Management
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VLCAD Nutrition Management Guidelines
First Edition
February 2019, v.1.0
Current version: v.1.1
Updated: February 2019
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Nutrition Recommendations
Question
1.  For healthy individuals with VLCAD, what nutrient intake goals are associated with positive outcomes?
Conclusion Statement
Derived from evidence and consensus based clinical practice

Very-long chain acyl-coA dehydrogenase deficiency (VLCAD) presents in a continuum of phenotypes ranging from a "severe" neonatal presentation with cardiac complications to a "mild" late-onset presentation of exercise intolerance. Medical nutrition therapy for individuals with VLCAD depends on the severity of the enzyme deficiency, but typically includes restricting the intake of long-chain fatty acids by limiting the intake of dietary fat, supplementing with medium chain triglycerides (MCT) and avoiding excessive fasting. The goals of nutrition therapy are to reduce the production of abnormal fatty acid metabolites and provide a fat source as MCT to by-pass the enzymatic block in β-oxidation, thus preventing the reliance on glucose stores and production of ketones as a source of energy. Nutrition therapy can reduce clinical complications associated with untreated VLCAD, including hypoglycemia, cardiomyopathy and rhabdomyolysis.

Evidence for medical nutrition therapy for VLCAD is based primarily on expert opinion and limited case series, many of which report outcomes for individuals diagnosed prior to the availability of newborn screening (NBS) for this disorder. Newer reports suggest that dietary changes for well-appearing infants with a positive NBS for VLCAD may not be necessary; however, specifics and consensus are limited. For neonates who develop clinical symptoms prior to diagnosis, breastfeeding or regular infant formula should be discontinued and a source of MCT added, preferably from a low-long chain fat (LCF), high MCT medical formula. If confirmatory testing suggests a severe or moderate phenotype, but the infant remains asymptomatic, a combination of breastfeeding and a MCT-supplemented formula may be possible. Infants remaining asymptomatic with confirmatory testing suggesting a milder form of VLCAD may tolerate breastfeeding ad lib without supplemental MCT.

The suggested diet composition for the healthy individual varies with age and severity of VLCAD. Energy requirements are not typically higher than those recommended by the Institute of Medicine (EER/DRI) guidelines. However, lower energy intake may be necessary for those with reduced lean body mass. Most evidence does not suggest the need for restriction of total fat, but rather modification in fat composition is recommended. Limits for LCF sources are dictated by the severity of the disorder, and then sources of MCT are added to meet total fat needs. Those with a mild phenotype may not require any modification in dietary fat composition. Minimally, protein requirements need to meet the DRI for age. Some preliminary evidence suggests a higher protein and lower carbohydrate diet may increase lean body mass and reduce body lipid content in those with disorders of long-chain fatty acid oxidation (LC-FAOD); however, further study is needed before specific recommendations for higher protein can be established for those with VLCAD.

All healthy individuals with possible and confirmed VLCAD should avoid long periods of fasting, regardless of severity of disease. Recommended fasting times vary, but intervals ranging from 3 to 4 hours between feedings are suggested for asymptomatic infants during the neonatal period. At 9 to <12 months of age, recommended night-time fasting ranges from 8 to 10 hours and after 12 months of age, maximum fasting ranges from 10 to12 hours. For those with a severe phenotype, fasting limits should be set at the low end of the recommended range.

There is little evidence to support the routine use of uncooked cornstarch as a component of medical nutrition therapy for VLCAD. A snack containing complex carbohydrate is preferred if a bedtime feeding is necessary to prevent metabolic decompensation after an overnight fast. Those with VLCAD on a LCF-restricted diet are at risk for essential fatty acid and fat-soluble micronutrient deficiencies; however, supplementation is not necessary unless there is documented low intake or lab confirmation of a nutrient deficiency.

Recommendation 1.1

For neonates with suspected VLCAD, initiate fasting precautions while awaiting confirmation of the diagnosis. Asymptomatic neonates can continue to breast feed (or feed expressed breast milk) without MCT supplementation, if appropriate fasting precautions are followed (RECOMMENDATION TABLE #7, Recommendations for Fasting Intervals for Individuals with VLCAD when well).

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Avoidance of excessive fasting is recommended while awaiting confirmation of a diagnosis (F.9, G.141). In a survey of metabolic physicians from the US and Canada, there was 100% agreement that all neonates should feed at least every 3 to 4 hours while awaiting confirmation of the diagnosis. There was marginal consensus (67%) that it is not necessary to adjust the diet for well-appearing infants (F.9).

Consensus based on clinical practice

Delphi 1

100% of MDs and RDs agreed that fasting precautions should be initiated while awaiting confirmation of the diagnosis in an asymptomatic infant with possible VLCAD detected by NBS.

