A 4-month-old boy is brought to his pediatrician for a well-child visit. His parents have noticed that he has had poor growth compared to his older siblings. The boy was delivered vaginally after a normal pregnancy. His temperature is 98.8°F (37.1°C), blood pressure is 98/68 mmHg, pulse is 88/min, and respirations are 20/min. On exam, his abdomen appears protuberant, and the boy appears to have abnormally enlarged cheeks. A finger stick reveals that the patient’s fasting blood glucose is 50 mg/dL. On further laboratory testing, the patient is found to have elevated blood lactate levels, as well as no response to a glucagon stimulation test. What enzymatic defect is most likely present?
Q2
While walking through a park with his wife, a 51-year-old man with type 2 diabetes mellitus develops nausea, sweating, pallor, and palpitations. For the past 3 weeks, he has been trying to lose weight and has adjusted his diet and activity level. He eats a low-carb diet and swims 3 times a week. The man returned home from a training session 2 hours ago. Current medications include basal insulin and metformin. Shortly before his wife returns from their car with his emergency medication kit, he becomes unconscious. Administration of which of the following is the most appropriate next step in management?
Q3
A 27-year-old Hispanic G2P1 presents for a routine antepartum visit at 26 weeks gestation. She has no complaints. The vital signs are normal, the physical examination is within normal limits, and the gynecologic examination corresponds to 25 weeks gestation. The oral glucose tolerance test (OGTT) with a 75-g glucose load is significant for a glucose level of 177 mg/dL at 1 hour and 167 mg/dL at 2 hour. The fasting blood glucose level is 138 mg/dL (7.7 mmol/L), and the HbA1c is 7%. Which of the following represents the proper initial management?
Q4
A 12-year-old girl comes to the clinic with a grossly enlarged abdomen. She has a history of frequent episodes of weakness, sweating, and pallor that are eliminated by eating. Her development has been slow. She started to walk unassisted at 2 years and was not performing well at school. Physical examination reveals a blood pressure of 100/60 mm Hg, heart rate of 80/min, and temperature of 36.9°C (98.4℉). On physical examination, the liver is enlarged, firm, and palpable up to the pelvis. The spleen and kidney are not palpable. Laboratory investigation reveals low blood glucose and pH with high lactate, triglycerides, ketones, and free fatty acids. The liver biopsy revealed high glycogen content. Hepatic glycogen structure was normal. The enzyme assay performed on the biopsy tissue revealed very low glucose-6-phosphatase levels. What is the most likely diagnosis?
Q5
A 4-year-old girl is brought to the physician by her mother because of fatigue and generalized weakness for 4 months. Examination shows decreased muscle tone. Her fasting serum glucose concentration is 41 mg/dL. The physician suspects a defect in one of the enzymes involved in the carnitine shuttle. Increased serum concentration of which of the following should most raise suspicion of a different diagnosis?
Q6
A 2-day-old newborn boy is brought to the emergency department because of apnea, cyanosis, and seizures. He is severely hypoglycemic and does not improve with glucagon administration. His blood pressure is 100/62 mm Hg and heart rate is 75/min. Blood tests show high lactate levels. Physical examination is notable for hepatomegaly. Which of the following enzymes is most likely to be deficient in this baby?
Q7
A 2-month-old boy is brought to the emergency department 25 minutes after having a seizure. He has had multiple seizures during the past week. His mother has noticed that he has become lethargic and has had a weak cry for the past month. He was born at 37 weeks' gestation. He is at the 20th percentile for height and 15th percentile for weight. His temperature is 36.7°C (98°F), respirations are 50/min, and pulse is 140/min. Examination shows a soft and nontender abdomen. The liver is palpated 4 cm below the right costal margin; there is no splenomegaly. Serum studies show:
Na+ 137 mEq/L
Cl- 103 mEq/L
K+ 3.9 mEq/L
Glucose 32 mg/dL
Calcium 9.6 mg/dL
Total cholesterol 202 mg/dL
Triglycerides 260 mg/dL
Lactate 4.2 mEq/L (N = 0.5 - 2.2 mEq/L)
A deficiency of which of the following enzymes is the most likely cause of this infant's symptoms?
