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

ManagemeManagement of nt of Metabolic Metabolic DiseaseDisease

Kathryn Camp, MS, RD, CSPKathryn Camp, MS, RD, CSP

Metabolic disease is all about Metabolic disease is all about Food and NutritionFood and Nutrition

Case Study--JCCase 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 1st 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

Cont: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): leucine 6,200 (47-155) valine 677 (64-294) isoleucine 392 (31-86)

Cont: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.

Maple Syrup Urine DiseaseMaple Syrup Urine Disease

Autosomal recessive inheritanceAutosomal recessive inheritance Infants are normal at birthInfants are normal at birth In severe forms, seizures, apnea, and In severe forms, seizures, apnea, and

death can occur within 10 days of birthdeath can occur within 10 days of birth Branched-chain Branched-chain -ketoacid -ketoacid

dehydrogenase complex (BCKAD) dehydrogenase complex (BCKAD) deficiencydeficiency

Elevated levels of branched-chain Elevated levels of branched-chain ketoacids, their amino acid precursors, ketoacids, their amino acid precursors, and alloisoleucineand alloisoleucine

TreatmentTreatment These children decompensate These children decompensate

within the first few days of lifewithin the first few days of life– Delayed or missed dx leads to coma Delayed or missed dx leads to coma

and deathand death Goal is to identify affected infants Goal is to identify affected infants

before they crashbefore they crash– Not all states screen for MSUDNot all states screen for MSUD– Screen is often not back before the Screen is often not back before the

child becomes symptomaticchild becomes symptomatic

Treatment cont:Treatment cont:

Diagnose and initiate treatment as Diagnose and initiate treatment as soon as possiblesoon as possible– Emergency therapyEmergency therapy– Life-time dietary treatmentLife-time dietary treatment– Liver transplantationLiver transplantation– Gene therapy and others are still Gene therapy and others are still

some years in the futuresome years in the future

Dietary ProteinDietary ProteinCatabolized Tissue ProteinCatabolized Tissue Protein

LeucineLeucine IsoleucineIsoleucine ValineValine

-ketoisocaproic-ketoisocaproic -keto-3-methylvaleric -keto-3-methylvaleric --ketoisovalketoisoval

acetyl-CoAacetyl-CoA ++ acetyl-CoA +acetyl-CoA + Propionyl-CoAPropionyl-CoA AcetoacetateAcetoacetate Propionyl-CoAPropionyl-CoA

Succinyl-CoASuccinyl-CoA Succinyl-CoASuccinyl-CoA

branched-chain branched-chain -ketoacid dehydrogenase -ketoacid dehydrogenase complexcomplex

NCA Metabolic Patient NCA Metabolic Patient PopulationPopulation

Glutaric Acidemia type 1Glutaric Acidemia type 1– 22 mo old dx at 6.5 mo after 1 mo of 22 mo old dx at 6.5 mo after 1 mo of

irritability, seizures, and dystonic irritability, seizures, and dystonic movements. You may see her some movements. You may see her some time over the winter.time over the winter.

Methylmalonic acidemiaMethylmalonic acidemia– 5 yr old was a frequent flyer; now in 5 yr old was a frequent flyer; now in

better controlbetter control Tyrosinemia type 2Tyrosinemia type 2

– 1 college student1 college student

PKUPKU– 10 mo old 10 mo old – A set of 2 yr old identical A set of 2 yr old identical

twins, former 25 wk premmiestwins, former 25 wk premmies– 2 high school students 2 high school students

HomocystinemiaHomocystinemia– 1 high school student1 high school student

MCADMCAD– 12 mo old dx on NBS12 mo old dx on NBS

Our population changes constantly and you never know what you might get!

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

OverviewOverview

Newborn ScreeningNewborn Screening Dietary treatmentDietary treatment Emergency managementEmergency management Long term issuesLong term issues

Newborn Screening Newborn Screening DefinitionDefinition

Newborn screening in the US is a Newborn screening in the US is a public health program aimed at the public health program aimed at the early identification of conditions for early identification of conditions for which early and timely intervention which early and timely intervention can prevent or reduce associated can prevent or reduce associated mortality and morbiditymortality and morbidity– Adapted from the “Newborn Screening Task Force Adapted from the “Newborn Screening Task Force

Report”, Pediatrics 106:383-427, 2000.Report”, Pediatrics 106:383-427, 2000.