80% of respondents (78% RDs; 83% MDs) agreed that while awaiting confirmation of the diagnosis in an asymptomatic infant with possible VLCAD, continuing to breastfeed (or feeding expressed breast milk) without supplementing MCT or reducing LCF intake is appropriate.

There was no agreement that a MCT-supplemented formula should be provided while awaiting confirmation of the diagnosis in an asymptomatic infant with possible VLCAD detected by NBS; in fact, 83% of MDs and 55% of RDs disagreed with this statement. Comments included that it depends on whether the infant is breastfeeding and laboratory results.

Recommendation 1.2

Consider age, disease severity and clinical history when establishing nutrition prescriptions for dietary fat composition (RECOMMENDATION TABLE #8, Recommended Fat (total, long chain and medium chain), Energy and Protein Intakes for Individuals with VLCAD when Well).  (For breastfeeding recommendations-see Recommendation 1.6)

  • When designing a diet for an individual with VLCAD, aim for, but do not exceed, the TOTAL fat intake recommended by the DRI for age. Total fat includes both LCF and MCT.
  • For individuals with a MILD form of VLCAD, it is not necessary to replace some of the LCF in the diet with MCT, as long as the individual remains asymptomatic and follows guidelines for fasting and illness management.
  • For individuals with a MODERATE form of VLCAD, restrict LCF to 15 to 30% of estimated energy needs considering age, disease severity and clinical history. 
  • For individuals with a SEVERE form of VLCAD, restrict LCF to 10 to 15% of estimated energy needs considering age, disease severity and clinical history.
  • Decreasing LCF below 10% of total energy intake may not provide additional clinical benefit, even for those with a SEVERE phenotype.
  • After LCF needs are determined, add a source of MCT to meet the individual's total fat needs.
Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Prior to newborn screening for VLCAD, published papers describing dietary management included either single case studies or small case series. Although not always specified in the paper, reported cases could be divided into mild, moderate and severe phenotypes, based on the described disease progression (RECOMMENDATION TABLE #1, VLCAD Phenotypes). A summary is provided below:

MILD phenotype:

There are 11 case studies of individuals diagnosed prior to NBS with a clinical picture suggesting a mild phenotype (F.4417, F.7, F.4415, F.636, F.17, F.3851, F.4052). Reported symptoms include muscle pain, muscle weakness, rhabdomyolysis, myoglobinuria and renal failure. Age at onset of symptoms range from 8 years to 47 years with exercise the primary stimulus for symptoms in all of these cases; prolonged fasting, temperature extremes, dehydration and poor energy intake are also indicated. Few specific diet details are provided in these cases, but when indicated, total fat restriction is in the DRI range for age or somewhat lower (range 20 to 35% of total energy) (F.636, F.17, F.4417). In 6 of 11 cases, MCT was not provided as part of the fat restriction. One case noted that an 11-year-old did not see improvement when treated with fat restriction only (F.636).

MODERATE phenotype:

There are 4 case reports of individuals diagnosed prior to NBS who presented in infancy or early childhood with symptoms suggesting a moderate phenotype (F.3896, F.3719, F.640, F.634), including hypoglycemia, "Reye-like syndrome" and episodes of rhabdomyolysis associated with illness and excessive exercise. There are limited details about diet treatment in these reports, although one case limited total fat to 30 to 35% of total energy at 25 months of age, consistent with DRI recommendations for age (F.640). MCT was included as part of treatment in 3 of 4 cases.

SEVERE phenotype:

There are 17 case reports of individuals diagnosed prior to NBS with cardiac symptomology reported as early as 2 days of age (F.635, F.3797); 11 of 17 developed cardiac complications before 6 months of age (F.4134, F.18, F.633, F.15, F.660, F.657, F.654, F.656, F.3896, F.626, F.3884). Three cases were infants with a previous sibling(s) with early onset cardiac complications. By treating from birth, these three infants were able to avoid cardiac problems up to 1 year of age (F.635, F.3820, F.4098). Three of 17 cases presented with cardiac symptoms after 6 months of age, including two who did not present in an initial episode until 5 years of age (F.654, F.3896, F.3884). All individuals were treated with a "low fat diet with MCT supplementation" with improved clinical status reported with this treatment. Cases providing details about the total fat content of the diet were consistent with DRI recommendations (34 to 48% of total energy up to 5 months of age) (F.3820, F.18, F.633, F.660, F.656) or somewhat below DRI (20% of total energy at 24 months of age) (F.633). LCF intake ranged from 4 to 16% of total energy or 1.5 to 1.8 g LCF/kg. MCT intake ranged from 10 to 40% of total energy or 0.4 to 0.7 g MCT/kg (F.660, F.656, F.4124, F.18, F.633, F.3820, F.657, F.15).

