Phenylketonuria (PKU) By: Adrienne Gebele

What is PKU? 1 Inherited disorder Occurrence varied due to ethnicity and geography – About 1 and 10,000 to 15,000 infants are born with in the U.S. People born with PKU have an inactive liver enzyme which causes a dangerous build up of phenylalanine in the blood To stay healthy a strict low-phenylalanine diet must be followed

Phenylalanine 1 An essential amino acid used by the body to form proteins for growth and tissue repair When excess amino acids are consumed they are chemically changed into other compounds for energy In people with PKU excess phenylalanine builds up in the blood and affects brain development

PKU & the effect on the brain 11 :

Phenylalanine Hydroxylase 1 Normally phenylalanine is converted to tyrosine in the liver by the enzyme phenylalanine hydroxylase Individuals with PKU do not have the enzyme phenylalanine hydroxylase which results in a dangerously high build up of phenylalanine 10

Metabolic Pathways 10 : Results in low tryosine levels and tryosine becomes essential to people with PKU 5

Genetics Autosomal, recessive error of metabolism. 12 Mutation of human phenylalanine hydroxylase (PAH), which maps to chromosome % chance in N. America if mother is a carrier father will also be a carrier and vise versa. 10 7

Registered Dietitian’s Role 10 : Provide on going guidance and support Introduce complementary foods (eg: solids) Implement/change dietary formulas Introduce nutrient supplements Provide nutrition and disease related education

Registered Dietitian’s Role 20

Early diagnosis and treatment lead to excellent cognitive outcomes and brain growth!! 10 19

PKU Symptoms: 6 Mental retardation Behavioral or social problems Seizures, tremors, jerking movements in the arms and legs Hyperactivity Stunted growth Skin rashes (eczema) Musty odor in child’s breath, skin or urine Microcephaly Fair skin and blue eyes (phenylalanine cannot transform into melanin) 18

How is it diagnosed? 4 Most babies in the U.S. and many other countries are screened immediately after birth with a blood test. Newborns are pricked on heel or hand and the blood is tested for high phenylalanine levels The filter paper with blood on it is placed on a plate of bacteria that can only grow with phenylalanine This test determines now much phenylalanine is in the newborns’ blood. The bigger halo of bacteria growth means the more phenylalanine is present in the blood. After 2 positive tests a urine and blood test is done to determine if there is a BH4 deficiency

Ohio Guidelines for PKU 16 : Newborn Screening Program – Currently tests all newborns for 36 disorders after birth. PKU being one of them. – PKU and Homocystinuria are treated with special metabolic formula provided through the Ohio Department of Health Metabolic Formula Program – Provides formula to 400 individuals in OH ($600,000 per year)

Common Diagnosis 9 : Altered GI function (NC-1.4) Altered nutrition-related lab values (NC-2.2) Inadequate protein-energy intake (NI-5.3) Inadequate fluid intake (NI-3.1) Malnutrition (NI-5.2)

How to monitor PKU: 12 Monthly blood phe levels – Blood phe level= 1-6 mg/dL – Blood drawn in clinic or filter paper blood sample mailed to lab Regular visits to the PKU clinic – Nutritional education for patient and parent, support groups, examination by a pediatrician, blood drawn, management of low-phe food patterns Food Records – 3 day recall or all food and beverage – Document protein, energy, vitamins, and minerals – Formula preparation and consumption Iron status Prealbumin Normal tyrosine blood levels Weight status

The Pediatric Nutrition Care Manual recommends the following be monitored for people with PKU 15 : Total energy intake and percentage of energy from formula/medical food and other foods Total protein intake and percentage of total protein from formula/medical food and other foods Phe intake from foods Tyrosine intake from medical foods/formula Vitamin and mineral intakes (including calcium, iron, vitamin D, and others) from formula/medical foods and other foods

PKU is now celebrated as one of the first human genetic diseases to have an effective rational therapy. 15

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Food phe levels 7 : FoodPhenylalanine (mg)Protein (g) 2% milk (1 cup)392 mg8 g Spaghetti (1 cup)324 mg6.8 g Medium egg (1 egg)300 mg5.6 g Vanilla Ice cream (1/2 cup)210 mg4.2 g White bread (1 slice)140 mg2.8 g Cooked brown rice (1/2 cup)116 mg2.2 g Potato (1/2 cup)75 mg1.8 g Mushrooms ( ½ cup)28 mg0.7 g Raisins (1/4 cup)24 mg1.2 g Low Protein white bread (1 slice)13 mg0.3 g Apples (1 cup)7 mg0.2 g Strawberry sorbet (1/2 cup)6 mg0.3 g Margarine (1 Tbsp)6 mg0.1 g Loprofin Macaroni (1 ½ cup)6 mg0.2 g

