degree relatives. Which of the following best explains the role of the p53 protein in preventing tumor formation?
(A) Activation of DNA repair enzymes that directly remove damaged bases
(B) Inhibition of BAX and PUMA to prevent apoptosis of damaged cells
(C) Induction of cell cycle arrest at the G1/S checkpoint to allow DNA repair
(D) Promotion of telomerase activity to prevent cellular senescence
(E) Inhibition of the retinoblastoma (Rb) protein to stop cell proliferation
Answer: (C) Induction of cell cycle arrest at the G1/S checkpoint to allow DNA repair
p53 induces cell cycle arrest at the G1/S checkpoint by upregulating p21, allowing time for DNA repair before replication proceeds. This mechanism prevents the proliferation of damaged cells, reducing the risk of tumor formation.
Question 2: A 45-year-old man is found to have a mutation in one allele of the p53 gene and a deletion in the other allele, leading to a complete loss of p53 function in his tumor cells. Which of the following cellular processes is most likely disrupted as a result of these genetic changes?
(A) Increased synthesis of cyclin D and progression through the G2/M checkpoint
(B) Impaired induction of p21, resulting in uncontrolled progression through the G1/S checkpoint
(C) Enhanced repair of DNA double-strand breaks by homologous recombination
(D) Suppression of MDM2-mediated degradation of p53 protein
(E) Activation of caspases leading to increased apoptosis
Answer: (B) Impaired induction of p21, resulting in uncontrolled progression through the G1/S checkpoint
Loss of p53 function leads to a failure to induce p21, which is critical for inhibiting CDKs and halting cell cycle progression at the G1/S checkpoint. Without p21, cells with damaged DNA continue to divide, contributing to tumorigenesis.
Question 3: A 50-year-old patient with a history of Li-Fraumeni syndrome presents with a new diagnosis of osteosarcoma. Analysis of the tumor cells shows upregulation of MDM2 protein expression. What is the most likely consequence of increased MDM2 levels in this patient’s tumor?
(A) Increased stabilization of p53 and enhanced tumor suppression
(B) Enhanced degradation of p53, leading to reduced transcription of pro-apoptotic genes
(C) Activation of the Bcl-2 pathway and inhibition of apoptosis
(D) Direct inhibition of p21, allowing unchecked cell cycle progression
(E) Increased repair of DNA damage and prevention of cell cycle arrest
Answer: (B) Enhanced degradation of p53, leading to reduced transcription of pro-apoptotic genes
MDM2 is a negative regulator of p53; increased MDM2 expression promotes ubiquitin-mediated degradation of p53, reducing its levels and impairing its ability to activate pro-apoptotic genes.
Question 4: A researcher studying a tumor sample from a patient with colon cancer discovers that one allele of the p53 gene has been deleted, while the other allele has a point mutation that prevents p53 from binding DNA. Which of the following gene products is most likely to be decreased as a direct consequence of this mutation?
(A) MDM2
(B) Bcl-2
(C) p21 (CDKN1A)
(D) Cyclin D1
(E) Cyclin E
Answer: (C) p21 (CDKN1A)
p21 is a direct target of p53 and is crucial for cell cycle arrest in response to DNA damage. A mutation in p53 that prevents it from binding DNA would result in decreased p21 expression.
Question 5: A 60-year-old woman with a history of smoking presents with a lung mass that is found to have a p53 mutation. This mutation prevents the activation of apoptosis in response to DNA damage. Which of the following best describes the mechanism by which p53 normally promotes apoptosis?
(A) Direct activation of caspases in the apoptotic pathway
(B) Upregulation of pro-apoptotic genes like BAX and PUMA, leading to mitochondrial membrane permeabilization
(C) Inhibition of the anti-apoptotic gene Bcl-2 through direct binding
(D) Recruitment of death receptors on the cell membrane to induce extrinsic apoptosis
(E) Activation of telomerase to promote cellular senescence and apoptosis
Answer: (B) Upregulation of pro-apoptotic genes like BAX and PUMA, leading to mitochondrial membrane permeabilization
p53 promotes apoptosis by upregulating pro-apoptotic genes such as BAX and PUMA, which increase mitochondrial membrane permeability, leading to the release of cytochrome c and activation of the intrinsic apoptotic pathway.
Which HLA subtype is associated with ankylosing spondylitis?
HLA-B27
Name the HLA subtypes associated with celiac disease.
HLA-DQ2
HLA-DQ8
What HLA subtype is linked to type 1 diabetes mellitus?
