A 10-year-old boy is brought into your clinic by his mother for sunburns that have not been healing. The mother states that he easily gets sunburned. The mother admits she gave birth to him at home and has never taken him to see a doctor. The patient walks with a wide stance gait and appears unstable on his feet. He has an extensive erythematous, scaling, hyperkeratotic rash on his face, neck, arms and legs. After extensive workup, the patient is found to have a genetic disorder that results in defective absorption of an important vitamin. Which of the following is likely to be low if measured?
Q212
An investigator is studying severely ill patients who experience hypoglycemia and ketonuria during times of fasting. The investigator determines that during these episodes, amino acids liberated from muscle proteins are metabolized to serve as substrates for gluconeogenesis. Nitrogen from this process is transported to the liver primarily in the form of which of the following molecules?
Q213
A 4-year-old boy is brought to the physician because of a rash and difficulty swallowing. His family emigrated from Nigeria 2 months ago. Examination shows an erythematous rash with fine yellow scales on his eyebrows and nasolabial folds. Oral examination shows an erythematous throat and swollen tongue. There is peeling and fissures of the skin at the corners of the mouth and cracking of the lips. His hemoglobin concentration is 9.6 g/dL; mean corpuscular volume is 89 μm3. Erythrocyte glutathione reductase assay shows an increased activity coefficient. This patient is most likely deficient in a vitamin that is a precursor to which of the following molecules?
Q214
An 18-month-old boy is brought in to the pediatrician by his mother for concerns that her child is becoming more and more yellow over the past two days. She additionally states that the boy has been getting over a stomach flu and has not been able to keep down any food. The boy does not have a history of neonatal jaundice. On exam, the patient appears slightly sluggish and jaundiced with icteric sclera. His temperature is 99.0°F (37.2°C), blood pressure is 88/56 mmHg, pulse is 110/min, and respirations are 22/min. His labs demonstrate an unconjugated hyperbilirubinemia of 16 mg/dL. It is determined that the best course of treatment for this patient is phenobarbital to increase liver enzyme synthesis. Which of the following best describes the molecular defect in this patient?
Q215
In a lab experiment, a researcher treats early cells of the erythrocyte lineage with a novel compound called Pb82. Pb82 blocks the first step of heme synthesis. However, the experiment is controlled such that the cells otherwise continue to develop into erythrocytes. At the end of the experiment, the cells have developed into normal erythrocytes except that they are devoid of heme. A second compound, anti-Pb82 is administered which removes the effect of Pb82.
Which of the following is likely to be true of the mature red blood cells in this study?
Q216
An investigator is studying nutritional deficiencies in humans. A group of healthy volunteers are started on a diet deficient in pantothenic acid. After 4 weeks, several of the volunteers develop irritability, abdominal cramps, and burning paresthesias of their feet. These symptoms are fully reversed after reintroduction of pantothenic acid to their diet. The function of which of the following enzymes was most likely impaired in the volunteers during the study?
Q217
A 54-year-old man comes to the physician because of generalized fatigue and numbness of his legs and toes for 5 months. He has hypertension and hypercholesterolemia. He underwent a partial gastrectomy for peptic ulcer disease 15 years ago. Current medications include amlodipine and atorvastatin. He is a painter. His temperature is 37°C (98.6°F), pulse is 101/min, respirations are 17/min, and blood pressure is 122/82 mm Hg. Examination shows conjunctival pallor and glossitis. Sensation to vibration and position is absent over the lower extremities. He has a broad-based gait. The patient sways when he stands with his feet together and closes his eyes. His hemoglobin concentration is 10.1 g/dL, leukocyte count is 4300/mm3, and platelet count is 110,000/mm3. Which of the following laboratory findings is most likely to be seen in this patient?
Q218
The balance between glycolysis and gluconeogenesis is regulated at several steps, and accumulation of one or more products/chemicals can either promote or inhibit one or more enzymes in either pathway. Which of the following molecules if increased in concentration can promote gluconeogenesis?
