Guidelines for the Nutritional Management of Tyrosinemia Type I A Practical Guide for the Use of Nutricia's TYR Products. TYR Anamix Next Tyrosinemia

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1 DHA is important for brain and eye development in children up to two years old. Multi-fiber mix to promote ot digestive health A medical food for the dietary management ment of proven (TYR) in children over 1 year of age. Guidelines for the Nutritional Management of Type I A Practical Guide for the Use of Nutricia's TYR Products TYR Anamix Next Amino Acid-based, Phenylalanine- anine- ne and Tyrosine-free Powdered ed Formula Brain and Eye Digestive Health Net Wt 14.1 oz (400 g) Powder Add water PLAIN Artificially flavored

2 Contents Introduction And Background Basic Overview... 4 Diet Principles... 6 Diet Prescription... 7 Managing the Diet... 9 Monitoring Illness Management Post-Transplant Case Studies Case Case Case Addendum Product Information Nutricia provides a range of metabolic formulas for the dietary management of tyrosinemia. In US these products are classified as Medical Foods. In Canada these foods are classified as Foods for Special Dietary Use. The following guidelines are provided to help support healthcare professionals involved in the dietary management of tyrosinemia patients. Practices may vary from clinic to clinic, and this booklet should serve as guidance, not as strict protocol. Acknowledgments Nutricia North America would like to thank Manon Bouchard, RD; CHU Sainte-Justine Mother and Child University Hospital Center, Montreal, Canada, for her contribution of background and clinical information and review of these guidelines. TYR Anamix Next Amino Acid-based, Phenylalanine- and Tyrosine-free Powdered Formula Brain and Eye DHA is important for brain and eye development in children up to two years old. Digestive Health Multi-fiber mix to promote digestive health A medical food for the dietary management of proven (TYR) in children over 1 year of age. Powder Add water PLAIN Artificially flavored Net Wt 14.1 oz (400 g) 3

3 Introduction and Background Basic Overview Table 1: Tyrosine disorders and corresponding enzyme defect 2,4 Disorder Enzyme defect Clinical Symptoms (if unmanaged) Biochemical Management There are five known inherited disorders of tyrosine metabolism 1. Table 1 provides an overview of their classification, including enzyme defect, clinical symptoms, biochemical finding and management. The following guidelines will focus on the management of hereditary tyrosinemia type I (HT-1). Please also note the most recent publication by de Laet (2013) Recommendations for the management of tyrosinemia type I (Orphanet J Rare Dis. 2013; 8: 8. Published online 2013 January 11) is available as an Open Access article on PubMed. type I or hepatorenal tyrosinemia (HT-1) is a rare metabolic condition characterized by liver, renal and neurological symptoms. The enzyme responsible for the disorder is fumarylacetoacetate hydrolase (FAH), the distal enzyme in the tyrosine degradation pathway (Figure 1). Tyrosine (TYR) is a semi-essential amino acid, derived from hydrolysis of either dietary or endogenous (body) protein, or from the hydroxylation of phenylalanine (PHE) 2. Clinical manifestations of HT-1 are variable. Typically, there is marked impairment of liver function in infancy, renal rickets because of tubular phosphate wasting and crises of peripheral neuropathy leading to intense pain and sometimes paralysis. Growth failure is seen in many children. In chronic forms, cirrhosis occurs and hepatocarcinoma is common 1,3. Figure 1* Phenylalanine and Tyrosine Pathway Phenylalanine Phenylalanine hydroxylase Tyrosine Aminotransferase 4-OH-Phenylpyruvate Oxidase Homogentisate Oxidase Maleylacetoacetate Fumarylacetoacetate Fumarate Acetoacetate Fumarylacetoacetase Phenylketones 4-OH-phenylcompounds 4-OH-phenylcompounds Succinylacetoacetate Succinylacetone type I (HT-1) type II type III and neonatal tyrosinemia Hawkinsinuria Alkaptonuria Fumarylacetoacetate hydrolase (FAH) Tyrosine aminotransferase (TAT) 4-hydroxy phenylpyruvic acid dioxygenase (4-HPPD) 4-hydroxyphenylpyruvic acid dioxygenase (4-HPPS); autosomal dominant mutation Homogentisate