MCADD is part of the existing blood spot newborn screening programme in the UK (since 2009 for England, all of the UK since 2012). In England newborn screening identifies about 60 babies per year, with a prevalence of about 1 in 10 000 [12]. For this a heel prick blood sample is collected between 5 and 8 days of age on the standard newborn screening collection cards. MCADD screening uses the quantitative assay of C8 and decanoylcarnitine (C10). More details on screening, diagnostic and clinical management protocols in the UK can be found at www.newbornbloodspot.screening.nhs.uk/mcadd and www.bimdg.org.

At risk neonate with a family history of MCADD

Neonatal deaths have been reported in MCADD in breast and formula fed babies [13, 14]. Newborns are at greatest risk during the first 72 hours of life, especially if they are being breast fed (see below). Therefore it is essential that at risk infants who have a family history of MCADD receive adequate feeds during the first few days of life. The 2012 UK guidelines for managing at risk babies for MCADD can be accessed from the above websites and are as follows:

• any at risk babies should be screened at 24–48 hours and results made available, promptly
  
• the baby should be fed regularly, a term baby at least 4 hourly and preterm 3 hourly day and night until a diagnosis of MCADD is confirmed or excluded
  
• breast fed babies are at particular risk because the energy content of breast milk is low for the first few days and only small volumes of breast milk are available and initially consumed; top-ups of formula milk are therefore recommended
  
• a volume of 60 mL/kg/day of standard infant formula is advised for the first three complete days (72 hours); ideally this should be divided evenly between 6 to 8 feeds and given after the breast feed
  
• if there are concerns about the baby or they are taking inadequate volumes of feeds they should be transferred to the neonatal unit and fed by nasogastric tube or given an intravenous infusion containing 10% glucose

Dietary management overview

Normal diets contain predominantly fatty acids with a chain length of C16 and C18. These long chain fatty acids undergo β-oxidation to release energy and the carbon chain length is progressively shortened to a medium, then short chain length. Under basal conditions, the oxidation of medium chain fatty acids has been reported to be near normal in patients with MCADD due to overlapping enzyme substrate specificity [9]. This only becomes a problem when there is an increased demand for fatty acids to provide energy such as during fasting or illness. The well child can therefore have a normal diet without restriction of long chain fat. It is important, however, to avoid prolonged fasts as fatty acid oxidation rates increase with fasting. In infants, fatty acid oxidation rates rise after a shorter duration of fasting and frequent feeding is therefore recommended. There are few published data on the safe duration of fasting in MCADD. Derks et al. have suggested treatment guidelines based on data from the literature and Dutch MCADD patients, but they note the paucity of data in the first 6 months of life [15]. Compared with the UK guidelines (Table 19.1) the fasting times are more restricted in younger children. Illness in any child is usually associated with loss of appetite and prolonged fasting; fatty acid oxidation rates increase to provide essential energy sources. In MCADD this process is limited and the child is at risk of encephalopathy. To prevent encephalopathy an emergency regimen (ER) of frequent feeding of high carbohydrate (CHO) drinks/feeds needs to be given. This will provide energy, stimulate insulin secretion and thereby minimise lipolysis and fatty acid oxidation.

^* Around 2 weeks of age.

Source: www.bimdg.org.

Children with MCADD need to avoid medium chain triglycerides (MCT). Medium chain fatty acids can enter mitochondria without being bound to carnitine, so bypassing the step at which fatty acid oxidation is normally regulated (CPTI). MCT ingestion could therefore lead to a more severe metabolic disturbance than with long chain fats.

Dietary guidelines and information leaflets (e.g. MCADD is Suspected, MCADD and Your Child) for screened patients have been developed and can be accessed from www.bimdg.org.uk and www.newbornbloodspot.screening.nhs.uk. There are dietary information sheets for use at specified ages, from a positive screening result throughout childhood; they can also be used for clinically presenting patients. Information on suggested safe fasting times and ER for management of illness is included. Another useful educational tool is an e-learning resource on MCADD which is specifically designed for dietitians and midwives, accessed from www.geneticseducation.nhs.uk.

Dietary management during illness

If a child with MCADD is unwell (particularly if there is fever, vomiting and/or diarrhoea) and has a reduced appetite they should be given the standard ER of at least 3 hourly drinks containing glucose polymer, day and night (p. 502) . The ER needs to be implemented at an early stage to prevent metabolic decompensation and risk of sudden death. Fat is usually excluded during the acute period, although there is little evidence to support if this is essential. As the child improves, the normal diet can be resumed but extra ER drinks should be given, particularly during the night, until the child is fully recovered and eating well. If the ER is refused or vomited the child should have rapid access to their local paediatric services, avoiding a wait in the accident and emergency department, so there is no delay in starting an intravenous (IV) infusion containing glucose; 10% glucose, 0.45% saline is generally suitable but electrolytes should be monitored. Management decisions should be based on the child’s clinical state. Monitoring of blood glucose at home is not recommended because precision is poor at low concentrations and hypoglycaemia is a relatively late finding during illness in MCADD [16]. If for any reason the child needs to be commenced on a special infant formula or paediatric enteral feed during illness, it should not contain added MCT (see below). Emergency regimen guidelines (IV and oral) for hospital use can be accessed from www.bimdg.org.uk Although newborn screening has markedly improved the outcome for children with MCADD [17], there is still a risk of sudden death, specifically associated with vomiting [18]. The child who is vomiting should therefore be managed with extra vigilance.

Dietary management of well infants

With the introduction of newborn screening for MCADD in the UK it was important to set ‘maximum safe fasting times’ (Table 19.1). These were based mainly on feeding practices used in screened populations elsewhere in the world that had proven successful in avoiding symptomatic episodes. A review of these guidelines are planned

Infants can be breast or bottle fed with a normal infant formula and weaned onto a normal diet without restriction of long chain triglycerides (LCT), but it is important they are fed at regular intervals day and night. Small amounts of MCT are present in the vegetable oils of normal infant formulas, but the quantities are not sufficient to cause a problem. However, MCT are added to some special infant formulas and energy supplements and these should not be given. It is important to check the current composition of all such products for added MCT. Examples include hydrolysed infant formulas Pregestimil Lipil, MCT Pepdite, Pepti-Junior; high MCT special infant formulas Monogen, Lipistart; high MCT energy supplements MCT Duocal, MCT Procal. Low birthweight infant formulas should also be checked for added MCT.