Q8
An 8-month-old infant is brought in with poor feeding, lethargy, hypotonia, and hepatomegaly. Labs reveal hypoglycemia and metabolic acidosis. Which condition is most likely?
Q9
A 3-month-old boy is brought to the emergency department by his mother after a seizure at home. The mother is not sure how long the seizure lasted, but says that the boy was unresponsive and had episodes of stiffness and jerking of his extremities throughout the episode. The mother states that the boy has not seemed himself for the past several weeks and has been fussy with feeds. He does not sleep through the night. He has not had any recent infections or sick contacts.
On exam, the boy is lethargic. His temperature is 99.5°F (37.5°C), blood pressure is 70/40 mmHg, and pulse is 120/min. He has no murmurs and his lungs are clear to auscultation bilaterally. His abdomen appears protuberant, and his liver span is measured at 4.5 cm below the costal margin. Additionally, the boy has abnormally enlarged cheeks. A finger stick in the ED reveals a blood glucose level of 35 mg/dL. What would this patient’s response to a fasting-state glucagon stimulation test most likely be, and what enzyme defect does he have?
Q10
A 5-month-old boy presents with increasing weakness for the past 3 months. The patient’s mother says that the weakness is accompanied by dizziness, sweating, and vertigo early in the morning. Physical examination shows hepatomegaly. Laboratory findings show an increased amount of lactate, uric acid, and elevated triglyceride levels. Which of the following enzymes is most likely deficient in this patient?
GSD type I (von Gierke disease) US Medical PG Practice Questions and MCQs
Question 1: A 4-month-old boy is brought to his pediatrician for a well-child visit. His parents have noticed that he has had poor growth compared to his older siblings. The boy was delivered vaginally after a normal pregnancy. His temperature is 98.8°F (37.1°C), blood pressure is 98/68 mmHg, pulse is 88/min, and respirations are 20/min. On exam, his abdomen appears protuberant, and the boy appears to have abnormally enlarged cheeks. A finger stick reveals that the patient’s fasting blood glucose is 50 mg/dL. On further laboratory testing, the patient is found to have elevated blood lactate levels, as well as no response to a glucagon stimulation test. What enzymatic defect is most likely present?
A. Alpha-1,4-glucosidase
B. Glycogen synthase
C. Alpha-1,6-glucosidase
D. Glucose-6-phosphatase (Correct Answer)
E. Glycogen phosphorylase
Explanation: ***Glucose-6-phosphatase***
- The patient's symptoms, including **hypoglycemia**, **hepatomegaly** (implied by protuberant abdomen), **lactic acidosis** (elevated lactate), and lack of response to **glucagon stimulation**, are classic for **Type I glycogen storage disease (von Gierke disease)**, which is caused by a deficiency in **glucose-6-phosphatase**.
- This enzyme is crucial for the final step of both **glycogenolysis** and **gluconeogenesis**, and its deficiency prevents the liver from releasing glucose into the bloodstream, leading to severe hypoglycemia.
*Alpha-1,4-glucosidase*
- A deficiency in **alpha-1,4-glucosidase (acid maltase)** causes **Type II glycogen storage disease (Pompe disease)**, which primarily affects muscle (cardiac and skeletal).
- Symptoms include **cardiomyopathy**, **hypotonia**, and muscle weakness, and it does **not** typically present with hypoglycemia or lactic acidosis.
*Glycogen synthase*
- A deficiency in **glycogen synthase** would lead to an inability to synthesize glycogen, resulting in **hypoglycemia** but **low** (rather than high) glycogen levels.
- Patients typically experience fasting hypoglycemia, but **no hepatomegaly** or lactic acidosis would be expected.
*Alpha-1,6-glucosidase*
- A deficiency in **alpha-1,6-glucosidase (debranching enzyme)** causes **Type III glycogen storage disease (Cori disease)**.
- This condition presents with **hepatomegaly**, **hypoglycemia**, and sometimes muscle weakness, but patients typically **do respond to glucagon** and have less severe lactic acidosis compared to Type I.
*Glycogen phosphorylase*
- A deficiency in **glycogen phosphorylase (hepatic form, Type VI GSD or Hers disease)** primarily affects the liver's ability to break down glycogen.