Published recommendations for diet for individuals identified by NBS

In consensus papers or practice surveys of diet composition of individuals identified by expanded NBS, a less restrictive diet was allowed for those remaining asymptomatic (F.4375, F.9, F.3) or found to have a milder phenotype (F.9). One paper noted that, initially, all individuals were prescribed a diet of 10% total energy from LCF and 20% total energy from MCT, regardless of the severity of the disorder. Their protocol was revised in 2010 to prescribe diet modifications based on whether an individual remained asymptomatic or not (F.4375).

Published recommendations (F.9, F.4375) for those older than 1 year of age are summarized below:

TABLE 11 - Long-chain Fat Restriction and MCT Supplementation Recommendations for Individuals with VLCAD over the age of 1 year

NOTE: This table is a summary of published literature used to inform the nutrition recommendation.

Reference

Age/Phenotype

History of Symptomology

Remains Asymptomatic

LCF 1

(% Energy)

MCT 2

(% Energy)

LCF 1

(% Energy)

MCT 2

(% Energy)

F.4375

1-5 years

10

20-25

15-20

15-20

> 5 years

10

20-25

"Heart Healthy"3

Use only in times of need (i.e. exercise)

F.9

Severe phenotype

>12 months

10

>20

10 4

>20 4

Mild phenotype

>12 months

"Heart Healthy"3

Supplement with MCT5

"Heart Healthy"3

Supplement with MCT5

LCF = long chain fat from diet sources, expressed as percent of total energy.

2 MCT = medium chain triglyceride supplementation, expressed as percent of total energy.

3 A "Heart Healthy" diet provides approximately 30% of total energy from fat sources.

In F.9, consensus was not reached for this recommendation, but majority response is provided.

Add a source of MCT to the diet; amount not specified.

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Evidence

The evidence addressing recommendations for total fat (LCF from diet + MCT) is mixed without data from controlled clinical studies. In a 2002 survey of 24 registered dietitians in the U.S., restriction of total fat was common practice with total fat ranging from 13 to 25% of total energy (F.4144). In a 2012 practice survey of 18 metabolic physicians in Canada, 61% recommended restricting overall dietary fat intake (F.661).

Gray literature sources suggest that there is no need to restrict total fat intake (G.134) and total fat recommendations can be based on the Institute of Medicine Adequate Intake (AI) for age (RECOMMENDATION TABLE #8, Recommended Fat (total, long chain and medium chain), Energy and Protein Intakes for Individuals with VLCAD when Well). Four individuals (mean age 4.7 years) with severe VLCAD achieved normal growth and metabolic control without reducing total fat intake (G.131).

Consensus based on clinical practice

Delphi 2

There was 89% (MD/RD) consensus that total fat intake should be set at the DRI for age.

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Evidence

Reducing intake of LCF sources is a frequent recommendation in the formal literature, at least for those with moderate or severe phenotypes (F.3, F.9, F.4375). Restricting dietary fat intake decreases the accumulation of potentially toxic metabolites such as long-chain acylcarnitines; however, the clinical benefit of normalizing acylcarnitine concentrations in VLCAD has not been demonstrated (G.141).

It is not always possible to normalize plasma acylcarnitine or creatine kinase (CK) concentrations with LCF restriction (G.28, G.131); in one patient consuming 4% of total energy as LCF, CK remained elevated (G.138). Depending on the severity of the disorder, recommendations for LCF restriction range from 8 to 25% of total energy (G.128, G.123, G.137) with some recommending 8 to 10% of energy in severe VLCAD (G.128, G.126, G.138). Based on body weight, LCF restriction ranged from 0.8 to 2.1 g/kg in a retrospective review of 75 individuals with LC-FAOD (F.2). Less restriction (G.123), or no restriction (G.134) in LCF is recommended if the infant is identified by NBS and remains clinically well. Also, including more polyunsaturated fatty acids and decreasing consumption of saturated fat may lower plasma acylcarnitine concentrations (G.141).

Consensus based on clinical practice

Delphi 1

There was no agreement that LCF should be restricted while awaiting confirmation of the diagnosis in an asymptomatic infant with possible VLCAD detected by NBS.

Delphi 2

There was 88% consensus among RDs, but only 64% of MDs, that decreasing LCF below 10% of total energy does not provide additional clinical benefit, even for those with a severe phenotype.