The following dietary guidelines should be followed when treating an infant with MCADD:

Infants (under 1 year of age)

• breast feeding or normal infant formula is suitable
  
• avoidance of long fasts (Table 19.1)
  
• demand feeding every 3–4 hours throughout the day
  
• night feeds according to guidelines for ‘maximum safe fasting times’ (Table 19.1)
  
• weaning is commenced at the normal time around 6 months (26 weeks) of age
  
• weaning onto a normal diet and encouragement of regular starchy foods as weaning progresses
  
• restriction of LCT is not necessary
  
• avoidance of special infant formulas which contain added MCT

Note that newborn infants at risk for MCADD because of family history must receive adequate feeds (as described above).

Dietary management of well children

Children with MCADD should be encouraged to adopt a ‘healthy lifestyle’ through diet and exercise. Some parents worry their child may not be eating enough but they need to be reassured that not always finishing a meal can be normal; if necessary a snack can be offered later. There may be a risk of overweight or obesity due to parental anxiety surrounding feeding [19, 20]. Children with MCADD should be encouraged to exercise as normal. The need for provision of additional CHO pre-exercise should be individually monitored as muscle pain and/or reduced exercise tolerance has been reported in some patients [19]. All children, including those with MCADD, can feel hungry after exercise and a CHO snack should be given to help replenish glycogen stores.

From 1 year of age children can fast for 12 hours at night. In the author’s centre a minority of patients are not able to fast all night as they develop early morning symptoms; these symptoms have been resolved by being given either a night feed or uncooked cornstarch before bed as it is slowly digested to release glucose.

It is not necessary to restrict dietary fat. MCT, C8 and C10, occur in only a few foods and in small amounts, e.g. in butter, cow’s milk, and these can be included in the diet. Coconut is the only exception where 5% of the fatty acids have a chain length of C8 or C10; for coconut oil, the figure is 13%. Precautions should be taken in countries, such as the Philippines, where coconut oil is used as the main cooking oil. Pure coconut and coconut oil may be best avoided as the effect of large amounts of these in children with MCADD is not known. Theoretically there is risk of accumulation of toxic medium chain fats. Coconut products such as coconut milk and coconut paste may be suitable (provided the C8 and C10 content is low) and small amounts of coconut as an ingredient in food are acceptable in healthy children with MCADD. MCT are added to some special paediatric feeds and energy supplements and these should not be given. It is important to check the current composition of all such products for added MCT. Examples include hydrolysed paediatric feeds Peptamen Junior, Paediasure Pepdite; paediatric enteral feeds Paediasure, Frebini Energy; high MCT energy supplements MCT Duocal, MCT Procal.

The following dietary guidelines should be followed when treating a child with MCADD:

Children (from 1 year of age)

• regular meals (three main meals daily, including breakfast which must not be missed)
  
• a bedtime snack containing starchy foods such as bread, crumpets, muffins, rice cakes, crackers, biscuits, pitta bread, chapatti or cereals
  
• missed meals can be replaced with a starchy snack if necessary
  
• avoidance of special dietetic products which contain added MCT
  
• a maximum fasting interval of 12 hours overnight (Table 19.1)
  
• encouragement of a ‘healthy lifestyle’ and maintenance of normal body mass index
  
• restriction of LCT is not necessary.

Alcohol

Adolescents (and adults) need to know that an excessive alcohol intake is hazardous. Alcohol intoxication with resultant vomiting has been a cause of presentation in adults [8]. Vomiting and loss of appetite associated with excessive alcohol intake can be particularly dangerous. Alcohol inhibits gluconeogenesis so both fatty acid oxidation and gluconeogenesis which provide fuel during fasting are impaired. Moreover, the symptoms of hypoglycaemia might be attributed to inebriation rather than MCADD. Teenagers and adults need to be educated about the risks associated with excessive alcohol intake. A sensible approach is to advise that alcohol intake is limited and must always be taken in combination with food.

Carnitine

Plasma carnitine concentrations are often below the normal range in patients with MCADD, particularly after illness. The consequences of this are not clear. Carnitine supplements are given by some but this is not universal [21]. Maintenance of free carnitine levels (albeit at the lower end of normal range) has been reported in 46 patients from one centre not receiving carnitine supplementation; no patient experienced significant episodes of rhabdomyolysis or decompensation [22]. In the author’s centre, a trial of carnitine is given to a minority of children who complain of muscle symptoms and also have low plasma carnitine levels. There is conflicting evidence concerning the beneficial effect of carnitine on exercise tolerance [23, 24].

Expanded newborn screening

A number of countries worldwide such as Germany, Australia and the USA undertake expanded newborn screening for LC-FAOD, using tandem mass spectrometry. Expanded newborn screening for VLCADD has identified a common milder phenotype for which less dietary modification is required (see below). A pilot project of expanded newborn screening has been under way since July 2012 in parts of England; LCHADD is one of the disorders being evaluated. Screening is by measurement of hydroxypalmitoyl (C16-OH) carnitine in dried blood spots using tandem mass spectrometry. More information on the screening, diagnostic and clinical management protocols can be accessed at www.expandedscreening.org. LCHADD is not part of the national screening programme in England.

Long chain triglycerides

The safe upper limit for long chain fat intake is unknown and varies with the severity of the disorder. Normalisation of acylcarnitine profiles is observed in LCHADD and MTPD when LCT intake is <10% total energy and MCT are given [34]. Recommendations from published guidelines suggest for severe VLCADD to limit LCT to 5%–10% total daily energy intake [32, 33]. This is also recommended by GMDI. For severe defects of LCHADD and MTPD it is recommended to restrict LCT to as low as practically possible (5%–10% energy intake) but in practice it is typically more likely to be <15% (including 3%–4% from essential fatty acids) [32, 34]. Importantly, in those presenting with a milder myopathic form of the disorder, as can be seen in VLCADD and CPTII deficiency (CPTIID), such restriction of LCT may not be necessary [32].

