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 6-month-old boy is referred to a geneticist after he is found to have persistent hypotonia and failure to thrive. He has also had episodes of what appears to be respiratory distress and has an enlarged heart on physical exam. There is a family history of childhood onset hypertrophic cardiomyopathy, so a biopsy is performed showing electron dense granules within the lysosomes. Genetic testing is performed showing a defect in glycogen processing. A deficiency in which of the following enzymes is most likely to be responsible for this patient's symptoms?

Lysosomal alpha 1,4-glucosidase

A 3-week-old newborn is brought to the pediatrician by his mother. His mother is concerned about her son’s irritability and vomiting, particularly after breastfeeding him. The infant was born at 39 weeks via spontaneous vaginal delivery. His initial physical was benign. Today the newborn appears mildly jaundiced with palpable hepatomegaly, and his eyes appear cloudy, consistent with the development of cataracts. The newborn is also in the lower weight-age percentile. The physician considers a hereditary enzyme deficiency and orders blood work and a urinalysis to confirm his diagnosis. He recommends that milk and foods high in galactose and/or lactose be eliminated from the diet. Which of the following is the most likely deficient enzyme in this metabolic disorder?

Galactose-1-phosphate uridyl transferase

Glucose-6-phosphate dehydrogenase

A 16-year-old boy comes to the physician because of muscle weakness and cramps for 5 months. He becomes easily fatigued and has severe muscle pain and swelling after 15 minutes of playing basketball with his friends. The symptoms improve after a brief period of rest. After playing, he sometimes also has episodes of reddish-brown urine. There is no family history of serious illness. Serum creatine kinase concentration is 950 U/L. Urinalysis shows: Blood 2+ Protein negative Glucose negative RBC negative WBC 1–2/hpf Which of the following is the most likely underlying cause of this patient's symptoms?

Medium-chain acyl-CoA dehydrogenase deficiency

Low levels of triiodothyronine and thyroxine

An 8-year-old boy is brought to the pediatrician by his mother with nausea, vomiting, and decreased frequency of urination. He has acute lymphoblastic leukemia for which he received the 1st dose of chemotherapy 5 days ago. His leukocyte count was 60,000/mm3 before starting chemotherapy. The vital signs include: pulse 110/min, temperature 37.0°C (98.6°F), and blood pressure 100/70 mm Hg. The physical examination shows bilateral pedal edema. Which of the following serum studies and urinalysis findings will be helpful in confirming the diagnosis of this condition?

Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and urate crystals in the urine

Hyperuricemia, hyperkalemia, hyperphosphatemia, and urinary monoclonal spike

Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, urine supernatant pink, and positive for heme

Hyperkalemia, hyperphosphatemia, hypocalcemia, and extremely elevated creatine kinase (MM)

Hyperuricemia, hyperkalemia, hyperphosphatemia, lactic acidosis, and oxalate crystals

A 22-year-old man comes to the physician because of a fall associated with a 6-month history of increasing difficulty walking. Over the last year, his friends have also noticed his speech becoming slower. During this period, he also gave up his hobby of playing video games because he has become clumsy with his hands. His father died of esophageal varices at the age of 40 years. The patient does not smoke or drink alcohol. He takes no medications. He appears sad. His temperature is 37°C (98.6°F), pulse is 70/min, and blood pressure is 120/80 mm Hg. He is alert and oriented to person, place, and time. His speech is slurred and monotonous; his gait is unsteady. Examination shows scleral icterus and some drooling. The liver is palpated 2 to 3 cm below the right costal margin, and the spleen is palpated 1 to 2 cm below the left costal margin. Further evaluation of this patient is most likely to show which of the following findings?