Child with PKU – born before NBS

Full expression of this genetic disease

+ gene mutation

+ environmental exposure

+ genetics- exposure

+ genetics+ exposure- genetics

Brief History of NBSBrief History of NBS Began in 1963 in MA with screening for PKUBegan in 1963 in MA with screening for PKU

– Guthrie developed a bacterial inhibition assay for Guthrie developed a bacterial inhibition assay for phenylalanine using a dried blood filter paper card.phenylalanine using a dried blood filter paper card.

By 1967, mandatory PKU testing in most statesBy 1967, mandatory PKU testing in most states 70’s and 80’s, additional tests from the “Guthrie” 70’s and 80’s, additional tests from the “Guthrie”

card were developed (galactosemia, MSUD, card were developed (galactosemia, MSUD, biotinidase, homocystinemia, congenital biotinidase, homocystinemia, congenital hypothyroidism, CAH)hypothyroidism, CAH)– Up to 8 diseases were included in NBS (varied by state)Up to 8 diseases were included in NBS (varied by state)

1990’s, tandum mass spectrometry technology 1990’s, tandum mass spectrometry technology was developed which allows for detection of a was developed which allows for detection of a greater number of disorders of amino acid, greater number of disorders of amino acid, organic acid, and fatty acid metabolism (see organic acid, and fatty acid metabolism (see handout)handout)

Newborn Screening is State Newborn Screening is State Public Health ActivityPublic Health Activity

Federal govt Federal govt recommendsrecommends screening screening for PKU, congenital hypothyroidism, for PKU, congenital hypothyroidism, and sickle cell diseaseand sickle cell disease

Each state is responsible for Each state is responsible for designing and implementing its own designing and implementing its own programprogram– Which disorders to include in the screenWhich disorders to include in the screen– Whether parental consent is requiredWhether parental consent is required

33 states allow exemptions for religious 33 states allow exemptions for religious reasonsreasons13 states allow exemptions for any reason13 states allow exemptions for any reason

– Whether they will use a state-run lab or Whether they will use a state-run lab or contract out to a private labcontract out to a private lab

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

Criteria for Newborn Criteria for Newborn Screening ProgramScreening Program

The DisorderThe Disorder– Clearly defined (known)Clearly defined (known)– Treatable, with trt initiated in the neonatal Treatable, with trt initiated in the neonatal

periodperiod– Reasonable incidenceReasonable incidence

The Screening TestThe Screening Test– Rapid turnaround timeRapid turnaround time– High sensitivity and specificityHigh sensitivity and specificity– Reasonable costReasonable cost

Follow-upFollow-up– Locate babies with + screensLocate babies with + screens– Provide appropriate referral to CONFIRM Provide appropriate referral to CONFIRM

diagnosis and provide treatmentdiagnosis and provide treatment

Relevance to YOURelevance to YOU

Don’t assume that a reportedly Don’t assume that a reportedly “normal” NBS on a sick baby rules out “normal” NBS on a sick baby rules out the possibility of a metabolic diseasethe possibility of a metabolic disease

Further, the New York state NBS Further, the New York state NBS program has reported through program has reported through genetic identification that the blood genetic identification that the blood sample for 1 out of 800 babies sample for 1 out of 800 babies screened was incorrectly labeled screened was incorrectly labeled

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

Why Does Dietary Treatment Why Does Dietary Treatment Keep these Kids Alive and Keep these Kids Alive and

Protect Their Brains?Protect Their Brains?

Because…...Because…...

Biochemical defect is knownBiochemical defect is known– absent or minimal production of enzyme absent or minimal production of enzyme

system that breaks down dietary constituentssystem that breaks down dietary constituents With the amino acidopathies (MSUD, With the amino acidopathies (MSUD,

MMA, PKU), defect involves dietary MMA, PKU), defect involves dietary constituents that are “essential” constituents that are “essential” – Restrict the precursors to the toxic Restrict the precursors to the toxic

metabolites metabolites We can use consequences of the defect We can use consequences of the defect

to design our therapyto design our therapy

What Happens What Happens in PKU?in PKU?