Q219
A 3-month-old boy presents for routine health maintenance. The patient has coarse facial features and stiff joint movements with restricted passive and active range of motion. He also has problems following objects with his eyes and seems not to focus on anything. On physical examination, the corneas are clouded, and the patient fails to meet any 3-month developmental milestones. Genetic testing and histopathology are performed and reveal failure of a cellular structure to phosphorylate mannose residues on glycoproteins. An electron microscopy image of one of this patient’s cells is shown. Which of the following is the most likely diagnosis in this patient?
Q220
A 6-day-old infant who was born via uncomplicated vaginal delivery at 39 weeks of gestation is brought to the family physician for poor feeding. The mother received adequate prenatal care throughout the pregnancy, and has no medical conditions. On physical exam, the infant's temperature is 36.5°C (97.7°F), blood pressure is 70/45 mmHg, pulse is 170/min, and respirations are 40/min. The infant has dry mucous membranes, capillary refill of 4 seconds, and a depressed anterior fontanelle. No abdominal masses are noted. Genital exam shows enlargement of the clitoris with fusion of the labioscrotal folds. Serum chemistry is remarkable for hyponatremia and hyperkalemia. The infant's karyotype is 46,XX. Which of the following findings are most likely to be discovered upon further workup?
Metabolism US Medical PG Practice Questions and MCQs
Question 211: A 10-year-old boy is brought into your clinic by his mother for sunburns that have not been healing. The mother states that he easily gets sunburned. The mother admits she gave birth to him at home and has never taken him to see a doctor. The patient walks with a wide stance gait and appears unstable on his feet. He has an extensive erythematous, scaling, hyperkeratotic rash on his face, neck, arms and legs. After extensive workup, the patient is found to have a genetic disorder that results in defective absorption of an important vitamin. Which of the following is likely to be low if measured?
A. Vitamin K
B. Niacin (Correct Answer)
C. Folate
D. Vitamin A
E. Vitamin B12
Explanation: ***Niacin***
- The constellation of **sunburns that don't heal**, a **wide-stanced unstable gait**, and an **erythematous, scaling, hyperkeratotic rash** (consistent with dermatitis) strongly suggests **pellagra**.
- Pellagra is caused by a deficiency of **niacin (Vitamin B3)**, which is characterized by the "3 Ds": **dermatitis**, **diarrhea**, and **dementia (or neurological symptoms like ataxia)**.
*Vitamin K*
- Deficiency typically leads to **bleeding disorders** due to impaired coagulation, which is not indicated by the patient's symptoms.
- While newborns often receive a **vitamin K shot**, his current symptoms are unrelated to its deficiency.
*Folate*
- Folate deficiency primarily causes **megaloblastic anemia** and can lead to **neural tube defects** in developing fetuses.
- It does not explain the characteristic dermatological and neurological symptoms described.
*Vitamin A*
- Vitamin A deficiency is known to cause **night blindness** and **xerophthalmia** (dry eyes), and impaired immune function.
- While it plays a role in skin health, the specific rash and gait abnormalities point away from primary vitamin A deficiency.
*Vitamin B12*
- Deficiency leads to **megaloblastic anemia** with **neurological symptoms** such as peripheral neuropathy, but the dermatological manifestations (scaling, hyperkeratotic rash) and unhealing sunburn are not typical.
- The gait could be linked to neurological symptoms, but the overall presentation is better explained by niacin deficiency.
Question 212: An investigator is studying severely ill patients who experience hypoglycemia and ketonuria during times of fasting. The investigator determines that during these episodes, amino acids liberated from muscle proteins are metabolized to serve as substrates for gluconeogenesis. Nitrogen from this process is transported to the liver primarily in the form of which of the following molecules?
A. Glutamate
B. α-ketoglutarate
C. Alanine (Correct Answer)
D. Arginine
E. Pyruvate
Explanation: ***Alanine***
- During prolonged fasting, **muscle proteins are catabolized** to provide amino acids for gluconeogenesis in the liver.
