It is known that those with VLCAD and other long-chain fatty acid oxidation disorders (LC-FAOD) are at risk for muscle fatigue, muscle pain, rhabdomyolysis, and myoglobinuria with excessive physical activity. During activity, those with LC-FAOD have a reduced capacity for fatty acid oxidation resulting in reduced production of free fatty acids and ketones as available substrates, and reduced mitochondrial capacity for adenosine triphosphate (ATP) production (F.4375, F.4363, F.4236, F.3962). Thus, individuals with VLCAD are commonly advised to avoid extreme or prolonged physical activity as a strategy to prevent rhabdomyolysis and metabolic decompensation (F.6, F.633, F.4052, F.4397, G.123, G.126).

Yet, there is evidence that in individuals with LC-FAOD, routine physical activity promotes LBM, lowers heart rate during activity, and may improve muscle substrate utilization (F.4236, G.123). Rather than recommending avoidance of physical activity, promoting regular exercise (adjusted to the individual’s disease severity and current clinical status while assuring sufficient energy and appropriate substrates to support energy production in muscle) may help prevent rhabdomyolysis and achieve other positive outcomes.

While research specific to physical activity and exercise in VLCAD is emerging, evidence-based guidelines for physical activity for the general population can inform management in VLCAD.

The 2018 Physical Activity Guidelines from the U.S. Department of Health and Human Services recommend regular physical activity for all, regardless of age or disability (Y.30). While the goal of 30 minutes of moderate physical activity five days per week, at a minimum, is recommended, the latest scientific report indicates that any increase in physical activity above the individual's baseline, replacing sedentary activity with low-intensity activity, and including bouts of moderate-to-vigorous physical activity of even 10 minutes or less, produce positive health benefits (Y.30). Benefits include increases in LBM, muscle and bone strength, improved perceived quality of life, and reduced incidence and progression of numerous chronic diseases.

The American Academy of Pediatrics Bright Future guidelines indicate children and adolescents should complete 60 minutes or more of physical activity throughout the day, including aerobic, muscle strengthening and bone strengthening activities (Y.29).

A Metabolic RD listerv commentary focusing on adults with VLCAD who have worsening symptoms with age suggested that routine exercise might prevent episodes of rhabdomyolysis and decline in function. The natural aging process puts additional stress on the fatty acid oxidation (FAO) system, possibly exacerbating symptoms with age. Natural age-related changes include decreases in fast-twitch fibers vs slow-twitch fibers, a decline in myocyte mitochondria, and a gradual decrease in LBM. Per commentator, there is a balance between sufficient activity and too much activity, which can induce decompensation. As patients with LC-FAOD age, providing adequate protein and energy to maintain as much LBM as possible is also helpful (G.140).

Nominal Group

There was consensus among participants that routine physical activity should be encouraged, with duration and intensity adjusted to tolerance, and that messages implying inactivity be avoided.

Delphi 2

There was 100% consensus to encourage asymptomatic individuals with VLCAD to participate in normal physical activity for age, as tolerated, and to discourage a sedentary lifestyle.

Tolerance for physical activity (participation without symptoms of fatigue, pain, or rhabdomyolysis) is affected by the severity of VLCAD and its effect on muscular energy production, as well as the amount, type, and timing of energy substrates provided through dietary intake.

Submaximal exercise for <20 minutes appears safe for individuals with mild muscular VLCAD. Using a bicycle ergometer test, respiratory exchange ratio (RER) was similar in two adult women with VLCAD compared to four matched controls, although mean heart rate was higher among the women with VLCAD compared to controls. At the end of the exercise test, blood glucose and lactate were not different in the two women compared to controls (G.143).

Maximal body fat oxidation (FATMAX) and exercise endurance were evaluated in 5 patients with VLCAD (4 with a history of myopathic presentations and 1 who remained asymptomatic) and 5 age-matched healthy controls who completed two separate cycle tests of 45 minutes duration (F.4236). Overall, this study demonstrated that the sustained workload of the myopathic patients with VLCAD was 46% lower than controls, although workload remained normal in the asymptomatic patient with VLCAD. Additionally, oxygen consumption (VO²) peak was 55% lower, and peak rate of fat oxidation/kg body mass was 46% lower in the myopathic patients compared to controls. The researchers discussed potential therapeutic strategies for minimizing risk of exertional rhabdomyolysis including exercise training programs to reverse any slow-to-fast phenotypic adaptation of skeletal muscle in VLCAD patients (F.4236).