Medium chain triglycerides

Dietary MCT are absorbed through the hepatic portal vein; they pass directly into the mitochondria primarily independent of the carnitine cycle and are then rapidly converted to ketone bodies, bypassing the long chain β-oxidation enzymes. Ketones inhibit the mobilisation of fatty acids from adipose tissue and the oxidation of fatty acids by cardiac muscle [35]. In patients with VLCADD, MTPD and LCHADD, MCT (C8, C10) can provide a useful energy source, 8.3 kcal (35 kJ)/g, and may have other beneficial effects. MCT have led to the resolution of cardiomyopathy in patients with VLCADD and LCHADD deficiencies [36, 37]. Medium chain fatty acids may also suppress long chain fatty acid oxidation without being converted to ketone bodies; they have been shown to inhibit the accumulation of potentially toxic long chain intermediates in cultured skin fibroblasts from LCHAD and MTP deficient patients [38]. It has been suggested that patients should maintain a high intake of MCT throughout life (10%–20% energy intake) [34]. The optimal amount or ratio of C8, C10 fatty acids to provide is not known. Skin fibroblast studies have shown that C10 undergoes elongation prior to oxidation, so it has been suggested that C8 may be preferable [39, 40]. Recommendations from published guidelines from GMDI and other authors [32, 33] suggest 20%–25% total daily energy intake be provided from MCT for severe LCHADD, MTPD and VLCADD. In the UK, infant formulas which can be prescribed for LC-FAOD provide either 17% or 30% total energy intake as MCT (Table 19.2).

Reconstitution: Monogen 1 scoop added to 25 mL water

Lipistart 1 scoop added to 30 mL water

In UK only Monogen and Lipistart are prescribable.

SHS, Scientific Hospital Supplies International; MCT, medium chain triglycerides; LCT, long chain triglycerides; DHA, docosahexaenoic acid; AA, arachidonic acid.

Source: Manufacturers.

The role of MCT is less clear in defects of the carnitine cycle. In several infants with CPTI deficiency, renal tubular acidosis has only resolved when they have been changed to an MCT based feed [41]. MCT has also been used with apparent benefit in patients with mild CACT deficiency (CACTD). In cases of severe CACTD and CPTIID, MCT has been reported to have caused markedly abnormal blood acylcarnitines and dicarboxylic aciduria [42, 43]. They suggest the amount of MCT, may need to be limited because it may in part enter the mitochondria by a carnitine dependent mechanism.

MCT is found in insignificant amounts in normal diets. Although MCT have benefits in LC-FAOD, their long term use in humans has never been systematically studied, so it is not known if there are any detrimental effects.

MCT and exercise

In the normal population the primary fuel source during low intensity prolonged exercise is fatty acids, and for high intensity exercise CHO (glucose and glycogen stores). Glucose is also the initial fuel during any exercise. Patients with VLCADD, LCHADD, MTPD and CPTIID can experience muscle pain and rhabdomyolysis with exercise. This may be due to their limited ability to oxidise long chain fatty acids as a fuel source for exercising muscle or the accumulation of toxic intermediates. Supplements of MCT pre-exercise have been reported to improve exercise capacity although only very small numbers of patients of varying ages and disorders have been studied [44–46]. In patients with the myopathic form of CPTIID and VLCADD there appears to be sufficient enzyme activity for fatty acid oxidation at rest, but not for the increased requirement of exercise [47, 48]. Some patients with CPTIID appear to benefit from taking a diet rich in polysaccharides pre-exercise [49]. As yet, no treatment has conclusively been shown to prevent rhabdomyolysis.

The effect of diet on exercise capacity has also been studied in the VLCADD knockout mouse. This has reduced exercise intolerance which is not improved by a low fat, CHO enriched diet [50]. Exercise capacity was improved by an MCT bolus prior to exercise but not by long term use of an MCT based diet. Moreover, long term use of MCT caused severe hepatic steatosis and increased long chain acylcarnitine accumulation [51] which was not seen following an MCT bolus [52]. Although these results are interesting it is not yet clear how they relate to human patients.

Triheptanoin

Triheptanoin, an oil containing C7 fatty acids, has been substituted for conventional MCT in a number of patients with LC-FAOD. Use of MCT leads to the production of acetyl-CoA but it is hypothesised that a shortage of oxaloacetate prevents this from being oxidised in the citric acid cycle. Triheptanoin generates acetyl-CoA and also propionyl-CoA. The latter can be converted to oxaloacetate, which acts as an ‘anaplerotic’ substrate for the citric acid cycle. Improved cardiac function and/or muscle weakness has been reported in three patients with VLCADD [53] and seven patients with myopathic CPTIID [54] given triheptanoin. However, triheptanoin was not compared with MCT in a controlled manner, so it is impossible to be certain if it conferred any specific benefit. Triheptanoin is not yet widely available outside the USA.

Frequency of feeding

Frequent feeding is recommended to reduce lipolysis. The safe duration of fasting for different disorders and ages has not been well defined and practices differ between countries and centres. Treatment recommendations from Spiekerkoetter et al. suggest a maximum safe fasting time at night of 8 hours from 6 months of age and 10 (−12) hours from 12 months in VLCADD, MTPD and LCHADD during stable metabolic condition [32]. In the USA no consensus on overnight feeding could be reached by an expert panel using the Delphi method [33]. The GMDI guidelines (www.gmdi.org) for VLCADD are similar to those of Speikerkoetter et al. In the UK, fasting is more severely limited to help reduce the risk of cardiomyopathy and onset of long term complications of retinopathy and neuropathy (although this has never been proved). Children with severe defects are fed 3–4 hourly during the day and by continuous nasogastric or gastrostomy feeding overnight (or the child is woken for feeds during the night). Overnight feeding is not standard practice but the literature suggests that some other countries do this, such as Scandinavia.

Questionnaire surveys have shown that uncooked cornstarch (UCCS) is used by some centres to provide a source of ‘slow release glucose’ [31, 55]. In older children continuous tube feeding overnight may be replaced with UCCS (personal practice). This may be a better option than stopping overnight feeds completely. Before use, the metabolic response to UCCS should be assessed since this varies between patients [56]. However, there are no published studies comparing the metabolic profiles of patients on overnight feeds, UCCS and those who fast overnight or the outcome between those given long term overnight feeding or not. Patients with milder defects are likely to tolerate overnight fasting without problems.

