The current state of our quest to better understand spinal muscular atrophy (SMA) has led scientists to consider the non-neurological pathologies attributable to survival motor neuron (SMN) deficiency. An area that is the subject of intense research is the relationship between SMA and fatty acid oxidation metabolism defects.
“The current therapeutic SMA landscape is at a turning point, whereby a holistic multisystemic approach to the understanding of disease pathophysiology is at the forefront of fundamental research and translational endeavors,” Watson and colleagues wrote in Brain Sciences.
Based on appearances, patients with SMA often seem to have a normal weight or be underweight. However, in-depth anthropometric studies have demonstrated that there appears to be a high incidence of increased adiposity among patients with SMA.
Studies have found that although patients with SMA tend to have a normal BMI, they tend to also have increased fat mass compared to age-matched individuals without SMA. This is likely due to the fact that SMA causes the loss of lean mass due to muscle wasting; this then masks any elevation in fat mass when the patient’s BMI is measured.
Read more about SMA etiology
The BMI does not differentiate between muscle mass and fat mass; hence, it may not be the best tool to estimate adiposity in patients with SMA.
“BMI is by no means a perfect measure of adiposity,” O’Rourke wrote in Surgery for Obesity and Related Diseases. “Further complicating analysis, BMI displays quantitatively and qualitatively different associations with various metabolic diseases, and when considered as a constellation of pathologies, the picture becomes even more confusing.”
Another possible cause for the higher adiposity observed in patients with SMA is an imbalance between dietary intake and the expenditure of energy. Because SMA causes progressive muscle wasting, patients tend to become less mobile as the disease progresses. This means that patients with SMA have fewer opportunities to spend energy, which eventually leads to fat accumulation.
Owing to the heterogeneity of disease severity among patients with SMA, some patients have little to no limitations in their mobility. Studies have revealed that some patients have high motor skills as measured by the Hammersmith Functional Motor Scale (HFMS). The culprit for excessive adiposity in these cases, therefore, is likely to be excessive calorie intake.
“However, it is also worth considering whether increased fat mass could be due to mechanistic defects in fat metabolism, specifically fatty acid oxidation, which could have a significant repercussion on whole-body homeostasis and health of SMA patients,” Watson and colleagues wrote.
Fatty Acid Oxidation Disorder
Fats have many important biological functions, such as energy metabolism. When a person is fasting, adipose tissue releases triglycerides that can be used for energy production. Glycerol is broken down via oxidation to ultimately form acetyl-CoA. Acetyl-CoA and glucose then enter the Krebs cycle.
“Krebs cycle is the main metabolic pathway, in supplying energy to the body, generating about 70% of the ATP,” Gasmi and colleagues wrote in Archives of Toxicology. “The oxidation pathways of fatty acids, glucose, amino acids, acetate, [and] ketone bodies generate acetyl-CoA, which constitutes its substrate.”
Read more about long chain fatty acid oxidation disorder
Fatty acid oxidation primarily occurs via beta oxidation in the matrix of the mitochondria. Outside the mitochondria, beta oxidation occurs inside peroxisomes. Very long chain fatty acids undergo omega oxidation in the endoplasmic reticulum; the endoplasmic reticulum, in turn, converts them into dicarboxylic acids, which then undergo beta oxidation inside peroxisomes.
“Omega oxidation accounts for only a small proportion of all fatty acid oxidations but compensates when there is defective/deficient beta oxidation, leading to an accumulation of [dicarboxylic acids], the excess of which is excreted into the urine,” Watson and colleagues wrote. “[Dicarboxylic acids] are an important, though often non-specific marker for fatty acid oxidation disorders.”
We understand that fatty acid metabolism is often disrupted in SMA patients, but we are unsure of how. Studies have demonstrated that patients with SMA are often deficient in acyl-CoA dehydrogenase, the enzyme involved in the first step of beta oxidation.
Watson and colleagues summarized fatty acid oxidation defects in SMA into 6 points: decreased free carnitine, decreased activity of the mitochondrial trifunctional protein (MTP), increased esterified carnitine, increased levels of dodecanoic acid (C12), decreased activity of acyl carnitine dehydrogenase (ACAD), and dicarboxylic aciduria.
The combination of increased fat mass in young patients with SMA and fatty acid oxidation defects creates a need for a patient’s dietary plan to be carefully designed.
In fact, physicians are increasingly realizing the importance of dietary intervention in patients with SMA. Current nutritional guidelines for SMA recommend dietary adjustments based on factors such as difficulty in swallowing and glycemic control. To control adiposity, the natural solution appears to be eating diets that are low in fat; however, these diets may be deficient in essential fatty acids.
“There is thus a clear need for more in-depth pre-clinical and clinical studies on dietary interventions in SMA to help inform clear and evidence-based nutritional guidelines aimed at reducing the impact of aberrant fatty acid metabolism on whole-body health,” Watson et al wrote.
Watson KS, Boukhloufi I, Bowerman M, Parson SH. The relationship between body composition, fatty acid metabolism and diet in spinal muscular atrophy. Brain Sci. 2021;11(2):131. doi:10.3390/brainsci11020131
Gasmi A, Peana M, Arshad M, Butnariu M, Menzel A, Bjørklund G. Krebs cycle: activators, inhibitors and their roles in the modulation of carcinogenesis. Arch Toxicol. 2021;95(4):1161-1178. doi:10.1007/s00204-021-02974-9
O’Rourke RW. Adipose tissue and the physiologic underpinnings of metabolic disease. Surg Obes Relat Dis. 2018;14(11):1755-1763. doi:10.1016/j.soard.2018.07.032