Phenylalanine

tyrosine

DOPA, NE, EPI, Melanin

Absent phenylalanine hydroxylaseFood

Catabolized tissue

Increased PHE and Increased PHE and Production of Production of

Alternate ProductsAlternate Products

Phenylpyruvate

Phenyllactate Phenylacetate

Phenylalanine

tyrosine

Product of Product of Blocked Reaction Blocked Reaction

Is Not MadeIs Not Made

Phenylpyruvate

Phenyllactate Phenylacetate

Phenylalanine

tyrosine

DOPA, NE, EPI, Melanin

Phenylalanine

tyrosine

Supply ProductRestrict Precursor

Solution:Solution:

Four TherapeuticFour TherapeuticStrategies to Treat Strategies to Treat Amino AcidopathiesAmino Acidopathies

1. Enhance Anabolism 1. Enhance Anabolism and Depress Catabolismand Depress Catabolism

Provide sufficient energy and protein Provide sufficient energy and protein to prevent catabolism of body muscle to prevent catabolism of body muscle and release of free amino acidsand release of free amino acids– high energy feedingshigh energy feedings– medical formulas devoid of the medical formulas devoid of the

offending amino acidsoffending amino acids– low protein productslow protein products

Prevent fastingPrevent fasting

2. Restrict Toxic Substrate2. Restrict Toxic Substrate

MSUD: leucine, isoleucine, and MSUD: leucine, isoleucine, and valinevaline

MMA:MMA: isoleucine, methionine, isoleucine, methionine, threonine, valine, odd-chained threonine, valine, odd-chained FA, gut origin short-chained fats FA, gut origin short-chained fats

Note: the amino acids are essential Note: the amino acids are essential and sufficient amounts must be and sufficient amounts must be provided to support normal growthprovided to support normal growth

3. Supplement 3. Supplement Conditionally Essential Conditionally Essential

NutrientsNutrients

MSUD, MMA, GA, MCADMSUD, MMA, GA, MCAD– CarnitineCarnitine

helps excrete organic acids in the helps excrete organic acids in the urineurine

PKUPKU– TyrosineTyrosine

HomocystinemiaHomocystinemia– cystinecystine

4. Replace Deficient 4. Replace Deficient CofactorsCofactors

MSUD: ThiaminMSUD: Thiamin– pharmacologic dosespharmacologic doses– 100 to 500 mg oral/day100 to 500 mg oral/day– USRDA is 1 mg/dayUSRDA is 1 mg/day

MMA: Vitamin B12MMA: Vitamin B12– 1 mg po or IM1 mg po or IM

GA: RiboflavinGA: Riboflavin– 200 mg/d200 mg/d

Goals of Dietary Goals of Dietary TreatmentTreatment

Correct biochemical abnormalitiesCorrect biochemical abnormalities Support normal growth and Support normal growth and

developmentdevelopment Maintain normal nutritional statusMaintain normal nutritional status Minimize physical manifestationsMinimize physical manifestations

– MSUD:MSUD: urine free of branched-urine free of branched-chain chain ketoacidsketoacids

– MMA: urine free of abn organic acidsMMA: urine free of abn organic acids

Designing a Diet for a Designing a Diet for a Person with MSUD, PKU, Person with MSUD, PKU,

MMA, GAMMA, GA Titrated amount of essential amino Titrated amount of essential amino

acids are provided by “whole” proteinacids are provided by “whole” protein Remaining protein needed for body Remaining protein needed for body

growth and maintenance is supplied growth and maintenance is supplied by “medical formula”by “medical formula”– purified amino acid based productspurified amino acid based products– also contain CHO, fat, vitamins, and also contain CHO, fat, vitamins, and

mineralsminerals Extra calories come from “free” foodsExtra calories come from “free” foods

Presentation Presentation and Illness are and Illness are

Life Life Threatening Threatening Situations!Situations!

Acute Mgt Acute Mgt ABC’sABC’s Hydrate—promote renal excretion of Hydrate—promote renal excretion of

offending metabolitesoffending metabolites Treat biochemical derangementsTreat biochemical derangements

– Bicarb for acidosis—IV dripBicarb for acidosis—IV drip– IV Glucose (D12 peripherally, more if central)IV Glucose (D12 peripherally, more if central)– Carnitine—MMA 100-150 mg/kg; MSUD 50 Carnitine—MMA 100-150 mg/kg; MSUD 50

mg/kgmg/kg Withhold whole protein (max 24-48 hrs) to Withhold whole protein (max 24-48 hrs) to

prevent further buildup of toxic metabolitesprevent further buildup of toxic metabolites

Acute Mgt, contAcute Mgt, cont Remove toxic metabolitesRemove toxic metabolites

– HydrationHydration– Dialysis (only at presentation in a comatose Dialysis (only at presentation in a comatose

patient with MMA)patient with MMA) Prevent catabolismPrevent catabolism

– Dextrose (>10%)Dextrose (>10%)– Insulin if neededInsulin if needed

Prevent constipation and promote gut Prevent constipation and promote gut motility for MMAmotility for MMA

Prevent increased ICP in MSUD—use zofran Prevent increased ICP in MSUD—use zofran for nauseafor nausea

Initiate Nutrition Support Initiate Nutrition Support Immediately!Immediately!

