Illness in very-long chain acyl-coA dehydrogenase deficiency (VLCAD) covers a wide spectrum, ranging from minor decompensation in mild VLCAD to cardiomyopathy in severe VLCAD. This guideline includes recommendations for treating symptomatic individuals as well as prophylaxis to prevent illness and inpatient care for those with moderate or severe VLCAD who are prone to developing cardiomyopathy and/or rhabdomyolysis. Most of the evidence about illness management in VLCAD comes from case studies of individuals presenting with cardiomyopathy, rhabdomyolysis, and/or hypoglycemia. There is no published literature on managing illness in mild VLCAD.
For individuals with cardiomyopathy (with or without rhabdomyolysis or hypoglycemia), nutrition intervention often includes supplemental medium chain triglycerides (MCT-enriched formula in infancy or MCT-based supplements) and restricting intake of long-chain fat (LCF). Diet modification is almost always recommended with other interventions (fluids, glucose, L-carnitine, fasting restrictions), making it difficult to assess the impact of any single intervention. A low-fat diet with MCT supplementation or MCT-containing formula has been shown to reverse cardiomyopathy.
The effect of a MCT-supplemented, low fat diet to prevent or reduce episodes of rhabdomyolysis is inconclusive. In some reports of individuals presenting with both cardiomyopathy and rhabdomyolysis, the cardiomyopathy improved with diet modification, but rhabdomyolysis persisted. In other case reports of individuals with late-onset rhabdomyolysis, providing extra carbohydrate (without MCT) improved symptoms.
Home precautions to prevent symptoms in VLCAD include avoiding long periods of fasting through frequent and/or overnight feedings. Use of uncooked cornstarch (UCCS) has been reported in the literature, but is infrequently used among Delphi survey respondents. Avoidance of extreme and prolonged physical exercise appears to be helpful in preventing rhabdomyolysis. Clear guidelines regarding the recommended duration and intensity of exercise are lacking and the emphasis is on providing sufficient energy to support exercise, as tolerated.
In acute illness, fasting duration is reduced as compared to when well. Moreover, early institution of IV dextrose and adequate hydration helps to prevent a metabolic or myopathic crisis and may resolve or improve cardiomyopathy and rhabdomyolysis. Use of IV lipids is contraindicated during an acute illness.
Caregivers should be provided with, and utilize, an emergency protocol in times-of or leading-up-to a symptomatic presentation. Emergency intervention should not wait for detection of hypoglycemia, which is a late finding in VLCAD. For the same reason, home monitoring of blood glucose for presence of hypoglycemia is not recommended.
The use of carnitine and other medications/supplements during illness is discussed in Recommendation 3.
During illness, adjust the composition of the diet according to the severity of current symptoms:
Individuals with VLCAD who were previously asymptomatic may develop complications related to VLCAD, including serious illnesses with rhabdomyolysis and/or cardiomyopathy. Diet modification may be necessary and is based on disease severity, as described in Recommendation 1.2.
Consensus about recommendations for diet composition are found in Recommendation 1.2
Rhabdomyolysis is skeletal muscle injury that can occur in VLCAD as a result of the inability of muscle cells to produce an adequate amount of energy (L.351). In individuals with VLCAD identified through newborn screening (NBS), rhabdomyolysis is more common than cardiomyopathy and the first episode may appear in the toddler years (between 1 and 3 years of age) as evidenced by elevated creatine kinase (CK) (F.4055). Rhabdomyolysis can also develop later in childhood or beyond and is not usually associated with cardiomyopathy (RECOMMENDATION TABLE #1, VLCAD Phenotypes). However, individuals with the cardiac phenotype may also exhibit rhabdomyolysis with elevated CK concentrations.
In case reports of VLCAD, treatment of rhabdomyolysis alone differs from treatment of rhabdomyolysis that is associated with cardiomyopathy. The table below summarizes 44 articles which includes 69 cases, and indicates that supplemental MCT is always given in patients with a cardiac phenotype, but much less frequently when rhabdomyolysis alone is the presenting symptom. Treatment with a low-fat diet was recommended in 71% of cases presenting with rhabdomyolysis and 60% of cases presenting with cardiomyopathy.