- **Alanine** is the primary amino acid released from muscle into the bloodstream to transport nitrogen to the liver through the **glucose-alanine cycle (Cahill cycle)**.
- In this cycle, pyruvate in muscle accepts an amino group from glutamate to form alanine, which is then transported to the liver, where it is deaminated back to pyruvate (for gluconeogenesis) and ammonia (for the urea cycle).
- **Glutamine** also serves as an important nitrogen transporter, particularly to the kidneys and intestines.
*Glutamate*
- **Glutamate** is an important amino acid in nitrogen metabolism within tissues, but it is not the primary form in which nitrogen is transported from muscle to the liver in significant quantities.
- While glutamate participates in transamination reactions within muscle, its efflux from muscle into the blood is less prominent than alanine for inter-organ nitrogen transport.
*α-ketoglutarate*
- **α-ketoglutarate** is a key intermediate in the **Krebs cycle** and accepts an amino group to form glutamate.
- It is an alpha-keto acid, not an amino acid, and therefore does not directly transport nitrogen in the form of an amino group to the liver via the bloodstream.
*Arginine*
- **Arginine** is primarily involved in the **urea cycle** within the liver, where it helps in the detoxification of ammonia, but it is not a major transporter of nitrogen from peripheral tissues to the liver for gluconeogenesis.
- Its role is mainly within the liver for urea synthesis, not for inter-organ nitrogen transport in this context.
*Pyruvate*
- **Pyruvate** is a keto acid that can be converted to alanine via transamination.
- While pyruvate is a precursor to alanine and a substrate for gluconeogenesis, it transports carbon skeletons and not nitrogen itself; **alanine is the actual nitrogen carrier** in this cycle.
Question 213: A 4-year-old boy is brought to the physician because of a rash and difficulty swallowing. His family emigrated from Nigeria 2 months ago. Examination shows an erythematous rash with fine yellow scales on his eyebrows and nasolabial folds. Oral examination shows an erythematous throat and swollen tongue. There is peeling and fissures of the skin at the corners of the mouth and cracking of the lips. His hemoglobin concentration is 9.6 g/dL; mean corpuscular volume is 89 μm3. Erythrocyte glutathione reductase assay shows an increased activity coefficient. This patient is most likely deficient in a vitamin that is a precursor to which of the following molecules?
A. Nicotinamide adenine dinucleotide
B. Thiamine pyrophosphate
C. Flavin adenine dinucleotide (Correct Answer)
D. Methylcobalamin
E. Pyridoxal phosphate
Explanation: ***Flavin adenine dinucleotide***
- The symptoms described, such as **seborrheic dermatitis-like rash** (eyebrows, nasolabial folds), **cheilosis** (cracking of lips, fissures at mouth corners), **glossitis** (swollen tongue), and **anemia** with normal MCV, are characteristic of **riboflavin (Vitamin B2) deficiency**.
- **Riboflavin** is a precursor to **Flavin adenine dinucleotide (FAD)**, a coenzyme vital for several redox reactions, and an **increased erythrocyte glutathione reductase activity coefficient** confirms riboflavin deficiency because this enzyme requires FAD.
*Nicotinamide adenine dinucleotide*
- This molecule is derived from **niacin (Vitamin B3)**.
- Deficiency of niacin typically causes **pellagra (dermatitis, diarrhea, dementia)**, which presents differently from the patient's symptoms.
*Thiamine pyrophosphate*
- This is the active form of **thiamine (Vitamin B1)**.
- Thiamine deficiency causes **beriberi** (wet, dry, or infantile) or **Wernicke-Korsakoff syndrome**, neither of which matches the presented clinical picture.
*Methylcobalamin*
- This is an active form of **cobalamin (Vitamin B12)**.
- Vitamin B12 deficiency primarily causes **megaloblastic anemia** and neurological symptoms, not the skin and oral manifestations described here.