Prevention of deficiencies on a low LCT diet

Patients on minimal LCT diets require supplements of fat soluble vitamins, essential fatty acids (EFA) and long chain polyunsaturated fatty acids (LCPUFA). In the UK at least 1% total energy intake from linoleic acid and 0.2% from α-linolenic acid are recommended [57]. Others recommend a much higher intake of 4.5% daily energy intake in infants <4 months of age, decreasing to 3% from age 4 years [32]. The joint FAO/WHO 2008 report recommended an adequate daily intake for children >6 months to be linoleic acid 3%–4% and α-linolenic 0.4%–0.6% of daily energy intake [58]. Most sources of EFA (such as walnut oil) do not provide LCPUFA, such as arachidonic acid (AA) and docosahexaenoic acids (DHA), but these are expected to be synthesised from the EFA that are provided. In the author’s experience, deficiency is rare if patients are receiving adequate EFA in the form of walnut oil [59].

It has been suggested that DHA deficiency may contribute to the pathogenesis of chorioretinopathy of LCHADD [60], although this is not prevented by supplementation. Nevertheless supplements of DHA at a dose of 60 mg/day in children <20 kg and 120 mg/day in children >20 kg are recommended in MTPD and LCHADD [32]. FAO/WHO recommends an adequate daily intake of DHA for normal children to be

• the amounts found in breast milk for infants
  
• 100–150 mg for children aged 2–4 years
  
• 150–200 mg for children aged 4–6 years
  
• 200–300 mg for children aged 6–10 years [58]

Fat soluble vitamin supplements (A, D, E) are essential for those on reduced LCT intake. Vitamin E deficiency is associated with a peripheral neuropathy which is one of the long term complications of MTPD and LCHADD. It is therefore essential that vitamin E is provided in normal requirements for age, at least.

Carnitine

It remains uncertain whether carnitine supplements should be given to patients with long chain fatty acid oxidation disorders. Plasma free carnitine concentrations are often below the normal range, particularly after episodes of illness, but tissue levels are probably not low enough to affect fatty acid oxidation. Supplements may facilitate the excretion of metabolites but, by increasing the level of long chain acylcarnitines, it is possible that they may increase the risk of arrhythmias [61].

Energy distribution of the diet

As LCT is restricted more energy needs to be provided from CHO and supplements of MCT. The optimal distribution of energy intake from CHO and MCT is not known. The following provides a guide to the typical energy distribution and long chain fat intake of the diet in severe defects (based on personal practice):

• 60%–65% energy from CHO
  
• 10%–15% energy from protein
  
• 20%–25% energy from medium chain fat (depending on the disorder)
  
• 1.2%–2% energy from EFA (based on FAO/WHO [58] higher intakes may be appropriate)

Minimal long chain fat diet

Children

Long chain triglycerides

Children should remain on a minimal LCT diet with an energy distribution as previously outlined (p. 599) . Inevitably, daily intake of long chain fat increases with age. The figures quoted are based on the lowest possible long chain fat intake that is practicably achievable for a given age, as the safe upper limit for long chain fat intake is not known. Ideally, the increased CHO intake should be derived from starchy foods (e.g. rice, pasta, potato, bread, cereals) because these are more slowly digested than sugary foods. It is recognised, however, that some children cannot manage such a bulky diet and sugar containing foods such as low fat ice cream, cake or biscuits should form part of their diet. The diet should contain very low fat sources of protein, such as white fish, white chicken or turkey meat, pulses (Table 19.5). There are many very low fat alternatives to regular high fat foods such as crisps, sauces, desserts, ice cream and cheeses which can also be incorporated into the diet. To allow a greater variety of manufactured foods to be included in the diet, parents need to be given guidance on interpreting food labels for fat content and on understanding the many and potentially misleading wordings used to describe the fat content of food, e.g. reduced fat, low fat, virtually fat free, 90% fat free. The different types of fat, e.g. saturated, mono-unsaturated and polyunsaturated, can cause confusion and it is helpful to explain that total fat should be used when calculating fat intake. Nutritional labelling expresses the total fat content as grams of fat per 100 g and often grams of fat per portion. To help parents work out if a food is suitable they can be taught to calculate and then weigh the amount of food which provides a certain amount of fat. This also makes it easier to monitor the daily fat intake. For example,

