Issue 117 imd watch maple syrup

IN ASSOCIATION WITH THE NSPKU

IMD WATCH

MAPLE SYRUP URINE DISEASE IN ADULTS: AN OVERVIEW Suzanne Ford, Dietitian in Metabolic Diseases

Louise Robertson Specialist Dietitian

Suzanne Ford works as a Metabolic Dietitian for Adults at North Bristol NHS Trust.

She has been a Dietitian for 21 years, with six of them working in Metabolic Disease.

Louise is a Specialist Dietitian working with adults with inherited metabolic disorders, with PKU being her biggest cohort of patients.

Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disease which affects the catabolism of branched chain amino acids (BCAA): leucine, isoleucine and valine. The treatment for MSUD is a low BCAA diet.1 This article outlines the dietetic treatment of MSUD, focusing on adults, since dietary treatment is lifelong.

MSUD is an autosomal recessive disorder (see Figure 2) with a UK incidence of one in 116,000.2 In MSUD, the multi-enzyme complex, branched chain alpha ketoacid dehydrogenase (BCKD) complex, is deficient (see Figure 1).

In affected individuals, this results in the accumulation of the branched chain amino acids and their corresponding alpha ketoacids. In high concentrations, these are toxic to the brain, especially leucine.

The first stage in leucine, isoleucine and valine catabolism is reversible transamination. The second stage is decarboxylation to the respective alpha ketoacids, and this is the defective step in people with MSUD. The coenzymes for BCKD complex include thiamine pyrophosphate - which is why some individuals respond to thiamine treatment.

MSUD is so called due to the smell of burnt sugar, or maple syrup, coming from an affected (untreated) individual’s urine. In neonates presenting early with classical MSUD, the smell would be apparent at 48 hours of life (and in ear wax - cerumen - at 12 hours of life).

From 2015, the NHS Newborn Screening Programme in England and Wales started screening all babies for MSUD. WHY IS DIETETIC INTERVENTION NEEDED?

High levels of leucine and BCAA metabolites can affect biochemistry, structure and functioning of brain cells within the central nervous system (CNS).3,4

Dietary treatment is needed to minimise exposure to toxic metabolites, by restricting BCAA intake to a level that allows individuals to maintain plasma BCAA concentrations within the targeted treatment ranges.

There are also some non CNS related side effects from poor metabolic control.

These include recurrent infections, as it is believed that both raised BCAAs and raised ketoacids act as immunosuppressants.

The most significant effect on quality of life in MSUD is on intellectual outcomes.

Intellectual outcome is most influenced by control in newborns. However, outcomes are also influenced by long-term control and any acute decompensations. Thus, early ongoing dietetic treatment and achieving a quick and appropriate treatment for any metabolic stress is vital.

HOW DO BRAIN CHANGES AFFECT INDIVIDUALS WITH MSUD?

Brain changes cause reduced cognitive, psychomotor and social functioning in people with MSUD. This could be due to delayed diagnosis and this effect is demonstrated in a 2006 report on a series of UK patients.5 Published reports (and anecdotal experience) suggest that, currently, adults with MSUD do have reduced social outcomes and social status.

German MSUD patients are reported to have low educational attainment and low levels of employment; this group could not live independently, did not have steady interpersonal relationships and had no children.6

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IMD WATCH Figure 1: MSUD pathway

People with MSUD do need a certain amount of natural BCAA from their diet to keep their blood concentrations within range and prevent protein catabolism. This is often taught to patients and their families using an exchange system whereby one exchange = 1.0g protein or 50mg leucine, (when the leucine content of food is known).

The protein restriction is based on leucine rather than other BCAAs, as it appears leucine is the most neurotoxic of the three BCAAs. Leucine tolerance depends on residual BCKD activity, as well as age, gender, life stage, weight and health of the individual with MSUD.

Older MSUD patients who had delayed diagnosis, may have more severe learning disabilities, which can leave them very vulnerable.

It is important to ensure that patients are looked after socially and that carers/care home staff are educated on the importance of the diet.

WHAT IS THE CURRENT CONSENSUS ON DIETETIC TREATMENT FOR ADULTS WITH MSUD?

The goals of treatment are to achieve appropriate BCAA blood concentrations, ensuring leucine levels are not too high and valine and isoleucine levels are not too low to cause catabolism. The guidelines recommend that plasma BCAA are maintained within the below ranges throughout life.

WHAT ARE THE DIFFERENT COMPONENTS OF THE DIET?