HLA-DR3
HLA-DR4
Which HLA subtype is associated with multiple sclerosis?
HLA-DR2
Which HLA subtype is linked to psoriatic arthritis?
HLA-B27
Which HLA subtype increases the risk for Graves’ disease and Hashimoto’s thyroiditis?
HLA-DR3
What HLA subtype is associated with rheumatoid arthritis?
HLA-DR4
Which HLA subtype is associated with Goodpasture syndrome?
HLA-DR2
What HLA subtype is linked to pernicious anemia?
HLA-DR5
Which HLA subtype is associated with abacavir hypersensitivity in HIV patients?
HLA-B57
Which HLA subtype is associated with hemochromatosis?
HLA-A3
Which HLA subtype is associated with systemic lupus erythematosus (SLE)?
HLA-DR2
HLA-DR3
Which HLA subtype is linked to reactive arthritis (Reiter syndrome)?
HLA-B27
What HLA subtype is associated with primary biliary cholangitis?
HLA-DR3
Which HLA subtype is associated with carbamazepine-induced Stevens-Johnson syndrome?
HLA-B15
Which HLA subtype is associated with allopurinol hypersensitivity?
HLA-B58
What HLA subtype is associated with myasthenia gravis?
HLA-DR3
What is the primary mechanism of vancomycin resistance in Enterococcus faecium?
Resistance is due to the modification of the peptidoglycan precursor from D-Ala-D-Ala to D-Ala-D-Lac or D-Ala-D-Ser, reducing vancomycin binding.
Which genes are responsible for vancomycin resistance in Enterococcus species?
The van genes (e.g., vanA, vanB) encode proteins that alter the terminal amino acids in the cell wall precursors.
What is the role of vancomycin in bacterial cell wall synthesis?
Vancomycin binds to the D-Ala-D-Ala terminus of peptidoglycan precursors, preventing their incorporation into the cell wall and inhibiting cell wall synthesis.
How do β-lactamases confer antibiotic resistance?
β-lactamases hydrolyze the β-lactam ring of penicillins, cephalosporins, and other β-lactam antibiotics, rendering them inactive.
What mechanism of resistance is associated with fluoroquinolones?
Mutations in DNA gyrase or topoisomerase IV, reducing drug binding to these enzymes.
How do efflux pumps contribute to antibiotic resistance?
Efflux pumps actively transport antibiotics out of bacterial cells, decreasing intracellular drug concentration and efficacy.
Which mechanism allows bacteria to resist macrolides like erythromycin?
Methylation of 23S rRNA at the ribosome binding site prevents macrolides from binding effectively to the bacterial ribosome.
How do mutations in penicillin-binding proteins (PBPs) cause resistance?
Reduce their affinity for β-lactam antibiotics, as seen in methicillin-resistant Staphylococcus aureus (MRSA).
What is a key treatment option for vancomycin-resistant Enterococcus (VRE) infections?
Linezolid
Daptomycin
Tigecycline
Quinupristin/dalfopristin.
What role does genetic material (plasmids and transposons) play in antibiotic resistance?
Plasmids and transposons often carry resistance genes (e.g., van genes) that can be transferred between bacteria, spreading resistance.
What clinical setting is associated with a high risk of VRE infections?
Hospitalized patients, especially those with prolonged antibiotic use, are at high risk for VRE infections.
What infection control measures help prevent the spread of VRE in healthcare settings?
- Hand hygiene
- Contact precautions
- Antibiotic stewardship
Why is porin mutation an important resistance mechanism for some Gram-negative bacteria?
Porin mutations decrease the permeability of the bacterial outer membrane, reducing antibiotic uptake.
What is the primary effect of vancomycin resistance on bacterial cell wall synthesis?
Vancomycin resistance leads to continued peptidoglycan synthesis despite the presence of the antibiotic, maintaining cell wall integrity.
Why is it important to understand different mechanisms of antibiotic resistance?
- Selecting appropriate antibiotics
- Managing resistant infections effectively.
Question 1: A 72-year-old woman is admitted to the intensive care unit with sepsis secondary to a urinary tract infection caused by Enterococcus faecium. She is started on vancomycin, but her condition does not improve. Further testing confirms that the isolate is vancomycin-resistant. Which genetic alteration is most likely responsible for this resistance?