oxygenase (HGD) Severe liver failure, vomiting, bleeding, neuropathy, neurological crises; cirrhosis; hepatocarcinoma Corneal lesions, hyperkeratosis Neurological complications Impaired mental function Uncertain clinical relevance Failure to thrive, acidosis; doubtful clinical relevance Arthritis, cardiac valve disease urine and blood succinylacetone (diagnostic) TYR; MET (when liver disease has progressed) TYR (blood and urine), increased PHE, urinary phenolic acids, TYR; urinary 4-HPPA urinary hawkinsin acetic acid (2-L-cystein-S-yl, 4-dihydroxycyclohex- 5-en-1-yl) homogentisic acid Nitisinone (NTBC); PHE- and TYRrestricted diet (liver transplantation for select patients) PHE- and TYRrestricted diet PHE- and TYR- restricted diet; short term protein restriction in neonatal tyrosinemia PHE- and TYR restricted diet + Vit.C supplementation in infancy Low protein diet, possibly NTBC The overall incidence of HT-1 is 1:100,000 births with a higher incidence in Québec, Canada (1:17,000 because of a genetic founder effect) Chakrapani A, et al. Disorders of Tyrosine Metabolism. In: Saudubray JM, et al, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th ed. Heidelberg, Germany: Springer; 2012: Russo PA, et al. : a review. Pediatr Dev Pathol. 2001;4: McKiernan PJ. Nitisinone in the treatment of hereditary tyrosinaemia type 1. Drugs. 2006;66: * Zschocke J, Hoffmann GF. Vademecum Metabolicum. 3rd ed. Friedrichsdorf, Germany: Milupa GmbH & Co. KG/Schattauer; Available from Nutricia North America by calling (option 2 for Nutrition Services Department). 4. Acosta PB, Matalon KM. Nutrition Management of Patients with Inherited Disorders of Aromatic Amino Acid Metabolism. In: Acosta PB, ed. Nutrition Management of Patients with Inherited Metabolic Disorders. Sudbury, MA: Jones and Bartlett Publishers; 2010: Mitchell GA, et al. Hypertyrosinemia. In: Scriver CR, et al, eds. The Metabolic & Molecular Bases of Inherited Disease. Volume II. 8th ed. New York: McGraw-Hill; 2001:

4 Screening and Clinical Diagnosis type I is most effectively screened in neonates by measuring succinylacetone, a highly sensitive and specific marker for this condition 1. Infants detected by effective neonatal screening are clinically asymptomatic. Regardless of how a patient comes to medical attention, treatment with Nitisinone together with PHE- and TYR-restricted diet is the therapy of choice. Both medical treatment and dietary management must be started immediately after diagnosis 6. II and III are typically successfully managed by a PHE and TYR diet alone and prognosis is excellent 5. Medication HT-1 is treated through the use of 2-(2-nitro-4) therapy and dietary restriction of PHE and TYR 4. Nitisinone is available under the name Orfadin (Swedish Orphan International; Stockholm, Sweden). Its introduction in 1991 changed the natural history of the disease. Prior to availability of Nitisinone, the outcome of patients with HT-1 was poor 7. The management regimen prevents the acute complications of HT-1 7. Nitisinone acts at the enzyme level of 4-hydroxyphenylpyruvate dioxygenase by inhibiting this enzyme. Nitsinone prevents production of toxic metabolites downstream from this enzyme step such as FAA, MAA and SA (see figure 1). However, the drug does not prevent blood accumulation of TYR and PHE; therefore, dietary management is still required. Liver Transplant Liver transplant provides a functional cure of tyrosinemia type I. A regular diet can be started after the transplant. Currently, liver transplantation for HT-1 is considered in patients with acute liver failure (not responding to Nitisinone treatment) and patients with suspected hepatocellular carcinoma 1. Diet Principles The goal of dietary intervention in tyrosinemia type I are: Stable biochemical environment to support normal growth and development; Prevent formation of tyrosine crystals in the cornea. Promote anabolism Monitor nutritional status and adjust diet as needed See Table 2 for plasma TYR and PHE levels for patients on Nitisinone. Table 2 Plasma TYR and PHE levels for patients on Nitisinone Plasma level Tyrosine µmol/l 1 Phenylalanine µmol/l 8 The diet is based on a restriction of TYR and PHE. Since both amino acids are present in all natural protein, the diet requires restriction of natural protein, whereas the remaining necessary protein is provided in form of PHE- and TYR-free metabolic formula. 