High energy feedsHigh energy feeds– 120-150 kcal/kg infants120-150 kcal/kg infants– 80-100 kcal/kg children80-100 kcal/kg children

If the gut works, use itIf the gut works, use it PO, n/g, g-tubePO, n/g, g-tube

– metabolic formula without added whole metabolic formula without added whole protein (initially restrict offending amino protein (initially restrict offending amino acids)acids)

Notify endocrine serviceNotify endocrine service

Acute Mgt, cont:Acute Mgt, cont:

If gut cannot be used or if sufficient If gut cannot be used or if sufficient formula cannot be delivered enterally:formula cannot be delivered enterally:

IV via IV via central linecentral line peripheral lineperipheral line hypertonic dextrosehypertonic dextrose 12% dex12% dex lipidslipids lipidslipids

– replace electrolytes incl 4-6 mEq sodiumreplace electrolytes incl 4-6 mEq sodium Can use a combination, e.g:Can use a combination, e.g:

– drip feeds of formula to supply non-offending drip feeds of formula to supply non-offending amino acids + IV dexamino acids + IV dex

Monitoring During Acute Monitoring During Acute Mgt MSUD and MMAMgt MSUD and MMA

Serum amino acids daily Serum amino acids daily – whole blood (green top) to Children’s (M-F)whole blood (green top) to Children’s (M-F)– Pediatrix filter paper card (available in endo Pediatrix filter paper card (available in endo

clinic conference room file cabinet) if 3-4 clinic conference room file cabinet) if 3-4 day turnaround OKday turnaround OK

MSUD MSUD – Add purified ILE and VAL to metabolic Add purified ILE and VAL to metabolic

formula when blood levels reach upper limit formula when blood levels reach upper limit of normal; add LEU as whole protein when of normal; add LEU as whole protein when levels reach upper limits of normal.levels reach upper limits of normal.

MMAMMA– Add VAL as whole protein when levels reach Add VAL as whole protein when levels reach

upper limits of normal.upper limits of normal.

Long-Term Dietary Long-Term Dietary ManagementManagement

Using published guidelines, clinical Using published guidelines, clinical picture, and biochemical picture, and biochemical parameters, establish the dietary parameters, establish the dietary prescriptionprescription

Establish the Dietary Rx Establish the Dietary Rx Newly dx 1 month old with Newly dx 1 month old with

MSUDMSUD

Per kg Per kg LEU:LEU: 60-100 mg60-100 mg ILE:ILE: 36-60 mg36-60 mg VAL:VAL: 42-70 mg42-70 mg Protein: 3-3.5 gProtein: 3-3.5 g Kcal:Kcal: 120120 Fluid:Fluid: 125-150 ml125-150 ml

Components of the Components of the Medical FormulaMedical Formula

Four ingredients:Four ingredients: 1. Infant formula provides LEU, ILE, VAL1. Infant formula provides LEU, ILE, VAL 2. Ketonex-1 provides remaining protein2. Ketonex-1 provides remaining protein 3. Polycose provides any needed 3. Polycose provides any needed

caloriescalories 4. Water4. Water Additional ILE and VAL Additional ILE and VAL

– solution of 10 mg purified amino acids/ml solution of 10 mg purified amino acids/ml prepared by pharmacy or parents (if they prepared by pharmacy or parents (if they have an appropriate scale)have an appropriate scale)

Metabolic FormulasMetabolic Formulas

Life After Exclusive Life After Exclusive Formula FeedingFormula Feeding

Solid foods are added to the infant’s Solid foods are added to the infant’s diet in an age appropriate mannerdiet in an age appropriate manner

Begin with cereals and advance to Begin with cereals and advance to vegetables then fruitvegetables then fruit

Amounts are calculated using Amounts are calculated using exchange lists and food composition exchange lists and food composition tablestables

Every bite of food must be weighed!Every bite of food must be weighed! Infant/child/adult continues to drink Infant/child/adult continues to drink

medical formulamedical formula

Foods in the Diet of a Foods in the Diet of a Person with PKU, MSUD, Person with PKU, MSUD,