Phenylalanine is in….PROTEIN 12 Fish Meat (bacon, beef, turkey, liver, chicken, gelatin) Eggs Dairy Nuts and Legumes Soy products (soy protein, tofu, soybean protein) Aspartame (Equal, NutraSweet) Diet foods & diet sodas Gum Drugs (Alka-Seltzer and Benadryl)

“Special Diet” 12 The phenylalanine-free medical food/formula is the primary source of protein. Ensures a person with PKU ingests enough total protein, energy an nutrient to maintain appropriate nutrition status and blood phe levels in the recommended range

Low-phe Supplements 5

Phenex vanilla powder -serving size: 100g

Sample Menu 20 : Active Teenager/young adult with PKU: Breakfast: 1 cup low-protein cereal with low protein milk substitute Harifen 21 (100ml=9 mg phe), apple, toast (low protein bread) with jelly or butter, fruit juice/coffee Lunch: grilled cheese (low protein bread, low protein cheese), vegetable soup, fruit juice/coke Dinner: Low protein pasta with tomato sauce, salad, buttered toast (low- protein bread), fruit juice Dessert: strawberry sorbet, and fresh strawberries **Low-Phe supplement 3 times a day (Phenex-2) – Per serving 410 kcals, 30g protein

Drug therapy 12,15 : Treatment with BH 4 – Kuvan is a form of cofactor for phenylalanine hydroxylase enzyme called BH4 – Can enhance enzyme activity, lower blood phenylalanine levels, improve dietary tolerance of phenylalanine. – Involves activation of phenylalanine oxidation via the PAH enzyme – Most effective with mild forms of PKU. Not classical PKU. – Diet will still need to be maintained – No long term experience with Kuvan. FDA approved based on short term evidence (26 weeks). – No obvious “serious adverse effects” have been reported

Enzyme Therapy 15 – Recombinant yeast phenylalanine ammonia lyse (PAL) given orally or injection – PAL converts phenylalanine to ammonia and trans-cinnamic acid – Study shows once a week injections for 12 weeks in a mouse with PKU the plasma phenylalanine levels dropped to normal levels Treatment with large neutral amino acids (LNAA) 15 – LNAA is a branched chain neutral amino acid supplement. – Low phe diet and supplements of LNAAs has reduced hyperphenylalaninemia by half. – Phenylalanine is blocked by LNAA so it cannot reach the brain. – May improve treatment of PKU.

Challenges with having PKU and living a “normal” life…

Being a teen & living with PKU 2 Tips for eating out with friends School Lunches Traveling Backpack snacks PKU accountability pals Formula drinking in thermos Wisdom teeth College bound

PKU & IQ Scores 1 IQ scores in individuals with PKU treated shortly after birth through 12 years of age and keep plasma phe levels within recommended treatment levels show a mean of 101 ± 11. It is reported that within the first 18 years of life for each 100 μmol increase in plasma phe concentration between 394 and 150 μM, there was a 1.3 to 3.9 point decline in IQ scores.

PKU & Learning Disabilities 11 : 25% of children with early-treated PKU receive stimulant medication for ADHD. 17

PKU and Psychiatric Symptoms 11 :

Pregnancy with PKU High phenylalanine levels during pregnancy is devastating to fetus 10 At risk for having children with microcephaly, congenial heart disease (CHD), and low birth weight 10 Study 6 : – 251 women with classical PKU were prescribed a diet of phe-free medical food supplements with low-protein foods during their pregnancy – Data showed: Untreated maternal PKU: 73% microcephaly & 12% CHD Prescribed diet maternal PKU: 33.9% microcephaly & 8.8% CHD

Maternal PKU & breastfeeding 10 Breastfeeding should not be a problem for mothers with PKU A low phenylalanine diet is recommended before the pregnancy, during the pregnancy and during breastfeeding Breast milk still the best source of nutrients for the infant with a mother with PKU

Breastfeeding an infant with PKU 3 Goal plasma phenylalanine level between μmol/l If phenylalanine levels are >1200 μmol/l breast feeding is postponed 1-3 days and infant is given a free intake of phe-free formula When phenylalanine is reduced by 40-50% the initial value a set amount of phe-free formula is determined per feeding(65% of total intake) and breastfeeding without restrictions Phe-free formula is reduced 5-15 mL every other day and increase breast milk Normally, day 7-10 infant is discharged and they are intaking 60% breast milk and 40% phe-free formula.

Breastfeeding & PKU Norway Study 3 74 Norwegian PKU infants were breastfed in combination with a phenylalanine-free formula Their weight, length, and head circumference grew within the normal of range of Norwegian growth charts Phenylalanine blood levels were easily controlled by 8 days after diagnosis

When living with PKU maintaining a lower phenylalanine levels by lifelong nutrition therapy can have a positive effect on concentration, mood, attention which results in improved cognitive behavior. 10