If BCAA concentrations are too high, then high protein foods will need to be restricted (e.g. meat, fish, dairy, soya, pulses and nuts).

Protein substitute A BCAA free amino acid supplement is important to avoid protein deficiency and prevent catabolism of muscle leading to high leucine concentrations. The product used depends on patient age and preference.

For optimal metabolic control, these amino acid supplements (powders or ready to drink), should be taken throughout the day. The balance between natural protein and BCAAfree supplement is individualised and adjusted to meet growth and development needs. The amount of BCAA free amino acids prescribed must account for inefficiencies in amino acid and protein metabolism, as much as 140% of the RNI for protein may be needed.

There is no disorder specific guidance on protein metabolism in MSUD and the proportion of natural protein to amino acid supplement making up total protein needs will vary depending on the severity of MSUD in an individual. Compliance must be monitored, in particular, as individuals may be prescribed significant daily volumes of protein substitute.

Amino acids can taste very bitter and acidic.

However, people with MSUD need to take these from infancy and might develop a tolerance to the taste.

Table 1: Suggested guidelines for blood BCAA concentrations in MSUD, five-year-olds and older Normal reference range

UK Expanded Newborn Screening2

USA guidelines7

Leucine

65-220

200-400

75-300

Isoleucine

26-100

200-400

200-400

Valine

90-300

200-400

300-400

Amino acid (umol/L)

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Table 2: Exchange examples8 Food

Figure 2: Autosomal recessive inheritance g providing 50mg leucine

Cows’ milk

15mL

Single cream

20mL

Double cream

35mL

Yoghurt

10mL

Custard

15mL

Ice cream

15

Baked Beans

15

Broccoli (boiled)

45

Peas (boiled)

15

Sweetcorn (tinned)

15

Boiled/jacket potato

60

Roast potatoes

45

Chips

35

Avocado

45

Banana

55

Kiwi fruit

90

Valine and isoleucine supplements As the natural protein exchange allowance is determined by leucine metabolism, there is a chance that valine and isoleucine intakes become deficient and these amino acids may need to be supplemented separately (although the powdered amino acid could be mixed in with the main protein substitute). Whether to supplement or not and determining the correct dose of these two amino acids will depend on the individual’s plasma amino acid profiles. Additional valine and isoleucine may also be given to promote anabolism of leucine when plasma leucine concentrations are high during illness. 9 Macronutrients and micronutrients are needed as per the relevant DRVs for an individual’s age group, subject to any deficiencies noted during nutritional monitoring of an individual with MSUD. On a reduced protein diet, it is possible that a wide range of nutritional deficiencies occur, such as B12, Essential fatty acids and long-chain polyunsaturated fatty acids.10 Micronutrients are present in the protein substitute, another reason for encouraging compliance.

LOW PROTEIN FOODS

Naturally occurring low protein foods are a cornerstone of the MSUD diet, such as fruit and vegetables. However, low protein foods on prescription (e.g. low protein pasta, bread, flour, biscuits) may be needed to add variety, calories and palatability to the low protein diet. Consistent and adequate energy intake is vital for people with MSUD as catabolism results in raised leucine levels.

People with MSUD ideally undergo frequent surveillance of a wide range metabolic and nutritional parameters to ensure that goals of treatment are met, as well as normal growth and development are occurring and that any adverse effects of treatment (deficiencies) are avoided.11 WHY IS AN EMERGENCY REGIMEN NEEDED FOR PEOPLE WITH MSUD AND WHAT IS IT?

During times of metabolic stress (illness, fasting, surgery), leucine concentrations can rise due www.NHDmag.com August / September 2016 - Issue 117

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IMD WATCH to protein catabolism leading to a metabolic decompensation. To prevent protein catabolism and promote anabolism, a high carbohydrate intake,7,8,9 alongside the patient’s usual BCAA free protein substitute, should be given. Natural protein should be stopped and extra valine and isoleucine should be supplemented if required to promote anabolism.

The BCAA free protein substitute, valine and isoleucine will help promote anabolism and provide a protective effect, stopping some of the leucine from crossing the blood brain barrier.

The Emergency Regimen (ER) instructions are to take 200mls of a 25% glucose polymer solutions every two to three hours, day or night, alongside the MSUD amino acid supplement and reduced/no natural protein at the first sign of any illness. The details of each person’s ER depends on their individual requirements (i.e. it is weight/gender/age dependent).