*Pyridoxal phosphate*
- This is the active form of **pyridoxine (Vitamin B6)**.
- Pyridoxine deficiency can cause **seborrheic dermatitis-like rash**, **cheilosis**, glossitis, and **anemia**, similar to riboflavin deficiency. However, an **increased erythrocyte glutathione reductase activity coefficient** is specific to **riboflavin deficiency**, not pyridoxine.
Question 214: An 18-month-old boy is brought in to the pediatrician by his mother for concerns that her child is becoming more and more yellow over the past two days. She additionally states that the boy has been getting over a stomach flu and has not been able to keep down any food. The boy does not have a history of neonatal jaundice. On exam, the patient appears slightly sluggish and jaundiced with icteric sclera. His temperature is 99.0°F (37.2°C), blood pressure is 88/56 mmHg, pulse is 110/min, and respirations are 22/min. His labs demonstrate an unconjugated hyperbilirubinemia of 16 mg/dL. It is determined that the best course of treatment for this patient is phenobarbital to increase liver enzyme synthesis. Which of the following best describes the molecular defect in this patient?
A. Silent mutation in the UGT1A1 gene
B. Nonsense mutation in the UGT1A1 gene
C. Deletion in the SLCO1B1 gene
D. Mutation in the promoter region of the UGT1A1 gene
E. Missense mutation in the UGT1A1 gene (Correct Answer)
Explanation: ***Missense mutation in the UGT1A1 gene***
- The presentation of **unconjugated hyperbilirubinemia** (16 mg/dL) with jaundice and sluggishness, triggered by a **stressor** (gastroenteritis, fasting) in an 18-month-old child, is characteristic of **Crigler-Najjar syndrome Type 2**.
- Crigler-Najjar Type 2 is caused by **missense mutations** in the coding region of the *UGT1A1* gene, resulting in a UGT1A1 enzyme with **reduced but present activity** (typically 10-30% of normal).
- **Phenobarbital treatment is effective** in Type 2 because it induces CYP enzyme expression and enhances the activity of the partially functional UGT1A1 enzyme, increasing bilirubin conjugation capacity.
- The severity (bilirubin 16 mg/dL with symptoms) distinguishes this from Gilbert syndrome, while the phenobarbital response distinguishes it from Type 1.
*Silent mutation in the UGT1A1 gene*
- A **silent mutation** does not alter the amino acid sequence and therefore would **not cause any functional deficit** in the UGT1A1 enzyme.
- This would not result in unconjugated hyperbilirubinemia or any clinical manifestations.
*Nonsense mutation in the UGT1A1 gene*
- A **nonsense mutation** creates a premature stop codon, resulting in a **truncated, non-functional protein** and complete or near-complete absence of UGT1A1 activity.
- This causes **Crigler-Najjar syndrome Type 1**, which presents in the **neonatal period** with severe jaundice (bilirubin often >20 mg/dL), high risk of kernicterus, and is **unresponsive to phenobarbital**.
- The patient's milder presentation, later onset, and response to phenobarbital rule out Type 1.
*Deletion in the SLCO1B1 gene*
- The **SLCO1B1 gene** encodes the **OATP1B1 transporter**, involved in hepatic uptake of conjugated bilirubin and other organic anions.
- Defects are associated with **Rotor syndrome**, which causes **conjugated hyperbilirubinemia**, not unconjugated hyperbilirubinemia.
- This does not match the patient's laboratory findings.
*Mutation in the promoter region of the UGT1A1 gene*
- **Promoter mutations** (specifically TA repeat polymorphism in the TATA box) cause **Gilbert syndrome**, resulting in mildly reduced UGT1A1 expression (~30% activity).
- Gilbert syndrome typically presents with **mild, intermittent jaundice** with bilirubin usually **1-5 mg/dL**, often asymptomatic, and does not routinely require treatment.