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Evidence

The recommendation for MCT in the diet is related to the degree of LCF restriction and varies widely, generally from 10 to 30% of total energy, depending on age and severity of VLCAD (F.3, F.9, F.4375, G.123, G.128). For severe VLCAD, suggested MCT intake ranges from 15 to 30% of total energy (G.128, G.123, G.131, G.97). For older individuals, MCT providing at least 10% of total energy is recommended (G.123). If an individual is thought to not have severe VLCAD, but the phenotype remains undefined, some initiate a diet providing 50% of total fat as LCF and 50% of total fat as MCT (G.123).

Six dietitians who responded to a listserv question about treating mild VLCAD recommended using supplemental MCT, but 2/6 would only prescribe MCT to younger children and not to older children (G.139). Others suggest that it is not necessary to prescribe MCT in mild forms of VLCAD (G.134).

If MCT is prescribed based on weight, recommended doses are approximately 2 to 3 g MCT/kg for infants and 1 to 1.25 g MCT/kg after the first year (L.343, G.123). A retrospective questionnaire of metabolic clinicians from Europe summarized diet information from 30 individuals with VLCAD (20/30 were diagnosed by NBS and 10/30 were diagnosed clinically) (F.2). MCT supplementation, ranging from 0.7 to 3.3 g/kg/day, reversed initial clinical symptoms, but 38% continued to have intermittent muscle myalgia or rhabdomyolysis (F.2).

Commercial sources of MCT are given in RECOMMENDATION TABLE #6, Sources of Medium Chain Triglycerides (MCT).  Both coconut oil and palm kernel oil provide ~50% of total fatty acids from MCT sources (MetabolicPro© data) and, thus, provide a significant source of LCF. 

Consensus based on clinical practice

Delphi 1

MCT-Mild

There was no agreement that MCT should be supplied in the diet of an infant with mild VLCAD.

MCT- Moderate

92% of respondents agreed that MCT should be supplied in the diet of an infant with moderate VLCAD.

MCT- Severe

100% of RDs and MDs agreed that MCT should be supplied in the diet of an infant with severe VLCAD.

Delphi 2

There was 82% consensus among RDs, but not MDs, that it is not necessary to replace some of the LCF with MCT in the diet of an asymptomatic individual with a mild form of VLCAD.

Recommendation 1.3

For infants and children with VLCAD who are healthy and gaining appropriate weight for age, use the Institute of Medicine Estimated Energy Requirement (EER) calculation for age and physical activity level (PAL) to estimate energy needs (RECOMMENDATION TABLE #8, Recommended Fat (total, long chain and medium chain), Energy and Protein Intakes for Individuals with VLCAD when Well).

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

In the few reports providing information about energy needs in VLCAD, a normocaloric diet was described (F.657, F.640, F.17), except a 2-year-old with a severe form of VLCAD who was prescribed an energy intake greater than the typical recommendation for age (120 kcal/kg/d) (F.640). Subjects with long-chain 3-hydroxyacyl-coA dehydrogenase deficiency (LCHAD) (and the author suggests perhaps other LC-FAOD), have lower total lean body mass, higher carbohydrate oxidation, lower fat oxidation, and lower energy expenditure, suggesting that traditional energy estimates may overestimate total energy needs (G.127).  This needs to be further investigated in individuals with VLCAD.

There are several reports of excessive weight gain in VLCAD (F.4417, F.4375, G.131). In a retrospective review of 23 individuals with VLCAD, one subject met the criteria for obesity and two met the criteria for overweight (F.4375). In a case report of 39-year-old woman with a BMI of 35 who consumed ~3000 kcal/d, diet was modified to 2000 kcal/d with 15% of total energy as LCF and 15% as MCT with bedtime cornstarch. The patient lost 40 kg over 2 years without signs of metabolic decompensation (F.4417).

Consensus based on clinical practice

Delphi 1

There was 100% agreement that energy recommendations, as defined by the DRI, are sufficient for asymptomatic children, adolescents and adults with VLCAD who are normal weight. However, consensus was not reached for infants: 71% of RDs and 83% of MDs (76% overall) agreed that the DRI for energy is sufficient for asymptomatic infants with VLCAD who are normal weight.

Recommendation 1.4
Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Most publications addressing protein needs for individuals with VLCAD recommend protein intake consistent with the DRI for age (F.8, F.640, G.139). A 2002 survey of 24 RDs in the U.S. found protein recommendations averaging 13% of total energy from protein (range 12 to 20%) (F.4144).

However, there is some suggestion that an increase in protein intake may have clinical benefits (F.4375, G.126, G.127, G.141). A retrospective review of health records for 23 individuals with VLCAD found a significant negative correlation between protein intake and percent body fat in those consuming diets with a higher protein to energy ratio (P:E ratio, g protein/100 kcal) (F.4375). ​​​​​​

A diet high in protein and lower in carbohydrate may reduce the total energy needs required to maintain good metabolic control (G.141). Some recommend increased protein for those experiencing muscle or cardiac symptoms (G.126). Significantly increased lean body mass (LBM) and lower body lipid content was measured in individuals with LC-FAOD (LCHAD, VLCAD, CPT-2) consuming a higher protein diet (mean 19% of total energy) for 4 months compared to a standard diet (mean 14% of total energy) (G.127).

