1. Management of Metabolic Disease Kathryn Camp, MS, RD, CSP

2. Metabolic disease is all about Food and Nutrition

3. Case Study--JC 11.5 mo male with MSUD presents to metabolic clinic for continued mgt of his IEM. PMHx: FT, normal at birth. Poor feeding and increased lethargy 1 st week of life. Frequent calls to MD--mother told this was normal behavior DOL 7 to 10--continued poor feeding and lethargy; was taken to the pediatrician and placed on Prosobee formula DOL 11--unarousable. Admitted to hospital for dehydration and begun on nasogastric tube feeds of Similac. Admit labs: WBC 12.0, UA 1+ ketones, CO2 19, anion gap 8, glucose 63. Sepsis workup begun

4. Cont: Neurological status began to deteriorate and by DOL 19 he was given the presumptive diagnosis of MSUD based on his course and the sweet smell noted in his urine. Several hours after the dx was given, he had respiratory arrest, was placed on the ventilator, and peritoneal dialysis was begun. Initial serum amino acid levels (umol/L): leucine6,200(47-155) valine677 (64-294) isoleucine 392(31-86)

5. Cont: G- tube and Nissen placed at 4 wks of age and he was begun on metabolic formula. He has had several hospitalizations since that time with reported difficulties with reflux, gagging, intolerance to feeds, and seizure activity. Normal growth. Diagnosed with static encephalopathy.

6. Maple Syrup Urine Disease n Autosomal recessive inheritance n Infants are normal at birth n In severe forms, seizures, apnea, and death can occur within 10 days of birth n Branched-chain -ketoacid dehydrogenase complex (BCKAD) deficiency n Elevated levels of branched-chain ketoacids, their amino acid precursors, and alloisoleucine

7. Treatment n These children decompensate within the first few days of life –Delayed or missed dx leads to coma and death n Goal is to identify affected infants before they crash –Not all states screen for MSUD –Screen is often not back before the child becomes symptomatic

8. Treatment cont: n Diagnose and initiate treatment as soon as possible –Emergency therapy –Life-time dietary treatment –Liver transplantation –Gene therapy and others are still some years in the future

9. Dietary Protein Catabolized Tissue Protein LeucineIsoleucineValine LeucineIsoleucineValine -ketoisocaproic -keto-3-methylvaleric -ketoisoval -ketoisocaproic -keto-3-methylvaleric -ketoisoval acetyl-CoA+acetyl-CoA +Propionyl-CoA acetyl-CoA+acetyl-CoA +Propionyl-CoA AcetoacetatePropionyl-CoA AcetoacetatePropionyl-CoA Succinyl-CoASuccinyl-CoA Succinyl-CoASuccinyl-CoA branched-chain -ketoacid dehydrogenase complex

10. NCA Metabolic Patient Population n Glutaric Acidemia type 1 –22 mo old dx at 6.5 mo after 1 mo of irritability, seizures, and dystonic movements. You may see her some time over the winter. n Methylmalonic acidemia –5 yr old was a frequent flyer; now in better control n Tyrosinemia type 2 –1 college student

11. n PKU –10 mo old –A set of 2 yr old identical twins, former 25 wk premmies –2 high school students n Homocystinemia –1 high school student n MCAD –12 mo old dx on NBS Our population changes constantly and you never know what you might get!

12. –Good possibility that one or more of these kids will be admitted to the ER or the Ward on YOUR watch

13. Overview n Newborn Screening n Dietary treatment n Emergency management n Long term issues

14. Newborn Screening Definition n Newborn screening in the US is a public health program aimed at the early identification of conditions for which early and timely intervention can prevent or reduce associated mortality and morbidity –Adapted from the Newborn Screening Task Force Report, Pediatrics 106:383-427, 2000.

15. Child with PKU – born before NBS Full expression of this genetic disease + gene mutation + environmental exposure

16. + genetics - exposure + genetics + exposure - genetics

17. Brief History of NBS n Began in 1963 in MA with screening for PKU –Guthrie developed a bacterial inhibition assay for phenylalanine using a dried blood filter paper card. n By 1967, mandatory PKU testing in most states n 70s and 80s, additional tests from the Guthrie card were developed (galactosemia, MSUD, biotinidase, homocystinemia, congenital hypothyroidism, CAH) –Up to 8 diseases were included in NBS (varied by state) n 1990s, tandum mass spectrometry technology was developed which allows for detection of a greater number of disorders of amino acid, organic acid, and fatty acid metabolism (see handout)

18. Newborn Screening is State Public Health Activity n Federal govt recommends screening for PKU, congenital hypothyroidism, and sickle cell disease n Each state is responsible for designing and implementing its own program –Which disorders to include in the screen –Whether parental consent is required n 33 states allow exemptions for religious reasons 13 states allow exemptions for any reason –Whether they will use a state-run lab or contract out to a private lab

19. n Just because TMS technology is used in a state, it does not mean that that state performs the expanded screen.

