Anny Vo, Celia Buetens, and John Jeong
4/3/2026
Case Study #7: Mitochondrial Citric Acid Cycle Disorder in Skeletal Muscles
Case Background1
A male infant at your hospital has failed a hearing test and developed permanent hearing loss. His development was delayed as shown by an exaggerated Moro response (startle reflex) and his height was below the 3rd percentile. He was given supplemental vitamins, such as thiamine and riboflavin. At 5 months, he had motor weakness and hypotonia. At 10 months, he had feeding problems, recurrent emesis (vomiting), and metabolic acidosis from elevated lactate.
Lab Findings1
| Test | Levels |
|---|---|
| Lactate/Pyruvate Panel | Blood lactate: 8.6 mM (normal: 0.5-2.2 mM)Blood pyruvate: 0.14 mM (normal: 0.03-0.08)L/P ratio: 61 |
| Liquid Chromatography tandem Mass Spectrometry | Serum methylmalonic acid: 1,909 nM (normal: 73-271) |
| Skeletal Muscle Acylcarnitine Analysis | Succinylcarnitine: 149 nmol/g (normal < 9.4 nmol/g) |
Key Words: SUCLA2, Anaplerotic Therapy, methylmalonic acid, succinylcarnitine
Analysis
Q1. Based on the Lactate and Pyruvate lab results, what type of dietary change would you recommend to help reduce the lactic acidosis in this patient?
Biochemistry1
Sanger sequencing revealed that the patient has a compound heterozygous mutation in SUCLA2. Mutations in this gene lead to a deficient succinyl-CoA synthetase, and therefore the accumulation of succinyl-CoA, along with methylmalonic acid and succinylcarnitine, both of which are succinyl-CoA–related metabolites. SUCLA2 is mostly expressed in the brain and skeletal muscle.
Q2. After the dietary intervention, the patient’s blood lactate returned to normal levels (1.8 mM). However, over time, the patient developed pronounced lethargy. Further analysis revealed elevated levels of methylmalonic acid and succinylcarnitine.1 Propose an explanation for why energy levels might have decreased despite the initial benefit.
Q3. You were discussing this case with a colleague who informed you of a recent experimental trial to alleviate symptoms of another citric acid cycle disease. This trial aimed to help pediatric twin patients who experienced seizures and exhibited low motor development, truncal hypotonia, and cerebellar atrophy. After genetic sequencing, both children were diagnosed with aconitase 2 deficiency. They were prescribed triheptanoin. While taking triheptanoin, lab findings revealed increased urinary succinate, fumarate, and malate, and the patients’ motor abilities improved. Alleviated symptoms were attributed to the metabolic conversion of triheptanoin to succinyl-CoA.2 Explain how triheptanoin helped to alleviate the twins’ symptoms.
Q4. Would you consider prescribing triheptanoin to your own patient?
References:
- Huang, X.; Bedoyan, J.; Demirbas, D.; Harris, D.; Miron, A.; Edelheit, S.; Grahame, G.; DeBrosse, S.; Wong, L.; Hoppel, C.; Kerr, D.; Anselm, I.; Berry, G. Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metabolism. 2017, 120 (3), 213-222. DOI: 10.1016/j.ymgme.2016.11.005
- Penkl, M.; Mayr, J.; Feichtinger, R.; Reilmann, R.; Debus, O.; Fobker, M.; Penkl, A.; Reunert, J.; Rust, S.; Marquardt, T. Anaplerotic Therapy Using Triheptanoin in Two Brothers Suffering from Aconitase 2 Deficiency. Metabolites. 2024, 14, 238.10.3390/metabo14040238
- Nelson, D. L.; Cox, M. M. Lehninger Principles of Biochemistry, 6th ed.; W.H. Freeman: New York, N.Y., 2013.