	Foods allowed	Foods to avoid
Milk	Skimmed milk, condensed skimmed milk	Full fat and semi-skimmed milk. Cream (all types)
	Natural yoghurt, very low fat yoghurt and fromage frais (<0.2 g/100 g)	Full fat yoghurt and fromage frais
	Low fat cottage cheese (<0.5 g/100 g)	Full and half fat cheeses
	*Very low fat cheeses
	Quark (skimmed milk soft cheese)
	Low fat ice cream	†Ice cream
Egg	Egg whites, egg white replacer, meringue	Egg yolks
Fish	White fish (no skin), e.g. haddock, cod, sole, plaice	Oily fish, e.g. sardines, kippers, salmon, mackerel
	Crab, crabsticks, tuna, prawns, shrimps, lobster	Fish in breadcrumbs, batter, sauces, pastry
	Tinned: tuna in brine or water, crab, prawns, shrimps	Tinned: fish in oil
Poultry	*Chicken, *turkey (white breast meat, no skin)	Chicken, turkey (dark meat and skin), basted poultry, duck, goose
		Chicken in breadcrumbs, batter, sauces, pastry
Meat	*Lean red meat (<5% fat content)	Fatty meat, sausages (normal and low fat), burgers, meat paste, paté, salami, pies
Meat substitutes	Soya mince, *Quorn, *tofu
Pulses	Peas, e.g. chick peas, split peas	None, unless in made-up dishes containing fat
	Beans, e.g. red, white, borlotti, black-eyed
Fats/oils	Medium chain triglyceride oil as advised	Butter, margarine, low fat spread, vegetable oils, lard, dripping, suet, shortening
Pasta and rice	Spaghetti, macaroni, other pasta, noodles, couscous, rice (white)	Wholemeal pasta, pasta in dishes, e.g. macaroni cheese, carbonara
		Brown rice, egg noodles
Flours and cereals	Flour (white), cornflour, custard powder, semolina, sago, tapioca	Flour (wholemeal), soya flour, oats, bran Foods made with flour which contain fat, e.g. pastry, sauces, cake, biscuits, batter, breadcrumb coatings
Breakfast cereals	Many are suitable	Cereals with nuts and chocolate, e.g. muesli
	Wholewheat cereals, e.g. Weetabix
	branflakes are higher in fat content than non-wholewheat cereals , e.g. Rice Krispies,	All-bran, Ready Brek
	cornflakes
Bread and crackers	*White bread, white pitta, crumpets, muffins Some crackers have a low fat content, e.g. rice cakes, Matzos, Ryvita (not sesame)	Wholemeal, wholegrain breads, nan bread, chapatti made with fat, croissants, oatcakes, cheese crackers, †crackers
Cakes and biscuits and pastry	Only those made from low fat ingredients 95% fat free cakes and biscuits	†Cakes, †biscuits, buns, pastry for sweet and savoury foods, e.g. apple pie, quiche
Desserts	Jelly, meringue, sorbet, very low fat ice cream, skimmed milk puddings, e.g. rice, custard	Most desserts, e.g. whole milk puddings, trifle, cheesecakes, gateaux, †mousse, fruit pie or crumble
Fruit	Most varieties – fresh, frozen, tinned, dried	Avocado pears, olives, yoghurt/chocolate covered dried fruit, banana chips
Vegetables	All vegetables and salad Very low fat crisps	Chips, †crisps, †low fat crisps, roast potato, potato or vegetable salad in mayonnaise or salad dressing, †coleslaw
Herbs and spices	Pickles, chutney Herbs, spices, salt, pepper
Nuts Seeds		Nuts, peanut butter, seeds, e.g. sesame, sunflower
Sauces and gravies	Tomato ketchup, brown sauce, soy sauce, Marmite, Oxo, Bovril, very low fat gravy mixes Fat free dressings and mayonnaise Minimal fat sauces (jars, tins, packets)	†Gravy granules, †stock cubes Salad cream, mayonnaise, oil and vinegar dressings †Sauce mixes (jars, tins, packets)
Soups	Some low calorie and ‘healthy eating type’ soups are very low fat	Most soups, cream soups
Confectionery	Boiled sweets, jelly sweets, fruit gums, pastilles, marshmallow, mints, ice lollies	Chocolate, chocolate covered sweets, toffee, fudge, butter mints
Sugars and preserves	Sugar, golden syrup, jam, marmalade, honey, treacle	Lemon curd, chocolate spread
Baking products	Baking powder, bicarbonate of soda, yeast, arrowroot, essences, food colouring
Drinks	Fruit juice, squash, fizzy drinks, milkshake flavourings, tea, coffee	†Instant chocolate drinks, cocoa, malted milk type drinks, e.g. Horlicks

^* Intake of these foods may need to be restricted because of their fat content.

^† These foods in the ‘avoid list’ often have very low fat equivalents which can be included in the diet.

Manufactured foods which have a fat content <0.5 g/100 g can generally be allowed in the diet freely, unless large amounts are being consumed.

Medium chain triglycerides

The intake of MCT naturally falls as less infant formula is consumed. Alternative sources of MCT should be incorporated into the diet because of the potential beneficial effects discussed above. A daily intake of 20%–25% of total energy intake is suggested which equates to 2.5–3 g/100 kcal (420 kJ) consumed. The optimal timing of administration has not been defined; however, it is common practice to divide the dose and give 3–4 times a day, as it is rapidly absorbed and used.

MCT can be added to the diet as an oil, emulsion or powder. These products vary in C8, C10 fatty acid composition (Table 19.6). MCT oil can increase the palatability of the diet. It has a low smoke point compared with other cooking oils. Care must be taken when cooking foods in MCT oil to ensure it does not burn or become overheated as it develops a bitter taste and an unpleasant odour. The optimum cooking temperature for MCT is 160°C. MCT oil can also be used in baking, e.g. cakes, biscuits and pastry, and can be added to a variety of foods such as pasta, soups. MCT emulsion such as Liquigen may be more acceptable as it can be easily mixed into skimmed milk without separating. It can also be added to other liquids or foods and used in baking. MCT Procal powder can be added to hot or cold food or drinks (not fruit juice as it curdles). MCT Procal comes in a convenient sachet form, making it easy to use away from home (p. 632). Recipes are available for all products from their manufacturers.

			MCT g/100 g fatty acids
Product	Energy kcal (kJ)	MCT	C8	C10	C12	Other nutrients
MCT oil (Nutricia)	855 (3.6 MJ)/100 mL	94 g/100 mL	58	38	1.7	Nil
Liquigen emulsion (Nutricia)	450 (1.9 MJ)/100 mL	50 g/100 mL	82.1	15.9	1.3	Nil
MCT Procal (Vitaflo)	657 (2.7 MJ)/100 g 105 (440 kJ)/16 g sachet	62.2 g/100 g 10 g/16 g sachet	54	39	–	Per sachet: 2 g protein, 3.3 g CHO

MCT, medium chain triglyceride.

Other MCT products such as MCT margarine can be sourced from www.ceres-mct.com or www.drschar.com. These are not prescribable in the UK.

Table 19.7 gives an example of how to provide the daily intake of MCT.

Daily MCT intake for a 4-year-old girl
Estimated average requirement for energy for age = 1400 kcal (5.9 MJ)/day [57]
Provide 20%–25% energy from MCT = 280–350 kcal (1.2–1.5 MJ) ÷ (8.3 kcal, 35 kJ/g MCT) = 34–42 g/day
Breakfast	20 mL MCT emulsion (10 g MCT) added to breakfast cereal
Lunch	1 sachet MCT Procal (10 g MCT) added to very low fat yoghurt at school
Evening meal	10 mL MCT oil (10 g MCT) added to cooked pasta
Another 10 g of MCT could be added to the night feed (Table 19.8) from MCT emulsion

MCT, medium chain triglyceride.

Other nutrients

EFA need to be provided in the diet and can be added from walnut oil or combinations of other oils as described for infants. LCPUFA can be given as one sachet of KeyOmega, 100 mg DHA and 200 mg AA, which is more than the suggested intake of 60 mg DHA/day for young children with LCHADD or TFPD. In children weighing >20 kg more DHA is needed to provide the suggested intake of 120 mg/day [32]. One sachet of DocOmega provides 200 mg DHA.