MMAMMA

NONO meat, poultry, fish, meat, poultry, fish, dairy, legumesdairy, legumes

LimitedLimitedgrains, vegetables, fruitgrains, vegetables, fruit

Unlimited Unlimited pure pure carbohydrates carbohydrates or or fatfat

Limited in MMA

Phenylalanine

tyrosine

Restrict precursor

Supply Product

dietary protein catabolized muscle

Typical Day’s Intake Typical Day’s Intake 8 year old with PKU—Reg 8 year old with PKU—Reg

FoodsFoodsDiet Rx:

Phe: 345 mg Pro: 52 g Kcal: 2000

3.5 x PHE Rx

mg Phemg Phe KcalKcalBreakfast:Breakfast: 1 slice white bread1 slice white bread 101101 6767

8 oz medical formula8 oz medical formula 00 200200LunchLunch 1 rice cake w 1 t marg1 rice cake w 1 t marg 4040

70701/2 cup noodle soup1/2 cup noodle soup 103103 89895 saltine crackers5 saltine crackers 1.41.4 6868 65658 oz medical formula8 oz medical formula 00 200200

Snack:Snack: 2 c popcorn w 4 t marg2 c popcorn w 4 t marg 91911901904 oz apple juice4 oz apple juice 22 107107

Dinner:Dinner: 120 g pasta120 g pasta 745745 4454453 T tomato sauce3 T tomato sauce 0.60.6 1313 14148 oz medical formula8 oz medical formula 00 200200Fruit iceFruit ice 1010 124124

Snack:Snack: 1/2 oz potato chips1/2 oz potato chips 4444 767612 oz fruit drink12 oz fruit drink 00 1601601,2231,223 20072007

Typical Day’s Intake—LP Typical Day’s Intake—LP FoodsFoods

Diet Rx:

Phe: 345 mg Pro: 52 g Kcal: 2000

mg Phemg Phe KcalKcalBreakfast:Breakfast: 1 slice low pro bread1 slice low pro bread 1111 104104

8 oz medical formula8 oz medical formula 00 200200LunchLunch 1 rice cake w 1 t marg1 rice cake w 1 t marg 4040 7070

1/2 cup low pro soup1/2 cup low pro soup 4848 67675 saltine crackers5 saltine crackers 1.41.4 6868 65658 oz medical formula8 oz medical formula 00 200200

Snack:Snack: 2 c popcorn w 4 t marg2 c popcorn w 4 t marg 9191 1901904 oz apple juice4 oz apple juice 22 107107

Dinner:Dinner: 120 g low protein pasta120 g low protein pasta 1212 4324323 T tomato sauce3 T tomato sauce 0.60.6 1313 14148 oz medical formula8 oz medical formula 00 200200Fruit iceFruit ice 1010 124124

Snack:Snack: 1/2 oz potato chips1/2 oz potato chips 4444 767612 oz fruit drink12 oz fruit drink 00 160160345345 20092009

Reality Check

1 oz cheese 355 mg

1 oz chicken 345 mg

Food ItemFood Item RegularRegular Low ProteinLow Protein

Flour, 16 ozFlour, 16 oz $0.27$0.27 $5.00$5.00

Spaghetti, 16 ozSpaghetti, 16 oz $1.25$1.25 $10.00$10.00

Crackers, 16 ozCrackers, 16 oz $0.79$0.79 $15.00$15.00

Rice, 16 ozRice, 16 oz $0.55$0.55 $10.00$10.00

Cream Cheese, 8 Cream Cheese, 8 ozoz

$1.99$1.99 $5.60$5.60

Am Cheese, 10 ozAm Cheese, 10 oz $2.30$2.30 $10.00$10.00

Tomato Sauce, 4 ozTomato Sauce, 4 oz $0.25$0.25 $4.00$4.00

Cost Comparison of LP Cost Comparison of LP Products and Their Regular Products and Their Regular

CounterpartsCounterparts

Shipping and handling runs $5.00 to $25.00 per order

Practical Issues of Dietary Practical Issues of Dietary TreatmentTreatment

ComplianceCompliance– these diets are complicated!! these diets are complicated!! – harder to adhere to as the child agesharder to adhere to as the child ages

CostCost– $$$$ medical formula and low protein $$$$ medical formula and low protein

foodsfoods– insurance coverageinsurance coverage

Repeated blood draws and doctor’s Repeated blood draws and doctor’s visitsvisits

New TherapiesNew Therapies

Liver transplantation in MSUD and Liver transplantation in MSUD and MMAMMA

Gene TherapyGene Therapy

MSUD Symposium 2000MSUD Symposium 2000Danvers, MADanvers, MA

Happy Happy Halloween Halloween

!!!!