In a practice survey, metabolic physicians from Canada recommended "avoidance of prolonged exercise" in LC-FAOD (but not specific to VLCAD) (F.661). Prolonged exercise has been identified as >45 minutes (G.126).

To avoid prolonged exercise and reduce, but not prevent, the incidence of rhabdomyolysis and improve exercise capacity of moderate intensity, the following recommendations have been suggested: provide MCT prior to exercise, take a 10 to 15 minute break after 30 to 45 minutes of exercise, and provide a carbohydrate-containing snack or beverage during each break (G.123, G.126).

Nominal Group

Nominal group participants agreed that it was prudent to avoid prolonged (>45 minutes) physical activity, although it was noted that laboratory evidence confirms that some individuals with VLCAD, depending on their training and usual activity level, can remain active for longer periods without apparent difficulty or excessive increases in creatine kinase (CK) concentrations. There was consensus that inactivity should be discouraged, and physical activity/exercise should be encouraged with adjustment of duration and intensity to the level tolerated by the individual. Additionally, there is a need to help families recognize the energy needs of, and prepare for, special exertional activities beyond the individual's baseline physical activity such as a day at the zoo or a swimming party.

The amount, type, and timing of energy intake to support physical activity have important implications for maximizing muscular energy production and supporting exercise tolerance (L.346).  Energy intake must be sufficient to prevent catabolism and must be balanced with energy expenditure to avoid contributing to weight gain. Energy sources (fat, carbohydrate, and/or protein) function differently at different stages of energy metabolism and recovery. Thus, the timing of macronutrient intake is important to assure substrate availability during and after exercise (F.3962, G.123).

Providing a MCT supplement prior to exercise can alter substrate oxidation for individuals with LC-FAOD and increase exercise tolerance (F.659). Carbohydrate and protein are used during exercise to replenish blood glucose; and up to 45 minutes post-exercise, a snack with a carbohydrate to protein ratio of 3:1 is recommended to maximize glycogen resynthesis (G.123) and repair muscle tissue (L.346).

Nominal Group

There was consensus among nominal group participants that the individual/family should plan for adequate calories and fluids for routine physical activity, as well as for activities that are outside the normal routine (such as a day at the zoo or a swimming party).

Concern was expressed about the additional calories from MCT when used as a "supplement" before exercise. To avoid extra weight gain, there was consensus that one of the individual's "usual" MCT doses should be given before exercise rather than providing an additional dose.

In unaffected individuals at rest, skeletal muscle utilizes fat for energy generation almost exclusively (85% to 90% of total energy). During the first 20 minutes of exercise, muscle glycogen stores provide the majority of energy.  Thereafter, the ratio of energy from stored carbohydrate and fatty acids is dependent on the intensity of the exercise. At low or moderate exercise intensity, fatty acids provide as much as 60% of the required energy for exercise (G.141).

In VLCAD, rhabdomyolysis may be related to an energy deficit in skeletal muscle resulting from the inability to oxidize long-chain fatty acids (LCFA) (G.141). Adults with a myopathic form of VLCAD are able to utilize glycogen stores for energy, but are not able to increase fatty acid oxidation in response to increased physical activity (F.4363), and the respiratory exchange ratio (RER), glucose disposal, and total carbohydrate needs increase (F.3962). Impaired fatty acid oxidation has implications particularly for individuals with VLCAD participating in long-term, low-intensity exercise compared to short term, high intensity exercise (F.4363).

A high-carbohydrate, MCT-supplemented diet is hypothesized to provide energy during prolonged exercise (F.4363). However, the preferred form of energy has been controversial. Carbohydrates before and during exercise may help to prevent the onset of exercise-induced rhabdomyolysis (G.141). Oral MCT supplementation, with or without carbohydrates, immediately prior to exercise may bypass the metabolic block in fatty acid oxidation and improve exercise tolerance. Oral MCT is rapidly absorbed into the circulatory system (within 20 minutes) and is preferentially oxidized by liver and muscle (G.141).

Two adult male patients with late onset myopathic VLCAD participated in an exercise intervention to see if intravenous (IV) dextrose or oral MCT (mixed in skim milk) improved exercise tolerance as measured by four blinded 60-minute cycle tests (placebo/glucose and placebo/MCT). No improvement in exercise tolerance (as measured by heart rate and perceived exertion) was found with either IV dextrose or MCT compared to placebo (F.4377).