- The **severe hyperbilirubinemia (16 mg/dL)** with significant symptoms and need for phenobarbital treatment is inconsistent with Gilbert syndrome and indicates Crigler-Najjar Type 2 instead.
Question 215: In a lab experiment, a researcher treats early cells of the erythrocyte lineage with a novel compound called Pb82. Pb82 blocks the first step of heme synthesis. However, the experiment is controlled such that the cells otherwise continue to develop into erythrocytes. At the end of the experiment, the cells have developed into normal erythrocytes except that they are devoid of heme. A second compound, anti-Pb82 is administered which removes the effect of Pb82.
Which of the following is likely to be true of the mature red blood cells in this study?
A. The cells will not produce heme since they lack mitochondria (Correct Answer)
B. The cells will not produce heme because they lack iron
C. The cells will not produce heme because they lack nucleoli
D. The cells will now produce heme
E. The cells will not produce heme because they lack cytosol
Explanation: ***The cells will not produce heme since they lack mitochondria***
- Mature **red blood cells** are **anucleated** and also **lack mitochondria**, which are essential organelles for the initial and final steps of **heme synthesis**.
- Since **anti-Pb82** is administered, it only reverses the block of the first step of **heme synthesis** by Pb82, but does not provide mitochondria where the remaining steps of **heme synthesis** can happen.
*The cells will not produce heme because they lack iron*
- The problem states that the cells continue to develop into **erythrocytes**, implying that their iron content would typically be normal for mature red blood cells.
- **Iron** is incorporated into the final heme molecule but its absence isn't specifically stated or implied as the primary reason for heme synthesis failure in this context.
*The cells will not produce heme because they lack nucleoli*
- **Nucleoli** are involved in ribosome biogenesis and are found within the nucleus.
- While mature red blood cells are **anucleated** and thus lack nucleoli, nucleoli are not directly involved in **heme synthesis**.
*The cells will now produce heme*
- Although the compound **anti-Pb82** is administered to remove the effect of Pb82 (which blocked the first step of heme synthesis), mature **erythrocytes** are incapable of synthesizing heme.
- This is because they lack the necessary **mitochondria** and enzymes required for the complete pathway of heme synthesis, as they extrude their organelles during maturation.
*The cells will not produce heme because they lack cytosol*
- **Mature red blood cells** have a **cytosol** (cytoplasm without organelles).
- Several steps of **heme synthesis** occur in the cytosol, but the process also requires mitochondrial enzymes, which are absent in mature red blood cells.
Question 216: An investigator is studying nutritional deficiencies in humans. A group of healthy volunteers are started on a diet deficient in pantothenic acid. After 4 weeks, several of the volunteers develop irritability, abdominal cramps, and burning paresthesias of their feet. These symptoms are fully reversed after reintroduction of pantothenic acid to their diet. The function of which of the following enzymes was most likely impaired in the volunteers during the study?
A. Gamma-glutamyl carboxylase
B. Alpha-ketoglutarate dehydrogenase (Correct Answer)
C. Dopamine beta-hydroxylase
D. Methionine synthase
E. Glutathione reductase
Explanation: ***Alpha-ketoglutarate dehydrogenase***
- **Pantothenic acid** (vitamin B5) is a precursor of **coenzyme A (CoA)**, which is essential for the function of alpha-ketoglutarate dehydrogenase in the **Krebs cycle**.
- Impairment of this enzyme, critical for energy production, can lead to widespread metabolic dysfunction, manifesting as neurological and gastrointestinal symptoms like **irritability, abdominal cramps**, and **burning paresthesias**, which are classic signs of pantothenic acid deficiency.
*Gamma-glutamyl carboxylase*
- This enzyme is involved in the post-translational modification of several proteins, including **clotting factors**, and requires **vitamin K** as a cofactor.
- Its deficiency leads to bleeding disorders, not the neurological and GI symptoms described.
*Dopamine beta-hydroxylase*
- This enzyme converts **dopamine to norepinephrine** and requires vitamin C and copper.
