A practical guide to the introduction and use of comida-TYRo A formula

1.0 Overview of feeding an infant with Tyrosinaemia type 1 (HT1).

1.1 Nutrition prescription using comida-TYRo A formula at diagnosis.

1.2 Example feeding plans.

1.3 Check list for blood tyr and phe monitoring.

1.4 Fine-tuning the nutrition prescription.

2.0 Practical feeding strategies to use with caregivers.

2.1 Practical points for effective communication between HCPs and caregivers.

3.0 References.

Tyrosine is a non-essential amino acid. It is found as part of dietary protein but is also synthesised from the precursor amino acid Phenylalanine, by the body.

The enzyme fumarylacetoacetate hydrolase (FAH) breaks down and processes Tyrosine, however a deficiency of the enzyme causes a build-up of toxic plasma and urine metabolites, known as Tyrosinaemia type 1 (HT1).

Newly diagnosed infants with HT1 are prescribed a tyr and phe-free infant formula (for example, comida-TYRo A formula) as soon as diagnosis is confirmed (phe is a precursor for tyr).

Feeding an infant with HT1 is a balance between providing tyr and phe-free formula, alongside small but adequate amounts of tyr and phe from HM/SIF. The goal is to maintain levels within the target therapeutic ranges for tyr (200-600 μmol/L)^{1, 2} and phe levels (20-80 μmol/L)^{1, 2}.

This balance can be achieved with HM or SIF as the source of tyr and phe. Families should be supported to make an appropriate choice for themselves and their infant between HM or SIF, with the help of healthcare professionals if necessary.

Healthcare providers should support a family’s decision to BF or provide HM as the source of intact protein for an infant with HT1. 

comida-TYRo A formula, combined with breastfeeding or bottle-fed HM can maintain satisfactory blood tyr control. However, there must be an adequate supply of HM available and blood tyr levels closely monitored. 

HM provides a range of nutritional benefits, including a higher concentration of long chain polyunsaturated fatty acids and a lower concentration of phe and tyr. The phe and tyr concentration of mature HM is 48 mg Phe + 55 mg tyr/100 ml3; in comparison to approximately 48-60 mg Phe and 35-61mg tyr /100 ml in SIF (phe and tyr ranges, quoted from 3 common SIF brands in Canada, accessed October 20244).

Breastfeeding an infant with HT1 is based on the principle of giving a measured volume of comida-TYRo A formula, to offset the infant’s appetite for breastfeeds. Feeding a measured amount of comida-TYRo A formula alongside each breastfeed, or alternating measured feeds of comida-TYRo A formula with breastfeeds, results in a reduction in the total amount of HM consumed, consequently leading to a decrease in total phe and tyr intake.

Infants can still feed on demand, varying the quantity of feeds from day to day provided that the prescribed quantity of comida-TYRo A formula is given throughout the day. 

Successful HT1 management with breastfeeding is achieved via close monitoring of blood tyr levels and adjustment of the prescribed volume of comida-TYRo A formula by the metabolic healthcare professional in order to maintain blood tyr control.

In practice, we start by alternating between breastfeeding and formula feeding. We then adjust the amount of formula according to the rate of lactation.

There are several options for feeding an infant with SIF and comida-TYRo A formula. With the help of the metabolic healthcare professional, families can choose a SIF supplemented with DHA and ARA, that is best suited to their child and family circumstances.

Powdered SIF is preferred (rather than liquid ready-to feed SIF) to avoid losses/wastage due to storage. A suitable nutritional recipe is calculated by the metabolic healthcare professional and given to the parents. 

It will be adjusted as needed according to tyr blood levels. It is recommended to give a calculated recipe of SIF plus comida-TYRo A formula, catering for individual and family circumstances.

Blood tyr levels are used to determine whether the volume of comida-TYRo A formula, and HM/SIF should be adjusted. 

The current recommendations (interpreted as minimum recommendations) are to assess blood tyr levels on a monthly basis from the time of diagnosis until the age of five^{1, 2}. However, general practice is to perform blood spot checks to assess blood tyr levels weekly and to adjust the feeding plan weekly, especially in the first two months of life.

The amount of phe and tyr tolerated by infants varies and is determined by blood tyr levels. Individual tolerance to phe and tyr varies significantly throughout childhood, depending on growth and development, and varies from one individual to another. 

It is essential to investigate the possible causes of variations in tyr levels before adapting the feeding plan. It is advisable to wait until two consecutive tyr blood levels indicate the need to adapt the feeding plan, unless the tyr blood level is very low or very high.

It’s also important to assess phe levels, as phe is an essential amino acid and a precursor of tyr. If phe levels are lower than 20 μmol/L, it may be appropriate to increase intact protein intake or supplement phe^{1, 2, 4}. 

Once stability has been achieved for tyr levels, it is appropriate to reduce the frequency of dried blood spots (according to the individual) to eventually.

comida-TYRo A formula and HM/SIF may continue to provide 100% of the infant’s nutritional requirements until the age of 6 months, or until the infant is developmentally ready for the introduction of solid foods.

Monitor blood phe and tyr levels weekly, to achieve stability: blood tyr ranges: 200 - 600 μmol/L and phe 20-80 μmol/L. 

