Glycogen storage diseases

Glycogen storage diseases US Medical PG Question 1: 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?

• A. Normal glycogen structure (Correct Answer)
• B. Short outer glycogen chains
• C. Accumulation of glycogen in lysosomes forming dense granules
• D. Glycogen without normal branching pattern
• E. Absence of glycogen in muscles

Glycogen storage diseases Explanation: ***Normal glycogen structure*** - The patient's symptoms (exercise-induced muscle cramps, myoglobinuria, and elevated CK) are classic for **McArdle disease** (Glycogen Storage Disease Type V), caused by a deficiency in **muscle glycogen phosphorylase**. - In McArdle disease, the enzyme responsible for breaking down glycogen (glycogen phosphorylase) is deficient, but the enzymes involved in synthesizing glycogen are normal. Therefore, the **structure of glycogen is normal**, but it accumulates in muscle cells because it cannot be catabolized. *Short outer glycogen chains* - **Short outer glycogen chains** are characteristic of **Cori disease** (Glycogen Storage Disease Type III), caused by a deficiency in **debranching enzyme**. - This condition also presents with hypoglycemia and hepatomegaly, which are not described in the patient's presentation. *Accumulation of glycogen in lysosomes forming dense granules* - **Accumulation of glycogen in lysosomes** and the formation of **dense granules** is characteristic of **Pompe disease** (Glycogen Storage Disease Type II), caused by a deficiency in **lysosomal alpha-glucosidase (acid maltase)**. - Pompe disease typically presents as a severe infantile form with cardiomegaly and hypotonia, or a later-onset form with proximal muscle weakness, which differs from the patient's primary complaint of exercise intolerance and myoglobinuria. *Glycogen without normal branching pattern* - **Glycogen without a normal branching pattern** (very long unbranched chains) is characteristic of **Andersen disease** (Glycogen Storage Disease Type IV), caused by a deficiency in **branching enzyme**. - This condition typically leads to cirrhosis and liver failure in infancy, which is not consistent with the patient's presentation. *Absence of glycogen in muscles* - While McArdle disease involves an inability to break down muscle glycogen, it does not result in the **absence of glycogen** in muscles; rather, there is an **over-accumulation** of normal-structured glycogen because it cannot be utilized. - The defect is in **glycogenolysis**, not glycogen synthesis, so glycogen is formed but not broken down.

Glycogen storage diseases US Medical PG Question 2: A 10-year-old boy is brought to the emergency department due to vomiting and weakness. He is attending a summer camp and was on a hike with the other kids and a camp counselor. His friends say that the boy skipped breakfast, and the counselor says he forgot to pack snacks for the kids during the hike. The child’s parents are contacted and report that the child has been completely healthy since birth. They also say there is an uncle who would have to eat regularly or he would have similar symptoms. At the hospital, his heart rate is 90/min, respiratory rate is 17/min, blood pressure is 110/65 mm Hg, and temperature is 37.0°C (98.6°F). Physical examination reveals a visibly lethargic child with slight disorientation to time and place. Mild hepatosplenomegaly is observed but no signs of dehydration are noted. A blood sample is drawn, and fluids are started via an intravenous line. Lab report Serum glucose 44 mg/dL Serum ketones absent Serum creatinine 1.0 mg/dL Blood urea nitrogen 32 mg/dL Alanine aminotransferase (ALT) 425 U/L Aspartate aminotransferase (AST) 372 U/L Hemoglobin (Hb%) 12.5 g/dL Mean corpuscular volume (MCV) 80 fl Reticulocyte count 1% Erythrocyte count 5.1 million/mm3 Which of the following is most likely deficient in this patient?

• A. Acyl-CoA dehydrogenase (Correct Answer)
• B. α-glucosidase
• C. Glucose-6-phosphatase
• D. Acetyl-CoA carboxylase
• E. Nicotinic acid

Glycogen storage diseases Explanation: ***Acyl-CoA dehydrogenase*** - This patient presents with **hypoglycemia** (44 mg/dL) and **absent ketone bodies** after prolonged fasting, along with elevated **liver transaminases** and **hepatosplenomegaly**, which are classic signs of a **fatty acid oxidation disorder**. - A deficiency in **acyl-CoA dehydrogenase**, particularly **medium-chain acyl-CoA dehydrogenase (MCAD)**, prevents adequate fatty acid breakdown for energy and ketone production, leading to **hypoketotic hypoglycemia** during periods of fasting. *α-glucosidase* - A deficiency in **α-glucosidase** (Pompe disease) leads to the accumulation of **glycogen** in lysosomes, primarily affecting muscles, heart, and liver. - While it can cause hepatomegaly and muscle weakness, it typically presents with **cardiomyopathy** and does not directly cause hypoketotic hypoglycemia. *Glucose-6-phosphatase* - A deficiency in **glucose-6-phosphatase** (Von Gierke disease) is a type of **glycogen storage disease** characterized by severe **fasting hypoglycemia with lactic acidosis**, **massive hepatomegaly**, and **hyperlipidemia**. - Unlike fatty acid oxidation disorders, Von Gierke disease typically presents with **lactic acidosis** as the predominant metabolic derangement, and patients often have a **doll-like face** and **growth retardation** from chronic presentation. *Acetyl-CoA carboxylase* - **Acetyl-CoA carboxylase** is a key enzyme in **fatty acid synthesis**, not fatty acid oxidation. - A deficiency would primarily impair the body's ability to synthesize fatty acids, which is not consistent with the hypoketotic hypoglycemia observed here. *Nicotinic acid* - **Nicotinic acid** (niacin or vitamin B3) is a precursor to **NAD+** and **NADP+**, coenzymes involved in various metabolic reactions, including fatty acid synthesis and breakdown. - While a deficiency (pellagra) can cause dermatitis, diarrhea, and dementia, it does not directly lead to **hypoketotic hypoglycemia** or fatty liver disease.