- Its impairment can affect neurotransmitter synthesis but is not directly linked to pantothenic acid deficiency.
*Methionine synthase*
- This enzyme is crucial for the metabolism of **homocysteine** and requires **vitamin B12** and **folate** as cofactors.
- Its deficiency is associated with megaloblastic anemia and neurological symptoms, but not the specific presentation seen with pantothenic acid deficiency.
*Glutathione reductase*
- This enzyme is essential for maintaining the reduced state of **glutathione**, an antioxidant, and requires **riboflavin** (vitamin B2) in its coenzyme form, FAD.
- Dysfunction typically leads to oxidative stress, hemolytic anemia, and other symptoms different from those described.
Question 217: A 54-year-old man comes to the physician because of generalized fatigue and numbness of his legs and toes for 5 months. He has hypertension and hypercholesterolemia. He underwent a partial gastrectomy for peptic ulcer disease 15 years ago. Current medications include amlodipine and atorvastatin. He is a painter. His temperature is 37°C (98.6°F), pulse is 101/min, respirations are 17/min, and blood pressure is 122/82 mm Hg. Examination shows conjunctival pallor and glossitis. Sensation to vibration and position is absent over the lower extremities. He has a broad-based gait. The patient sways when he stands with his feet together and closes his eyes. His hemoglobin concentration is 10.1 g/dL, leukocyte count is 4300/mm3, and platelet count is 110,000/mm3. Which of the following laboratory findings is most likely to be seen in this patient?
A. Oligoclonal bands in cerebrospinal fluid
B. Elevated methylmalonic acid levels (Correct Answer)
C. Positive rapid plasma reagin test
D. Decreased serum iron levels
E. Basophilic stippling on peripheral smear
Explanation: ***Elevated methylmalonic acid levels***
- The patient's history of **partial gastrectomy**, followed by **fatigue**, **neurological symptoms** (numbness, gait instability, absent vibration/position sensation, positive Romberg sign), **conjunctival pallor**, **glossitis**, and **pancytopenia** (anemia, leukopenia, thrombocytopenia) are all classic signs of **vitamin B12 deficiency**.
- **Methylmalonic acid (MMA)** and **homocysteine** are biochemical markers that accumulate when vitamin B12 is deficient, as vitamin B12 acts as a cofactor in their metabolism. Elevated MMA is a more specific indicator of vitamin B12 deficiency than homocysteine.
*Oligoclonal bands in cerebrospinal fluid*
- **Oligoclonal bands** in the CSF are characteristic of **multiple sclerosis** and other inflammatory disorders of the central nervous system, which do not align with this patient's clinical presentation, particularly the history of gastrectomy and pancytopenia.
- While the patient has neurological symptoms, they are more consistent with a metabolic neuropathy secondary to vitamin B12 deficiency rather than demyelinating disease.
*Positive rapid plasma reagin test*
- A **positive rapid plasma reagin (RPR) test** indicates **syphilis**, which can cause neurological symptoms (neurosyphilis).
- However, the patient's **pancytopenia**, **glossitis**, and history of **gastrectomy** are not typical features of syphilis.
*Decreased serum iron levels*
- **Decreased serum iron levels** would suggest **iron deficiency anemia**. While iron deficiency can cause fatigue and pallor, it typically does not lead to the specific neurological symptoms (demyelinating neuropathy) seen here or pancytopenia.
- The patient's **glossitis** can be seen in both iron and B12 deficiency, but the neurological signs point specifically to B12 deficiency.
*Basophilic stippling on peripheral smear*
- **Basophilic stippling** on a peripheral smear is a classic finding in **lead poisoning** or other conditions causing ribosomal precipitation, such as **thalassemia** or **sideroblastic anemia**.
- While lead poisoning can cause neuropathy and anemia, it would not typically present with the specific history of gastrectomy or the pronounced pancytopenia seen in this patient.