(A) Point mutation in the bacterial DNA gyrase gene
(B) Substitution of D-alanine with D-lactate in the peptidoglycan precursor
(C) Overproduction of efflux pumps
(D) Methylation of 23S ribosomal RNA
(E) Mutations in the penicillin-binding protein (PBP) gene
Answer: (B) Substitution of D-alanine with D-lactate in the peptidoglycan precursor
Vancomycin-resistant Enterococcus (VRE) resists vancomycin by substituting D-alanine with D-lactate or D-serine in its peptidoglycan precursor, which prevents vancomycin from binding effectively to the target
Question 2: A 58-year-old man develops hospital-acquired pneumonia after a long stay in the intensive care unit. The causative agent is identified as methicillin-resistant Staphylococcus aureus (MRSA). Which of the following resistance mechanisms does MRSA primarily use to resist the action of β-lactam antibiotics?
(A) Production of β-lactamase enzymes
(B) Methylation of the 23S ribosomal RNA
(C) Alteration of porin channels in the bacterial outer membrane
(D) Overexpression of efflux pumps
(E) Mutation in penicillin-binding proteins (PBPs)
Answer: (E) Mutation in penicillin-binding proteins (PBPs)
MRSA resists β-lactam antibiotics primarily through a mutation in the penicillin-binding proteins (PBPs), particularly PBP2a, which has a low affinity for β-lactams.
Question 3: A 67-year-old patient has been receiving broad-spectrum antibiotics for a prolonged period due to recurrent infections. He now presents with a new urinary tract infection, and cultures grow Enterococcus faecium resistant to vancomycin. Which gene is most likely responsible for this resistance mechanism?
(A) mecA gene
(B) vanA gene
(C) blaZ gene
(D) tetM gene
(E) gyrA gene
Answer: (B) vanA gene
The vanA gene is responsible for vancomycin resistance in Enterococcus faecium by encoding enzymes that alter the terminal D-Ala-D-Ala to D-Ala-D-Lac.
Question 4: A 45-year-old woman presents with severe cellulitis, and a tissue biopsy reveals an infection with vancomycin-resistant Enterococcus faecium (VRE). She is started on daptomycin. Which of the following best explains why daptomycin is effective in treating VRE infections?
(A) Daptomycin inhibits DNA synthesis by binding to DNA gyrase.
(B) Daptomycin depolarizes the bacterial cell membrane, causing rapid cell death.
(C) Daptomycin prevents protein synthesis by binding to the 50S ribosomal subunit.
(D) Daptomycin binds to and inhibits bacterial RNA polymerase.
(E) Daptomycin disrupts folate synthesis by inhibiting dihydropteroate synthase.
Answer: (B) Daptomycin depolarizes the bacterial cell membrane, causing rapid cell death.
Daptomycin works by binding to bacterial cell membranes and causing depolarization, which leads to the loss of membrane potential and cell death.
Question 5: A 60-year-old man with a history of cirrhosis develops spontaneous bacterial peritonitis. Cultures from ascitic fluid grow Enterococcus faecium resistant to vancomycin. Which of the following changes in the bacterial cell wall is most likely responsible for this resistance?
(A) Substitution of D-alanine with D-glutamate
(B) Substitution of D-alanine with D-serine or D-lactate
(C) Methylation of peptidoglycan precursors
(D) Increased synthesis of N-acetylmuramic acid
(E) Cross-linking of glycine residues in peptidoglycan
Answer: (B) Substitution of D-alanine with D-serine or D-lactate
VRE achieves resistance to vancomycin by substituting the terminal D-alanine in its peptidoglycan precursors with either D-serine or D-lactate, reducing vancomycin binding affinity.
What is Kartagener Syndrome?
A subtype of Primary Ciliary Dyskinesia (PCD) characterized by the triad of recurrent sinusitis, bronchiectasis, and situs inversus (e.g., dextrocardia).
What is the main cause of Primary Ciliary Dyskinesia (PCD)?
Genetic mutations that result in defective ciliary structure or function, leading to impaired mucociliary clearance.
Which genes are commonly mutated in PCD?
DNAI1 and DNAH5, which encode proteins crucial for ciliary function.
What are the classic clinical features of Kartagener Syndrome?
The triad of recurrent sinusitis, bronchiectasis, and situs inversus totalis (mirror image reversal of thoracic and abdominal organs).
Why does Kartagener Syndrome cause infertility?
Infertility in males is due to immotile or dysfunctional sperm (defective flagella). In females, impaired ciliary function in the fallopian tubes can reduce fertility or cause ectopic pregnancies.
What diagnostic tests are used to confirm Primary Ciliary Dyskinesia (PCD)?