8 The diet can be calculated by counting either grams of total natural protein; mg PHE and TYR combined; or exchanges (or equivalent), whereas one exchange is equal to 25 mg of PHE and TYR combined ( g of natural protein). Using the exchange system or counting milligrams PHE and TYR provide a more exact calculation of these two amino acids. The principles of HT-1 diet management include: Use of a metabolic formula without PHE and TYR to provide sufficient protein, energy, vitamins and minerals Restriction of natural protein to maintain plasma TYR and PHE in the goal range. Special low protein food products to support energy requirements and provide variety in the diet Diet Prescription The diet for HT-1 patients must be individualized depending on each patient s nutrient and growth needs. The amount of allowed PHE and TYR depends, in part, on the patient s tolerance. Tolerance can vary from one patient to another and within the same patient depending on growth rate, energy and protein intake. Close monitoring is essential. Adequate energy intake to prevent catabolism 6. Schiff M, et al. Heterogeneity of follow-up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines. J Inherit Metab Dis. 2012;35: Larochelle J, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab. 2012;107: Daly A, et al. Diurnal variation of phenylalanine concentrations in tyrosinaemia type 1: should we be concerned? J Hum Nutr Diet. 2012;25:

5 Protein needs: Table 3: Suggested Daily Intakes for Individuals Ingesting Elemental Diets 9,12 Protein requirements must be adjusted for age and body weight. Use adjusted body weight to determine protein requirements. Age Protein 9 Protein DRI 12 Protein DRI + 35% Energy 9 Fluid 9 Since the majority of patients protein requirements are met by rapidly digested free amino acids from metabolic formulas, a protein intake higher than the Dietary Reference Intakes (DRIs) is recommended 9. In addition, recent work by Elango et al. (2011) suggests a need for higher protein intake in the healthy population 10. Calculate protein requirements using DRI + approximately 35 percent. For infants, protein needs may be higher. (See table 3 for protein intake suggestions.) Patients and parents must be taught to distribute the protein intake throughout the day (both natural protein and protein equivalent from the formula) 11. Establishing a prescription is done in a stepwise manner: Step1: Fill the TYR and PHE requirements through the use of measured quantities of intact protein from breast milk, regular infant formula, or complete amino acid mixtures (all with known PHE and TYR content per g PRO). Beyond infancy, TYR and PHE requirements are met by foods of known TYR and PHE or natural protein content. Step 2: Fill the protein (PRO) requirement by adding the metabolic formula that provides a TYR- and PHE-free mixture of amino acids (as well as other nutrients). Step 3: Fill energy requirement by adding non-protein calorie sources as needed. Energy needs should be based on ideal body weight whenever possible and are the same as for non-tyrosinemia patients. Step 4: Adjust fluid volume to meet requirements. Step 5: Calculate vitamin, mineral and micronutrient content of the final mixture; adjust or supplement as needed. 9. Acosta PB. Evaluation of Nutrition Status. In: Acosta PB, ed. Nutrition Management of Patients with Inherited Metabolic Disorders. Sudbury, MA: Jones and Bartlett Publishers; 2010: Elango R, et al. Protein requirement of healthy school-age children determined by the indicator amino acid oxidation method. Am J Clin Nutr. 2011;94: MacDonald A, et al. Administration of protein substitute and quality of control in phenylketonuria: a randomized study. J Inherit Metab Dis. 2003;26: <6 mo g/100 kcal 1.5 g/kg/d 2.0 g/kg/d 120 kcal/kg 1.5 ml/kcal 6 < 12 mo g/100 kcal 1.5 g/kg/d 2.0 g/kg/d 110 kcal/kg 1.5 ml/kcal 1 < 4 yr 35 g g/kg/d g/kg/d kcal 1 ml/kcal 4 < 7 yr g/kg/d 1.3 g/kg/d kcal 1 ml/kcal 7 < 11 yr g/kg/d 1.3 g/kg/d kcal 1 ml/kcal 11 < 19 yr g/kg/d g/kg/d kcal 1 ml/kcal 19 + yr g/kg/d 