The emphasis in treating rhabdomyolysis is to provide sufficient energy, primarily as carbohydrate, as well as adequate fluid especially in acute presentations (see Recommendation 2.4.1). For chronic management, a high carbohydrate diet or carbohydrate-rich food sources is often recommended for patients with rhabdomyolysis and is associated with a reduction in symptoms; however, specifics about the type and amount of carbohydrate is rarely provided (F.3896, F.6, F.7, F.3851). In one published survey of practitioners, 67% of physicians recommended a high carbohydrate diet, but only about half recommended a carbohydrate supplement such as a glucose polymer (F.661).
TABLE 13 - MCT Use in Individuals with VLCAD and Cardiomyopathy and/or Rhabdomyolysis
NOTE: This table is a summary of published literature used to inform the nutrition recommendations.
|Presenting symptom(s)||Number of cases||Percent of patients prescribed MCT||References|
|Cardiomyopathy only||14||100||F.3712, F.4118, F.660, F.657, F.635, F.626, F.3797, F.4098, F.633, F.4124, F.18, F.15, F.4422, F.656|
|Rhabdomyolysis only||25||44||F.3851, F.7, F.6, F.4052, F.621, F.4049, F.4380, F.4, F.4417, F.622, F.4164, F.4117, F.4051. F.3858, F.3851, F.630, F.17, F.4397, F.3719, F.636, F.658|
|Cardiomyopathy and Rhabdomyolysis||10||90||F.14, F.3884, F.3896, F.654, F.4382|
|Cardiomyopathy, rhabdomyolysis and hypoglycemia||20||80||F.4140, F.4415, F.4, F.3896, F.3735, F.3717|
81% of RDs agree that when treating individuals with acute rhabdomyolysis, emphasize carbohydrate (oral or IV) rather than MCT as an energy source, whereas only 50% of MDs agreed with this statement, with one MD commenting that MCT could be used, as well.
The nominal group experts emphasized that provision of sufficient fluid (at least 1.5 times maintenance) is crucial in treating rhabdomyolysis.
For all individuals with VLCAD, employ strategies to prevent conditions that may lead to metabolic decompensation:
Avoiding extreme or prolonged physical activity to prevent metabolic decompensation is a strategy often mentioned in the VLCAD literature. Yet, there is evidence that in individuals with long-chain fatty acid oxidation disorders (LC-FAOD), physical activity promotes lean body mass (LBM), lowers heart rate, and lowers respiratory quotient (G.123). Thus, promoting regular exercise and providing sufficient energy to support activity may be beneficial in preventing rhabdomyolysis. Guidelines for supporting exercise are given in Recommendation 5.
In reported case studies, avoiding extreme and prolonged physical exercise was recommended along with one or more other precautions such as fasting avoidance and modifying intake by increasing carbohydrate, reducing fat and/or supplementing with MCT. To increase energy intake, MCT was recommended in 5 studies involving 8 adults (ages 30 to 51 years) who presented with rhabdomyolysis. To prevent new episodes of rhabdomyolysis, avoiding excessive exercise was recommended for a 51-year-old female (F.4397), a 47-year-old male (F.3851) for 9 months, and a 32-year-old male (F.622). Another 36-year-old male experienced decreased episodes of myoglobinuria (F.622) and 57-year-old twin sisters (F.6) were able to run 3 kilometers with reduced severity of symptoms by following exercise precautions along with one or more other recommendations. A 30-year-old male (F.4052), however, experienced two more episodes of rhabdomyolysis despite following exercise precautions along with fluid recommendations and a diet with moderate restriction of fat. However, these studies recommending avoidance of extreme exercise provided no specifics regarding the duration or type of exercise.
