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USMLE® Step 1 Question of the Day: Sleep episodes

Osmosis Team
Published on Dec 20, 2023. Updated on Nov 29, 2023.

This week, we are sharing another USMLE® Step 1-style practice question to test your knowledge of medical topics. Today's case focuses on a 6-month-old infant facing poor weight gain, weak cry, and muscle hypotonia. With genetic work-up pointing to a PDHA1 gene mutation and elevated serum lactate levels, can you identify the normal function of the enzyme likely deficient in this challenging pediatric presentation? Test your diagnostic skills with this USMLE Step 1 question.

A 6-month-old male infant is brought to the pediatrician for evaluation of poor weight gain. The patient was born at 38-weeks gestational age via an uncomplicated vaginal delivery. According to his parents, the patient has had poor feeding, a weak cry, and appears more frail than other children of a similar age. The patient is at the 15th percentile for length and 5th percentile for weight. Temperature is 37.0°C (98.6°F), blood pressure is 95/50 mmHg, and pulse is 102/min. Widespread muscle hypotonia is noted on physical examination. Laboratory testing reveals elevated serum lactate and alanine levels. Further genetic work-up reveals a mutation in the PDHA1 gene. Which of the following best describes the normal function of the enzyme likely deficient in this patient’s condition?

A. Conversion of glucose to glucose-6-phosphate

B. Reduction of NADP+ plus to NADPH

C. Phosphorylation of fructose to fructose-1-phosphate

D. Conversion of pyruvate to acetyl-CoA

E. Breakdown of fructose-1-phosphate to glyceraldehyde

Scroll down for the correct answer!

The correct answer to today's USMLE® Step 1 Question is...

D. Conversion of pyruvate to acetyl-CoA

Before we get to the Main Explanation, let's look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!

Incorrect answer explanations

A. Conversion of glucose to glucose-6-phosphate

Incorrect: Hexokinase and glucokinase are involved in converting glucose to glucose-6-phosphate. A deficiency in either of these enzymes would result in elevated serum glucose levels, as opposed to lactate and alanine levels.

B. Reduction of NADP+ plus to NADPH 

Incorrect: Glucose-6-phosphate dehydrogenase (G6PD) is responsible for converting NADP+ to NADPH. G6PD deficiency predisposes patients to hemolytic anemia when exposed to oxidative stress. The condition would not manifest with muscle hypotonia, poor weight gain, or a weak cry.

C. Phosphorylation of fructose to fructose-1-phosphate

Incorrect: Fructokinase converts fructose to fructose-1-phosphate. A defect in this enzyme would result in essential fructosuria. The condition is largely asymptomatic, and laboratory testing would instead demonstrate elevated serum and urine fructose levels. 

E. Breakdown of fructose-1-phosphate to glyceraldehyde

Incorrect: Aldolase B is responsible for breaking down fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate. Deficiency of this enzyme would cause hereditary fructose intolerance, which manifests with cirrhosis, jaundice, and vomiting. Symptoms generally begin only after sources of fructose (e.g., fruits, juices) are introduced into a child’s diet at around 6 months of age.

Main Explanation

This patient is presenting with hypotonia, a weak cry, and poor weight gain. Laboratory testing demonstrates elevated alanine and lactate levels along with a PDHA1 gene mutation. In combination, these findings are concerning for pyruvate dehydrogenase complex (PDC) deficiency

PDC deficiency is an X-linked recessive condition caused by mutations in the PDHA1 gene. PDC utilizes the cofactors thiamine, lipoic acid, CoA, FAD, and NAD+ to convert pyruvate into acetyl-CoA, which enters the Krebs cycle to produce ATP. In PDC deficiency, acetyl-CoA production is impaired, and there is reduced ATP synthesis. Hence, the condition primarily affects cells with high energy requirements, such as neurons and myocytes. At the same time, pyruvate accumulates and is converted into lactate and alanine

Symptoms of PDC deficiency typically begin during infancy and include lethargy, hypotonia, and poor feeding. In addition, PDC deficiency may lead to developmental delay, intellectual disability, and seizures

Laboratory testing will demonstrate elevated lactate and alanine levels. Treatment consists of adopting a ketogenic diet, which is a diet low in carbohydrates and high in fat and ketogenic amino acids. This diet results in the generation of ketone bodies, which can be used as an alternative energy source by body tissues.

pyruvate dehydrogenase complex (PDC) deficiency

Major Takeaway

Pyruvate dehydrogenase complex (PDC) deficiency is an X-linked recessive disorder characterized by hypotonia, poor feeding, developmental and intellectual delay, and seizures. Laboratory testing will demonstrate elevated lactate and alanine levels. Treatment involves adhering to a ketogenic diet.  


Gupta, N., Rutledge, C. (2019) Pyruvate dehydrogenase complex deficiency: An unusual cause of recurrent lactic acidosis in a paediatric critical care unit. The Journal of Critical Care Medicine. 5(2), 71-75. Doi: 10.2478/jccm-2019-0012. 

Haddad, A., Mohiuddin, S.S. (2020) “Biochemistry, citric acid cycle”. StatPearls [Internet]. Web Address:


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The United States Medical Licensing Examination (USMLE®) is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). Osmosis is not affiliated with NBME nor FSMB.