Supplements of fat soluble vitamins (A, D and E) are needed unless the child is still taking around 600 mL infant formula. Intakes of iron, zinc and B₁₂ should be regularly calculated as these can also be low in minimal LCT diets. The choice of supplement will depend on need, age and desired format: powder, tablets or soluble tablets are available. Ketovite tablets and liquid provide an adequate intake of fat soluble vitamins and are suitable for all ages. Alternatively, more complete vitamin and mineral supplementation can be provided: Fruitivits (from age 3 years), Paediatric Seravit (all ages), Phlexyvit sachets or tablets (from age 10 years), Forceval Soluble Junior (from age 6 years) and Forceval Soluble (from age 12 years) (p. 21) .

Frequency of feeding

Lipolysis can be minimised by 3–4 hourly feeding during the day and continuous overnight tube feeds. It is difficult to be sure, however, whether overnight feeding is necessary, particularly in older children who have larger glycogen stores. In LCHADD it may help delay the onset of retinopathy or neuropathy. If overnight feeding is used the amount of glucose given overnight should equal basal glucose production rates for age (around 0.3–0.4 g CHO/kg/hour) (p. 544) . It is not yet known whether the addition of MCT to the night feed is helpful [63]. Less CHO energy may be needed if MCT is added to the night feed. Table 19.8 gives examples of overnight feeds.

Overnight feed for a 6-year-old boy, weight 22 kg

25% CHO from glucose polymer, administered at 25 mL/hour from 10 pm to 6 am via gastrostomy

Fluid 200 mL

Energy 200 kcal (840 kJ)

Glucose polymer 53 g (95% CHO)

CHO 0.3 g CHO/kg/hour

or

Glucose polymer and MCT feed, administered at 25 mL/hour from 10 pm to 6 am via gastrostomy

Fluid 200 mL

Energy 200 kcal (840 kJ)

Glucose polymer 30 g (95% CHO) = 114 kcal, 479 kJ

MCT = ¼ of daily dose (10 g MCT) as 20 mL Liquigen (=5 g MCT/100 mL) = 90 kcal, 370 kJ

MCT, medium chain triglyceride.

Fasting tolerance increases with age; therefore in older children it may be possible to stop the overnight feeds completely or substitute with one or more doses of UCCS. Before changing management, it is the author’s and others’ practice [56] to assess the child’s metabolic response by serial measurement of plasma free fatty acids, blood glucose and long chain 3-hydroxyacylcarnitines on their usual regimen and after a dose of UCCS. This needs to be done in hospital under controlled conditions, ensuring the child is not fasted for longer than planned. If UCCS is to be used the results of these studies are used to plan how frequently a dose of UCCS needs to be given. Doses of cornflour used are 1–1.5 g/kg/dose in older children. UCCS is generally introduced at home to test its palatability and tolerance. It should be given raw because cooking or heating disrupts the starch granules and thus makes it much less effective. It is usually mixed with skimmed milk. The dose of UCCS is gradually increased, starting with 5 g and increasing in 5 g increments every few days/week to the full amount.

Exercise management

Patients with VLCADD, LCHADD, MTPD and CPTIID can experience episodes of rhabdomyolysis, with myalgia, elevated creatine kinase levels and, in severe cases, myoglobinuria. These episodes are sometimes triggered by infection but more often they are induced by exercise in children or young adults as they become more active and play sports for longer periods. Rhabdomyolysis can be the only clinical symptom in patients with partial deficiencies of CPTII or VLCAD and management can be difficult. Under normal circumstances CHO is the main fuel used for moderate to high intensity exercise such as sprinting, whereas fatty acids are the main fuel for low to moderate intensity exercise. Thus ‘short burst exercise’ may be more suitable for these patients than prolonged low intensity exercise because CHO will be used in preference to long chain fatty acids. Several papers suggest that dietary modification may reduce the risk of rhabdomyolysis. In one study patients with partial CPTIID tolerated exercise better on a CHO rich diet than on a fat rich diet [49]; a bolus of glucose before exercise did not help [64]. In contrast pre-exercise boluses of MCT (0.3–0.4 g/kg/dose) have been reported to improve exercise capacity in patients with various fatty acid oxidation disorders [65]. Pre-exercise dietary treatment may need to be adjusted according to the intensity and duration of the exercise being undertaken. MCT can be given as a prescribed dose of Liquigen, or MCT Procal, and CHO can be given from food such as a low fat cereal bar, banana, bread or high CHO drink such as Lucozade. Some children may not be able to do prolonged periods of exercise without developing muscle pain, so this must be avoided. In some patients, drug treatment with bezafibrate may also be helpful [66].

If a child develops rhabdomyolysis and muscle pain during or following exercise they may find it very difficult to walk for 24–48 hours. These episodes must be treated promptly as there is a risk of acute renal failure. An emergency regimen using the standard glucose polymer ER (p. 502) and extra fluids (determined on an individual basis), is implemented and may help reduce the risk of worsening rhabdomyolysis. MCT can be added to the ER (personal practice with a few patients). The ER feed should aim to provide at least the normal energy intake for age. The feed can be given orally but if there is associated loss of appetite then it should be given via a tube to ensure the full amount of fluid and energy is taken. Rest is important until symptoms resolve. It is essential parents and patients know to look for signs of myoglobinuria (dark, cola coloured urine) and make immediate contact with their metabolic team as a hospital admission may be necessary. Plasma creatine kinase can be markedly elevated during episodes of rhabdomyolysis and may be helpful in determining the extent of muscle damage and management needed.

Feeding problems

Feeding problems are common in children with LCHADD, particularly in early childhood, and they occur despite good metabolic and clinical condition [67]. With age these problems either improved or resolved in this cohort. However, early recognition and management of feeding problems remains important and newborn screening may help prevent the development of these.