Providing additional energy from MCT along with avoiding excessive physical activity was also recommended in two studies involving children. Creatine kinase did not rise above 1000 U/L in an 8-year-old male, who had initially presented with a CK of 20,000 U/L, with the avoidance of excessive physical activity and use of an unknown dose of MCT before exercise (F.7). No new episodes of rhabdomyolysis were reported in a 17-year-old female who previously presented with a CK of 305,100 U/L and 40,000 U/L after exertional exercise when she was advised to avoid excessive activity, as well as excessive dieting (F.4051). In contrast, a male who first presented at 2 months of age continued to experience several episodes of rhabdomyolysis with elevated CK and reduced cardiac function until eight years of age, even though he followed recommendations to avoid excessive physical activity, avoid fasting and was prescribed an MCT-based formula and L-carnitine (F.4382).
Episodes of rhabdomyolysis were prevented and biochemical and physiological parameters improved in a randomized cross-over trial of 40 subjects with LC-FAOD (number with VLCAD not known) who received either a pre-exercise carbohydrate (1 g/kg LBM or MCT (0.5 g/kg LBM) and performed the same duration and intensity of exercise on each treatment (G.123).
Allowing breaks of 10-15 minutes after 30 to 45 minutes of physical activity, along with providing extra calories from MCT and carbohydrate prior to exercise, can improve exercise capacity and reduce, but not prevent, the incidence of rhabdomyolysis and muscle cramps (G.126). However, no scientific literature was reported to support the above claim. Up to 45 minutes post-exercise, a snack with a carbohydrate to protein ratio of 3:1 has been recommended to maximize glycogen synthesis, although specific research evidence for this recommendation was not provided (G.123).
100% of MDs and RDs agreed with the statement to "encourage asymptomatic individuals with VLCAD to participate in normal physical activity for age, as tolerated, and discourage a sedentary lifestyle".
In individuals with VLCAD, hypoglycemia can develop during illness because of the inability to oxidize free fatty acids for ATP production and the decreased synthesis of ketones as an alternative energy source, thus increasing the reliance on limited glucose stores. However, clinical symptoms such as lethargy, sweating and tachypnea often proceed hypoglycemia. Thus, home monitoring of blood glucose is not recommended during illness as it can provide a false sense of security (G.141, G.123).
100% of MDs agreed that parents/caregivers should NOT be taught to use a home glucose monitor for routine monitoring of their child's glucose status.
Enteral feedings are a useful alternative feeding method for an ill child who is unable to meet energy needs with oral feedings (L.341). In VLCAD, lack of sufficient energy intake can cause metabolic decompensation, therefore alternative feeding methods such as naso-gastric feedings for the short term, or gastrostomy tube feedings for chronic poor feeders, are important to consider, especially in cases when poor intake leads to frequent complications and hospitalizations.
In the literature, one case study of a symptomatic infant with moderate VLCAD, admitted from birth, initially received parenteral nutrition and later, enteral nutrition (the details of which are unclear), to recover from metabolic crisis (F.4118). Two case studies detail symptomatic infants with VLCAD <8 months of age who successfully received an appropriate medical food via an enteral nutrition route, although detailed clinical outcomes were not reported (F.4118, F.4104).
This topic was not addressed in the Delphi surveys.
The emergency letter provides instructions for urgent care providers to manage individuals with VLCAD during metabolic decompensation, including urgent provision of appropriate energy sources and fluids, as well as laboratory indices to monitor. All caregivers should receive an emergency protocol with detailed information about when to seek emergency medical treatment (G.141, G.28, G.123, G.128) if the individual with VLCAD is not tolerating the prescribed carbohydrate-containing feedings at home, or if there is a decline in mental status or other signs of metabolic decompensation (G.28). In one cohort study, 98% of patients with VLCAD were provided an emergency letter (F.4055).
100% of MDs and RDs agreed that individuals with mild, moderate or severe VLCAD should be provided with an emergency management protocol.