1.1 g/kg/d kcal 1 ml/kcal Managing the Diet To meet protein requirements for tyrosinemia patients, metabolic formulas without PHE and TYR are needed. Over the years, new metabolic formulas have been developed to not only address the nutritional needs of patients, but also the challenges of being on a restricted diet. Nutricia offers a range of products for individuals with tyrosinemia to respond to different nutrient requirements of each life stage and to offer variety, convenience and choice to patients. XPhe, XTyr Analog, TYR Anamix Next, XPhe, XTyr Maxamaid, and TYR Lophlex LQ are provided in Appendix 1. For an overview, please see Table 4. For detailed product information, see page 20. Weighing powdered metabolic formula on a gram scale is the most accurate way of measuring. Add water to provide a caloric density of 20 to 30 kcal/fl oz depending on the individual s age. If the product is consumed in a more concentrated form, advise patient to drink sufficient amount of water. Divide the volume of the formula throughout the day. Prepared formula should be refrigerated and used within 24 h of preparation. PHE and TYR intake, calculated by either an exchange system, counting of TYR and PHE (milligrams) or with total natural protein must be well measured. Typically, fruits and vegetables are the mainstay of the diet. Food composition resources are available for both families and professionals to provide accurate amino acids content for various foods and beverages. In addition, modified low protein foods may be added to the diet to provide energy, variety and some normalcy. 12. Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Washington, DC: The National Academies Press;

6 Amino Acid-based, Phenylalanine- and Tyrosine-free Powdered Formula Brain and Eye DHA is important for brain and eye development in children up to two years old. Digestive Health Multi-fiber mix to promote digestive health A medical food for the dietary management of proven (TYR) in children over 1 year of age. Powder Add water GUIDELINES FOR THE NUTRITIONAL MANAGEMENT OF TYROSINEMIA TYPE I The following resources are available for families. Exchange Food list by CHU Sainte-Justine (2012) (in French); contact Manon Bouchard, RD. Phone (514) ext. 5185; manon.bouchard.hsj@ssss.gouv.qc.ca PKU Food List by Virginia Schuett (2010); (use the column for amount of food and total protein) Table 4 Nutricia Metabolic Formula Characteristics TYR Anamix Next For professionals: Bowes and Church s Food Values of Portions Commonly Used. 19 th ed. Lippincott Williams and Wilkins; 2010 MetabolicPro diet analysis program ( USDA food composition tables ( Canadian Nutrient File (CNF) ( XPhe, XTyr Analog (per 100 g) TYR Anamix Next (per 100 g) XPhe, XTyr Maxamaid a (XPHEN, TYR Maxamaid b ) (per 100 g) XPHEN, TYR Maxamum b (per 100 g) TYR Lophlex LQ (per 125 ml) a Form powder powder powder powder ready-to-drink Availability 400 g (14.1 oz) can Net Wt 14.1 oz (400 g) PLAIN Artificially flavored 400 g (14.1 oz) can) 454 g (1 lb) can 454 g can 125 ml (4.1 fl oz) pouches Recommended age 0-12mos > 1 year of age Toddlers and younger children Older children, teenagers and adults, including maternal patients 4 years Added vit/min c Yes Yes Yes Yes Yes PRO equiv 13 g 28 g 25 g 39 g 20 g d CHO 59 g g (51 g) 34 g 9.3 g FAT 20.9 g 12.5 < 0.1 g (<0.5 g) <0.5 g 0.44 g Contains fat, including EFA and DHA Contains no fat, must be added in the diet to meet EFA requirements Contains no fat, must be added in the diet to meet EFA requirements Contains DHA; essential fatty acids must be added in the diet to meet EFA requirements DHA mg mg Fiber g g KCAL (309) KCAL: PRO (12.4) a b c d TYR Lophlex LQ is flavored with real fruit juice (from concentrate); XPhe, XTyr Maxamaid has artificial orange flavoring XPHEN, TYR Maxamaid and Maxamum available in Canada only; products are unflavored Vitamin and mineral content appropriate for the recommended age TYR Lophlex LQ may contain traces of tyrosine at a level of <2.5 mg/100 ml and phenylalanine at a level of <5 mg/100 ml from fruit juice (from concentrate). 11