- This typically causes **hepatomegaly** and **hypoglycemia**, but usually, the patients **respond to glucagon** because other pathways for glucose release (like gluconeogenesis) are intact.
Question 2: While walking through a park with his wife, a 51-year-old man with type 2 diabetes mellitus develops nausea, sweating, pallor, and palpitations. For the past 3 weeks, he has been trying to lose weight and has adjusted his diet and activity level. He eats a low-carb diet and swims 3 times a week. The man returned home from a training session 2 hours ago. Current medications include basal insulin and metformin. Shortly before his wife returns from their car with his emergency medication kit, he becomes unconscious. Administration of which of the following is the most appropriate next step in management?
A. Sublingual nitroglycerine
B. Oral glucose
C. Intramuscular glucagon (Correct Answer)
D. Rectal lorazepam
E. Intra-arterial dextrose
Explanation: ***Intramuscular glucagon***
- This patient is experiencing severe **hypoglycemia** (nausea, sweating, pallor, palpitations, unconsciousness) exacerbated by his weight loss efforts, diet, and recent exercise while on insulin and metformin. As he is unconscious and cannot take oral glucose, **intramuscular glucagon** is the most appropriate emergency treatment to raise blood glucose levels in this pre-hospital setting.
- **Glucagon** mobilizes glucose from the liver by stimulating hepatic glycogenolysis, making it vital when oral intake is compromised due to altered consciousness and IV access is not immediately available.
*Sublingual nitroglycerine*
- **Nitroglycerine** is used for chest pain suspected to be angina or myocardial infarction, not for hypoglycemia.
- Administering nitroglycerine in a hypoglycemic patient could cause **vasodilation** and further lower blood pressure, potentially worsening their condition.
*Oral glucose*
- While oral glucose is the primary treatment for mild to moderate hypoglycemia, this patient is **unconscious** and therefore cannot safely swallow.
- Giving oral substances to an unconscious person risks **aspiration pneumonia** and choking.
*Rectal lorazepam*
- **Lorazepam** is an anxiolytic and anticonvulsant, used primarily to treat seizures or severe anxiety.
- It does not address the underlying hypoglycemia and could further **depress the central nervous system**, worsening the patient's altered mental status.
*Intra-arterial dextrose*
- **Intra-arterial dextrose** is not a standard or safe route for treating hypoglycemia. While **intravenous dextrose** would be appropriate in a hospital setting, it is not available in this pre-hospital emergency scenario.
- Administering substances intra-arterially can cause severe damage, including **arterial spasm**, thrombosis, and tissue necrosis.
Question 3: A 27-year-old Hispanic G2P1 presents for a routine antepartum visit at 26 weeks gestation. She has no complaints. The vital signs are normal, the physical examination is within normal limits, and the gynecologic examination corresponds to 25 weeks gestation. The oral glucose tolerance test (OGTT) with a 75-g glucose load is significant for a glucose level of 177 mg/dL at 1 hour and 167 mg/dL at 2 hour. The fasting blood glucose level is 138 mg/dL (7.7 mmol/L), and the HbA1c is 7%. Which of the following represents the proper initial management?
A. Sitagliptin
B. Dietary and lifestyle modification
C. Metformin
D. Glyburide
E. Insulin (Correct Answer)
Explanation: **Insulin**
- The patient's **fasting glucose of 138 mg/dL** and **HbA1c of 7%** indicate pre-existing **Type 2 Diabetes Mellitus**, not just gestational diabetes. Both values exceed the diagnostic thresholds for overt diabetes in pregnancy.
- **Insulin** is the preferred initial pharmacologic treatment for **overt diabetes in pregnancy** because it does not cross the placenta, ensuring fetal safety, and is highly effective in controlling maternal glucose levels.
*Sitagliptin*
- **Sitagliptin** is a **DPP-4 inhibitor** and is not recommended during pregnancy due to limited safety data and the availability of safer alternatives.
- Oral hypoglycemic agents are generally avoided as first-line therapy for established diabetes in pregnancy due to potential for placental transfer and adverse fetal effects.
*Dietary and lifestyle modification*
- While crucial, **dietary and lifestyle modification** alone are insufficient for managing overt diabetes with such high fasting glucose and HbA1c levels.