Monitoring

Emergency regimen for treatment of illness in LC-FAOD

If the child becomes unwell and is unable to take their usual regimen the standard ER of very frequent feeds of glucose polymer, day and night, should be given (p. 502) . In mild illnesses it will probably not be necessary to implement the ER. In patients with a gastrostomy or nasogastric tube, the drinks can be given via the tube if refused orally. The ER needs to be started promptly to inhibit the mobilisation of fatty acids as decompensation may be rapid. Long chain fat is strongly contraindicated. The role of MCT during acute illness is not clear. As the child improves, the normal diet can be resumed. While this is being reintroduced it is essential to maximise energy intake and continue with frequent feeding, usually 2–3 hourly by day and continuous tube feeds overnight. If the child does not tolerate the ER enterally they need to be admitted to hospital for an IV infusion containing glucose; 10% glucose, 0.45% saline is generally suitable but electrolytes should be monitored. Emergency regimen guidelines (IV and oral) for hospital use can be accessed from www.bimdg.org.uk. IV carnitine should not be given because long chain acylcarnitines may be arrythmogenic.

Patients with cardiomyopathy should probably be admitted during any intercurrent illness since there is a risk of deteriorating cardiac function. Families should also be warned to look for dark urine since illness (or exercise) can precipitate rhabdomyolysis with myoglobinuria. If there is myoglobinuria it is essential that the child is admitted to hospital for further management because of the risk of acute renal failure. A high fluid intake is recommended to increase myoglobin excretion and help prevent renal failure. Blood glucose monitoring by parents is not recommended as a marker of metabolic status, since hypoglycaemia is a relatively late finding and treatment should be initiated long before this develops [16].

Dietary management during illness

During illness the standard ER (p. 502) of very frequent feeds/drinks, day and night, of glucose polymer should be given to minimise lipolysis and endogenous protein catabolism (specifically the ketogenic amino acids).

In defects of ketogenesis provision of glucose will help prevent hypoglycaemia and limit the production of potentially toxic metabolites. Blood glucose monitoring by parents is not recommended as a marker of metabolic status, since hypoglycaemia is a relatively late finding and treatment should be initiated long before this develops. In defects of ketolysis, providing glucose will prevent illness from leading to ketoacidosis. Patients can become anorexic at an early stage, refusing ER drinks. It is essential feeds/drinks are therefore given via a nasogastric tube. In the event of persistent vomiting or the child not improving a hospital admission is needed for IV 10% glucose. Sodium bicarbonate may also be necessary to correct acidosis. Extra fluids will be needed if the child is dehydrated, which is common in the ketone body utilisation defects. Emergency management guidelines for use in hospital can be accessed at www.bimdg.org.uk.

As the child recovers and begins to eat again it is important that additional ER drinks of glucose polymer are given until the normal diet is fully resumed, particularly if they have not eaten well for several days. This needs to be managed carefully to prevent subsequent hypoglycaemia. If for any reason the child needs to be commenced on a special infant formula or paediatric feed during the recovery phase these should not contain added MCT which, once absorbed, are rapidly converted to ketones. In these disorders where there is a defect in either formation or utilisation of ketones, MCT may be of potential harm. Theoretically in SCOT and beta-ketothiolase deficiency MCT may increase concentrations of ketones (which cannot be utilised) and inhibit long chain fatty acid oxidation, thus contributing to the energy deficit. In the defects of formation of ketones, the conversion of MCT to ketones may be limited and so will not provide an energy source.

Dietary management – long term

There is little published information on the detailed dietary management of these disorders. Between episodes of metabolic decompensation patients are likely to be clinically asymptomatic. In the well child avoidance of prolonged fasts and provision of adequate energy is important. There are no published guidelines on safe fasting times for any of these disorders. In infants regular feeding, day and night, is important and it seems reasonable to continue a night time feed until the age of 1 year. Older children should tolerate overnight fasting (10–12 hours) without problems but they should be given a bedtime snack containing starch. Missed meals should be replaced with a high CHO drink if there is any risk of impending illness. MCT are theoretically best avoided as either they cannot be used to form ketones or they will add to the total ketone load which cannot be utilised.

A moderate protein (leucine) restriction (1–2 g protein/kg/day) is recommended for HMG-CoA lyase and beta-ketothiolase deficiency because these enzymes are involved in the catabolism of the ketogenic amino acids [82–84]. Also, in HMG-CoA lyase deficiency this has been combined with a modest fat restriction in some cases [82, 83]. However, opinions differ about the necessity of these dietary manipulations. Stable isotope studies suggest that protein catabolism contributes little to the abnormal metabolites in HMG-CoA lyase deficiency and fatty acid catabolism may be more important [85]. In the well child it is reasonable to suggest a generous CHO intake and avoidance of a high protein and fat intake.

Mild protein restriction (1.5–2.0 g/kg/day) has been described in SCOT deficiency (probably to limit increased concentrations of ketones being formed from the ketogenic amino acids) and avoidance of a fat rich diet which would cause ketosis [86, 87]. In the well child it is reasonable to suggest a generous CHO intake and avoidance of a high protein and fat intake.

A recent publication highlighted the potential foetal and maternal risks to women with HMG-CoA lyase deficiency, particularly the risk of metabolic decompensation associated with nausea and vomiting which needs careful management at an early stage [88].

Ketogenic diet in mitochondrial disorders

Ketone bodies can form ATP via the Krebs cycle and the OXPHOS system and may partially bypass complex I, thus potentially providing an alternative energy source for the brain and other tissues. In mitochondrial disorders a ketogenic diet (KD), high fat and low carbohydrate, may be beneficial to treat epilepsy in some specific subgroups. Complex I and IV deficiency represent a significant proportion of the group of patients with mitochondrial epilepsy: in a study of 48 children, 73% and 23% respectively [100]. KD was trialled in 24 of those children; 50% became seizure free and seizures were reduced by up to half in 25%. Kang et al. [95] reported safe and effective use of the classical KD in treatment of intractable epilepsy in 14 patients mostly complex I or IV, with seizure reduction (3/14) or seizure free (7/14). The same group describe better tolerance and adherence with use of the modified KD in 14 patients; 3/14 were seizure free and 5/14 had >50% seizure reduction [101]. However, it is unclear whether the KD affects disease progression in different mitochondrial subgroups and formal clinical trials are necessary [90, 95, 96, 101].

Characteristics of patients with SLO are given in Table 19.10.

ONS, oral nutritional supplements.

Abetalipoproteinaemia (ABL) is an autosomal recessive disorder, incidence <1 in 100 000, caused by mutations in the microsomal triglyceride transfer protein (MTP) gene resulting in the absence of plasma apolipoproteins (apo), B-containing lipoproteins, chylomicrons, VLDL and LDL [150]. MTP facilitates the transfer of lipids onto apo B. Presenting features are given in Table 19.12.

