Acute Mitochondrial Dysfunction in Proprionic Acidemia
Biochemical/Metabolic and Therapeutics
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Introduction
Propionic acidemia (PA) is a rare inborn error of metabolism resulting in an inability to break down specific amino acids, odd-chain fatty acids, and cholesterols. The toxic metabolites which build up are known to inhibit pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. While mitochondrial dysfunction is known to be an integral component of PA pathophysiology, guidelines on incorporating this paradigm into acute management are not well defined.
Case Presentation
We present a patient admitted to Boston Children’s Hospital for an acute PA decompensation. He is a known patient with biallelic pathogenic variants in the PCCB gene. He initially presented for emesis and fatigue and was admitted for fluid rehydration. After initial clinical and biochemical improvement, on day 3 of hospitalization the patient had an abrupt metabolic decompensation.
Diagnostic Workup
Labs in the evening of hospitalization day 3 showed a venous blood gas with pH of 7.035 and a bicarbonate of 9 mmol/L. His anion gap was 26 mmol/L. He was hyperglycemic to 558 mg/dL and his lactate levels rose to 13.8 mmol/L. The next day, after initially settling, he had altered mental status and again was hyperglycemic to 450 mg/dL, and his lactate had risen back up to 11 mmol/L. Evaluation for diabetic ketoacidosis was negative: his A1C and β-hydroxybutyrate were both normal. His ammonia levels were also trended during this period, all of which were normal.
Treatment and Management
In consideration of severe metabolic decompensation without a clear etiology and a normal ammonia, our treatment plan framework shifted towards consideration of mitochondrial dysfunction in a patient under significant physiologic stress. Due to concern for altered mental status head CT was done and was normal. Dextrose infusion was stopped and the patient was placed on a bicarbonate drip until his blood pH normalized. Nutritional support was given via TPN with limited dextrose. He was given a mitothondrial cocktail consisting of Co-Q10, thiamine, and N-acetylcysteine.
Outcome and Follow-Up
Over the next 6 days in the hospital after these interventions were made, our patient stabilized and was discharged home.
Discussion
We report an acute, severe decompensation in a PA patient with patterns consistent with severe mitochondrial dysfunction. This clinical picture is rare, and not reported commonly in literature (with 5 case reports discussing hyperglycemia in PA or MMA in total). Furthermore, outcomes in these cases are poor, with a high mortality rate. In our case, shifting therapy away from usual PA management or management of DKA (a common pattern) and aggressively correcting blood pH and eliminating dextrose allowed for our patient to stabilize. Our framework for understanding the pathophysiology of this decompensation is that significantly inhibited mitochondrial function resulted in an inability to tolerate high glucose loads and energetic demands from a stress state. This then led to further lactate shunting, acidosis, and worsening clinical status until these values were corrected.
Conclusion
Mitochondrial dysfunction in PA can present as a severe acidosis with life-threatening complications. Aggressive correction of the patient’s acid/base status and elimination of dextrose were critical to changing the clinical outcome in this case.
Propionic acidemia (PA) is a rare inborn error of metabolism resulting in an inability to break down specific amino acids, odd-chain fatty acids, and cholesterols. The toxic metabolites which build up are known to inhibit pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. While mitochondrial dysfunction is known to be an integral component of PA pathophysiology, guidelines on incorporating this paradigm into acute management are not well defined.
Case Presentation
We present a patient admitted to Boston Children’s Hospital for an acute PA decompensation. He is a known patient with biallelic pathogenic variants in the PCCB gene. He initially presented for emesis and fatigue and was admitted for fluid rehydration. After initial clinical and biochemical improvement, on day 3 of hospitalization the patient had an abrupt metabolic decompensation.
Diagnostic Workup
Labs in the evening of hospitalization day 3 showed a venous blood gas with pH of 7.035 and a bicarbonate of 9 mmol/L. His anion gap was 26 mmol/L. He was hyperglycemic to 558 mg/dL and his lactate levels rose to 13.8 mmol/L. The next day, after initially settling, he had altered mental status and again was hyperglycemic to 450 mg/dL, and his lactate had risen back up to 11 mmol/L. Evaluation for diabetic ketoacidosis was negative: his A1C and β-hydroxybutyrate were both normal. His ammonia levels were also trended during this period, all of which were normal.
Treatment and Management
In consideration of severe metabolic decompensation without a clear etiology and a normal ammonia, our treatment plan framework shifted towards consideration of mitochondrial dysfunction in a patient under significant physiologic stress. Due to concern for altered mental status head CT was done and was normal. Dextrose infusion was stopped and the patient was placed on a bicarbonate drip until his blood pH normalized. Nutritional support was given via TPN with limited dextrose. He was given a mitothondrial cocktail consisting of Co-Q10, thiamine, and N-acetylcysteine.
Outcome and Follow-Up
Over the next 6 days in the hospital after these interventions were made, our patient stabilized and was discharged home.
Discussion
We report an acute, severe decompensation in a PA patient with patterns consistent with severe mitochondrial dysfunction. This clinical picture is rare, and not reported commonly in literature (with 5 case reports discussing hyperglycemia in PA or MMA in total). Furthermore, outcomes in these cases are poor, with a high mortality rate. In our case, shifting therapy away from usual PA management or management of DKA (a common pattern) and aggressively correcting blood pH and eliminating dextrose allowed for our patient to stabilize. Our framework for understanding the pathophysiology of this decompensation is that significantly inhibited mitochondrial function resulted in an inability to tolerate high glucose loads and energetic demands from a stress state. This then led to further lactate shunting, acidosis, and worsening clinical status until these values were corrected.
Conclusion
Mitochondrial dysfunction in PA can present as a severe acidosis with life-threatening complications. Aggressive correction of the patient’s acid/base status and elimination of dextrose were critical to changing the clinical outcome in this case.