- These measures are usually the first step for **gestational diabetes**, but a patient with overt diabetes requires immediate pharmacologic intervention to prevent complications.
*Metformin*
- **Metformin** can be used in pregnancy but is primarily considered for **gestational diabetes** or as an alternative to insulin if the patient has milder hyperglycemia, or if insulin is poorly tolerated.
- Given the patient's significantly elevated fasting glucose and HbA1c, **insulin** is a more effective and immediate treatment to achieve glycemic control and reduce risks.
*Glyburide*
- **Glyburide** is an **oral sulfonylurea** that can cross the placenta, leading to potential fetal hyperinsulinemia and neonatal hypoglycemia.
- Its use in pregnancy is generally discouraged due to these risks, making **insulin** a safer and more appropriate choice.
Question 4: A 12-year-old girl comes to the clinic with a grossly enlarged abdomen. She has a history of frequent episodes of weakness, sweating, and pallor that are eliminated by eating. Her development has been slow. She started to walk unassisted at 2 years and was not performing well at school. Physical examination reveals a blood pressure of 100/60 mm Hg, heart rate of 80/min, and temperature of 36.9°C (98.4℉). On physical examination, the liver is enlarged, firm, and palpable up to the pelvis. The spleen and kidney are not palpable. Laboratory investigation reveals low blood glucose and pH with high lactate, triglycerides, ketones, and free fatty acids. The liver biopsy revealed high glycogen content. Hepatic glycogen structure was normal. The enzyme assay performed on the biopsy tissue revealed very low glucose-6-phosphatase levels. What is the most likely diagnosis?
A. Pompe's disease
B. Cori's disease
C. Hereditary hemochromatosis
D. Von-Gierke's disease (Correct Answer)
E. McArdle disease
Explanation: ***Von-Gierke's disease***
- The combination of **hepatomegaly**, **hypoglycemia** (causing weakness, sweating, pallor), **lactic acidosis**, **hyperlipidemia**, and elevated ketones points to a severe defect in glucose metabolism.
- **Very low glucose-6-phosphatase levels** on liver biopsy and normal hepatic glycogen structure are pathognomonic for Von-Gierke's disease (Glycogen Storage Disease Type I).
*Pompe's disease*
- This is a **lysosomal storage disease** affecting **alpha-1,4-glucosidase**, leading to glycogen accumulation in lysosomes.
- It primarily affects the **heart** and skeletal muscles and would not present with severe lactic acidosis and hyperlipidemia.
*Cori's disease*
- This is **Glycogen Storage Disease Type III**, caused by a deficiency in the **debranching enzyme** (amylo-alpha-1,6-glucosidase).
- While it can cause hepatomegaly and hypoglycemia, the hepatic glycogen structure would be abnormal due to incompletely debranched glycogen, and glucose-6-phosphatase levels would be normal.
*Hereditary hemochromatosis*
- This is an **iron overload disorder** leading to iron deposition in organs like the liver, heart, and pancreas.
- It would present with symptoms related to organ damage from iron accumulation, such as liver cirrhosis and diabetes, not the metabolic derangements seen here.
*McArdle disease*
- This is **Glycogen Storage Disease Type V**, due to a deficiency in **muscle glycogen phosphorylase**.
- It primarily causes exercise-induced muscle pain, cramping, and fatigue due to an inability to break down muscle glycogen for energy, not systemic metabolic disturbances or hepatomegaly.
Question 5: A 4-year-old girl is brought to the physician by her mother because of fatigue and generalized weakness for 4 months. Examination shows decreased muscle tone. Her fasting serum glucose concentration is 41 mg/dL. The physician suspects a defect in one of the enzymes involved in the carnitine shuttle. Increased serum concentration of which of the following should most raise suspicion of a different diagnosis?
A. Ammonia (Correct Answer)
B. Creatine kinase
C. Alanine aminotransferase
D. Uric acid
E. β-hydroxybutyrate
Explanation: ***Ammonia***
- An elevated **ammonia** level in the context of hypoglycemia and muscle weakness in a child suggests an **inborn error of metabolism** that affects the **urea cycle** or **organic acidemia**, not primarily the carnitine shuttle.
- Urea cycle disorders lead to **hyperammonemia**, which can cause neurological symptoms, fatigue, and muscle weakness, often exacerbated by catabolic states.