Low serum ceruloplasmin concentration

Increased number of CAG repeats

Oligoclonal bands on CSF analysis

Ventriculomegaly on CT scan of the brain

Increased transferrin saturation

Diagnostic approaches to GSDs for USMLE Step 3: High-Yield Biochemistry Lessons

Initial Clues - Spotting the Suspect

Clinical Presentation: Varies by type, but classic signs raise suspicion.
- Hepatic forms: Present in infancy/early childhood.
  - Hepatomegaly (protuberant abdomen).
  - Fasting hypoglycemia (seizures, lethargy).
  - Poor growth, doll-like facies (Von Gierke).
- Myopathic forms: Present in adolescence/adulthood.
  - Exercise intolerance, muscle cramps, weakness.
  - Second-wind phenomenon (McArdle).
  - Progressive weakness (Pompe).
Initial Lab Panel:
- Blood glucose (fasting): ↓
- Lactate, uric acid, triglycerides, cholesterol: ↑ (especially in GSD I)
- Liver transaminases (ALT/AST): ↑
- Creatine kinase (CK): ↑ (in myopathic forms)

⭐ High-Yield Clue: A key initial test is the glucagon stimulation test. In GSD I, there is no rise in blood glucose after glucagon administration, but a marked rise in lactate.

Child with hepatomegaly and doll-like facies in GSD

Lab Investigations - The Bloodwork Story

Fasting State Analysis: The cornerstone of initial workup.
- Hypoglycemia: Severe, hallmark of GSD I (Von Gierke).
- Lactic Acidosis: ↑↑ Lactate, especially in GSD Ia.
- Hyperuricemia: ↑ Uric acid, leading to gout.
- Hyperlipidemia: ↑ Triglycerides and cholesterol.
Enzyme Markers: Pinpoint organ involvement.
- Liver Transaminases (AST/ALT): ↑ in hepatic types (I, III, IV).
- Creatine Kinase (CK-MM): ↑ in myopathic types (II, V, VII).
Provocative Testing:
- Glucagon Challenge: Assesses hepatic glycogenolysis.

⭐ In GSD Type I, a glucagon challenge fails to raise blood glucose but significantly increases lactate levels.

📌 Mnemonic (Von Gierke): Think Very Poor Liver. ↑ VLDL (lipids), ↑ Purines (uric acid), ↑ Lactate.

Diagnostic algorithm for hepatic glycogen storage diseases

Confirmatory Tests - Naming the Culprit

Gold Standard: Enzyme Assay & Genetic Testing
- Definitive diagnosis via measurement of specific enzyme activity.
- Samples: Leukocytes, cultured skin fibroblasts, or tissue biopsy (muscle/liver).
- Molecular genetic testing identifies specific gene mutations (e.g., G6PC, PYGM).
Tissue Biopsy
- Liver Biopsy: Demonstrates ↑ glycogen content and potential fibrosis or fatty change.
- Muscle Biopsy: Crucial for myopathic forms (e.g., McArdle, Pompe).
  - Histology: Periodic acid-Schiff (PAS) stain reveals excess glycogen.

⭐ Pompe disease (Type II) is unique as both a GSD and a lysosomal storage disease. Muscle biopsy distinctively shows glycogen accumulation within lysosomes.

Muscle biopsy: subsarcolemmal glycogen in McArdle disease

Tissue & Imaging - A Deeper Look

Tissue Biopsy: The definitive diagnostic standard for many GSDs.
- Liver Biopsy: Primarily for hepatic forms (e.g., Von Gierke, Cori). Assesses glycogen content and specific enzyme activity.
- Muscle Biopsy: For myopathic forms (e.g., Pompe, McArdle). Shows excess glycogen in muscle fibers.
Histopathology:
- Periodic acid-Schiff (PAS) stain: Stains glycogen magenta. Tissue is PAS-positive.
- Diastase Digestion: Pre-treatment with diastase enzyme digests glycogen; the PAS stain will then be negative.
Imaging:
- Ultrasound/CT/MRI: Primarily to assess hepatomegaly and detect liver adenomas, a common complication in GSD I.

⭐ In GSDs, the PAS stain is positive, revealing glycogen accumulation. Crucially, this staining disappears after treatment with diastase (diastase-labile), confirming the substance is indeed glycogen.

PAS stain with and without diastase in liver biopsy

High‑Yield Points - ⚡ Biggest Takeaways

Initial labs for a suspected GSD include blood glucose, lactate, uric acid, and lipids.

Definitive diagnosis requires enzyme assays on liver or muscle biopsy or, increasingly, genetic testing.

Von Gierke (Type I) classically shows severe hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia.

Pompe disease (Type II) is unique for its massive cardiomegaly and profound hypotonia with normal glucose.

McArdle disease (Type V) presents with exercise intolerance, myoglobinuria, and a characteristic flat venous lactate curve with exercise.

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