Consensus based on clinical practice

Delphi 1

There was no consensus (62% overall agreement) that protein recommendations defined by the DRI are sufficient for an asymptomatic infant, child, adolescent, or adult with VLCAD. Comments included that the diet must be individualized and that protein intake depends on the degree of LCF restriction.

Nominal Group

Experts at the Nominal Group meeting felt that further study is needed before protein intakes greater than the DRI can be recommended for individuals with VLCAD.

Recommendation 1.5

Use standard equations to determine fluid requirements for an asymptomatic individual with VLCAD.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Fluid recommendations for asymptomatic individuals with VLCAD can be estimated using standard equations that are widely used in clinical practice (L.340). For infants, 1.5 ml/kcal and for children and adults, 1.0 ml/kcal is suggested (G.28).

Consensus based on clinical practice

Delphi 1: 100% of MDs, but only 57% of RDs, agreed that fluid recommendations as predicted by standard equations are sufficient for an asymptomatic individual with VLCAD.

Recommendation 1.6

Support breastfeeding of infants with VLCAD, taking into consideration the following:

  • For an asymptomatic infant with a MILD form of VLCAD, allow breastfeeding (or expressed breast milk) without MCT, as long as breast milk supply remains adequate, age appropriate weight gain is maintained, and fasting recommendations are followed.
  • For an asymptomatic infant with a MODERATE form of VLCAD, allow breastfeeding (or expressed breast milk) but consider supplementing breast milk with a low LCF, high MCT medical food. (RECOMMENDATION TABLE #5, Medical Foods for the Nutrition Management of VLCAD).
  • For an asymptomatic infant with a SEVERE form of VLCAD, the primary source of nutrition should be a low long-chain fat, high MCT medical food.
  • For a symptomatic infant, depending on the severity of symptoms and lab monitoring, consider allowing some breast milk while using a low LCF, high MCT medical food to meet energy needs.
  • If breastfeeding was discontinued during metabolic decompensation, consider reintroduction of partial breast feeding (or expressed breast milk) after the infant returns to an asymptomatic clinical state, if the mother's breast milk supply remains adequate to do so.
Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Prior to NBS, the available formal and gray literature notes that infants presenting before 1 year of age - with or without cardiac symptoms - were treated with a low LCF, high MCT formula without breast milk (F.3820, F.4124, F.18, F.3797, F.633, F.15, F.4098, F.660, F.657, F.654, F.656, F.626). However, for infants diagnosed with VLCAD after the availability of expanded NBS, growing evidence suggests that the decision to allow breastfeeding (or expressed breast milk) with or without MCT depends primarily on an infant's phenotype and whether he/she remains asymptomatic during the first year of life (F.2, F.3, F.9, F.4375, G.128, G.134, G.137). The following table summarizes clinician consensus recommendations for breastfeeding (or including expressed breast milk) in the diet for an infant with VLCAD (F.3, F.9, F.4375).

TABLE 12 - Long-chain Fat Restriction and MCT Supplementation Recommendations for Infants with VLCAD

NOTE: This table is a summary of published literature used to inform the nutrition recommendations.

Reference

Age/Phenotype

Symptomatic

Asymptomatic

F.4375

0-6 months

100% MCT formula1

Breast milk2 +/- MCT formula

6-12 months

MCT formula

Low fat diet with 10% of energy from LCF

Breast milk +/- MCT formula

Low fat diet with 15% of energy from LCF

F.3

0-4 months

100% MCT formula

50% Breast milk

50% MCT formula

> 4 months

Total fat (LCF + MCT): 25-30% of energy3

20% of energy as MCT

Total fat (LCF + MCT): 30-40% of energy

10-15 % of energy as MCT

F.9

Breastfeeding

Severe phenotype

< 12 months

Change to MCT formula

No consensus.

Majority: Continue breast feeding as long as infant remains asymptomatic with normal cardiac function

Mild phenotype

< 12 months

Continue breast feeding

Supplement with source of MCT

Continue breast feeding

Bottle Feeding

Severe phenotype

< 12 months

Change to MCT formula

Change to MCT formula

Mild phenotype

< 12 months

Change to MCT formula

No consensus to change to MCT formula

MCT formula = a medical food restricted in long chain fat (LCF) and supplemented with medium chain triglycerides (MCT). (RECOMMENDATION TABLE #5, Medical Foods for the Nutrition Management of VLCAD)

Breast milk from the breast or expressed breast milk

Total fat = long chain fat from diet + MCT supplement

Consensus based on clinical practice

Breastfeeding a symptomatic infant

Delphi 2

90% of MDs had some level of agreement that infants with possible or confirmed VLCAD who develop symptoms associated with the disorder should discontinue breast milk and initiate a low LCF, high MCT medical food to meet energy needs.