Eleven participants with LC-FAOD, including one adult with VLCAD, were given an isocaloric oral dose of carbohydrate (1g/kg LBM) or MCT oil (0.5 g/kg LBM) 20 minutes prior to a 45-minute moderate intensity exercise session. (Moderate exercise intensity was defined as 60 to 70% maximal heart rate). On MCT, participants showed a lower RER, suggesting greater oxidation of lipid during the bout of exercise with MCT compared to carbohydrate supplementation. This study also found a lower steady-state heart rate, increased ketone production and increased concentrations of intermediates of glycolysis (pyruvate/lactate) following a MCT dose compared to a carbohydrate dose. The researchers concluded that individuals with LC-FAOD, including VLCAD, may benefit from MCT prior to exercise as this provides an alternate substrate particularly for cardiac muscle, thus reducing overall cardiac workload and increasing exercise tolerance (F.659).

Delphi 2

There was 100% overall consensus (MD/RD) with the statement "For individuals not tolerating physical activity with usual diet modifications, suggest MCT supplementation prior to exercise."

There was 100% overall consensus (MD/RD) to provide MCT 20 minutes prior to exercise for the maximum benefit.

Five reports include information about the dose of pre-exercise MCT. Doses ranged from 0.25-0.5 g/kg LBM or 0.1-0.3 g/kg total body weight (F.659, F.4375, G.97, G.127, G.128). Muscle pain was reduced with a MCT dose of 0.3 g/kg LBM or 0.15-0.2 g/kg total body weight with or without carbohydrate (G.127). Another report listed the same dose (0.15-0.2 g/kg total body weight) but recommended providing it with a complex carbohydrate source (no dose specified) (G.128). In a retrospective review including 22 patients with VLCAD diagnosed through newborn screening (NBS), the 8 patients who remained symptom-free at 5 years of age were on a "relaxed" healthy low fat diet with 0.25 g/kg MCT given prior to exercise (F.4375). Based on long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)/trifunctional protein (TFP) studies, a dose of 0.5 g/kg LBM given 20 minutes before exercise was suggested for older individuals with VLCAD who have exercise intolerance (G.97). In a webinar presentation, the pre-exercise dosing recommendation for MCT was 0.1-0.2 g/kg total body weight mixed in a 6-8% glucose solution (Gatorade/apple juice), given 20-45 minutes before exercise (G.123).

MCT acceptance and gastrointestinal tolerance may be an issue for individuals with mild and moderate VLCAD who do not routinely consume MCT. Smaller doses and mixing with carbohydrate sources have been used to address this problem (F.659, G.123).

To avoid the potential of excess energy intake and weight gain, the individual's pre-exercise MCT dose can be calculated as part of the total nutrition prescription, and one of the individual's "usual" doses of MCT can be timed to coincide with exercise to avoid the need for an additional dose (G.123).

Delphi 2

There was 85% consensus (MD/RD) with the recommendation "Adjust MCT dose to improve exercise tolerance and prevent or minimize symptoms. Start with the low end of the recommended range and titrate to achieve exercise goal (MCT dose ranges from 0.25-0.5 g/kg LBM or 0.1-0.3 g/kg total body weight)." An MD commented that an additional dose during the activity may be needed depending on its duration.

Specific recommendations for fluid intake before, during, and after exercise were not identified in the reviewed evidence specific to VLCAD management. Thus, recommendations for the healthy population were reviewed.

Fluid needs are highly variable and depend on the intensity and duration of the activity and environmental conditions. General guidelines for active children include 100 to 250 ml of fluid every 20 minutes for 9 to 12-year-old children and up to 1 to 1.5 L per hour in adolescents, provided their pre-activity hydration is sufficient (L.340).

A joint statement on nutrition and athletic performance from the Academy of Nutrition and Dietetics, Dietitians of Canada, and the American College of Sports Medicine provides recommendations for fluid intake for active adults and athletes (L.346).

Fluid for hydration and to replace sweat losses:

• Before exercise: fluid volume equivalent to 5 to 10 ml/kg body weight in the 2 to 4 hours before exercise.
• During exercise: 0.4 to 0.8 L fluid per hour.
• After exercise: sufficient fluids to replace sweat loss and restore dehydration; typically, 1.25 to 1.5 L fluid for every 1 kg body weight lost during the activity.

Delphi 1

85% of MD and RD respondents agreed that providing extra fluids before, during and after exercise is an appropriate dietary intervention to help individuals with VLCAD tolerate physical activity or exercise.