- This finding would **strongly suggest a different diagnosis** from a carnitine shuttle defect.
*Creatine kinase*
- **Creatine kinase (CK)** levels are typically **elevated in carnitine shuttle defects** due to muscle damage and myopathy.
- Elevated CK would **support** the suspected diagnosis of a carnitine shuttle defect rather than suggest an alternative.
- This is an **expected finding** in fatty acid oxidation disorders.
*Alanine aminotransferase*
- **Alanine aminotransferase (ALT)** can be elevated in **carnitine shuttle defects** due to liver involvement and hepatic dysfunction.
- While elevated ALT indicates liver damage, it can occur in fatty acid oxidation disorders and would not necessarily point away from a carnitine shuttle defect.
- This finding is **consistent with** rather than against the suspected diagnosis.
*Uric acid*
- **Uric acid** levels are not directly affected by defects in the **carnitine shuttle**.
- While an elevated uric acid level might prompt investigation into conditions like **glycogen storage diseases** or purine metabolism disorders, it is not a strong discriminator for alternative diagnoses in this clinical context.
*β-hydroxybutyrate*
- **β-hydroxybutyrate** is a **ketone body** produced from fatty acid oxidation during fasting states.
- In carnitine shuttle defects, the body **cannot effectively oxidize fatty acids** to produce ketones, resulting in **hypoketotic hypoglycemia** (low or inappropriately low ketones despite low glucose).
- If β-hydroxybutyrate is **elevated** during fasting hypoglycemia, this indicates **intact fatty acid oxidation** and would suggest a different diagnosis such as **hyperinsulinism**, **glycogen storage disease**, or other causes of hypoglycemia where ketogenesis is preserved.
- However, **ammonia elevation** is a stronger indicator of an alternative diagnosis (urea cycle disorder) compared to the scenario presented.
Question 6: A 2-day-old newborn boy is brought to the emergency department because of apnea, cyanosis, and seizures. He is severely hypoglycemic and does not improve with glucagon administration. His blood pressure is 100/62 mm Hg and heart rate is 75/min. Blood tests show high lactate levels. Physical examination is notable for hepatomegaly. Which of the following enzymes is most likely to be deficient in this baby?
A. α-ketoacid dehydrogenase
B. Phenylalanine hydroxylase
C. Glucose-6-phosphatase (Correct Answer)
D. Glucocerebrosidase
E. Sphingomyelinase
Explanation: ***Correct: Glucose-6-phosphatase***
- The presentation of severe **hypoglycemia** not responsive to glucagon, coupled with **hepatomegaly** and **lactic acidosis** in a neonate, is highly suggestive of **Type I glycogen storage disease (von Gierke disease)**.
- Deficiency of **glucose-6-phosphatase** prevents the liver from releasing glucose into the bloodstream (the final step of both gluconeogenesis and glycogenolysis), leading to profound hypoglycemia.
- **Key diagnostic clue**: Lack of response to glucagon occurs because glucagon stimulates glycogenolysis, but without functional glucose-6-phosphatase, glucose-6-phosphate cannot be converted to free glucose for release.
- Accumulated glucose-6-phosphate shunts to glycolysis, producing **lactate** (lactic acidosis), and to glycogen synthesis, causing **hepatomegaly**.
*Incorrect: α-ketoacid dehydrogenase*
- Deficiency of **branched-chain α-ketoacid dehydrogenase** causes **maple syrup urine disease (MSUD)**, which presents with poor feeding, vomiting, lethargy, and a characteristic maple syrup odor in urine.
- While MSUD can cause neurological symptoms and seizures, **severe hypoglycemia unresponsive to glucagon** and **hepatomegaly** as primary features are not typical.
*Incorrect: Phenylalanine hydroxylase*
- Deficiency in **phenylalanine hydroxylase** causes **phenylketonuria (PKU)**, which is primarily characterized by intellectual disability, seizures (if untreated), and a musty odor, usually manifesting later in infancy.
- PKU does not present with acute neonatal hypoglycemia, lactic acidosis, or hepatomegaly.
*Incorrect: Glucocerebrosidase*
- Deficiency in **glucocerebrosidase** leads to **Gaucher disease**, a lysosomal storage disorder characterized by hepatosplenomegaly, bone crises, and neurological symptoms in severe infantile forms.