20. Criteria for Newborn Screening Program n The Disorder –Clearly defined (known) –Treatable, with trt initiated in the neonatal period –Reasonable incidence n The Screening Test –Rapid turnaround time –High sensitivity and specificity –Reasonable cost n Follow-up –Locate babies with + screens –Provide appropriate referral to CONFIRM diagnosis and provide treatment

21. Relevance to YOU n Dont assume that a reportedly normal NBS on a sick baby rules out the possibility of a metabolic disease n Further, the New York state NBS program has reported through genetic identification that the blood sample for 1 out of 800 babies screened was incorrectly labeled

22. http://genes-r-us.uthscsa.edu

24. Why Does Dietary Treatment Keep these Kids Alive and Protect Their Brains?

25. Because…... n Biochemical defect is known –absent or minimal production of enzyme system that breaks down dietary constituents n With the amino acidopathies (MSUD, MMA, PKU), defect involves dietary constituents that are essential –Restrict the precursors to the toxic metabolites n We can use consequences of the defect to design our therapy

26. What Happens in PKU? Phenylalaninetyrosine DOPA, NE, EPI, Melanin Absent phenylalanine hydroxylase Food Catabolized tissue

27. Increased PHE and Production of Alternate Products Phenylpyruvate PhenyllactatePhenylacetate Phenylalanine tyrosine

28. Product of Blocked Reaction Is Not Made Phenylpyruvate PhenyllactatePhenylacetate Phenylalanine tyrosine DOPA, NE, EPI, Melanin

29. Phenylalanine tyrosine Supply Product Restrict Precursor Solution:

30. Four Therapeutic Strategies to Treat Amino Acidopathies

31. 1. Enhance Anabolism and Depress Catabolism n Provide sufficient energy and protein to prevent catabolism of body muscle and release of free amino acids –high energy feedings –medical formulas devoid of the offending amino acids –low protein products n Prevent fasting

32. 2. Restrict Toxic Substrate n MSUD: leucine, isoleucine, and valine n MMA:isoleucine, methionine, threonine, valine, odd-chained FA, gut origin short-chained fats n Note: the amino acids are essential and sufficient amounts must be provided to support normal growth

33. 3. Supplement Conditionally Essential Nutrients n MSUD, MMA, GA, MCAD –Carnitine n helps excrete organic acids in the urine n PKU –Tyrosine n Homocystinemia –cystine

34. 4. Replace Deficient Cofactors n MSUD: Thiamin –pharmacologic doses –100 to 500 mg oral/day –USRDA is 1 mg/day n MMA: Vitamin B12 –1 mg po or IM n GA: Riboflavin –200 mg/d

35. Goals of Dietary Treatment n Correct biochemical abnormalities n Support normal growth and development n Maintain normal nutritional status n Minimize physical manifestations –MSUD:urine free of branched-chain ketoacids –MMA: urine free of abn organic acids

36. Designing a Diet for a Person with MSUD, PKU, MMA, GA n Titrated amount of essential amino acids are provided by whole protein n Remaining protein needed for body growth and maintenance is supplied by medical formula –purified amino acid based products –also contain CHO, fat, vitamins, and minerals n Extra calories come from free foods

37. Presentation and Illness are Life Threatening Situations!

38. Acute Mgt n ABCs n Hydratepromote renal excretion of offending metabolites n Treat biochemical derangements –Bicarb for acidosisIV drip –IV Glucose (D12 peripherally, more if central) –CarnitineMMA 100-150 mg/kg; MSUD 50 mg/kg n Withhold whole protein (max 24-48 hrs) to prevent further buildup of toxic metabolites

39. Acute Mgt, cont n Remove toxic metabolites –Hydration –Dialysis (only at presentation in a comatose patient with MMA) n Prevent catabolism –Dextrose (>10%) –Insulin if needed n Prevent constipation and promote gut motility for MMA n Prevent increased ICP in MSUDuse zofran for nausea

40. Initiate Nutrition Support Immediately! n High energy feeds –120-150 kcal/kg infants –80-100 kcal/kg children n If the gut works, use it n PO, n/g, g-tube –metabolic formula without added whole protein (initially restrict offending amino acids) n Notify endocrine service

41. Acute Mgt, cont: n If gut cannot be used or if sufficient formula cannot be delivered enterally: n IV via central lineperipheral line n hypertonic dextrose12% dex n lipidslipids –replace electrolytes incl 4-6 mEq sodium n Can use a combination, e.g: –drip feeds of formula to supply non-offending amino acids + IV dex

42. Monitoring During Acute Mgt MSUD and MMA n Serum amino acids daily –whole blood (green top) to Childrens (M-F) –Pediatrix filter paper card (available in endo clinic conference room file cabinet) if 3-4 day turnaround OK n MSUD –Add purified ILE and VAL to metabolic formula when blood levels reach upper limit of normal; add LEU as whole protein when levels reach upper limits of normal. n MMA –Add VAL as whole protein when levels reach upper limits of normal.