There was 100% (MD/RD) agreement that, depending on the severity of symptoms and lab monitoring, allowing some breast milk can be considered while using a low LCF, high MCT medical food to meet energy needs.

There was 88% total (MD/RD) agreement that if breastfeeding was discontinued during metabolic decompensation, reintroduction of partial breastfeeding (or expressed breast milk) can be considered once the infant returns to an asymptomatic clinical state, if the mother's breast milk supply remains adequate to do so.

Breastfeeding an asymptomatic infant

Delphi 2

Breastfeeding- Mild

There was 88% agreement (RD/MD) that exclusive breastfeeding can be allowed in mild VLCAD, as long as the infant remains asymptomatic.

Breastfeeding- Moderate

Agreement was not reached for either MDs or RDs that an asymptomatic infant with moderate VLCAD may exclusively breastfeed. One MD suggested that exclusive breastfeeding can be tried, but MCT needs to be added if follow-up testing or disease course suggests suboptimal control.

Breastfeeding- Severe

Only 8 percent of respondents (MDs and RDs) agreed that an infant with severe VLCAD can be allowed to breastfeed without supplemental MCT.

Recommendation 1.7

Advise all individuals with VLCAD to avoid excessive fasting, taking into consideration the severity of disease (RECOMMENDATION TABLE #7, Recommendations for Fasting Intervals for Individuals with VLCAD when well).

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Avoidance of excessive fasting is a frequent recommendation in published case studies for those with a severe phenotype (F.657, F.626, F.633) as well as milder forms of the disorder (F.634, F.6, F.636, F.3851, F.660, F.4052, F.4415, F.4124, F.3719, F.654).

Published consensus papers recommend avoidance of fasting for all asymptomatic individuals with VLCAD with the age of the individual dictating the maximum length of fasting (F.2,F.9, F.4375):

0 to 1 months: 3 to 4 hours

2 to 5 months: 4 to 5 hours

6 to 8 months: 6 to 8 hours

9 to 11 months: 6 to 11 hours

≥12 months: 8 to 12 hours

Some practitioners have established a recommendation of feeding every 3 to 4 hours during the first months of life with addition of an hour of allowed fasting per month of age after 4 months to a maximum of 8 to 12 hours (F.9, G.141, G.28). Others consider the weight of the infant recommending 1 hour/kg body weight up to 8 hours at 8 kg weight (F.9).  There was also consensus from gray literature sources that fasting precautions are required for treatment of asymptomatic individuals, irrespective of the severity of VLCAD (G.28, G.123, G.126, G.128, G.136, G.137, G.139, G.141). Those with severe forms of the disorder may require stricter fasting guidelines than those with milder forms (G.126). The risk of night-time hypoglycemia appears to decrease as a child ages and most can safely sleep through the night after age 4 years, when well (G.141).

Consensus based on clinical practice

Delphi 1

100% of MDs and RDs agreed that fasting precautions should be initiated while awaiting confirmation of the diagnosis in an asymptomatic infant with possible VLCAD detected by NBS.

Delphi 2

There was 81% MD and 88% RD agreement that the recommended fasting guidelines are appropriate for moderate and mild forms of VLCAD (RECOMMENDATION TABLE #7, Recommendations for Fasting Intervals for Individuals with VLCAD when well). One MD commented that overnight fasting guidelines are only safe if daytime intake is adequate.

Consensus was not reached that the recommended fasting guidelines are appropriate for severe VLCAD. One MD suggested caution to allow fasting beyond 10 hours, even after the first year.

Recommendation 1.8

Consider an individual's age, dietary LCF restriction and plasma or red blood cell (RBC) fatty acid profiles to determine if additional sources of essential fatty acids are required:

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Biochemical evidence of essential fatty acid deficiency has been found in treated individuals with VLCAD, although clinical symptoms of deficiency are rarely documented (G.141). Low concentrations of DHA have been noted in some children with VLCAD deficiency. Whether the cause of the DHA deficiency is dietary restriction of fat or lack of synthesis of DHA from its precursor ALA is not clear (G.141).  All low LCF, high MCT medical foods used for dietary management of VLCAD now contain preformed ARA and DHA to prevent deficiency (RECOMMENDATION TABLE #5, Medical Foods for the Nutrition Management of VLCAD).