For an individual with VLCAD who has mild illness managed at home (in consultation with medical team):
Providing sufficient energy is especially important during illness when energy needs are increased and appetite is often suppressed. In addition, the cytokines and hormones release during infection or other stress promote lipolysis and reduce fasting tolerance (G.126). Even when well, individuals with VLCAD are counseled to eat frequently and avoid fasting (see Recommendation 1.7). During illness, the interval between meals should be shorter to assure that energy needs are met. Exactly how much shorter is not well-defined and depends on clinical judgement. "Strict fasting precautions" is often mentioned in case studies as a component of management during illness. Two sources suggest limiting fasts to 4 hours (G.123, F.4104). One source suggests that fasting for more than 8 hours should be avoided, especially when ill or compromised (G.141).
Literature review indicates that fasting precautions are often a component of VLCAD management. In a study of genetically-confirmed cases of VLCAD, long-term follow-up of 4 to 18 years of data was available for seven patients among the ten who had survived the initial episode (F.3776). All had nearly normal cardiac function and all were treated with avoidance of fasting, low fat diet with frequent feeding, and vigilance during illness. Episodic skeletal myopathy continued to limit exercise tolerance in three patients.
Four infants presenting with cardiomyopathy in the first year of life and treated with strict fasting precautions along with MCT supplementation were reported (F.657, F.15, F.626). The outcome is not known in one of these patients (a 5 month old male) (F.657) but was reported to be normal at 3 years of age in another patient (F.15), and 2 years after diagnosis in two other patients (F.626).
Another neonate (F.4124) who was treated with avoidance of fasting alone was readmitted at 7 weeks with worsening cardiac function. He, however, had normal growth, cardio-respiratory function and exercise tolerance at 4 years of age.
Three infants presenting with acute cardiac symptoms and high CK between 9 and 10 months of age were treated with avoidance of fasting, low LCT, MCT supplemented diet and L-carnitine. One infant had normal cardiac function at 2 years although his CK was 40,000 U/L even when asymptomatic (F.654). The outcome of the other two children (who were siblings) was not reported, but the younger sibling had three acute episodes in the first year, despite treatment (F.635).
After experiencing repeated hospitalizations for rhabdomyolysis, an 11-year-old was advised to limit fasting to 8 hours along with dietary fat restriction to 20% of total calories. She experienced elevated CK and muscle cramps after an incident of prolonged fasting (F.636). A 13-year-old female who presented with CK of 215,800 U/L after playing soccer was advised to follow a low fat, high carbohydrate diet, avoid fasting for >8 hours, and supplement with MCT before exercise (F.3858). Her compliance with above recommendations was questionable and she experienced another episode of rhabdomyolysis within two months after playing soccer without food and hydration.
A 19-year-old female was advised to avoid fasting >8 hours along with a low-fat diet supplemented with MCT after she experienced rhabdomyolysis with a CK of 83,344 U/L after doing a household chore (vacuum cleaning). She continued to have muscle pain on a regular basis, although it is not known if she developed rhabdomyolysis (F.4164).
For the severe form of VLCAD, fasting avoidance with a restricted diet providing 10% of total energy from LCF and 20% of total energy from MCT was recommended in a book chapter (G.126). This regimen improved cardiomyopathy, reduced plasma long-chain acylcarnitine concentrations and reduced the frequency of, but did not prevent, rhabdomyolysis, although no specific research was mentioned to support this statement.
A webinar (G.123) providing fasting and dietary guidelines for LC-FAOD, including VLCAD, recommended greater reduction of LCT fat (20-30% of fat calories) and higher MCT (60-80% of fat calories) for symptomatic/severe neonates compared to 50% of fat calories from LCT and 50% of fat calories from MCT for asymptomatic neonates. A maximum of 4 hours fasting during illness was recommended, with emphasis on calories from simple carbohydrates, as needed.
In four case studies involving a total of six symptomatic individuals with mild VLCAD (ages 8 to 47 years), precautions for fasting were provided (F.7, F.3851, F.6, F.4415). For two adults in their 40's, avoidance of fasting, coupled with other dietary interventions, reduced the incidence of illness secondary to physical exertion (F.6). For a 47-year-old with frequent muscle symptoms, the recommendation to avoid prolonged exercise while fasting or unwell, along with other dietary interventions, prevented episodes of muscle pain following physical exertion (F.3851).
