Abnormal Fatty Acid Oxidation in Spinal Muscular Atrophy


Fatty acids are an important source of cellular energy, and deficiencies in fatty acids and their oxidation can lead to a variety of health issues, including liver dysfunction, cardiomyopathy, skeletal myopathy and hepatic disease.1 Cancer studies have shown that excessive fatty acid oxidation can induce muscle atrophy,2 and research in spinal muscular atrophy (SMA) has indeed demonstrated that SMA is associated with abnormal fatty acid oxidation.3 

The types and degrees of fatty acid oxidation abnormalities in SMA patients vary depending on factors such as SMA type.3 For instance, total to free serum carnitine ratios have higher esterified fractions than normal in most SMA type 1 children and some SMA type 2 children but are within the normal range for other SMA type 2 patients and for SMA type 3 patients. Similarly, mild to moderate medium-chain dicarboxylic aciduria has been demonstrated through urinary organic acid analysis in SMA type 1 patients and SMA type 2 patients, but these organic acids have been found to be normal in some SMA type 2 patients and in most SMA type 3 patients. 

The measurement of beta-oxidation of muscle intramitochondrial has demonstrated changes in fatty acid activity in SMA patients.3 Activity has been shown to be significantly reduced in both short-chain and long-chain L-3-hydroxyacyl-CoA dehydrogenase, in acetoacetyl-CoA thiolase, and in 3-ketoacyl-CoA thiolase. However, crotonase activity appears to be normal, resulting in a drastic increase in activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase with short-chain and long-chain substrates. These ratios have been observed to be as much as five times higher than normal in SMA patients. 

The cause for changes in fatty acid oxidation in SMA patients is not clear, but long-chain fatty acid oxidation disorders may reflect inflammation and lipid accumulation secondary to progressive muscle damage. Experts suggest that the abnormalities of mitochondrial multifunctional enzyme complex that are seen in SMA patients may be improved through dietary and nutritional measures that could minimize dependence on fatty acid oxidation.4 

Creatine monohydrate supplementation is one nutritional intervention that has been studied in neuromuscular disorders and has been shown to enhance mitochondrial function and provide benefits for those with fatty acid oxidation defects.5 Clinical trials in patients with Duchenne muscular dystrophy and Becker’s muscular dystrophy, for example, have provided evidence that creatine monohydrate supplementation improves bone health. Future research into the causes and impacts of abnormal fatty acid oxidation in SMA patients should help to clarify how these issues can best be addressed to help this set of patients.


1. Vishwanath VA. Fatty acid beta-oxidation disorders: A brief review. Ann Neurosci. 2016;23(1):51-55. doi:10.1159/000443556

2. Fukawa T, Yan-Jiang BC, Min-Wen JC, et al. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nat Med. 2016;22(6):666-671. doi:10.1038/nm.4093

3. Tein I, Sloane AE, Donner EJ, Lehotay DC, Millington DS, Kelley RI. Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)? Pediatr Neurol. 1995;12(1):21-30.

4. Diekman EF, van der Pol WL, Nievelstein RAJ, Houten SM, Wijburg FA, Visser G. Muscle MRI in patients with long-chain fatty acid oxidation disorders. J Inherit Metab Dis. 2014;37(3):405-413. doi:10.1007/s10545-013-9666-3

5. Tarnopolsky MA. Clinical use of creatine in neuromuscular and neurometabolic disorders. Subcell Biochem. 2007;46:183-204.