In the formal literature, intakes for LA ranged from 2 to 4% of total energy and ALA ranged from 0.3 to 1.4% of total energy (F.3, F.8, F.10). In patients with VLCAD > 7 years of age, 4% of total energy from LA and 0.6% from ALA normalized plasma essential fatty acid concentrations (G.127). Recommendations from a European consensus group included the following (F.3):

TABLE 14 - European Consensus of Essential Fatty Acid Intakes

NOTE: This table is a summary of published literature used to inform the nutrition recommendations.

Age1

Linoleic Acid (LA)

(% of total energy)

α-Linolenic Acid (ALA)

(% of total energy)

0 to 4 months

4.0

0.5

4 to 12 months

3.5

0.5

1 to 4 years

3.0

0.5

Over 4 years

2.5

0.5

1 Source: (F.3)

A summary of recommendations for essential fatty acid intake from the Institute of Medicine (IOM) and World Health Organization (FAO/WHO) for individuals of different ages is provided (RECOMMENDATION TABLE #3, Recommended Intakes of Essential Fatty Acids for Individuals with VLCAD). The IOM provides DRI recommendations for LA and ALA in total mg per day. The Acceptable Macronutrient Distribution Range (AMDR) established by the IOM includes 5 to 10% of total energy for LA and 0.6 to1.2% of total energy for ALA. The FAO/WHO provides recommendations for LA, ALA, DHA and ARA based on a percent of total energy or per kg body weight (L.342, L.344). Essential fatty acid recommendations for premature infants are published by the European Society for Pediatric Gastroenterology and Nutrition (ESPGHAN) (L.345). 

The ranges listed in this guideline of 3 to 6% total energy for LA and 0.5 to 1.2% total energy for ALA were estimated from the mg of LA and ALA recommended by the DRI and applied to the reference weight and total energy needs for different ages.  In general, these intakes are on the higher end of recommendations found in the literature and in FAO/WHO guidelines.  Those with severe VLCAD may require lower intakes of LA and ALA to be able to maintain a total LCF intake of 10% total energy.  In these cases, applying the recommendations from the FAO/WHO (RECOMMENDATION TABLE #3, Recommended Intakes of Essential Fatty Acids for Individuals with VLCAD) or consensus intakes suggested in (F.3) may be more realistic.

Canola, flax, safflower, sunflower, soy, or walnut oils have been added to the diet to supply LA and ALA to improve blood concentration of various essential fatty acids (F.2, F.3, F.8, F.4055, G.131, G.28, G.128). (RECOMMENDATION TABLE #9, Essential Fatty Acid Content of Selected Oils). Of these oils, safflower oil and flax oil provides the most concentrated source of LA and ALA, respectively.  In two infants with VLCAD (3 and 5 months of age) treated with a low LCF, high MCT medical food showed low plasma concentrations of LA, ARA and DHA. Initial treatment included only 0.06% of total energy from ALA, which normalized ALA, but not DHA concentrations. When soybean oil was added to the medical food to achieve 4% of total energy from LA and 0.4 to 0.5% total energy from ALA, DHA concentrations normalized (F.8).

Acylcarnitine concentrations were measured in an individual with VLCAD who consumed either walnut + flax oil or canola oil to provide 3% of total energy from LA and 1.4% of total energy as ALA. Use of walnut/flax oil reduced the intake of nonessential fatty acids resulting in a 35% lower C14:1 acylcarnitine concentration compared to canola oil (F.10). This suggests a benefit of using an oil source with more concentrated sources of essential fatty acids.

Consensus based on clinical practice

Delphi 1

Essential fatty acid intake:

There was 85% overall consensus (71% RDs and 100% MDs) that meeting the DRI for the essential fatty acids LA and ALA is sufficient for an infant, child, adolescent or adult with VLCAD.

Delphi 2

There was 96% overall (MD/RD) consensus that dietary sources of essential fatty acids (including oils) should be used to supplement an individual's diet to normalize plasma fatty acid concentrations. One RD commented that the oil chosen should be based on which essential fatty acid is low. One MD commented that LCF in the diet should not be reduced to a level that results in essential fatty acid deficiency.

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Evidence

Based on studies in individuals with LCHAD, preformed DHA supplements can be included in the diet to improve plasma or RBC DHA concentrations. Recommended doses include 60 mg/day for infants and toddlers and 100 mg/day for children and teens (G.141, G.127). Evidence specific to VLCAD was not available.

Consensus based on clinical practice

Delphi 2

There was 86% overall (MD/RD) consensus that a preformed DHA supplement should be considered if DHA concentrations cannot be normalized by diet modification.

There was 96% overall (MD/RD) consensus that appropriate doses of DHA are 60 mg/d for infants and toddlers and 100 mg/d for older age groups.