- While hepatomegaly may be present, Gaucher disease does not cause acute, severe neonatal hypoglycemia, lactic acidosis, or lack of response to glucagon.
*Incorrect: Sphingomyelinase*
- Deficiency in **sphingomyelinase** causes **Niemann-Pick disease**, another lysosomal storage disorder, which typically presents with hepatosplenomegaly, neurological deterioration, and "cherry-red spots" in the retina.
- This condition does not cause acute neonatal hypoglycemia, lactic acidosis, or glucagon unresponsiveness.
Question 7: A 2-month-old boy is brought to the emergency department 25 minutes after having a seizure. He has had multiple seizures during the past week. His mother has noticed that he has become lethargic and has had a weak cry for the past month. He was born at 37 weeks' gestation. He is at the 20th percentile for height and 15th percentile for weight. His temperature is 36.7°C (98°F), respirations are 50/min, and pulse is 140/min. Examination shows a soft and nontender abdomen. The liver is palpated 4 cm below the right costal margin; there is no splenomegaly. Serum studies show:
Na+ 137 mEq/L
Cl- 103 mEq/L
K+ 3.9 mEq/L
Glucose 32 mg/dL
Calcium 9.6 mg/dL
Total cholesterol 202 mg/dL
Triglycerides 260 mg/dL
Lactate 4.2 mEq/L (N = 0.5 - 2.2 mEq/L)
A deficiency of which of the following enzymes is the most likely cause of this infant's symptoms?
A. Galactose 1-phosphate uridyltransferase
B. Glycogen branching enzyme
C. Glucose 6-phosphatase (Correct Answer)
D. Fructokinase
E. Acid maltase
Explanation: ***Glucose 6-phosphatase***
- The constellation of **hypoglycemia**, **lactic acidosis**, **hepatomegaly**, and **hyperlipidemia** in an infant is characteristic of **Type I glycogen storage disease (von Gierke's disease)**, which is caused by a deficiency of glucose 6-phosphatase.
- Seizures and lethargy are common manifestations of severe hypoglycemia in infants.
*Galactose 1-phosphate uridyltransferase*
- Deficiency of this enzyme causes **classic galactosemia**, which typically presents with **jaundice**, **cataracts**, **vomiting**, and **failure to thrive**, usually after initiation of milk feeds.
- While patients can develop hepatomegaly and hypoglycemia, the prominent lactic acidosis and hyperlipidemia seen here are less typical.
*Glycogen branching enzyme*
- Deficiency causes **Type IV glycogen storage disease (Andersen's disease)**, characterized by **hepatosplenomegaly**, **failure to thrive**, and progressive cirrhosis.
- Hypoglycemia is generally less severe, and lactic acidosis and hyperlipidemia are not primary features in the same way as Type I GSD.
*Fructokinase*
- Deficiency causes **essential fructosuria**, a benign condition where fructose accumulates in the urine.
- It is typically asymptomatic and does not lead to hypoglycemia, lactic acidosis, or hepatomegaly.
*Acid maltase*
- Deficiency (alpha-1,4-glucosidase) causes **Type II glycogen storage disease (Pompe's disease)**, which primarily affects skeletal and cardiac muscle.
- The infantile form presents with **severe hypotonia** ("floppy baby"), **cardiomyopathy**, and **macroglossia**. Hepatomegaly, hypoglycemia, and lactic acidosis are not prominent features.
Question 8: An 8-month-old infant is brought in with poor feeding, lethargy, hypotonia, and hepatomegaly. Labs reveal hypoglycemia and metabolic acidosis. Which condition is most likely?
A. Hereditary fructose intolerance
B. Galactosemia
C. Pompe disease
D. Von Gierke disease (Correct Answer)
E. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
Explanation: ***Von Gierke disease***
- **Type I glycogen storage disease** (GSD I) typically presents in infancy with **hypoglycemia** (due to impaired glucose release from glycogen), **hepatomegaly** (due to glycogen accumulation), and **lactic acidosis**.
- Other common findings include **hyperlipidemia** and **hyperuricemia**, while **hypotonia** and **poor feeding** are generalized symptoms stemming from metabolic derangements.
