Triheptanoin in Pyruvate Dehydrogenase Deficiency

In pyruvate dehydrogenase (PDH) deficiency, conversion of pyruvate to acetyl CoA is impaired. As acetyl CoA is the end product of glucose and other monosaccharides to enter the tricarboxylic acid (TCA) cycle for ATP generation, there is deficiency of energy production from carbohydrates. Glucose is the main energy source of brain and hence, neurological abnormalities are the predominant manifestations in PDH deficiency. However, clinical presentation of PDH varies in severity.[1] Neonatal form presents with severe lactic acidosis, tachypnea, hypotonia, and encephalopathy. Patients may present later in infancy with global developmental delays, seizures, encephalopathy, breathing abnormalities, hypotonia, and microcephaly. Rare late onset patients may present with unexplained chronic or recurrent neurological symptoms such as intermittent ataxia.[2] [3] Thiamine supplementation and ketogenic diet are the current cornerstones of management, but these are ineffective in severe cases. Acetyl CoA derived from fat in the ketogenic diet enters TCA cycle and generate ATP thus bypassing the enzyme defect in PDH.[4]

Triheptanoin is a medium-chain triglyceride of three 7-carbon fatty acids. Triheptanoin is metabolized rapidly in the gut to form glycerol and heptanoate. Heptanoate is a 7-carbon fatty acid and unlike even-chain fatty acids which are oxidized to acetyl-coA only, heptanoate oxidation can provide both acetyl-coA and propionyl-CoA.[5] Propionyl-CoA is converted to succinyl-CoA, a TCA cycle intermediate. Thus metabolism of triheptanoin provides two key substrates for the TCA cycle, acetyl-CoA and succinyl-CoA. Hence, triheptanoin can be an efficient energy source in PDH compared with even-chain fatty acids in ketogenic diet. Thus far, there is no report of triheptanoin use in PDH deficiency in literature. Here, I share observations of triheptanoin use in a patient with PDH deficiency.

Patient was born full term to a 39-year-old mother. She was diagnosed with the Down syndrome (trisomy 21) antenatally which was also confirmed by postnatal chromosome analysis. Shortly after birth, she developed lactic acidosis and respiratory failure. PDH was clinically suspected and confirmed by molecular genetic testing (c.858_861dupTTAC, frame shift mutation in PDHA1). In addition, she had severe brain malformations (marked reduction in cerebral volume, diffuse thinning of cerebral mantle with a three layered appearance, grossly enlarged ventricles, and multicystic encephalomalacia), and large perimembranous ventricular septal defect of heart. Her neuroimaging findings were previously reported.[6] Lactic acidosis improved with low-carbohydrate high-fat diet and thiamine supplementation. However, patient started to have frequent apneic episodes and developed progressive respiratory failure secondary to pulmonary hypertension. This led to further elevation in plasma lactate. Due to her poor prognosis, triheptanoin was started on a compassionate basis at 2.5 months old. It was started at a dose of 4 g/kg/day in four divided doses to provide approximately 25% of daily calorie requirement. It was administered via gastrostomy tube mixed with the patient's formula which consisted of Nutramigen supplemented with amino acids mixture. After a week of starting triheptanoin, there was no change in baseline lactate level which stayed between 7 and 10 mmol/L. However, the apneic episodes became less frequent. Triheptanoin was stopped after a week of start as there was no improvement in plasma lactate. This led to further worsening of respiratory status and elevation of lactate (up to 14.7 mmol/L). Hence, it was restarted after 10 days with subsequent return of lactate and respiratory status to the baseline. Triheptanoin dose was later adjusted to provide approximately 35% of daily calorie requirements. The patient continued to have apneic episodes and died of respiratory failure at 6 months old. Interestingly, patient did show significant weight gain after staring triheptanoin. Her weight as compared with girls with the Down syndrome and Center for Disease Control and Prevention (CDC) growth curves for girls has been shown in [Fig. 1].

Fig. 1 Weight of the patient with age as compared with girls with the Down syndrome (A) and CDC growth curves for girls of age 0–36 months (B). Triheptanoin was started at 2.5 months old shown by arrow. CDC, Center for Disease Control and Prevention.

Due to severe comorbidities, effect of triheptanoin is difficult to assess in this patient except an objective evidence of improvement in growth. Triheptanoin has been found to be useful in disorders associated with brain energy deficit.[5] [7] [8] PDH deficiency is also a disorder of brain energy metabolism. Systemic studies are needed to assess the effectiveness of triheptanoin in PDH deficiency. It may be particularly helpful in milder, late onset variants.

Author's Contribution

P.P. drafted the first manuscript, was involved in patient care, laboratory interpretation, and revising the manuscript critically for important intellectual content.

Publication History

Received: 08 April 2020

Accepted: 25 May 2020

Article published online:
05 August 2020

• References

• 1 Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012; 106 (03) 385-394
• 2 Mellick G, Price L, Boyle R. Late-onset presentation of pyruvate dehydrogenase deficiency. Mov Disord 2004; 19 (06) 727-729
• 3 Barnerias C, Saudubray JM, Touati G. et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol 2010; 52 (02) e1-e9
• 4 Sofou K, Dahlin M, Hallböök T, Lindefeldt M, Viggedal G, Darin N. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis 2017; 40 (02) 237-245
• 5 Mochel F. Triheptanoin for the treatment of brain energy deficit: A 14-year experience. J Neurosci Res 2017; 95 (11) 2236-2243
• 6 Chapel-Crespo CC, Lala S, Prasun P. Severe brain malformations in an infant with pyruvate dehydrogenase deficiency and Down syndrome. Pediatr Neurol 2017; 75: 101-102
• 7 Wehbe Z, Tucci S. Therapeutic potential of triheptanoin in metabolic and neurodegenerative diseases. J Inherit Metab Dis 2019(e-pub ahead of print)
• 8 Adanyeguh IM, Rinaldi D, Henry PG. et al. Triheptanoin improves brain energy metabolism in patients with Huntington disease. Neurology 2015; 84 (05) 490-495