If the illness continues after 24 to 48 hours, or if the ER isn’t tolerated, then intravenous dextrose and other supportive treatments, as well as close monitoring, may be needed, so a hospital admission is indicated. Nasogastric feeding might be indicated in order to supply the emergency regimen and MSUD protein substitute if the patient is unable to drink sufficient quantities to bring their leucine levels down.

Living with the possibility of metabolic decompensation is reported as burdensome and stressful by families living with MSUD and

similar disorders.12 The emergency regimen is applicable during any period of reduced food intake or period of catabolism and people with MSUD and their families are strongly encouraged to carry around with them both the details of their ER recipe and the ingredients.

Emergency regimen information is available in detail from the website www.bimdg.org.

WHAT DOES THE FUTURE HOLD FOR PEOPLE AFFECTED BY MSUD?

Our knowledge of MSUD in adults is still in its infancy as the patient cohort is still young.

Adolescence is a worrying time when patients are more likely to stray from their diets and experiment with alcohol and drugs. The number of females reaching childbearing age will increase, due to newborn screening. There have been case reports of successful pregnancy in MSUD women.13,14 Careful dietary management is needed during pregnancy as protein requirements increase13 and there is a risk of decompensation if the women suffers from morning sickness, or during a prolonged labour, or if an anesthetic/Csection is needed.

We do not know what challenges old age and MSUD will bring. Will this group be affected with other co-morbidities associated with older age and how will this affect their diet? There is a need for a greater understanding of the disease which can help achieve better outcomes for individuals affected with MSUD.

References 1 Ogier de Baulny H, Dionisi-Vici C and Wendel U (2012). Branched Chain Organic Acidurias/Acidaemias (277-296) in Saudubray JM, van den Berghe G and Walter JH: Inborn Metabolic Disease: Diagnosis and Treatment, 5th Ed, Springer, Berlin, Heidelburg 2 www.expandedscreening.org/site/home/metabolic-msud-facts.asp (accessed 2 July 2016) 3 Walterfang M, Bonnot O, Mocelline R and Velakoulis D (2013). The neuropsychiatry of inborn errors of metabolism 4 Klee D, Thimm E, Wittsack HJ et al (2013). Structural white matter changes in adolescents and young adults with maple syrup urine disease. J Inherit Metab Dis 36: 945-953 5 Le Roux C, Murply E, Hallam P et al (2006). Neuropsychometric outcome predictors with adults with maple syrup urine disease. J Inherit Metab Dis 29:201-202 6 Simon E, Schwarz M, Wendel U (2007). Social Outcomes in adults with maple syrup urine disease. J Inherit Metab Dis 30: 264 7 Frazier D et al (2014). Nutrition management guideline for maple syrup urine disease: an evidence and consensus based approach; Molecular Genetics and Metabolism 112; 210-217 8 Dixon M, MacDonald A, White F and Stafford J (2014). Disorders of Amino Acid Metabolism, Organic Acidaemias and Urea Cycle Disorders in Clinical Paediatric Dietetics; Ed Shaw V, 4th Ed, Wiley Blackwell, Oxford 381-525 9 Marriage B (2010). Nutrition management of patients with inherited disorders of Branched Chain Amino Acid metabolism. Acosta P Nutrition Management in Patients with Inherited Metabolic Disorders 10 Mazer LM, Yi SHL and Singh RH (2010). Docosahexaenoic acid status in females of reproductive age with maple syrup urine disease; J Inherit Metab Dis 33:121-127 11 Strauss KA, Wardley B, Robinson D et al (2010). Classical maple syrup disease and brain development: Principles of management and formula design.

Molecular Genetics and Metabolism 99: 333-345 12 Grader G, Haege G, Glahn EM et al (2014). Living with an inborn error of metabolism detected by newborn screening - Parents’ perspectives on child development and impact on family life; J Inherit Metab Dis 37: 189-195 13 Stefanie Heiber, Henryk Zulewski, Marianne Zaugg, Caroline Kiss and Matthias Baumgartner (2015). Successful pregnancy in a woman with Maple Syrup Urine Disease: Case Report. JIMD Rep. 2015; 21: 103-107 14 Wessel AE, Mogensen KM, Rohr F, Erick M, Neilan EG, Chopra S, Levy HL, Gray KJ, Wilkins-Haug L, Berry GT (2015). Management of a woman with Maple Syrup Urine Disease during pregnancy, delivery and lactation. JPEN J Parenteral Enteral Nutr. 2015 Sep;39(7): 875-9. doi: 10.1177/0148607114526451. Epub 2014 Mar 11

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