Question 218: The balance between glycolysis and gluconeogenesis is regulated at several steps, and accumulation of one or more products/chemicals can either promote or inhibit one or more enzymes in either pathway. Which of the following molecules if increased in concentration can promote gluconeogenesis?
A. ADP
B. Acetyl-CoA (Correct Answer)
C. AMP
D. Fructose-2,6-bisphosphate
E. Insulin
Explanation: ***Acetyl-CoA***
- **Acetyl-CoA** promotes gluconeogenesis by activating **pyruvate carboxylase**, the enzyme that converts pyruvate to oxaloacetate, effectively pushing the pathway forward.
- High levels of **Acetyl-CoA** generally signal a state of abundant energy from fatty acid oxidation, indicating that glucose is not immediately needed for energy and can be synthesized for storage or use elsewhere.
*ADP*
- **ADP** is a key indicator of low cellular energy and **stimulates** glycolysis while **inhibiting** gluconeogenesis to produce ATP.
- Its presence signals a need for energy synthesis rather than glucose production.
*AMP*
- **AMP** also signals low energy status and is a powerful **allosteric activator** of **phosphofructokinase-1 (PFK-1)**, the rate-limiting enzyme in glycolysis.
- Activates **AMP-activated protein kinase (AMPK)**, which promotes catabolic processes like glycolysis and inhibits anabolic processes like gluconeogenesis.
*Fructose-2,6-bisphosphate*
- **Fructose-2,6-bisphosphate** is a potent **allosteric activator** of **PFK-1** in glycolysis and a strong **inhibitor** of **fructose-1,6-bisphosphatase** in gluconeogenesis.
- Its levels increase in response to insulin, promoting glucose utilization and inhibiting glucose production.
*Insulin*
- **Insulin** is a hormone that **promotes glucose uptake** and utilization by tissues and **inhibits gluconeogenesis**.
- It achieves this by activating enzymes involved in glycolysis and glycogen synthesis while inhibiting key enzymes in gluconeogenesis, such as **fructose-1,6-bisphosphatase**.
Question 219: A 3-month-old boy presents for routine health maintenance. The patient has coarse facial features and stiff joint movements with restricted passive and active range of motion. He also has problems following objects with his eyes and seems not to focus on anything. On physical examination, the corneas are clouded, and the patient fails to meet any 3-month developmental milestones. Genetic testing and histopathology are performed and reveal failure of a cellular structure to phosphorylate mannose residues on glycoproteins. An electron microscopy image of one of this patient’s cells is shown. Which of the following is the most likely diagnosis in this patient?
A. Adrenoleukodystrophy
B. Kartagener syndrome
C. Tay-Sachs disease
D. Inclusion cell disease (Correct Answer)
E. Diamond-Blackfan anemia
Explanation: ***Inclusion cell disease***
- This condition is characterized by a **failure to phosphorylate mannose residues** on glycoproteins due to a defective **N-acetylglucosaminyl-1-phosphotransferase** enzyme.
- The clinical presentation of **coarse facial features, stiff joint movements**, clouded corneas, and developmental delay is classical for **I-cell disease** (mucolipidosis II), where lysosomal enzymes are **mistargeted and secreted from cells** instead of being properly delivered to lysosomes, resulting in **lysosomes that lack hydrolytic enzymes** and accumulate undigested substrates (visible as inclusions on electron microscopy).
*Adrenoleukodystrophy*
- This is an **X-linked disorder** affecting very long chain fatty acid metabolism, leading to their accumulation in the **adrenal glands** and **white matter of the brain**.
- While it causes **neurological dysfunction** and adrenal insufficiency, it does not typically present with the coarse facial features, corneal clouding, and skeletal abnormalities seen in this patient.
*Kartagener syndrome*
- This is a form of **primary ciliary dyskinesia** characterized by impaired ciliary movement due to structural defects in **dynein arms**.
- It presents with **recurrent respiratory infections** (sinusitis, bronchitis, bronchiectasis), **situs inversus** (in about 50% of cases), and infertility, which are unrelated to the patient's symptoms.