Glycogen storage diseases US Medical PG 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)

Glycogen storage diseases 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.

Glycogen storage diseases US Medical PG 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

Glycogen storage diseases 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.

Glycogen storage diseases US Medical PG Question 5: A 49-year-old woman presents to the family medicine clinic with concerns about her weight. She has been constantly gaining weight for a decade now as she has not been able to control her diet. She has tried exercising but says that she is too lazy for this method of weight loss to work. Her temperature is 37° C (98.6° F), respirations are 15/min, pulse is 67/min, and blood pressure is 122/88 mm Hg. Her BMI is 30. Her labs from her past visit show: Fasting blood glucose: 149 mg/dL Glycated hemoglobin (HbA1c): 9.1% Triglycerides: 175 mg/dL LDL-Cholesterol: 102 mg/dL HDL-Cholesterol: 35 mg/dL Total Cholesterol: 180 mg/dL Serum creatinine: 1.0 mg/dL BUN: 12 mg/dL Serum: Albumin: 4.2 gm/dL Alkaline phosphatase: 150 U/L Alanine aminotransferase: 76 U/L Aspartate aminotransferase: 88 U/L After discussing the long term issues that will arise if her health does not improve, she agrees to modify her lifestyle and diet. Which of the following would be the best pharmacotherapy for this patient?

• A. Insulin
• B. Metformin (Correct Answer)
• C. Dietary modification alone
• D. Sitagliptin
• E. Glipizide

Glycogen storage diseases Explanation: ***Metformin*** - This patient has newly diagnosed **type 2 diabetes mellitus** (Fasting blood glucose 149 mg/dL, HbA1c 9.1%) in the setting of obesity (BMI 30). **Metformin** is the **first-line pharmacotherapy** for type 2 diabetes due to its efficacy, favorable safety profile, and potential for weight neutrality or modest weight loss. - Metformin works by **decreasing hepatic glucose production**, decreasing intestinal glucose absorption, and increasing insulin sensitivity. *Insulin* - While insulin is highly effective in lowering blood glucose, it is typically reserved for patients with **very high HbA1c** (often >10%), **symptomatic hyperglycemia**, or those who have failed oral pharmacotherapy, it can also cause **weight gain**. - Initiating insulin as first-line therapy can be overly aggressive and may lead to **hypoglycemia** in patients who can respond to oral agents. *Dietary modification alone* - Although **lifestyle changes** (diet and exercise) are crucial and can be remarkably effective, this patient's **HbA1c of 9.1%** indicates that **monotherapy with diet and exercise alone is insufficient** to achieve glycemic control. - Pharmacotherapy is generally recommended for HbA1c levels **above 7.5%**, even with a commitment to lifestyle changes. *Sitagliptin* - **Sitagliptin** is a **DPP-4 inhibitor** that increases insulin secretion and decreases glucagon secretion in a glucose-dependent manner. - It is often considered a **second-line agent** or an add-on therapy, as its HbA1c-lowering effect is generally less potent than metformin. *Glipizide* - **Glipizide** is a **sulfonylurea** that works by stimulating insulin release from pancreatic beta cells. - It can cause **weight gain** and has a significant risk of **hypoglycemia**, making it a less favorable first-line agent, especially in an obese patient, compared to metformin.

Glycogen storage diseases Flashcard 1 of 5

Question: Which glycogen storage disorder is associated with severe fasting hypoglycemia? _____

Answer: Von Gierke disease

Glycogen storage diseases Flashcard 2 of 5

Question: The hallmark of what glycogen storage disease is a flat venous lactate curve with a rise in ammonia levels during exercise?_____

Answer: McArdle disease

Glycogen storage diseases Flashcard 3 of 5

Question: Which glycogen storage disease has an increased risk for gout? _____

Answer: Von Gierke disease

Glycogen storage diseases Flashcard 4 of 5

Question: Glucocorticoids increase hepatic _____ storage

Answer: glycogen

Glycogen storage diseases Flashcard 5 of 5

Question: Which glycogen storage disorder is associated with accumulation of limit dextrin-like structures? _____

Answer: Cori disease