*Hereditary fructose intolerance*
- This condition presents when **fructose** is introduced into the diet, typically after 4-6 months of age, with symptoms like **nausea, vomiting, abdominal pain**, and **hepatomegaly**.
- While it can cause **hypoglycemia** and **metabolic acidosis**, the profound **hypotonia** and general metabolic collapse described in an 8-month-old on a typical diet makes GSD I more likely initially.
*Galactosemia*
- Symptoms usually appear within days or weeks of birth upon the initiation of **milk feeding**, including **vomiting, lethargy, poor feeding, jaundice, hepatomegaly**, and **cataracts**.
- While it causes **hypoglycemia** and can lead to acidosis and hypotonia, the age of presentation and lack of specific mention of jaundice or cataracts makes it a less precise fit.
*Pompe disease*
- Also known as **glycogen storage disease type II**, it is characterized by the accumulation of glycogen in **lysosomes**, primarily affecting muscles.
- The infantile form presents with severe **cardiomyopathy**, **muscle weakness**, and **hypotonia**, but **hypoglycemia** and **hepatomegaly** are not its primary or most prominent features.
*Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency*
- A **fatty acid oxidation disorder** that presents with episodic **hypoglycemia** (particularly during fasting or illness), **lethargy**, and **hepatomegaly**.
- Key distinguishing features include **hypoketotic hypoglycemia** and elevated **dicarboxylic acids** on urine organic acids, but the **lactic acidosis** and overall metabolic profile are more consistent with GSD I.
Question 9: A 3-month-old boy is brought to the emergency department by his mother after a seizure at home. The mother is not sure how long the seizure lasted, but says that the boy was unresponsive and had episodes of stiffness and jerking of his extremities throughout the episode. The mother states that the boy has not seemed himself for the past several weeks and has been fussy with feeds. He does not sleep through the night. He has not had any recent infections or sick contacts.
On exam, the boy is lethargic. His temperature is 99.5°F (37.5°C), blood pressure is 70/40 mmHg, and pulse is 120/min. He has no murmurs and his lungs are clear to auscultation bilaterally. His abdomen appears protuberant, and his liver span is measured at 4.5 cm below the costal margin. Additionally, the boy has abnormally enlarged cheeks. A finger stick in the ED reveals a blood glucose level of 35 mg/dL. What would this patient’s response to a fasting-state glucagon stimulation test most likely be, and what enzyme defect does he have?
A. Rise in plasma glucose; alpha-1,4-glucosidase
B. Rise in plasma glucose; liver phosphorylase
C. Rise in plasma glucose; glycogen debranching enzyme
D. No change in plasma glucose; glucose-6-phosphatase (Correct Answer)
E. Rise in plasma glucose; muscle phosphorylase
Explanation: ***No change in plasma glucose; glucose-6-phosphatase***
- The clinical presentation, including **hypoglycemia** (35 mg/dL), **hepatomegaly** (liver span 4.5 cm below costal margin), and **enlarged cheeks** (due to fat deposition), is classic for **Glycogen Storage Disease Type I (von Gierke disease)**. This condition is caused by a deficiency in **glucose-6-phosphatase**.
- In von Gierke disease, the body cannot convert **glycogen to glucose** or perform **gluconeogenesis** efficiently. Therefore, a **glucagon stimulation test** (which typically promotes glycogenolysis and gluconeogenesis to raise blood glucose) would show **no change** in plasma glucose levels because the final enzyme in this pathway, glucose-6-phosphatase, is deficient.
*Rise in plasma glucose; alpha-1,4-glucosidase*
- A deficiency in **alpha-1,4-glucosidase** (acid maltase) causes **Glycogen Storage Disease Type II (Pompe disease)**, which primarily affects muscles and the heart.
- While it can present with profound hypotonia and cardiomegaly, it typically **does not cause hypoglycemia** or marked hepatomegaly with fasting, and a glucagon test would likely show a rise in plasma glucose as the enzymes involved in glucose production are intact.
*Rise in plasma glucose; liver phosphorylase*
- A deficiency in **liver phosphorylase** causes **Glycogen Storage Disease Type VI (Hers disease)**. This can lead to hepatomegaly and hypoglycemia.