*Tay-Sachs disease*
- This is a **lysosomal storage disorder** caused by a deficiency of **hexosaminidase A**, leading to the accumulation of **GM2 ganglioside**.
- It causes **progressive neurological deterioration**, motor weakness, and a **cherry-red spot** on the macula, but not the coarse facial features or skeletal abnormalities described.
*Diamond-Blackfan anemia*
- This is a **congenital hypoplastic anemia** characterized by a defect in **erythroid progenitor cells**, leading to severe macrocytic anemia.
- It can be associated with various congenital anomalies, but the primary presentation is **anemia** and it does not involve the lysosomal storage defects or the characteristic facial and joint features seen in this case.
Question 220: A 6-day-old infant who was born via uncomplicated vaginal delivery at 39 weeks of gestation is brought to the family physician for poor feeding. The mother received adequate prenatal care throughout the pregnancy, and has no medical conditions. On physical exam, the infant's temperature is 36.5°C (97.7°F), blood pressure is 70/45 mmHg, pulse is 170/min, and respirations are 40/min. The infant has dry mucous membranes, capillary refill of 4 seconds, and a depressed anterior fontanelle. No abdominal masses are noted. Genital exam shows enlargement of the clitoris with fusion of the labioscrotal folds. Serum chemistry is remarkable for hyponatremia and hyperkalemia. The infant's karyotype is 46,XX. Which of the following findings are most likely to be discovered upon further workup?
A. Increased aldosterone, decreased cortisol
B. Decreased aldosterone, increased 11-deoxycorticosterone
C. Increased sex hormones, decreased renin activity
D. Increased sex hormones, increased 17-hydroxyprogesterone (Correct Answer)
E. Decreased cortisol, decreased sex hormones
Explanation: ***Increased sex hormones, increased 17-hydroxyprogesterone***
- The combination of **ambiguous genitalia** (clitoral enlargement, labioscrotal fusion) in a 46,XX infant along with signs of **salt-wasting** (hyponatremia, hyperkalemia, dehydration) points to **classic 21-hydroxylase deficiency**.
- In 21-hydroxylase deficiency, the block in cortisol and aldosterone synthesis leads to a buildup of precursors (**17-hydroxyprogesterone**) and shunting towards **androgen production**, causing virilization.
*Increased aldosterone, decreased cortisol*
- **Decreased cortisol** is consistent with congenital adrenal hyperplasia (CAH), but **increased aldosterone** would not be seen in salt-wasting 21-hydroxylase deficiency.
- Salt-wasting forms of CAH, particularly 21-hydroxylase deficiency, result in **decreased aldosterone** due to the enzyme block.
*Decreased aldosterone, increased 11-deoxycorticosterone*
- **Decreased aldosterone** aligns with salt-wasting CAH, but **increased 11-deoxycorticosterone** (DOC) is characteristic of **11β-hydroxylase deficiency**, not 21-hydroxylase deficiency.
- 11β-hydroxylase deficiency leads to **hypertension** due to excess DOC, which is not described in this patient presenting with signs of dehydration and hypotension.
*Increased sex hormones, decreased renin activity*
- **Increased sex hormones** are expected in congenital adrenal hyperplasia due to enzyme deficiencies leading to excessive androgen production.
- However, **decreased renin activity** would occur with conditions causing hyperaldosteronism or mineralocorticoid excess (like 11β-hydroxylase deficiency with high DOC), which contradicts the signs of salt-wasting and likely hypotension in this infant.
*Decreased cortisol, decreased sex hormones*
- While **decreased cortisol** is a hallmark of CAH, **decreased sex hormones** would typically be seen in deficiencies affecting the early steps of steroidogenesis or in primary gonadal failure.
- In 21-hydroxylase deficiency, the blocked pathway upstream of cortisol synthesis diverts precursors towards **increased androgen production**, leading to virilization.