Once stable, healthcare professionals may consider reducing the frequency of blood monitoring as appropriate.

This will vary according to the local resources and policy.

• comida-TYRo A formula and phe + tyr source should be given together at each feed, or at alternating feeds (if breastfeeding) to ensure nutrient availability throughout the day.
• If the prescribed volume of comida-TYRo A formula is not taken, it may cause a rise in blood tyr levels.
• Blood tyr levels are used to determine whether comida-TYRo A formula, SIF/HM prescription should be adjusted.
• The infant should be weighed at each clinic visit or more frequently if there is clinical concern.

_{* These figures are provided only as a guide. Appetite can change from day to day and from feed to feed - sometimes infants drink less, sometimes more - so some variation in intake is to be expected.} 

_{Infants should never be force fed.} 

_{Equally, feed volume should not be limited to establish tyr level formula control. If the estimated volume intake does not satisfy the infant, then additional feeds, either of comida-TYRo A formula alone or mixed comida-TYRo A formula + HM/SIF may be given, depending on what is clinically appropriate.}

_{It may be appropriate to provide infants with slightly more than their theoretical requirements at each bottle-feed - this will allow a hungrier infant to continue feeding uninterrupted, as there won’t be a need to prepare an additional bottle.} 

_{Regular communication with families, combined with ongoing monitoring of blood biochemistry is key.}

If parents choose to use SIF: Aim: to meet fluid, energy, phe and tyr requirements (Note - this is one example of practice to determine a feeding regime and local clinical practice may vary);

• Estimate total volume intake per day using 150 ml/kg⁴ = 525 ml/day (or use infant’s usual total volume intake if known).
• Energy requirement = using 100 kcal/kg/day² to start = 350 kcal/day (95-145 kcal/kg/day).
• Phe requirements and tyr requirements^{1, 2}, stated as a combined requirement figure for 0-3 months⁵ = using an assumed average2 tolerance 80 mg/kg/day (65-155 mg/kg/day).

Using SIF in combination with comida-TYRo A formula in a 3.5 kg newborn infants.

(calculations are shown in brackets).

_{* These figures are provided only as a guide.} 

_{Appetite can change from day to day and from feed to feed - sometimes infants drink less, sometimes more - so some variation in intake is to be expected. Infants should never be force fed. Equally, feed volume should not be limited to establish tyr level formula control.} 

_{If the estimated volume intake does not satisfy the infant, then additional feeds, either of comida-TYRo A formula alone or mixed comida-TYRo A formula + HM/SIF may be given, depending on what is clinically appropriate.} 

_{It may be appropriate to provide infants with slightly more than their theoretical requirements at each bottle-feed - this will allow a hungrier infant to continue feeding uninterrupted, as there won’t be a need to prepare an additional bottle.} 

_{Regular communication with families, combined with ongoing monitoring of blood biochemistry is key.}

_{** As SIFs provide 20 kcal/ fl oz (0.67 kcal/ml), it is advisable to begin with that concentration. If growth is below the recommended level and/or if the plasma amino acid profile indicates deficiency, the concentration should be increased.}

_{*** It is challenging to achieve a protein intake of 3.0-3.5 g/kg/day. Infants should not be forced to drink high volumes of formula to achieve this intake. Adequacy of protein intake can be assessed on an ongoing basis using parameters such as growth and biochemical control.}

Many factors can affect blood tyr levels. Always check for causes of high or low blood tyr level before making a change to the nutrition prescription.

For all infants, frequent monitoring of tyr levels is key, but try not to make changes to a feeding plan too frequently.

Consider:

Many factors affect phe and tyr levels; review all causes in this section.

• Monitor tyr level trends
  • Unless tyr level is very low or very high consider continuation of the current plan.
  • Continuation of the current plan.
• Awaiting 2 consecutive tyr levels before adjusting prescription.
• In general, do not make more than 1 change to the plan in 1 week.

For tyr levels that ARE very low or very high:

• Consider repeating blood tyr level sooner than 1 week to guide interventions or other intervention as recommended by metabolic healthcare professional.

_{* If the infant is still hungry after the feed, there are different approaches that may be used to achieve satiety for the infant while maintaining blood tyr control (infants should always be fed to appetite, and total feeding volume should not be restricted to achieve tyr level control): Caregivers should call the healthcare provider to adjust the amount of formula or feeding routine. The healthcare provider will then take tyr blood levels into account when making recommendations.}

Feeding bottles with necessary measuring demarcation for infant’s recipe.

• Appropriately staged nipples for infant feeding
• Adequate supply of comida-TYRo A formula
• HM pump and supplies if needed to express
• Adequate supply of SIF (if using)

• Use comida-TYRo A formula scoop (or gram scale) to mix comida-TYRo A formula. Do not
  use scoops from other formula containers to mix comida-TYRo A formula.
• Ensure family has access to a source of safe water for mixing formula.
• Inquire about the most effective written method for family to receive new recipes and mixing
  instructions.
• Review mixing and recipe at every visit.

Confirm that family/caregivers are able to procure more comida-TYRo A formula and SIF (if using) when supplies are low. 

Consider providing written guidance on where families can obtain these formulas. 

Direct families to appropriate agencies and services if needed to obtain SIF at low-cost or for free.