The correct answer is D. This patient has signs of McArdle disease, a glycogen storage disease that impairs phosphorolysis of glycogen.
McArdle disease:
- Autosomal recessive.
- Caused by mutations in the PYGM gene, which encodes a muscle isoform of glycogen phosphorylase (myophosphorylase).
- Myophosphorylase catalyzes the removal of α1,4-glucoside residues from the outer branches of glycogen, releasing glucose-1-phosphate.
- Uniquely restricted to skeletal muscle, unlike most other glycogen storage diseases (see table below).
- Presents in adolescence or early adulthood with exercise intolerance, weakness, fatigue, cramps, and muscle swelling.
- Symptoms relieved by pausing exercise briefly, allowing for fatty acid and glucose release to relieve the dependency on muscle glycogen ("second wind" phenomenon).
- Lab findings: Myoglobinuria and elevated creatine kinase.
Definitive diagnosis is based on either demonstration of myophosphorylase deficiency by enzyme analysis or by the accumulation of cytoplasmic glycogen granules in a muscle biopsy.
Krabbe disease is a lysosomal storage disease (galactocerebrosidase deficiency; choice A) that affects the myelin sheaths of the central nervous system. Signs and symptoms include hypertonia, irritability, hyperesthesia, psychomotor retardation, and early death. Krabbe is transmitted with an autosomal recessive pattern.
Von Gierke disease is a glycogen storage disease (glucose 6-phosphatase deficiency; choice B) with prominent involvement of liver, intestine, and kidney. Clinical features include severe hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperuricemia, and short stature.
Niemann-Pick disease is a lysosomal storage disease (sphingomyelinase deficiency; choice C). Hallmarks of the disease include hepatosplenomegaly, microcephaly, severe intellectual disability, and early death. Some, but not all, patients have cherry-red spots in the macula.
Hartnup disease is an autosomal recessive disorder characterized by a defective neutral amino acid transport (choice E) in the small intestine and kidneys. Patients present with pellagra-like skin eruptions, cerebellar ataxia, and aminoaciduria.
This is a multi-step question.
What is the question asking?
The question is asking you to make a diagnosis of the condition presented, determine the enzyme deficiency, and then identify a consequence of the enzyme deficiency.
What is the first step?
The first step is to diagnose the patient's condition. A patient who has, throughout their life, experienced severe muscle cramps and weakness on moderate exercise, coupled with reddish-brown urine, points to a deficiency in myophosphorylase.
What is the next step?
The next step is to recall what myophosphorylase does. Myophosphorylase (muscle glycogen phosphorylase) is necessary to degrade muscle glycogen via a phosphorolysis reaction to glucose 1-phosphate in order for the muscle to use the glucose for energy.
Can other answers be eliminated?
- Hydrolysis of galactocerebroside (choice A) leads to galactose and sphingosine, neither of which is used as an energy source by the muscle.
- Hydrolysis of glucose 6-phosphate (choice B) is defective in type 1 glycogen storage disease, but would not interfere with the muscle?s ability to generate energy and does not lead to the patient?s symptoms.
- Hydrolysis of sphingomyelin (choice C) produces sphingosine and choline, neither of which is used as an energy source by the muscle.
- A defect in the transport of neutral amino acids (choice E) is associated with Hartnup disease, and such a disorder does not interfere with muscle energy generation during exercise.
What is the single best answer and why?
Phosphorolysis of glycogen (choice D) is the single best answer because it is the only pathway that, if defective, would lead to an inability to provide muscle with glucose during exercise, leading to the symptoms present in the patient.
MedEssentials (4th Ed.): pp. 43
First Aid (2019): pp. 87.1
First Aid (2018): pp. 87.1
First Aid (2017): pp. 83.1