Case studies involving admitted, symptomatic infants with moderate VLCAD (age range <1 month to 8 months) describe recommendations to enact frequent feedings or avoid fasting (F.6, F.4104). One infant, admitted on the second day-of-life without evidence of cardiomyopathy, was treated with frequent feeds and LCF reduction and recovered with reduction in CK concentrations. At 11 months of age, this infant underwent a 10-hour fasting test and demonstrated stable blood glucose, insignificant changes in plasma acylcarnitines, but elevated CK at 1446 U/L (F.624). Another case study describes a 3.5 year old who underwent an 8-hour fast for dental reconstruction surgery, followed by >20 hours of limited intake post-operation. After 29.5 hours of minimal nutritional intake, this child developed unusual jerking movements, dysconjugate eye movements, and posturing. Upon admission, her blood glucose was 6 mg/dl and she passed away despite emergency care. VLCAD was diagnosed postmortum (F.629).
There was overall consensus (87% RD/MD) that patients with severe VLCAD should have shorter intervals between feedings than those with mild or moderate forms of the disorder.
The discussion emphasized ensuring adequate energy intake, rather than prescribing a specific feeding interval, for individuals with VLCAD during illness. In many cases, many small frequent feedings are needed.
One case study of an acutely ill infant with severe VLCAD, age 5 months, described the use of glucose polymers (Polycose) in addition to other dietary interventions including LCF-restriction, MCT supplementation, and night-time formula feedings. Details about the use of glucose polymers for this infant were not provided, although acute symptomatology resolved and cardiomyopathy was prevented (F.633).
Two case studies of symptomatic individuals with mild VLCAD, ages 8 and 47 years, described supplementation with extra carbohydrate during prolonged exercise and reported a reduction in episodes of muscle pain (F.7, F.3851).
An article detailing expert opinion based on treatment of 75 individuals with LC-FAOD (the number with VLCAD unspecified) suggests that in symptomatic individuals, routine enrichment of the diet with glucose polymers or cornstarch is not recommended unless clinically indicated (F.3). A retrospective health record review of 23 individuals with VLCAD followed by one center describes their original recommendation to consume carbohydrate-rich drinks at regular intervals when unwell or during increased physical activity, but this practice was later changed to supplementation with MCT oil (F.4375).
There was no consensus (69% overall; 86% of RDs, 50% of MDs) that glucose polymers are the preferred source of supplemental carbohydrate for an individual who is ill and not consuming sufficient energy. Furthermore, there was less agreement about the concentration of glucose solutions to be recommended for any age group (infants, preschool children, children, adolescents or adults with VLCAD). Eighty-three percent of MDs, but only 17% of RDs, agreed that for management of illness at home for infants with VLCAD, simple carbohydrate food sources (i.e. juice, popsicles, energy drinks) are appropriate substitutions for glucose polymers. There was more agreement for this practice for children, adolescents and adults (77% overall; 83% MDs, 71% RDs).
For individuals with VLCAD who are hospitalized for illness (regardless of cause), in consultation with the medical team:
A number of case studies emphasize the importance of adequate energy and fluid administration in the acutely ill individual with VLCAD.
One case study described a 24-year-old asymptomatic individual with mild VLCAD requiring a surgical procedure with anesthesia who received 10% IV dextrose at a rate of 2 mg/kg/min. This individual was intentionally scheduled for the first procedure of the day to limit necessary fasting time and was able to resume his usual diet without complications shortly after the surgery (F.4401).
Intravenous administration of 10% dextrose during acute illness in four case studies of infants (ages 1.5 to 2.5 years) with rhabdomyolysis and/or cardiomyopathy resulted in successful clinical resolution (F.4, F.4098, F.654, F.4117) and normal development was reported in 3 of the 4 infants. In two infants, an MCT-containing medical food was provided with fluids at 1.5 times (F.4) to 2.5 times maintenance (F.4117). Another 5-month-old infant died of cardiac manifestations after her second hospitalization despite administration of 10% IV dextrose, L-carnitine and micronutrient supplementation. She was successfully treated with 10% IV dextrose alone during her first hospitalization (F.4422).
