A 25-year-old graduate student presents to the outpatient clinic with a 9-month history of progressive fatigue, shortness of breath during mild exercise, and generalized muscle weakness that worsens with activity. He reports difficulty climbing stairs and occasional muscle cramps. His medical history is unremarkable, and he takes no medications. Vital signs are within normal limits. Physical examination reveals mild proximal muscle weakness with 4/5 strength in the deltoids and hip flexors. Laboratory studies show an elevated serum lactate level of 4.8 mmol/L (normal <2.0 mmol/L), normal blood glucose, and mildly elevated creatine kinase. Electromyography shows myopathic changes. A muscle biopsy reveals characteristic ragged red fibers on Gomori trichrome staining.
Which of the following enzymes are most likely deficient in this patient’s condition?
E) Pyruvate dehydrogenase
This patient’s presentation, including progressive fatigue, exertional dyspnea, muscle weakness, lactic acidosis, and ragged red fibers on muscle biopsy, strongly suggests a mitochondrial myopathy. Pyruvate dehydrogenase deficiency impairs the conversion of pyruvate to acetyl-CoA, a critical step linking glycolysis to the tricarboxylic acid cycle in mitochondria. This disruption causes pyruvate to accumulate, which is then converted to lactate by lactate dehydrogenase, leading to lactic acidosis. The compensatory mitochondrial proliferation in muscle fibers results in ragged red fibers, seen on biopsy as clumps of abnormal mitochondria. The elevated creatine kinase (CK) and myopathic EMG further support a primary muscle disorder.
Answer choice A: Alpha-1-antitrypsin, is incorrect. Alpha-1-antitrypsin (AAAT) deficiency results from mutations in the SERPINA1 gene, leading to uninhibited neutrophil elastase activity. It is unrelated to mitochondrial function, lactate metabolism, or muscle pathology.
Answer choice B: Carnitine palmitoyl transferase I, is incorrect. This deficiency impairs the transport of long-chain fatty acids into mitochondria for beta-oxidation. This leads to hypoketotic hypoglycemia, liver dysfunction, and muscle cramps, particularly during fasting or prolonged exercise. Patients may present with rhabdomyolysis, but lactic acidosis and ragged red fibers are not features, as the defect is in fatty acid metabolism, not glycolysis or tricarboxylic acid (TCA) cycle function.
Answer choice C: Glucose-6-phosphate dehydrogenase, is incorrect. Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects the pentose phosphate pathway, reducing NADPH production and predisposing red blood cells to oxidative damage, which results in hemolytic anemia. It does not cause lactic acidosis, muscle weakness, or mitochondrial abnormalities like ragged red fibers, and CK is typically normal unless hemolysis causes secondary muscle stress.
Answer choice D: Phenylalanine hydroxylase is incorrect. Phenylalanine hydroxylase deficiency causes phenylketonuria, which results in intellectual disability, seizures, hypopigmentation, and a musty body odor if untreated. Phenylalanine hydroxylase deficiency does not affect mitochondrial function, cause muscle weakness, or produce ragged red fibers, and lactate levels are normal.
Key Learning Point
Pyruvate dehydrogenase deficiency disrupts aerobic metabolism by impairing pyruvate’s entry into the TCA cycle, leading to lactic acidosis and mitochondrial proliferation (ragged red fibers). It is a hallmark of mitochondrial myopathies, diagnosed through clinical presentation, elevated lactate, and muscle biopsy findings, with management focusing on supportive care.