7 Monitoring To maintain good metabolic control and ensure normal growth, frequent adjustments of the diet are necessary. Monitoring should include the following markers. However, check your clinic policy. For monitoring guidelines, also see King LS et al (2011) 13. Plasma amino acids: In order to avoid potential complications from hypertyrosinemia, such as ocular problems and theoretical risks of neurological complications, plasma TYR levels must be kept between µmol/l 1. (Monitoring PHE level is important because lower levels may occur as a result of the conversion of PHE into TYR.) Plasma PHE must be kept within normal plasma reference. (See table 2) If PHE plasma level is low, a PHE supplement may be necessary or additional natural protein from milk or other sources may be added. Growth parameters: height and weight must be measured every 3 months and more often in the first year of life. Intervene as necessary: Add additional calories if needed for weight gain Reduce caloric density of the formula if weight gain is too rapid See for growth charts for infants and older children Indices of protein status: Total protein, Albumin, prealbumin (transthyretin), and plasma essential amino acids level must be routinely monitored to assure adequate overall protein status. Nutrition status: various markers of nutrition status, especially iron and vitamin D (25-OH vitamin D), need to be routinely monitored. Diet record analysis for macro- and micronutrient intake is also recommended. Illness Nitisinone-treated patients are usually stable. During intermittent mild illness, patients may be managed at home with close monitoring by metabolic clinicians via phone. General principles include: Decrease of dietary PHE and TYR intake 50% of the usual intake for hours. Increase of PHE- and TYR-free metabolic formula to provide sufficient energy intake and fluid. Increase of low protein foods to increase energy intake If patient cannot tolerate his/her Nitisinone, he/she must be hospitalized. Families and patients should be instructed to contact their metabolic team any time a sick-diet is started. Management Post-Transplant With the availability of Nitisinone therapy, combined with a PHE- and TYR-restricted diet, liver transplants are not required for most patients. Patients who need a liver transplant do not need to restrict their diet after transplant. A regular diet without restriction is possible. 15 Liver function tests, blood gases, urine or plasma succinylacetone, blood Nitisinone, coagulation, urea and electrolytes α-fetal protein, imaging, eye examination based on clinic policy and patient status. Bone mineral density: Although there is no study on bone mineral density and tyrosinemia patients, studies from PKU show that potential factors such as dietary deficiency of protein, calcium, vitamin D or trace elements can contribute to low bone density. An early follow-up with DEXA for early detection and treatment is important 14. Vitamin D supplementation may be required to help prevent osteoporosis. 15. Paradis K, et al. Liver transplantation for hereditary tyrosinemia: the Quebec experience. Am J Hum Genet.1990;47: Sniderman King L, et al. Type 1. In: Pagon RA, et al, eds. GeneReviews TM [Internet]. Seattle, WA: University of Washington, Seattle; Available from: Koura HM, et al. A long-term study of bone mineral density in patients with phenylketonuria under diet therapy. Arch Med Sci. 2011;7:

8 CASE STUDIES Case 1: A 3 month-old boy with type I Usage of XPhe, XTyr Analog (Case report as an example of diet calculation only.) Patient was detected through neonatal screening and confirmatory testing Succinylacetone level: 30 μmol/l (normal < 2.5 μmol/l) TYR level: 143 μmol/l (normal μmol/l) PHE level: 55μmol/L (normal μmol/l Dietary and medical management begins as soon as the patient is immediately referred to the metabolic clinic to confirm diagnosis and initiate medical and nutrition management (before the appearance of symptoms). Patient is stable and tolerating diet. At 3 months of age, parents call the dietitian at the metabolic clinic. They report baby is hungry with an increase of formula (mix of baby formula and metabolic formula) intake for the last 3 to 4 days. His PHE + TYR intake is not well distributed throughout the day. Height and weight are normal for age Blood TYR level is in the