- Nasal nitric oxide test (low levels)
- High-speed video microscopy (abnormal ciliary beat)
- Genetic testing
- Electron microscopy (revealing ciliary defects).
How does situs inversus manifest in Kartagener Syndrome?
Situs inversus refers to the mirror-image reversal of internal organs, such as the heart on the right side (dextrocardia) and abdominal organs reversed.
What is the main treatment strategy for Kartagener Syndrome?
- Airway clearance techniques (e.g., chest physiotherapy)
- Antibiotics for infections
- Supportive care (e.g., bronchodilators, management of hearing loss).
What are potential complications of Kartagener Syndrome?
- Chronic respiratory issues such as bronchiectasis
- Hearing loss from recurrent otitis media
- Potential fertility problems.
What is the role of cilia in the body, and how is it affected in PCD?
Cilia are hair-like structures that move mucus and fluids; in PCD, ciliary dysfunction leads to poor mucus clearance and recurrent infections.
Why do patients with PCD often have recurrent respiratory infections?
Defective ciliary function impairs mucociliary clearance, leading to mucus stasis and recurrent infections like sinusitis and bronchitis.
A 5-year-old boy presents with chronic cough, recurrent episodes of pneumonia, and otitis media. Physical examination reveals decreased breath sounds in the right lower lung field and crackles on auscultation. Imaging shows bronchiectasis, and an abdominal ultrasound reveals situs inversus. Which of the following is the most likely underlying cause of this patient’s condition?
(A) Defective chloride transport in epithelial cells
(B) Ciliary dysfunction due to dynein arm defects
(C) IgA deficiency
(D) Deficiency of the CFTR gene product
(E) Alpha-1 antitrypsin deficiency
Answer: (B) Ciliary dysfunction due to dynein arm defects
The patient’s symptoms (chronic cough, recurrent pneumonia, otitis media, bronchiectasis, and situs inversus) suggest Kartagener Syndrome, a subtype of Primary Ciliary Dyskinesia (PCD) caused by dynein arm defects.
A 25-year-old man with a history of recurrent sinusitis, chronic productive cough, and situs inversus totalis presents to the fertility clinic due to difficulty conceiving with his partner. A semen analysis shows a significantly reduced sperm motility. Which of the following is the most likely explanation for his findings?
(A) Genetic mutations leading to defective sperm head formation
(B) Defective chloride transport resulting in thickened secretions
(C) Absent or dysfunctional dynein arms in the sperm flagella
(D) Autoimmune destruction of spermatogenic cells
(E) Decreased testosterone production by Leydig cells
Answer: (C) Absent or dysfunctional dynein arms in the sperm flagella
Infertility in males with Kartagener Syndrome is due to defective ciliary function in the sperm flagella, leading to reduced sperm motility
A 12-year-old girl with recurrent upper respiratory tract infections, chronic sinusitis, and frequent episodes of otitis media is suspected of having primary ciliary dyskinesia (PCD). Which of the following diagnostic tests is most likely to confirm the diagnosis?
(A) Sweat chloride test
(B) Measurement of nasal nitric oxide levels
(C) Spirometry to assess lung function
(D) Serum immunoglobulin levels
(E) Erythrocyte sedimentation rate (ESR)
Answer: (B) Measurement of nasal nitric oxide levels
Low nasal nitric oxide levels are characteristic of PCD and are used as a diagnostic test to support the diagnosis.
A 4-year-old boy is brought to the clinic for evaluation of recurrent bronchitis and sinusitis since birth. Physical examination reveals dextrocardia. Given the suspected diagnosis, which of the following findings would most likely also be present?
(A) Elevated sweat chloride levels
(B) Presence of Kartagener Syndrome triad
(C) Elevated IgE levels and eosinophilia
(D) Positive tuberculin skin test
(E) Absence of beta-lactamase production
Answer: (B) Presence of Kartagener Syndrome triad
The patient’s presentation suggests Kartagener Syndrome, which includes the triad of recurrent sinusitis, bronchiectasis, and situs inversus.
A 30-year-old woman presents with a history of chronic cough, recurrent pneumonia, and difficulty becoming pregnant. Physical examination reveals crackles in the lung bases and situs inversus. What is the most likely underlying cause of her infertility?