In a large study of infants and children with VLCAD, 10 of 18 patients survived their initial metabolic crisis (F.3776). Early institution of IV dextrose to abort metabolic and myopathic crisis was considered crucial to reduce the frequency and severity of life-threatening episodes in the surviving patients.
Increasing energy intake from 160 kcal/day to 800-1000 kcal/day via TPN, enteral and oral routes, along with supplementing L-carnitine at 100 mg/kg/day, resulted in progressive improvement in cardiomyopathy in a 5-year-old male with VLCAD (F.3884).
Providing an IV dextrose solution resulted in resolution of hypotonia and drowsiness in a 1-month-old male (F.3896); while a 19-year-old female continued to experience frequent episodes of muscle pain despite an emergency regime of oral high-glucose polymers with fat-soluble vitamins during illness (F.4164).
Providing IV dextrose along with restriction of LCF without L-carnitine supplementation (when plasma free carnitine was 5.3 umol/L) resulted in resolution of severe cardiomyopathy in a 5-month-old male (F.657).
Aggressive administration of a 40% IV dextrose solution was required to resolve hypoglycemia in a comatose 32-year-old female with late-onset VLCAD with cardiomyopathy and rhabdomyolysis. She had a slow but successful recovery from her illness (F.3717).
There was 100% overall (MD/RD) consensus to provide a minimum of 10% IV dextrose with electrolytes at a rate of at least 1.5 times maintenance fluids if an ill individual is unable to consume adequate energy. One RD commented that this rate might be too high for adults.
It is not known if the administration of L-carnitine is safe for patients with VLCAD, nor is it known if the benefit of preventing carnitine deficiency outweighs the potential cardiac risk of accumulating long chain acylcarnitines (F.9).
Based on experience with 75 patients with LC-FAOD, the expert opinion of 18 physicians from Europe is that L-carnitine should not be used in acute illness due to the potential for increased concentrations of toxic long-chain acylcarnitines (F.3)
L-carnitine was given to normalize low plasma concentrations in a 3-month-old with VLCAD who passed away during an acute illness with cardiomyopathy. The case study did not report the dose of carnitine or provide details of other nutrition interventions (F.3896).
There was no consensus about use of L-carnitine in ill individuals with VLCAD; 23% of respondents (MDs and RDs) agreed with the statement that L-carnitine supplementation (oral or IV) should not be prescribed for an acutely ill individual. The need for research about L-carnitine supplementation for individuals without cardiac involvement was noted.
Participants in the nominal group meeting felt strongly that L-carnitine is contraindicated in individuals with VLCAD during illness.
One case study describes a neonate presenting at 2 days of age in crisis who was treated effectively with dietary interventions including MCT supplementation and LCF-restriction. The child received a central line placement (Port-O-Cath) that was used during two subsequent metabolic crises for rapid resolution of hypoglycemia (F.635).
This topic was not addressed in the Delphi surveys or in the Nominal Group Meeting.
Intravenous lipid sources are high in LCF and should be avoided. However, there are two parenteral products containing MCT and LCF, Lipofundin (available only in Europe and contains 50% MCT and 50% LCF) and Smoflipid (available in the US and contains 30% MCT and 70% LCF) have been used without adverse effects in critically ill patients (G.144).
If prolonged parenteral nutrition without a lipid source is provided, there is risk of essential fatty acid (EFA) deficiency and a source of EFA should be added (via naso-gastric tube, for example).
There was 88% total (MD/RD) consensus that acute administration of IV lipids should be avoided; however, after 7 days, a source of EFA should be provided. An RD commented that if a patient is NPO >3 days, a limited amount of IV lipids should be added as an energy source and to prevent EFA deficiency; newer lipid MCT sources are available.
Nominal Group participants concluded, based on clinical experience, that infants on enteral or parenteral nutrition should receive a source of EFA after 1 week and adults by 10 days to prevent EFA deficiency.