management range: 350 µmol/l All other metabolites are also in the normal range Dietary PHE and TYR tolerance is 400 mg/day The metabolic dietitian will: Evaluate protein and energy needs Evaluate formula intake to make sure that baby received all PHE + TYR prescription (well distributed throughout the day) Evaluate other nutrients to meets patient requirements Teach parents how to make the formula Weight Height Energy needs Protein needs PHE and TYR tolerance Formula intake OTHER DATA for calculation 6.0 kg 61.5 cm 120 kcal/kg/d = 720 kcal/d 2.9 g/kg/d = 17.4 g/d 400 mg/d 900 ml/d Amount PHE TYR PRO KCAL Infant formula (Nestle Good Start ) 100 g 350 mg 210 mg 11 g 510 XPhe, XTyr Analog 100 g g 475 Refer back to steps outlined in the DIET PRESCRIPTION section. Always begin with meeting the PHE and TYR requirement with natural PRO, and then calculate the contribution to the total PRO requirement that is to be met by the metabolic formula. Determine PHE + TYR prescription from the regular infant formula to meet 400mg /day. 350 mg PHE mg TYR = 560 mg/100 g of regular Infant formula 400 mg = 72 g of regular infant formula powder Amount PHE + TYR PRO KCAL Infant formula 72 g powder 403 mg 7.9 g 367 XPhe, XTyr Analog 74 g powder g 352 Water Add to make final volume of 900 ml TOTAL 900 ml 403 mg 17.5 g 719 kcal = 23 kcal/fl oz (=0.79 kcal/ml For infants, it is recommended to mix both regular infant formula and metabolic formula in one bottle (measure both powders and then add water to complete volume). 15

9 The choice of metabolic formula depends on, among others, the nutritional needs of the individual, formula access, taste and form preferences.the following case study is hence used as examples of diet calculation; other Nutricia products may be suitable as well. Refer to product overview (Table 4) and detailed nutrition information tables (Appendix 1). Case 2 : 4 year old girl with type 1 Usage of TYR Anamix Next (Case report as an example of diet calculation only) MB is a 4 year old girl with generally good metabolic control but has some difficulties with the taste of her formula. The dietitian and parents decided to try TYR Anamix Next. Her last blood TYR level was a little low (210 µmol/l). Her dietary PHE and TYR intake as just been increased by 25 mg for a total of 525 mg/day (about 8.4 gram of intact protein). Case 3: A 17 year old adolescent Usage of TYR Lophlex LQ (Case report as an example of diet calculation only.) JCM is a 17 year old female who is in her last year of high school. She lives at home, but is managing her diet independently. She has been in good control and done well in taking Nitisinone and metabolic formula. However, lately she is complaining of formula fatigue. Her height is 165 cm, her weight is 60 kg. JCM would like to have more flexibility with her metabolic formula and is considering a ready-to-drink formula that tastes better and is easier to take to school. GOALS: GOALS Weight 60 kg Weight 19 kg (normal for age) Height 165 cm Height 108 cm (normal for age) PHE + TYR tolerance 600 mg PHE + TYR tolerance 525 mg Total protein needs 1.2 g/kg/d = 72 g Total protein needs Intact protein a Energy needs 1.3 g/kg/d = 25 g 8.4 g 1500 kcal Intact protein a Energy needs 10 g 1800 kcal a These are approximate calculations based on a mixed and varied diet containing on average: 25 mg of PHE and TYR combined = g natural protein Refer back to the steps outlined in the DIET PRESCRIPTION section. Always begin with meeting the PHE and TYR requirements with intact PRO, and then calculate the contribution to the total PRO requirement that is to be met by the metabolic formula. a These are approximate calculations based on a mixed and varied diet containing on average: 25 mg of PHE and TYR combined = g natural protein Refer back to steps outlined in the DIET PRESCRIPTION section. Always begin with meeting the PHE and TYR requirement with intact PRO, and then calculate the contribution to the total PRO requirement that is to be met by the metabolic formula. Amount PHE + TYR Protein Calories Natural protein (food) + Free foods Varies 525 mg 8.4 g 1270 TYR Anamix Next 60 g g 231 Add water for a make final volume of ml Total Amount PHE + TYR PRO KCAL Natural protein (food) + Free foods Varies 600 mg 10g 1440 TYR Lophlex LQ 3 packs 0 60 g 360 TOTAL 600 mg 70 g 1800 In order to facilitate an easy transition from the child s previous formula to TYR Anamix Next, the family introduced TYR Anamix Next in 25% increments over the course of 4 days. MB tolerated the TYR Anamix Next well and continued to be in good control. 17