Recommendation 1.9

Supplementation with uncooked cornstarch (UCCS) at bedtime is not indicated in the treatment of VLCAD since hypoglycemia is not likely to develop when an individual is asymptomatic, if he/she avoids excessive periods of fasting and meets energy needs.

  • To meet fasting guidelines and prevent catabolism in children and adults, consider adding a bedtime snack emphasizing complex carbohydrates.
  • For those with a severe phenotype who do not tolerate extended fasting times, an overnight enteral feeding should be considered when a bedtime snack is not sufficient.
Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 1.9.1  Link to Topic 1.9.1
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Evidence

Providing an evening/bedtime snack for asymptomatic individuals with VLCAD is advocated in the literature (F.633, G.136).  Complex carbohydrate is emphasized; however, specific details about establishing an energy or carbohydrate goal for different ages or severity of VLCAD is lacking.

Consensus based on clinical practice

Delphi 2

94% of RDs agree that supplementation with UCCS at bedtime is not indicated in the treatment of VLCAD since hypoglycemia will not develop when an individual is asymptomatic, if he/she avoids excessive periods of fasting and meets energy needs.

100% of respondents agreed a bedtime snack emphasizing complex carbohydrates should be considered to meet fasting guidelines and prevent catabolism in children and adults.

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Evidence

Uncooked cornstarch is a slowly digested carbohydrate that provides a slow-release source of glucose. It is a standard part of treatment for glycogen storage disease to prevent hypoglycemia (blood glucose < 70 mg/dl).  More recently, UCCS has been used in treatment of LC-FAOD, especially at bedtime, to prevent low glucose concentrations after an overnight fast. In the VLCAD literature, providing a night-time dose of UCCS is described in 12 published cases ranging in age from 1 year to 5.5 years when treatment was initiated (F.3884, F.660, F.2, F.3797, F.633, F.4415, F.4144, F.3896) and an adult with frequent episodes of rhabdomyolysis (F.4417). Details about UCCS dosing is infrequently reported, but 1 to 2 g/kg body weight has been reported (F.633, G.141).

In a retrospective questionnaire of 18 European metabolic centers, 22/32 patients with VLCAD were given additional carbohydrate as part of their treatment. Of these individuals, 9/22 received additional carbohydrates as food sources, 4/22 as glucose polymers, 5/22 as UCCS after 1 year of age, and 3/22 as night-time nasogastric feeds (F.2). In a retrospective summary of individuals with VLCAD followed by centers in the US, 10% (4/40) received cornstarch at bedtime (F.4055).

While providing UCCS has been frequently reported, the clinical benefit of its use has been questioned.  Experts from the nominal group felt that UCCS before bed is not necessary for well individuals if sufficient energy is provided from food sources before bed to prevent excessive fasting.  Clinicians from 18 centers in central Europe also did not recommend routine use of UCCS (F.3).

Consensus based on clinical practice

Delphi 1

There was no consensus about the use of UCCS in asymptomatic infants with VLCAD. There was more agreement, but still no consensus, about the use of UCCS in individuals with documented hypoglycemia in the fasting state with RDs more in agreement with this practice than MDs.

Cornstarch- Mild phenotype

None of the respondents agreed that UCCS should be added to the bedtime feeding for asymptomatic infants with mild VLCAD; 57% of RDs and 67% of MDs disagreed.

Cornstarch- Moderate phenotype

42% of RDs and 67% of MDs disagreed that UCCS should be added to the bedtime feeding for asymptomatic infants with moderate VLCAD.

86% of RDs agreed but only 17% of MDs agreed that UCCS is indicated in individuals with moderate VLCAD who have documented hypoglycemia in the fasting state.

Cornstarch- Severe phenotype

42% of RDs and 33% of MDs disagreed that UCCS should be added to the bedtime feeding for asymptomatic infants with severe VLCAD.

86% of RDs, but only 33% of MDs, agreed that UCCS is indicated in individuals with severe VLCAD who have documented hypoglycemia in the fasting state.

Delphi 2

94% of RDs agreed that supplementation with UCCS at bedtime is not indicated in the treatment of VLCAD since hypoglycemia will not develop when the individual is asymptomatic if he/she avoids excessive periods of fasting and meets energy needs; however only 30% of MDs agreed with this statement.

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Evidence

Use of night-time nasogastric feedings is described in a few case studies of infants with a history of cardiac complications (F.633, F.657, F.626). During a hospitalization, a 5-month old was started on a 6-hour continuous overnight nasogastric feeding of Vivonex®. Between 8 and 30 months, the infant was transitioned to a formula feeding at 2 am (F.633). Another infant received overnight feedings containing glucose polymers as part of his routine care (F.657).

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