- However, in Hers disease, the **glucose-6-phosphatase** enzyme is functional, so a glucagon stimulation test would eventually lead to a **rise in plasma glucose** once glycogen breakdown products reach this final step.
*Rise in plasma glucose; glycogen debranching enzyme*
- A deficiency in **glycogen debranching enzyme** causes **Glycogen Storage Disease Type III (Cori disease)**. This condition also presents with hepatomegaly and hypoglycemia, similar to von Gierke disease.
- However, because the **glucose-6-phosphatase** enzyme is functional, a glucagon stimulation test would eventually show a **rise in plasma glucose**, albeit a blunted or delayed rise, after partial glycogenolysis occurs.
*No change in plasma glucose; muscle phosphorylase*
- A deficiency in **muscle phosphorylase** causes **Glycogen Storage Disease Type V (McArdle disease)**, which primarily affects skeletal muscles.
- Patients typically present with **exercise intolerance**, muscle cramps, and myoglobinuria, and do not experience **hypoglycemia** or hepatomegaly. The liver enzymes for glucose production would be intact, so a glucagon test would show a rise in plasma glucose.
Question 10: A 5-month-old boy presents with increasing weakness for the past 3 months. The patient’s mother says that the weakness is accompanied by dizziness, sweating, and vertigo early in the morning. Physical examination shows hepatomegaly. Laboratory findings show an increased amount of lactate, uric acid, and elevated triglyceride levels. Which of the following enzymes is most likely deficient in this patient?
A. Hepatic glycogen phosphorylase
B. Debranching enzyme
C. Glucose-6-phosphatase (Correct Answer)
D. Muscle glycogen phosphorylase
E. Lysosomal α-1,4-glucosidase
Explanation: ***Glucose-6-phosphatase***
- The constellation of **hypoglycemia** (weakness, dizziness, sweating, vertigo, especially early morning), **hepatomegaly**, **lactic acidosis**, **hyperuricemia**, and **hypertriglyceridemia** are classic features of **Type I glycogen storage disease (von Gierke disease)**, which is caused by a deficiency of **glucose-6-phosphatase**.
- This enzyme is crucial for the final step of both **glycogenolysis** and **gluconeogenesis**, releasing free glucose into the bloodstream; its deficiency leads to an inability to maintain normal blood glucose levels during fasting and accumulation of glucose-6-phosphate, which shunts into other metabolic pathways.
*Hepatic glycogen phosphorylase*
- Deficiency in **hepatic glycogen phosphorylase** (Type VI glycogen storage disease, Hers disease) would cause **hepatomegaly** and **hypoglycemia**, but typically does not present with severe **lactic acidosis**, **hyperuricemia**, or **hypertriglyceridemia** to the same degree as von Gierke disease.
- The primary defect is in breaking down glycogen, leading to its accumulation in the liver, but the products of glycolysis can still exit the liver via gluconeogenesis.
*Debranching enzyme*
- Deficiency in **debranching enzyme** (Type III glycogen storage disease, Cori or Forbes disease) causes **hepatomegaly** and **hypoglycemia**, but usually presents with milder symptoms and less severe **lactic acidosis**, **hyperuricemia**, and **hypertriglyceridemia**.
- Patients often present with symptoms similar to Type I, but muscle involvement is also common, and **glycogen structures with short outer branches** are characteristic.
*Muscle glycogen phosphorylase*
- Deficiency in **muscle glycogen phosphorylase** (Type V glycogen storage disease, McArdle disease) primarily affects **skeletal muscle**, leading to exercise intolerance, muscle pain, and myoglobinuria.
- It does not typically cause **hypoglycemia** or **hepatomegaly**, as the liver enzyme is functional, and the symptoms described are systemic rather than muscle-specific.
*Lysosomal α-1,4-glucosidase*
- Deficiency in **lysosomal α-1,4-glucosidase** (Type II glycogen storage disease, Pompe disease) primarily affects the **heart, muscle, and liver**, causing severe **cardiomyopathy**, hypotonia, and **hepatomegaly**.
- While it involves glycogen accumulation, it typically does not present with **hypoglycemia** (as cytoplasmic glycogen metabolism is intact), **lactic acidosis**, or the specific metabolic derangements seen in this patient.
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