A 15-year-old boy is sent from gym class with a chief complaint of severe muscle aches. In class today he was competing with his friends and therefore engaged in weightlifting for the first time. A few hours later he was extremely sore and found that his urine was red when he went to urinate. This concerned him and he was sent to the emergency department for evaluation. Upon further questioning, you learn that since childhood he has always had muscle cramps with exercise. Physical exam was unremarkable. Upon testing, his creatine kinase level was elevated and his urinalysis was negative for blood and positive for myoglobin. Thinking back to biochemistry you suspect that he may be suffering from a hereditary glycogen disorder. Given this suspicion, what would you expect to find upon examination of his cells?

Accumulation of glycogen in lysosomes forming dense granules

Glycogen without normal branching pattern

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?

Galactose 1-phosphate uridyltransferase

A 28-year-old man is brought in by ambulance to the ER, barely conscious, after feeling drowsy and falling to the floor during a presentation several hours ago. His colleague who accompanied him says he has had similar episodes 5 times in the past 3 months. No significant past medical history. His blood pressure is 110/80 mm Hg and pulse is 114/min. His capillary blood glucose is 15 mg/dL. Immediate IV dextrose with thiamine is started, and he rapidly regains consciousness. A contrast CT of the abdomen is performed which reveals a tumor in the pancreas. Which of the following relative laboratory findings would you most likely expect to find in this patient?

Glucose: ↓, Insulin: ↑, C-Peptide: ↑, Ketoacidosis: Absent

Glucose: ↑, Insulin: ↓, C-Peptide: ↓, Ketoacidosis: Present

Glucose: Normal, Insulin: Normal, C-Peptide: Normal, Ketoacidosis: Absent

Glucose: ↓, Insulin: ↑, C-Peptide: ↓, Ketoacidosis: Absent

Glucose: ↑, Insulin: ↑/Normal, C-Peptide: ↑/Normal, Ketoacidosis: Absent

A newborn infant presents with severe weakness. He was born to a G1P1 mother at 40 weeks gestation with the pregnancy attended by a midwife. The mother's past medical history is unremarkable. She took a prenatal vitamin and folic acid throughout the pregnancy. Since birth, the child has had trouble breastfeeding despite proper counseling. He also has had poor muscle tone and a weak cry. His temperature is 99.5°F (37.5°C), blood pressure is 57/38 mmHg, pulse is 150/min, respirations are 37/min, and oxygen saturation is 96% on room air. Physical exam reveals poor muscle tone. The patient's sucking reflex is weak, and an enlarged tongue is noted. An ultrasound is performed, and is notable for hypertrophy of the myocardium. Which of the following is the most likely diagnosis?

Familial hypertrophic cardiomyopathy

Spinal muscular atrophy type I disease

Clostridium botulinum infection

A 1-year-old male with a history of recurrent pseudomonal respiratory infections and steatorrhea presents to the pediatrician for a sweat test. The results demonstrate a chloride concentration of 70 mEq/L (nl < 40 mEq/L). Which of the following defects has a similar AUTOSOMAL RECESSIVE mode of inheritance as the disorder experienced by this patient?

Accumulation of glycogen in the lysosome

Abnormal production of type IV collagen

Trinucleotide repeat expansion of CAG on chromosome 4

Mutated gene for mitochondrial-tRNA-Lys

Inability to convert carbamoyl phosphate and ornithine into citrulline

Clinical manifestations by tissue involvement for USMLE Step 1: High-Yield Biochemistry Lessons

Hepatic GSDs - Sugar-Stuffed Livers

Primary Defect: Impaired glycogenolysis & gluconeogenesis.
Hallmark Presentation: Severe fasting hypoglycemia & massive hepatomegaly.
- Glycogen accumulation → "Sugar-Stuffed" liver.
- Failure to release glucose → ↓ Blood sugar.
Key Metabolic Derangements:
- Lactic Acidosis: ↑ Shunting of pyruvate to lactate.
- Hyperuricemia: ↑ Purine catabolism & competition for renal excretion with lactate.
- Hyperlipidemia: ↑ Acetyl-CoA diversion to fatty acid & cholesterol synthesis.
Major Types & Distinctions:
- Von Gierke (Type I): Glucose-6-phosphatase def. Most common & severe.
  - Doll-like face, thin extremities, short stature.
- Cori (Type III): Debranching enzyme def. Milder hypoglycemia; muscle involvement.
- Andersen (Type IV): Branching enzyme def. Abnormal glycogen → cirrhosis, liver failure.

Metabolic consequences of Glucose-6-Phosphatase deficiency

⭐ Exam Tip: In Von Gierke's (Type I), the enzyme defect (G6Pase) is in the ER. This blocks the final step for both glycogenolysis and gluconeogenesis, explaining the profound hypoglycemia and metabolic chaos.

📌 Mnemonic (4 "H"s): Hepatomegaly, Hypoglycemia, Hyperuricemia, Hyperlipidemia.

Myopathic GSDs - Weak & Weary Muscles

Primarily affect skeletal muscle, causing exercise intolerance, progressive weakness, and cramps.
Type V (McArdle Disease):
- Defect: Myophosphorylase deficiency.
- Symptoms: Temporary weakness & cramping after exercise. No rise in lactate post-exercise.
- "Second wind" phenomenon: Symptoms improve with rest as alternative fuels (fatty acids) are utilized.
- Risk: Rhabdomyolysis → myoglobinuria → acute kidney injury.
- 📌 Mnemonic: McArdle's = Muscle pain, Myoglobinuria.
Type II (Pompe Disease):
- Defect: Lysosomal acid α-1,4-glucosidase (acid maltase).
- Infantile-onset: Severe cardiomegaly, macroglossia, profound hypotonia ("floppy baby"). Death by 2 years.
- Late-onset: Progressive proximal muscle weakness, respiratory insufficiency.
- 📌 Mnemonic: Pompe Pummels the Pump (heart).

⭐ In McArdle disease, a forearm ischemic exercise test shows a flat venous lactate curve (no increase), which is virtually diagnostic.

Systemic GSDs - Heart & Beyond

Type II (Pompe Disease): Lysosomal α-1,4-glucosidase (acid maltase) deficiency.
- Affects heart, liver, & muscle, leading to glycogen accumulation in lysosomes.
- Infantile form: Massive cardiomegaly (hypertrophic), profound hypotonia ("floppy baby"), macroglossia.
- 📌 Pompe breaks down the Pump (heart).
Type IV (Andersen Disease): Branching enzyme deficiency.
- Forms amylopectin-like structures, causing cirrhosis and liver failure.
- Can also present with cardiomyopathy and muscular atrophy.

Infant chest X-ray and echo showing cardiomegaly

⭐ In Pompe disease, ECGs may show giant QRS complexes and a short PR interval due to the severe ventricular hypertrophy.

High‑Yield Points - ⚡ Biggest Takeaways

Hepatic GSDs like Von Gierke (Type I) and Cori (Type III) primarily cause hepatomegaly and fasting hypoglycemia.

Myopathic GSDs, such as McArdle (Type V), lead to exercise intolerance, muscle cramps, and myoglobinuria.

Pompe disease (Type II) is systemic, uniquely causing massive cardiomegaly and profound hypotonia in infants.

Von Gierke disease is marked by severe hypoglycemia, lactic acidosis, and hyperuricemia.

McArdle disease presents with a characteristic "second wind" phenomenon during prolonged exercise.

Unlike many other storage diseases, splenomegaly is typically absent in GSDs.

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