10 Amino Acid-based, Phenylalanine- and Tyrosine-free Powdered Formula Brain and Eye DHA is important for brain and eye development in children up to two years old. Digestive Health Multi-fiber mix to promote digestive health A medical food for the dietary management of proven (TYR) in children over 1 year of age. Powder Add water GUIDELINES FOR THE NUTRITIONAL MANAGEMENT OF TYROSINEMIA TYPE I JCM tried the ready-to-drink TYR Lophlex LQ and liked the easy-to-consume formula as well as the taste. The lower volume also helped her in consuming all of her metabolic formula. Since JCM was previously on a higher calorie formula, her diet needed adjustment. We added more low protein foods. The following is an easy reference when prescribing other Nutricia formulas. Table 5: Amount of formula (grams) to meet protein requirements from metabolic formula for different age groups. TYR Anamix Next Net Wt 14.1 oz (400 g) PLAIN Artificially flavored Formula TYR Anamix Next XPhe, XTyr Maxamaid XPHEN,TYR Maxamaid (Canada) XPHEN, TYR Maxamum (Canada) TYR Lophlex LQ pouch Age Indications For individuals over 1 year of age For toddlers and young children For toddlers and young children For older children, teenagers and adults For children and adults Protein requirement from metabolic formula grams powder grams powder grams powder grams powder # pouches 20 g 71 g 80 g 80 g -- 1 pack 30 g 107 g 120 g 120 g packs 40 g 143 g 160 g 160 g 103 g 2 packs 50 g 179 g g 2.5 packs 60 g 214 g g 3 packs 70 g 250 g g 3.5 packs 19

11 ADDENDUM Nutricia s Products Product XPhe, XTyr TYR Anamix XPhe, XTyr TYR Lophlex XPHEN, TYR XPHEN, TYR Analog Next Maxamaid LQ Maxamaid Maxamum Availability in US& Canada US & Canada US & Canada US & Canada Canada Canada Flavor Unflavored Plain Orange Mixed Berry Blast Unflavored Unflavored Weight, g ml (4.2 fl oz) Energy, kcals Protein Equivalent, g Amino Acids, g L- Alanine L-Arginine L-Aspartic Acid L-Cystine L-Glutamic Acid Glycine L-Histidine L-Isoleucine L-Leucine L-Lysine L-Methionine L-Phenylalanine* none none none nil added none none L-Proline L-Serine L-Threonine L-Tryptophan L-Tyrosine* none 0 none nil added none none L-Valine L-Carnitine Taurine L-Glutamine Carbohydrate, g Fiber, g Fat, g < <0.5 <0.5 Saturates, g trace 0.10 trace trace Monosaturates, g trace 0.13 trace trace Polyunsaturates,g trace 0.21 trace trace Linoleic Acid, g Linolenic Acid, g Product XPhe, XTyr TYR Anamix XPhe, XTyr TYR Lophlex XPHEN, TYR XPHEN, TYR Analog Next Maxamaid LQ Maxamaid Maxamum Vitamins Vitamin A, IU Vitamin A, mcg RE Vitamin D, IU Vitamin D, mcg Vitamin E, IU Vitamin E, mg a TE Vitamin K, mcg Thiamine, mg Riboflavin, mg Vitamin B6, mg Vitamin B12, mcg Niacin, mg Folic Acid, mcg Pantothenic Acid, mg Biotin, mcg Vitamin C, mg Choline, mg Inositol, mg Minerals Calcium, mg Phosphorus, mg Magnesium, mg Iron, mg Zinc, mg Manganese, mg Copper, mcg Iodine, mcg Molybdenum, mcg Chromium, mcg Selenium, mcg Sodium, mg < Potassium, mg Chloride, mg < DHA, mg * TYR Lophlex LQ may contain traces of tyrosine and phenylalanine from fruit juice (from concentrate) at a level of <2.5 mg/100ml and <5 mg/100ml respectively. 21

12 DHA is important for brain and eye development in children up to two years old. Multi-fiber mix to promote ot digestive health A medical food for the dietary management ment of proven (TYR) in children over 1 year of age. Guidelines for the Nutritional Management of A Practical Guide for the Use of Nutricia's TYR Products TYR Anamix Next Amino Acid-based, Phenylalanine- anine- ne and Tyrosine-free Powdered ed Formula Brain and Eye Digestive Health Net Wt 14.1 oz (400 g) Powder Add water PLAIN Artificially flavored For more information or product samples, please visit MedicalFood.com or call US: (800) Canada: (877) For more tools and resources for the management of your metabolic patients, please visit