43. Long-Term Dietary Management

44. n Using published guidelines, clinical picture, and biochemical parameters, establish the dietary prescription

45. Establish the Dietary Rx Newly dx 1 month old with MSUD Per kg Per kg LEU:60-100 mg LEU:60-100 mg ILE:36-60 mg ILE:36-60 mg VAL:42-70 mg VAL:42-70 mg Protein: 3-3.5 g Protein: 3-3.5 g Kcal:120 Kcal:120 Fluid:125-150 ml Fluid:125-150 ml

46. Components of the Medical Formula n Four ingredients: 1. Infant formula provides LEU, ILE, VAL 1. Infant formula provides LEU, ILE, VAL 2. Ketonex-1 provides remaining protein 2. Ketonex-1 provides remaining protein 3. Polycose provides any needed calories 3. Polycose provides any needed calories 4. Water 4. Water n Additional ILE and VAL –solution of 10 mg purified amino acids/ml prepared by pharmacy or parents (if they have an appropriate scale)

47. Metabolic Formulas

48. Life After Exclusive Formula Feeding n Solid foods are added to the infants diet in an age appropriate manner n Begin with cereals and advance to vegetables then fruit n Amounts are calculated using exchange lists and food composition tables n Every bite of food must be weighed! n Infant/child/adult continues to drink medical formula

49. Foods in the Diet of a Person with PKU, MSUD, MMA NO meat, poultry, fish, dairy, legumes

50. Limited grains, vegetables, fruit

51. Unlimited pure carbohydrates or fat Limited in MMA

54. Phenylalanine tyrosine Restrict precursor Supply Product dietary protein catabolized muscle

55. Typical Days Intake 8 year old with PKUReg Foods Diet Rx: Phe: 345 mg Pro: 52 g Kcal: 2000 3.5 x PHE Rx mg PheKcal Breakfast:1 slice white bread10167 8 oz medical formula0200 Lunch1 rice cake w 1 t marg4070 1/2 cup noodle soup10389 5 saltine crackers1.468 65 8 oz medical formula0200 Snack:2 c popcorn w 4 t marg91190 4 oz apple juice2107 Dinner:120 g pasta745445 3 T tomato sauce0.613 14 8 oz medical formula0200 Fruit ice10124 Snack:1/2 oz potato chips4476 12 oz fruit drink0160 1,2232007

56. Typical Days IntakeLP Foods Diet Rx: Phe: 345 mg Pro: 52 g Kcal: 2000 mg PheKcal Breakfast:1 slice low pro bread11104 8 oz medical formula0200 Lunch1 rice cake w 1 t marg4070 1/2 cup low pro soup4867 5 saltine crackers1.468 65 8 oz medical formula0200 Snack:2 c popcorn w 4 t marg91190 4 oz apple juice2107 Dinner:120 g low protein pasta12432 3 T tomato sauce0.613 14 8 oz medical formula0200 Fruit ice10124 Snack:1/2 oz potato chips4476 12 oz fruit drink0160 3452009 Reality Check 1 oz cheese 355 mg 1 oz chicken 345 mg

58. Food Item Regular Low Protein Flour, 16 oz $0.27$5.00 Spaghetti, 16 oz $1.25$10.00 Crackers, 16 oz $0.79$15.00 Rice, 16 oz $0.55$10.00 Cream Cheese, 8 oz $1.99$5.60 Am Cheese, 10 oz $2.30$10.00 Tomato Sauce, 4 oz $0.25$4.00 Cost Comparison of LP Products and Their Regular Counterparts Shipping and handling runs $5.00 to $25.00 per order

59. Practical Issues of Dietary Treatment n Compliance –these diets are complicated!! –harder to adhere to as the child ages n Cost –$$$$ medical formula and low protein foods –insurance coverage n Repeated blood draws and doctors visits

60. New Therapies n Liver transplantation in MSUD and MMA n Gene Therapy

62. MSUD Symposium 2000 Danvers, MA

64. Happy Halloween !!