The onset of neurological symptoms usually begins in the first or second decade of life [153]. Prior to the use of high dose oral fat soluble vitamin treatment, neurological complications developed before the second decade and in some cases survival was not past the third decade [154]. Ophthalmic involvement is variable and covers a wide range of symptoms and manifestations [155]. The neurological and ophthalmic manifestations appear to be secondary to deficiency of vitamin E; vitamin A deficiency may also contribute to retinopathy.

Dietary management

Treatment involves reduction of dietary fat to prevent steatorrhoea and supplementation with tocopherol to prevent progression of the neuromuscular and retinal degenerative disease [156]. Fat restriction is determined by individual tolerance (monitoring gastrointestinal, GI, symptoms) which increases with age and can vary from 5 g fat/day in infants up to 20 g/day in the older child. In the author’s centre fat intake has been maintained at 10 g/day, not inclusive of fat derived from walnut oil, which is given to provide essential fatty acids (EFA). Despite the inability to secrete chylomicrons, there does appear to be some absorption of long chain fatty acids [157]. These are probably transferred to the liver as free fatty acids. Dietary treatment should aim to alleviate GI symptoms and increase energy intake to allow for catch up growth.

Medium chain triglycerides

The fatty acids derived from medium chain triglycerides (MCT) (C:8, C10:0, C12:0) do not require chylomicrons for their absorption as they are transported directly from the intestine to the liver via the hepatic portal system. The use of MCT as an energy source in ABL is controversial. There have been several reports of hepatic fibrosis with the use of MCT [158, 159], but there have also been reports of children who developed cirrhosis independent of the use of MCT oil [160, 161]. There are case reports of the benefit of MCT [162] and absence of adverse effects with its use [163]. Historically, MCT has not been used in the treatment of ABL, but some metabolic centres have started to use it; regular liver ultrasound scans and biochemical monitoring of liver function is required.

Infant feeds

An example of a minimal fat modular feed is outlined in Table 19.13. The feed requires a minimal fat protein source (e.g. Protifar, Vitapro, skimmed milk powder), a carbohydrate source as glucose polymer (e.g. Polycal, Vitajoule), electrolytes, a source of EFA (e.g. walnut oil), vitamins and minerals (e.g. Paediatric Seravit). Long chain triglycerides (LCT), given as a fat emulsion, e.g. Calogen, are added gradually to the feed as tolerated. LCPUFA can be given as KeyOmega. Consideration could be given to the use of Walnut oil as a LCT source if EFA remain low.

16-week-old boy, prior to weaning, weight 5.4 kg (2nd centile), length 60 cm (9th centile)
Daily requirements:
fluid 150 mL/kg, energy 95 kcal (400 kJ) to 130 kcal (545 kJ)/kg, protein 1.6 g to 3 g/kg
EFA given as walnut oil to provide 0.1 mL/56 kcal (235 kJ) of the estimated average requirement (EAR) for energy for age [57]
This can be given as 180 mL × 6 feeds
	Energy (kcal)	Protein (g)	CHO (g)	LCT (g)	Na+ (mmol)	K+ (mmol)
Vitapro 15 g	54 (225 kJ)	11.3	1.4	0.9	2.0	2.7
Polycal 115 g	442 (1850 kJ)	–	110.4	–	0.2	0.1
Paediatric Seravit 15 g	45 (190 kJ)	–	11.3	–	0.1	–
Calogen 6 mL	27 (115 kJ)	–	–	3.0	–	–
Walnut oil 1 mL	8.4 (35 kJ)	–	–	0.9	–	–
KCl 6 mL (2 mmol/mL)	–	–	–	–	–	12.0
NaCl 1.5 mL (5 mmol/mL)	–	–	–	–	7.5	–
Water to 840 mL
Total	576 (2415 kJ)	11.3	123.1	4.8	9.8	14.8
Per 100 mL	69 (285 kJ)	1.3	14.6	0.6	1.2	1.8
Per kg	107 (445 kJ)	2.1	22.8	0.9	1.8	2.7

An extremely low fat infant formula, Basic-f (Milupa), is available providing, per 100 mL (13% dilution), 49 kcal (207 kJ), 10.2 g CHO, 1.8 g protein and <0.1 g fat (p. 597). A source of EFA must be added together with LCT (to tolerance) and glucose polymers to provide adequate energy.

Historically breast feeding has been considered to be contraindicated in ABL; however, partial breast feeding may be possible [164] in combination with a minimal fat feed. Close monitoring is required and the ratio of breast feeding to formula feeding altered according to biochemical parameters, clinical symptoms and growth.

Weaning

At the usual time for weaning, around 26 weeks of age, minimal fat foods can be commenced, e.g. baby rice mixed with the minimal fat feed, fruits and vegetables (except avocado pears and olives), pulses, meats and fish naturally low in fat (Table 19.14). As a guide for using commercial baby foods, wet baby foods and dried baby foods containing ≤0.5 g fat/100 g and ≤2 g fat/100 g, respectively, are allowed freely if given in usual portion sizes. Other baby foods with a higher fat content would need to be counted as part of the total daily fat allowance.

On waking	Minimal fat feed
Breakfast	Suitable commercial baby cereal* mixed with minimal fat feed
Mid-morning	Minimal fat feed
Lunch	Purée turkey, chicken (white only), white fish or lentils
	Purée or mashed potato/sweet potato/pasta/rice (white)
	Purée or mashed vegetables
	Suitable savoury commercial baby food*
	Purée fruit or suitable commercial baby fruit dessert*
	Very low fat yoghurt/fromage frais
	Milk pudding (custard, ground rice) made with minimal fat feed or skimmed milk
Mid-afternoon	Minimal fat feed
Evening meal	As lunch
Bedtime	Minimal fat feed
Extra feeds or water can be given with meals
Suitable finger foods from 6–9 months: fingers of toast (white bread)* (no spreading fat), soft cooked broccoli florets/carrots, soft pear/mango, banana slices

^* Check fat content of product.

Families can calculate the fat content of baby foods from nutrition labels so that higher fat foods can be counted in the total daily fat intake.

To calculate 1 g fat from a food product:

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