(A) Blockage of fallopian tubes due to thick mucus secretions
(B) Defective ciliary motility in the fallopian tubes
(C) Autoimmune oophoritis leading to ovarian failure
(D) Polycystic ovarian syndrome with anovulation
(E) Cervical stenosis due to chronic infections
Answer: (B) Defective ciliary motility in the fallopian tubes
Infertility in females with Kartagener Syndrome is typically due to defective ciliary motility in the fallopian tubes, which affects the transport of the ovum.
What is the most common urea cycle disorder?
Ornithine Transcarbamylase (OTC) Deficiency.
How is OTC deficiency inherited?
X-linked recessive.
What enzyme is deficient in OTC deficiency, and what reaction does it catalyze?
Ornithine Transcarbamylase (OTC) catalyzes the conversion of carbamoyl phosphate and ornithine to citrulline in the urea cycle.
What are the characteristic laboratory findings in OTC deficiency?
- Elevated plasma ammonia
- Low blood urea nitrogen (BUN)
- Elevated orotic acid in urine
- Low or absent plasma citrulline.
Why is orotic acid elevated in OTC deficiency?
Due to excess carbamoyl phosphate being diverted into the pyrimidine synthesis pathway, leading to increased orotic acid production.
What are the main clinical features of OTC deficiency in neonates?
- Poor feeding
- Vomiting
- Lethargy
- Hypotonia (decreased muscle tone)
- Seizures
- Hyperammonemic encephalopathy.
What is the primary acute management strategy for hyperammonemia in OTC deficiency?
- Hemodialysis to rapidly reduce ammonia levels
- Ammonia scavenger drugs (e.g., sodium phenylacetate, sodium benzoate)
- Intravenous glucose and lipids to prevent catabolism.
What are the key components of long-term management in OTC deficiency?
- Low-protein diet
- Ammonia scavenger medications (e.g., sodium phenylbutyrate)
- Essential amino acid supplementation
- Consideration of liver transplantation in severe cases.
Which laboratory test differentiates OTC deficiency from other urea cycle disorders?
- Elevated orotic acid in urine
- Low or absent citrulline in plasma
Why is blood urea nitrogen (BUN) low in OTC deficiency?
Because urea synthesis is impaired due to the enzyme defect in the urea cycle.
What triggers the symptoms of late-onset OTC deficiency?
- High protein intake
- Illness
- Fasting
What is a mnemonic to remember the key features of OTC deficiency?
“OTC: Out of The Citrulline”
O: Orotic aciduria (elevated orotic acid in urine)
T: Toxic Ammonia (hyperammonemia)
C: Citrulline Low (low or absent plasma citrulline)
What is the role of L-arginine in managing OTC deficiency?
L-arginine provides substrates to enhance residual urea cycle function and helps promote the excretion of nitrogen.
Why is OTC deficiency more common in males?
Because it is an X-linked recessive disorder, and males have only one X chromosome, making them more likely to express the disease.
What is the primary biochemical hallmark of urea cycle disorders like OTC deficiency?
Hyperammonemia due to impaired conversion of ammonia to urea.
A 3-day-old male infant presents with lethargy, poor feeding, and vomiting. He has had a tonic-clonic seizure at home. Physical examination reveals jaundice, hypotonia, and tachypnea. Laboratory tests show plasma ammonia of 300 μmol/L (normal: 10-40 μmol/L), a blood urea nitrogen (BUN) of 1.5 mg/dL, and elevated orotic acid in the urine. Which of the following is the most likely diagnosis?
(A) Maple syrup urine disease
(B) Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
(C) Phenylketonuria (PKU)
(D) Ornithine transcarbamylase (OTC) deficiency
(E) Hereditary fructose intolerance
Answer: (D) Ornithine transcarbamylase (OTC) deficiency
The infant presents with symptoms of hyperammonemia, poor feeding, seizures, and elevated orotic acid, which is characteristic of OTC deficiency, a urea cycle disorder.
A 5-day-old male neonate presents with irritability, poor feeding, and a tonic-clonic seizure. The child is found to have hyperammonemia and elevated orotic acid levels in the urine. Which of the following findings would most likely be present in a genetic analysis of this patient?
(A) Autosomal recessive mutation in the PAH gene
(B) X-linked recessive mutation in the OTC gene
(C) Autosomal recessive mutation in the GALT gene
(D) Autosomal dominant mutation in the LDLR gene
(E) Mitochondrial inheritance mutation in the MTND1 gene
Answer: (B) X-linked recessive mutation in the OTC gene
OTC deficiency is inherited in an X-linked recessive pattern, making this the most likely genetic finding in a patient with hyperammonemia and elevated orotic acid.
